Impaired peripheral vasodilation during graded systemic hypoxia in healthy older adults: role of the sympathoadrenal system

PubMed Central

Richards, Jennifer C.; Crecelius, Anne R.; Larson, Dennis G.; Luckasen, Gary J.

2017-01-01

Systemic hypoxia is a physiological and pathophysiological stress that activates the sympathoadrenal system and, in young adults, leads to peripheral vasodilation. We tested the hypothesis that peripheral vasodilation to graded systemic hypoxia is impaired in older healthy adults and that this age-associated impairment is due to attenuated β-adrenergic mediated vasodilation and elevated α-adrenergic vasoconstriction. Forearm blood flow was measured (Doppler ultrasound), and vascular conductance (FVC) was calculated in 12 young (24 ± 1 yr) and 10 older (63 ± 2 yr) adults to determine the local dilatory responses to graded hypoxia (90, 85, and 80% O2 saturations) in control conditions, following local intra-arterial blockade of β-receptors (propranolol), and combined blockade of α- and β-receptors (phentolamine + propranolol). Under control conditions, older adults exhibited impaired vasodilation to hypoxia compared with young participants at all levels of hypoxia (peak ΔFVC at 80% SpO2 = 4 ± 6 vs. 35 ± 8%; P < 0.01). During β-blockade, older adults actively constricted at 85 and 80% SpO2 (peak ΔFVC at 80% SpO2 = −13 ± 6%; P < 0.05 vs. control), whereas the response in the young was not significantly impacted (peak ΔFVC = 28 ± 8%). Combined α- and β-blockade increased the dilatory response to hypoxia in young adults; however, older adults failed to significantly vasodilate (peak ΔFVC at 80% SpO2= 12 ± 11% vs. 58 ± 11%; P < 0.05). Our findings indicate that peripheral vasodilation to graded systemic hypoxia is significantly impaired in older adults, which cannot be fully explained by altered sympathoadrenal control of vascular tone. Thus, the impairment in hypoxic vasodilation is likely due to attenuated local vasodilatory and/or augmented vasoconstrictor signaling with age. NEW & NOTEWORTHY We found that the lack of peripheral vasodilation during graded systemic hypoxia with aging is not mediated by the sympathoadrenal system, strongly implicating local vascular control mechanisms in this impairment. Understanding these mechanisms may lead to therapeutic advances for improving tissue blood flow and oxygen delivery in aging and disease. PMID:28159810

Role of nitric oxide in adenosine-induced vasodilation in humans

NASA Technical Reports Server (NTRS)

Costa, F.; Biaggioni, I.; Robertson, D. (Principal Investigator)

1998-01-01

Vasodilation is one of the most prominent effects of adenosine and one of the first to be recognized, but its mechanism of action is not completely understood. In particular, there is conflicting information about the potential contribution of endothelial factors. The purpose of this study was to explore the role of nitric oxide in the vasodilatory effect of adenosine. Forearm blood flow responses to intrabrachial adenosine infusion (125 microg/min) were assessed with venous occlusion plethysmography during intrabrachial infusion of saline or the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) (12.5 mg/min). Intrabrachial infusions of acetylcholine (50 microg/min) and nitroprusside (3 microg/min) were used as a positive and negative control, respectively. These doses were chosen to produce comparable levels of vasodilation. In a separate study, a second saline infusion was administered instead of L-NMMA to rule out time-related effects. As expected, pretreatment with L-NMMA reduced acetylcholine-induced vasodilation; 50 microg/min acetylcholine increased forearm blood flow by 150+/-43% and 51+/-12% during saline and L-NMMA infusion, respectively (P<.01, n=6). In contrast, L-NMMA did not affect the increase in forearm blood flow produced by 3 microg/min nitroprusside (165+/-30% and 248+/-41% during saline and L-NMMA, respectively) or adenosine (173+/-48% and 270+/-75% during saline and L-NMMA, respectively). On the basis of our observations, we conclude that adenosine-induced vasodilation is not mediated by nitric oxide in the human forearm.

Flow-mediated vasodilation is augmented in a corkscrew collateral artery compared with that in a native artery in patients with thromboangiitis obliterans (Buerger disease).

PubMed

Fujii, Yuichi; Fujimura, Noritaka; Mikami, Shinsuke; Maruhashi, Tatsuya; Kihara, Yasuki; Chayama, Kazuaki; Noma, Kensuke; Higashi, Yukihito

2011-12-01

A healthy endothelium maintains vascular tone and structure. The purpose of this study was to evaluate endothelial function in corkscrew collateral arteries in Buerger disease. We measured flow-mediated vasodilation (FMD) in corkscrew arteries in 26 patients with Buerger disease, in control arteries in 26 healthy subjects, and in native arteries in 16 patients with Buerger disease. Hyperemic flow was lower in corkscrew arteries than in native arteries in patients with Buerger disease and in control arteries in healthy subjects. There was no significant difference between hyperemic flow in patients with Buerger disease in whom measurements were performed in native arteries and that in healthy subjects. FMD was lower in corkscrew arteries and native arteries in patients with Buerger disease than in control arteries in healthy subjects. There was no significant difference between FMD in corkscrew arteries in patients with Buerger disease and in that in native arteries. The ratio of FMD to hyperemic flow was significantly smaller in native arteries in patients with Buerger disease than in corkscrew arteries and in control arteries in healthy subjects (5.5 ± 6.2 vs 8.8 ± 8.9 and 9.6 ± 7.6 mL/min, P < .001, respectively). There was no significant difference in the ratio of FMD to hyperemic flow between corkscrew arteries in Buerger disease and control arteries in healthy subjects. Nitroglycerin-induced vasodilation was similar in all leg arteries. Endothelial function of a corkscrew collateral artery in patients with Buerger disease is maintained, while endothelial function is impaired in a native artery in Buerger disease. Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Effects of chronic hypoxia on maternal vasodilation and vascular reactivity in guinea pig and ovine pregnancy.

PubMed

White, Margueritte M; Zhang, Lubo

2003-01-01

During pregnancy, exposure to chronic hypoxia is thought to be associated with an increased risk of preeclampsia and fetal intrauterine growth restriction (IUGR). While some studies suggest that this process may be mediated through effects of chronic hypoxia on uterine artery vasodilation and growth, these observations are likely to be species specific and may represent genetic variability in maternal adaptation to hypoxia. This review is a comparative analysis of the effects of chronic hypoxia on vascular reactivity in pregnant and nonpregnant guinea pig and sheep. Data suggest that exposure to chronic hypoxia is associated with enhanced uterine artery blood flow in the sheep, whereas, in the guinea pig, blood flow is decreased.

Microvascular Function Contributes to the Relation Between Aortic Stiffness and Cardiovascular Events: The Framingham Heart Study.

PubMed

Cooper, Leroy L; Palmisano, Joseph N; Benjamin, Emelia J; Larson, Martin G; Vasan, Ramachandran S; Mitchell, Gary F; Hamburg, Naomi M

2016-12-01

Arterial dysfunction contributes to cardiovascular disease (CVD) progression and clinical events. Inter-relations of aortic stiffness and vasodilator function with incident CVD remain incompletely studied. We used proportional hazards models to relate individual measures of vascular function to incident CVD in 4547 participants (mean age, 51±11 years; 54% women) in 2 generations of Framingham Heart Study participants. During follow-up (0.02-13.83 years), 232 participants (5%) experienced new-onset CVD events. In multivariable models adjusted for cardiovascular risk factors, both higher carotid-femoral pulse wave velocity (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.07-1.63; P=0.01) and lower hyperemic mean flow velocity (HR, 0.84; 95% CI, 0.71-0.99; P=0.04) were associated significantly with incident CVD, whereas primary pressure wave amplitude (HR, 1.12; 95% CI, 0.99-1.27; P=0.06), baseline brachial diameter (HR, 1.09; 95% CI, 0.90-1.31; P=0.39), and flow-mediated vasodilation (HR, 0.85; 95% CI, 0.69-1.04; P=0.12) were not. In mediation analyses, 8% to 13% of the relation between aortic stiffness and CVD events was mediated by hyperemic mean flow velocity. Our results suggest that associations between aortic stiffness and CVD events are mediated by pathways that include microvascular damage and remodeling. © 2016 American Heart Association, Inc.

Effects of raloxifene on carotid blood flow resistance and endothelium-dependent vasodilation in postmenopausal women.

PubMed

Ceresini, Graziano; Marchini, Lorenzo; Rebecchi, Isabella; Morganti, Simonetta; Bertone, Luca; Montanari, Ilaria; Bacchi-Modena, Alberto; Sgarabotto, Maria; Baldini, Monica; Denti, Licia; Ablondi, Fabrizio; Ceda, Gian Paolo; Valenti, Giorgio

2003-03-01

Raloxifene is one of the most important selective estrogen receptor modulators currently employed for the treatment of postmenopausal osteoporosis. However, it has also been suggested that this compound affects the vascular system. We evaluated both carotid blood flow resistance and endothelium-dependent vasodilation in 50 healthy postmenopausal women randomly assigned to receive, in a double blind design, either raloxifene (60 mg per day; N=25 subjects) or placebo (N=25 subjects) for 4 months. Indices of carotid blood flow resistance, such as the pulsatility index (PI) and resistance index (RI), as well as the flow-mediated brachial artery dilation were measured both at baseline and at the end of treatment. Changes in PI were -1.86+/-2.24 and -2.15+/-2.22% after placebo and raloxifene treatment, respectively, with no significant differences between groups. Changes in RI were -0.77+/-1.72 and -1.81+/-1.54% after placebo and raloxifene treatment, respectively, with no significant differences between groups. At the end of the treatment period, the increments in artery diameter measured after the flow stimulus were 10.79+/-2.39 and 6.70+/-1.23% for placebo and raloxifene, respectively, with no significant differences between groups. These results demonstrate no significant effects of raloxifene on either carotid blood flow resistance or brachial artery flow-mediated dilation in postmenopausal women.

Acetazolamide-induced vasodilation does not inhibit the visually evoked flow response

PubMed Central

Yonai, Yaniv; Boms, Neta; Molnar, Sandor; Rosengarten, Bernhard; Bornstein, Natan M; Csiba, Laszlo; Olah, Laszlo

2010-01-01

Different methods are used to assess the vasodilator ability of cerebral blood vessels; however, the exact mechanism of cerebral vasodilation, induced by different stimuli, is not entirely known. Our aim was to investigate whether the potent vasodilator agent, acetazolamide (AZ), inhibits the neurovascular coupling, which also requires vasodilation. Therefore, visually evoked flow parameters were examined by transcranial Doppler in ten healthy subjects before and after AZ administration. Pulsatility index and peak systolic flow velocity changes, evoked by visual stimulus, were recorded in the posterior cerebral arteries before and after intravenous administration of 15 mg/kg AZ. Repeated-measures ANOVA did not show significant group main effect between the visually evoked relative flow velocity time courses before and after AZ provocation (P=0.43). Visual stimulation induced significant increase of relative flow velocity and decrease of pulsatility index not only before but also at the maximal effect of AZ. These results suggest that maximal cerebral vasodilation cannot be determined by the clinically accepted dose of AZ (15 mg/kg) and prove that neurovascular coupling remains preserved despite AZ-induced vasodilation. Our observation indicates independent regulation of vasodilation during neurovascular coupling, allowing the adaptation of cerebral blood flow according to neuronal activity even if other processes require significant vasodilation. PMID:19809468

Renal and femoral venous blood flows are regulated by different mechanisms dependent on α-adrenergic receptor subtypes and nitric oxide in anesthetized rats.

PubMed

Fioretti, Alexandre C; Ogihara, Cristiana A; Cafarchio, Eduardo M; Venancio, Daniel P; de Almeida, Roberto Lopes; Antonio, Bruno B; Sato, Monica A

2017-12-01

Venous and arterial walls are responsive to sympathetic system and circulating substances, nevertheless, very few is known about the venous blood flow regulation simultaneously to arterial vascular beds. In this study, we compared the venous and arterial blood flow regulation in visceral and muscular beds upon injection of different doses of vasoactive drugs which act in arterial vascular beds. Anesthetized adult male Wistar rats underwent to right femoral artery and vein cannulation for hemodynamic recordings and infusion of drugs. Doppler flow probes were placed around the left renal artery and vein, and left femoral artery and vein to evaluate the changes in flood flow. Phenylephrine (PHE) injection (α 1 -adrenergic receptor agonist) elicited vasoconstriction in all arteries and veins. Intravenous prazosin (PZS) (1mg/kg, α 1 -adrenergic receptor blocker) caused renal artery vasodilation, but not in the other beds. Vasoconstrictor effect of PHE was abolished by PZS in all vascular beds, except in femoral vein. Phentolamine (PTL) injection (1mg/kg, α 1 /α 2 -adrenergic receptor blocker) produced renal artery vasodilation with no change in other beds. After PTL, the vasoconstriction evoked by PHE was abolished in all vascular beds. Sodium Nitroprusside (SNP), a nitric oxide donor, elicited vasodilation in all beds, and after PTL but not post PZS injection, SNP enhanced the vasodilatory effect in femoral vein. Our findings suggest that the vasoconstriction in renal and femoral veins is mediated by different subtypes of α-adrenoceptors. The nitric oxide-dependent vasodilation in femoral vein enhances when α 2 -adrenoceptors are not under stimulation, but not in the other vascular beds investigated. Copyright © 2017 Elsevier Inc. All rights reserved.

Acute increases in intraluminal pressure improve vasodilator responses in aged soleus muscle feed arteries.

PubMed

Seawright, John W; Luttrell, Meredith J; Woodman, Christopher R

2014-10-01

We tested the hypothesis that exposure to an acute increase in intraluminal pressure, to mimic pressure associated with a bout of exercise, improves nitric oxide (NO)-mediated endothelium-dependent dilation in aged soleus muscle feed arteries (SFA) and that improved endothelial function would persist after a 2 h recovery period. SFA from young (4-month) and old (24-month) Fischer 344 rats were cannulated and pressurized at 90 (P90) or 130 (P130) cmH2O for 60 min. At the end of the treatment period, pressure in the P130 SFA was lowered to 90 cmH2O for examination of endothelium-dependent [flow or acetylcholine (ACh)] and endothelium-independent [sodium nitroprusside (SNP)] vasodilation. To determine the role of NO, vasodilator responses were assessed in the presence of N (ω)-nitro-L-arginine (L-NNA). To determine whether the effects of pressure persisted following a recovery period at normal pressure, SFA were pressurized to 130 cmH2O for 60 min and subsequently lowered to 90 cmH2O for 2 h before assessing function. ACh- and flow-induced dilations were impaired in old SFA. Treatment with increased pressure for 60 min improved ACh- and flow-induced dilations in old SFA. SNP-induced dilation was improved in old and young SFA. The beneficial effect of pressure treatment on ACh- and flow-induced dilation in old SFA was blocked by L-NNA and was not present following a 2 h recovery period. These results indicate that an acute increase in intraluminal pressure improves NO-mediated endothelium-dependent dilation in aged SFA; however, the beneficial effect does not persist after 2 h.

Vascular Inward Rectifier K+ Channels as External K+ Sensors in the Control of Cerebral Blood Flow

PubMed Central

LONGDEN, THOMAS A.; NELSON, MARK T.

2015-01-01

For decades it has been known that external potassium (K+) ions are rapid and potent vasodilators that increase cerebral blood flow (CBF). Recent studies have implicated the local release of K+ from astrocytic endfeet—which encase the entirety of the parenchymal vasculature—in the dynamic regulation of local CBF during neurovascular coupling (NVC). It has been proposed that the activation of strong inward rectifier K+ (KIR) channels in the vascular wall by external K+ is a central component of these hyperemic responses; however, a number of significant gaps in our knowledge remain. Here, we explore the concept that vascular KIR channels are the major extracellular K+ sensors in the control of CBF. We propose that K+ is an ideal mediator of NVC, and discuss KIR channels as effectors that produce rapid hyperpolarization and robust vasodilation of cerebral arterioles. We provide evidence that KIR channels, of the KIR2 subtype in particular, are present in both the endothelial and smooth muscle cells of parenchymal arterioles and propose that this dual positioning of KIR2 channels increases the robustness of the vasodilation to external K+, enables the endothelium to be actively engaged in neurovascular coupling, and permits electrical signaling through the endothelial syncytium to promote upstream vasodilation to modulate CBF. PMID:25641345

NONINVASIVE, CONTINUOUS MEASUREMENT OF RAT TAIL SKIN TEMPERATURE BY RADIOTELEMETRY.

EPA Science Inventory

Tail skin temperature (Tsk) can provide a wealth of information on the thermoregulatory status of the rat. Drug- and toxic-induced changes in body temperature are often mediated by vasodilation or constriction of blood flow to the tail and Tsk can generally be used as an indica...

Cerebrovascular regulation in men and women: stimulus-specific role of cyclooxygenase

PubMed Central

Peltonen, Garrett L; Harrell, John W; Rousseau, Cameron L; Ernst, Brady S; Marino, Mariah L; Crain, Meghan K; Schrage, William G

2015-01-01

Greater cerebral artery vasodilation mediated by cyclooxygenase (COX) in female animals is unexplored in humans. We hypothesized that young, healthy women would exhibit greater basal cerebral blood flow (CBF) and greater vasodilation during hypoxia or hypercapnia compared to men, mediated by a larger contribution of COX. We measured middle cerebral artery velocity (MCAv, transcranial Doppler ultrasound) in 42 adults (24 women, 18 men; 24 ± 1 years) during two visits, in a double-blind, placebo-controlled design (COX inhibition, 100 mg oral indomethacin, Indo). Women were studied early in the follicular phase of the menstrual cycle (days 1–5). Two levels of isocapnic hypoxia (SPO2 = 90% and 80%) were induced for 5-min each. Separately, hypercapnia was induced by increasing end-tidal carbon dioxide (PETCO2) 10 mmHg above baseline. A positive change in MCAv (ΔMCAv) reflected vasodilation. Basal MCAv was greater in women compared to men (P < 0.01) across all conditions. Indo decreased baseline MCAv (P < 0.01) similarly between sexes. Hypoxia increased MCAv (P < 0.01), but ΔMCAv was not different between sexes. Indo did not alter hypoxic vasodilation in either sex. Hypercapnia increased MCAv (P < 0.01), but ΔMCAv was not different between sexes. Indo elicited a large decrease in hypercapnic vasodilation (P < 0.01) that was similar between sexes. During the early follicular phase, women exhibit greater basal CBF than men, but similar vasodilatory responses to hypoxia and hypercapnia. Moreover, COX is not obligatory for hypoxic vasodilation, but plays a vital and similar role in the regulation of basal CBF (∼30%) and hypercapnic response (∼55%) between sexes. PMID:26149282

Nitroglycerin-mediated, but not flow-mediated vasodilation, is associated with blunted nocturnal blood pressure fall in patients with resistant hypertension.

PubMed

Fontes-Guerra, Priscila C A; Cardoso, Claudia R L; Muxfeldt, Elizabeth S; Salles, Gil F

2015-08-01

Endothelial function by flow-mediated (FMD) and nitroglycerin-mediated vasodilations (NMD) was scarcely investigated in resistant hypertension. We aimed to assess the independent correlates of FMD and NMD in resistant hypertensive patients, particularly their associations with ambulatory blood pressures (BP) and nocturnal BP fall patterns. In a cross-sectional study, 280 resistant hypertensive patients performed 24-h ambulatory BP monitoring, carotid-femoral pulse wave velocity, polysomnography, and brachial artery FMD and NMD by high-resolution ultrasonography. Independent correlates of FMD, NMD, and brachial artery diameter (BAD) were assessed by multiple linear and logistic regressions. Median (interquartile range) FMD was 0.75% (-0.6 to +4.4%) and NMD was 11.8% (7.1-18.4%). Baseline BAD and diabetes were independently associated with both FMD and NMD. Older age and prior cardiovascular diseases were associated with altered FMD, whereas higher night-time SBP and lower nocturnal SBP fall were associated with impaired NMD. Moreover, there was a significant gradient of impaired NMD according to blunted nocturnal BP decline patterns. BAD was independently associated with age, sex, BMI, albuminuria, and nocturnal SBP fall. Further adjustments to blood flow velocity, aortic stiffness, plasma aldosterone concentration, and sleep apnea did not change these relationships. NMD, but not FMD, is independently associated with unfavorable night-time BP levels and nondipping patterns, and may be a better cardiovascular risk marker in patients with resistant hypertension. BAD also may provide additional prognostic information.

Oral atorvastatin therapy increases nitric oxide-dependent cutaneous vasodilation in humans by decreasing ascorbate-sensitive oxidants

PubMed Central

Kenney, W. Larry

2011-01-01

Elevated low-density lipoproteins (LDL) are associated with cutaneous microvascular dysfunction partially mediated by increased arginase activity, which is decreased following a systemic atorvastatin therapy. We hypothesized that increased ascorbate-sensitive oxidant stress, partially mediated through uncoupled nitric oxide synthase (NOS) induced by upregulated arginase, contributes to cutaneous microvascular dysfunction in hypercholesterolemic (HC) humans. Four microdialysis fibers were placed in the skin of nine HC (LDL = 177 ± 6 mg/dl) men and women before and after 3 mo of a systemic atorvastatin intervention and at baseline in nine normocholesterolemic (NC) (LDL = 95 ± 4 mg/dl) subjects. Sites served as control, NOS inhibited, L-ascorbate, and arginase-inhibited+L-ascorbate. Skin blood flow was measured while local skin heating (42°C) induced NO-dependent vasodilation. After the established plateau in all sites, 20 mM ≪ngname≫ was infused to quantify NO-dependent vasodilation. Data were normalized to maximum cutaneous vascular conductance (CVC) (sodium nitroprusside + 43°C). The plateau in vasodilation during local heating (HC: 78 ± 4 vs. NC: 96 ± 2% CVCmax, P < 0.01) and NO-dependent vasodilation (HC: 40 ± 4 vs. NC: 54 ± 4% CVCmax, P < 0.01) was reduced in the HC group. Acute L-ascorbate alone (91 ± 5% CVCmax, P < 0.001) or combined with arginase inhibition (96 ± 3% CVCmax, P < 0.001) augmented the plateau in vasodilation in the HC group but not the NC group (ascorbate: 96 ± 2; combo: 93 ± 4% CVCmax, both P > 0.05). After the atorvastatin intervention NO-dependent vasodilation was augmented in the HC group (HC postatorvastatin: 64 ± 4% CVCmax, P < 0.01), and there was no further effect of ascorbate alone (58 ± 4% CVCmax, P > 0.05) or combined with arginase inhibition (67 ± 4% CVCmax, P > 0.05). Increased ascorbate-sensitive oxidants contribute to hypercholesteromic associated cutaneous microvascular dysfunction which is partially reversed with atorvastatin therapy. PMID:21715698

Endothelial function across an oral contraceptive cycle in women using levonorgestrel and ethinyl estradiol.

PubMed

Torgrimson, Britta N; Meendering, Jessica R; Kaplan, Paul F; Minson, Christopher T

2007-06-01

Oral contraceptive pills (OCPs) are a popular contraception method. Currently, lower-dose ethinyl estradiol formulations are most commonly prescribed, although they have been linked to increased arterial vascular risk. The aim of this study was to investigate endothelial function in healthy young women using lower-dose ethinyl estradiol OCPs. We examined flow-mediated, endothelium-dependent and nitroglycerin-mediated, endothelium-independent vasodilation of the brachial artery, comparing two doses of ethinyl estradiol/levonorgestrel OCPs in 15 healthy young women on two study days: once during the active phase and once during the placebo phase of an OCP cycle. Group low dose (LD) (n=7) active pills contained 150 microg levonorgestrel/30 microg ethinyl estradiol versus Group very low dose (VLD) (n=8) with 100 microg levonorgestrel/20 microg ethinyl estradiol. Endothelium-dependent vasodilation was lower during the active phase in Group VLD (5.33 +/- 1.77% vs. 7.23 +/- 2.60%; P=0.024). This phase difference was not observed in Group LD (8.00 +/- 0.970% vs. 7.61 +/- 1.07%; P=0.647). Endothelium-independent vasodilation did not differ between phases in either group. Finally, we measured endothelium-dependent vasodilation in two additional women who received 10 microg of unopposed ethinyl estradiol. Endothelium-dependent vasodilation was increased by unopposed ethinyl estradiol compared with the placebo phase (10.88 +/- 2.34% vs. 6.97 +/- 1.83%). These results suggest that levonorgestrel may antagonize the activity of ethinyl estradiol. Thus both the progestin type and estradiol dose need to be considered when assessing arterial vascular risk of OCP use in women.

Endothelial function varies according to insulin resistance disease type.

PubMed

Beckman, Joshua A; Goldfine, Allison B; Dunaif, Andrea; Gerhard-Herman, Marie; Creager, Mark A

2007-05-01

We examined the relationship between insulin resistance and vascular function in three insulin-resistant states (type 2 diabetes, non-HIV lipodystrophic diabetes, and nondiabetic polycystic ovary syndrome [PCOS]) and in healthy control subjects. The population included 12 women with type 2 diabetes, 6 with lipodystrophic diabetes, 10 with PCOS, and 19 healthy female subjects. Metabolic measures included insulin sensitivity by the homeostasis model assessment, lipids, free fatty acids, and adiponectin. High-resolution B-mode ultrasound was used to determine endothelium-dependent and -independent vasodilation. Type 2 diabetic, liposdystrophic, and PCOS subjects were insulin resistant compared with control subjects (P = 0.001). Flow-mediated vasodilation was reduced in diabetic (3.4 +/- 1.3%) compared with control (7.3 +/- 1.1%) subjects but not in lipodystrophic (7.7 +/- 1.2%) or PCOS (9.9 +/- 0.7%) subjects (P = 0.005). Nitroglycerin-mediated vasodilation was attenuated in both diabetic (15.2 +/- 2.0%) and lipodystrophic (16.7 +/- 3.6%) subjects compared with healthy control (24.6 +/- 2.4%) and PCOS (23.2 +/- 1.8%) subjects (P = 0.019). Insulin resistance, free fatty acids, adiponectin, or C-reactive protein did not associate with vascular dysfunction. Among these different types of patients with insulin resistance, we found abnormal endothelium-dependent vasodilation only in the patients with type 2 diabetes. We postulate that variations in the mechanism of insulin resistance may affect endothelial function differently than glucose homeostasis.

Cross-Sectional Associations of Flow Reversal, Vascular Function, and Arterial Stiffness in the Framingham Heart Study.

PubMed

Bretón-Romero, Rosa; Wang, Na; Palmisano, Joseph; Larson, Martin G; Vasan, Ramachandran S; Mitchell, Gary F; Benjamin, Emelia J; Vita, Joseph A; Hamburg, Naomi M

2016-12-01

Experimental studies link oscillatory flow accompanied by flow reversal to impaired endothelial cell function. The relation of flow reversal with vascular function and arterial stiffness remains incompletely defined. We measured brachial diastolic flow patterns along with vasodilator function in addition to tonometry-based central and peripheral arterial stiffness in 5708 participants (age 47±13 years, 53% women) in the Framingham Heart Study Offspring and Third Generation cohorts. Brachial artery diastolic flow reversal was present in 35% of the participants. In multivariable regression models, the presence of flow reversal was associated with lower flow-mediated dilation (3.9±0.2 versus 5.0±0.2%; P<0.0001) and reactive hyperemic flow velocity (50±0.99 versus 57±0.93 cm/s; P<0.0001). The presence of flow reversal (compared with absence) was associated with higher central aortic stiffness (carotid-femoral pulse wave velocity 9.3±0.1 versus 8.9±0.1 m/s), lower muscular artery stiffness (carotid-radial pulse wave velocity 9.6±0.1 versus 9.8±0.1 m/s), and higher forearm vascular resistance (5.32±0.03 versus 4.66±0.02 log dyne/s/cm 5 ; P<0.0001). The relations of diastolic flow velocity with flow-mediated dilation, aortic stiffness, and forearm vascular resistance were nonlinear, with a steeper decline in vascular function associated with increasing magnitude of flow reversal. In our large, community-based sample, brachial artery flow reversal was common and associated with impaired vasodilator function and higher aortic stiffness. Our findings are consistent with the concept that flow reversal may contribute to vascular dysfunction. © 2016 American Heart Association, Inc.

New assessment of endothelial function measured by short time flow-mediated vasodilation: Comparison with conventional flow-mediated vasodilation measurement.

PubMed

Matsui, Shogo; Kajikawa, Masato; Maruhashi, Tatsuya; Hashimoto, Haruki; Kihara, Yasuki; Chayama, Kazuaki; Goto, Chikara; Aibara, Yoshiki; Yusoff, Farina Mohamad; Kishimoto, Shinji; Nakashima, Ayumu; Noma, Kensuke; Kawaguchi, Tomohiro; Matsumoto, Takeo; Higashi, Yukihito

2018-05-04

Measurement of flow-mediated vasodilation (FMD) is an established method for assessing endothelial function. Measurement of FMD is useful for showing the relationship between atherosclerosis and endothelial function, mechanisms of endothelial dysfunction, and clinical implications including effects of interventions and cardiovascular events. To shorten and simplify the measurement of FMD, we have developed a novel technique named short time FMD (stFMD). We investigated the validity of stFMD for assessment of endothelial function compared with conventional FMD. We evaluated stFMD and conventional FMD in 82 subjects including patients with atherosclerotic risk factors and cardiovascular disease (66 men and 16 women, 57 ± 16 years). Both stFMD and conventional FMD were significantly correlated with age, systolic blood pressure, diastolic blood pressure and baseline brachial artery diameter. In addition, stFMD was significantly correlated with conventional FMD (r = 0.76, P < 0.001). Bland-Altman plot analysis showed good agreement between stFMD and conventional FMD. Moreover, stFMD in the at risk group and that in the cardiovascular disease group were significantly lower than that in the no risk group (4.6 ± 2.3% and 4.4 ± 2.2% vs. 7.3 ± 1.9%, P < 0.001, respectively). Optimal cutoff value of stFMD for diagnosing atherosclerosis was 7.0% (sensitivity of 71.0% and specificity of 85.0%). These findings suggest that measurement of stFMD, a novel and simple method, is useful for assessing endothelial function. Measurement of stFMD may be suitable for screening of atherosclerosis when repeated measurements of vascular function are required and when performing a clinical trial using a large population. URL for Clinical Trial: http://UMIN; Registration Number for Clinical Trial: UMIN000025458. Copyright © 2017 Elsevier B.V. All rights reserved.

Capillary response to skeletal muscle contraction: evidence that redundancy between vasodilators is physiologically relevant during active hyperaemia.

PubMed

Lamb, Iain R; Novielli, Nicole M; Murrant, Coral L

2018-04-15

The current theory behind matching blood flow to metabolic demand of skeletal muscle suggests redundant interactions between metabolic vasodilators. Capillaries play an important role in blood flow control given their ability to respond to muscle contraction by causing conducted vasodilatation in upstream arterioles that control their perfusion. We sought to determine whether redundancies occur between vasodilators at the level of the capillary by stimulating the capillaries with muscle contraction and vasodilators relevant to muscle contraction. We identified redundancies between potassium and both adenosine and nitric oxide, between nitric oxide and potassium, and between adenosine and both potassium and nitric oxide. During muscle contraction, we demonstrate redundancies between potassium and nitric oxide as well as between potassium and adenosine. Our data show that redundancy is physiologically relevant and involved in the coordination of the vasodilator response during muscle contraction at the level of the capillaries. We sought to determine if redundancy between vasodilators is physiologically relevant during active hyperaemia. As inhibitory interactions between vasodilators are indicative of redundancy, we tested whether vasodilators implicated in mediating active hyperaemia (potassium (K + ), adenosine (ADO) and nitric oxide (NO)) inhibit one another's vasodilatory effects through direct application of pharmacological agents and during muscle contraction. Using the hamster cremaster muscle and intravital microscopy, we locally stimulated capillaries with one vasodilator in the absence and the presence of a second vasodilator (10 -7 m S-nitroso-N-acetylpenicillamine (SNAP), 10 -7 m ADO, 10 mm KCl) applied sequentially and simultaneously, and observed the response in the associated upstream 4A arteriole controlling the perfusion of the stimulated capillary. We found that KCl significantly attenuated SNAP- and ADO-induced vasodilatations by ∼49.7% and ∼128.0% respectively and ADO significantly attenuated KCl- and SNAP-induced vasodilatations by ∼94.7% and ∼59.6%, respectively. NO significantly attenuated KCl vasodilatation by 93.8%. Further, during muscle contraction we found that inhibition of NO production using l-N G -nitroarginine methyl ester and inhibition of ADO receptors using xanthine amine congener was effective at inhibiting contraction-induced vasodilatation but only in the presence of K + release channel inhibition. Thus, only when the inhibiting vasodilator K + was blocked was the second vasodilator, NO or ADO, able to produce effective vasodilatation. Therefore, we show that there are inhibitory interactions between specific vasodilators at the level of the capillary. Further, these inhibitions can be observed during muscle contraction indicating that redundancies between vasodilators are physiologically relevant and influence vasodilatation during active hyperaemia. © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

Endothelin B receptor blockade attenuates pulmonary vasodilation in oxygen-ventilated fetal lambs.

PubMed

Ivy, D Dunbar; Lee, Dong-Seok; Rairigh, Robyn L; Parker, Thomas A; Abman, Steven H

2004-01-01

Endothelin-1 (ET-1) contributes to the regulation of pulmonary vascular tone in the normal ovine fetus and in models of perinatal pulmonary hypertension. In the fetal lamb lung, the effects of ET-1 depend on the balance of at least two endothelin receptor subtypes: ETA and ETB. ETA receptors are located on smooth muscle cells and mediate vasoconstriction and smooth muscle proliferation. Stimulation of endothelial ETB receptors causes vasodilation through release of nitric oxide and also functions to remove ET-1 from the circulation. However, whether activation of ETB receptors contributes to the fall in pulmonary vascular tone at birth is unknown. To determine the role of acute ETB receptor blockade in pulmonary vasodilation in response to birth-related stimuli, we studied the hemodynamic effects of selective ETB receptor blockade with BQ-788 during mechanical ventilation with low (<10%) and high FiO2 (100%) in near-term fetal sheep. Intrapulmonary infusion of BQ-788 did not change left pulmonary artery (LPA) blood flow and pulmonary vascular resistance (PVR) at baseline. In comparison with controls, BQ-788 treatment attenuated the rise in LPA flow with low and high FiO2 ventilation (p <0.001 vs. control for each FiO2 concentration). PVR progressively decreased during mechanical ventilation with low and high FiO2 in both groups, but PVR remained higher after BQ-788 treatment throughout the study period (p <0.001). We conclude that selective ETB receptor blockade attenuates pulmonary vasodilation at birth. We speculate that ETB receptor stimulation contributes to pulmonary vasodilation at birth in the ovine fetus.

The catecholamines strike back. What NO does not do.

PubMed

Joyner, Michael J; Casey, Darren P

2009-10-01

The discovery of endothelial-derived relaxing factor, and later nitric oxide (NO), as a biologically active substance led to intense focus on the vascular endothelium as a major site of physiological regulation and pathophysiological dysfunction. NO is clearly a potent vasodilator and plays a key role in establishing both whole body and regional "vascular tone". In this context, skeletal muscle and human skin have the remarkable capacity to increase their blood flow 50-100-fold and this increase is caused almost exclusively by local vasodilation. In general, the mechanisms responsible for these vasodilator phenomena have been poorly understood. In the early 1990s, investigators started to ask if NO might explain the "unexplained" vasodilator responses seen in skeletal muscle and skin. They also asked how "NO tone" interacted with "sympathetic tone" and whether NO can override the vasoconstrictor responses normally generated when sympathetic nerves release norepinephrine. Surprisingly, it was found that NO plays only a modest (non-obligatory) role in exercise hyperemia, reactive hyperemia and the neurally mediated rise in skin blood flow during whole body heat stress. By contrast, NO plays a major role in the skeletal muscle vasodilator responses to mental stress and the skin dilator responses to local heating. In animals, but not humans, NO can limit the ability of the sympathetic nerves to cause vasoconstriction in exercising muscles. Thus the role of NO in two of the most extreme dilator responses seen in nature is limited and in muscle the sympathetic nerves can restrain the dilation to defend arterial blood pressure.

Low-Renin Hypertension With Relative Aldosterone Excess Is Associated With Impaired NO-Mediated Vasodilation

PubMed Central

Duffy, Stephen J.; Biegelsen, Elizabeth S.; Eberhardt, Robert T.; Kahn, David F.; Kingwell, Bronwyn A.; Vita, Joseph A.

2009-01-01

Recent studies suggest that hypertension associated with low renin status and hyperaldosteronism is associated with increased risk for end-organ damage and cardiovascular events compared with other forms of hypertension. Additionally, experimental studies have demonstrated impaired nitric oxide-mediated bioactivity in these states. To investigate the relation between renin/aldosterone status and resistance vessel function, we examined plasma renin activity, serum aldosterone level, and forearm blood flow responses to the endothelium-dependent vasodilator methacholine and the endothelium-independent vasodilators sodium nitroprusside and verapamil using venous occlusion plethysmography in 130 volunteers (43 hypertensive, 87 normotensive). Low renin status was associated with impaired responses to methacholine and nitroprusside in patients with hypertension. Peak methacholine response was 8.7±5.6 mL/min per dL in the lowest renin quartile (0.1 to 0.3 ng/mL per hour) versus 14.3±7.3 mL/min per dL in the highest 3 renin quartiles combined (0.4 to 4.6 ng/mL per hour; P<0.001). Peak nitroprusside response was 5.6±2.3 mL/min per dL in the lowest renin quartile versus 13.3±4.1 mL/min per dL in the highest 3 renin quartiles combined (P<0.001). Blood pressure and other clinical characteristics were similar in all 4 quartiles. Vasodilator responses to verapamil did not relate to renin activity. Methacholine and nitroprusside responses did not relate to renin status in normotensive controls (P=0.34). Importantly, hypertensive patients with a high aldosterone/renin ratio also had impaired responses to methacholine. This study demonstrates that low-renin hypertension is associated with marked impairment of nitric oxide-mediated vasodilation of resistance vessels in the forearm vasculature of humans. This impairment could contribute to adverse outcomes in patients with low-renin hypertension and relative aldosterone excess. PMID:16172426

Ascorbate elevates perfusion pressure in the bovine extraocular long posterior ciliary artery: role of endothelium-derived hyperpolarizing factor (EDHF).

PubMed

Stirrat, Alison; Nelli, Silvia; McGuckin, Alicia; Ho, Vivian Wing Man; Wilson, William S; Martin, William

2006-03-18

Ascorbate blocks agonist-induced, endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilatation in the bovine perfused ciliary artery and this is associated with a rise in perfusion pressure. We now report the origins of this ascorbate-induced rise in perfusion pressure. In segments of ciliary artery perfused at 2.5 ml/min, the addition of ascorbate (10-150 microM) enhanced U46619-induced perfusion pressure. Ascorbate produced no enhancement in the absence of U46619, suggesting that its effects resulted not from a constrictor action but through removal of a tonic vasodilator influence. Experiments revealed the endothelial source of this vasodilator influence, and EDHF, but not nitric oxide or prostanoids, appeared to be involved. The ascorbate-induced enhancement of vasoconstrictor tone was not seen in a static myograph or in segments perfused at low rates of flow, but was seen at flow rates of 2.5 ml(-1) and above. We conclude that ascorbate augments vasoconstrictor tone through inhibition of flow-induced EDHF activity.

Ebselen does not improve oxidative stress and vascular function in patients with diabetes: a randomized, crossover trial.

PubMed

Beckman, Joshua A; Goldfine, Allison B; Leopold, Jane A; Creager, Mark A

2016-12-01

Oxidative stress is a key driver of vascular dysfunction in diabetes mellitus. Ebselen is a glutathione peroxidase mimetic. A single-site, randomized, double-masked, placebo-controlled, crossover trial was carried out in 26 patients with type 1 or type 2 diabetes to evaluate effects of high-dose ebselen (150 mg po twice daily) administration on oxidative stress and endothelium-dependent vasodilation. Treatment periods were in random order of 4 wk duration, with a 4-wk washout between treatments. Measures of oxidative stress included nitrotyrosine, plasma 8-isoprostanes, and the ratio of reduced to oxidized glutathione. Vascular ultrasound of the brachial artery and plethysmographic measurement of blood flow were used to assess flow-mediated and methacholine-induced endothelium-dependent vasodilation of conduit and resistance vessels, respectively. Ebselen administration did not affect parameters of oxidative stress or conduit artery or forearm arteriolar vascular function compared with placebo treatment. There was no difference in outcome by diabetes type. Ebselen, at the dose and duration evaluated, does not improve the oxidative stress profile, nor does it affect endothelium-dependent vasodilation in patients with diabetes mellitus. Copyright © 2016 the American Physiological Society.

Lipid emulsions enhance the norepinephrine-mediated reversal of local anesthetic-induced vasodilation at toxic doses.

PubMed

Lee, Soo Hee; Sung, Hui-Jin; Ok, Seong-Ho; Yu, Jongsun; Choi, Mun-Jeoung; Lim, Jin Soo; Sohn, Ju-Tae

2013-11-01

Intravenous lipid emulsions have been used to treat the systemic toxicity of local anesthetics. The goal of this in vitro study was to examine the effects of lipid emulsions on the norepinephrine-mediated reversal of vasodilation induced by high doses of levobupivacaine, ropivacaine, and mepivacaine in isolated endothelium-denuded rat aorta, and to determine whether such effects are associated with the lipid solubility of local anesthetics. The effects of lipid emulsions (0.30, 0.49, 1.40, and 2.61%) on norepinephrine concentration-responses in high-dose local anesthetic (6×10(-4) M levobupivacaine, 2×10(-3) M ropivacaine, and 7×10(-3) M mepivacaine)-induced vasodilation of isolated aorta precontracted with 60 mM KCl were assessed. The effects of lipid emulsions on local anesthetic- and diltiazem-induced vasodilation in isolated aorta precontracted with phenylephrine were also assessed. Lipid emulsions (0.30%) enhanced norepinephrine-induced contraction in levobupivacaine-induced vasodilation, whereas 1.40 and 2.61% lipid emulsions enhanced norepinephrine-induced contraction in both ropivacaine- and mepivacaine-induced vasodilation, respectively. Lipid emulsions (0.20, 0.49 and 1.40%) inhibited vasodilation induced by levobupivacaine and ropivacaine, whereas 1.40 and 2.61% lipid emulsions slightly attenuated mepivacaine (3×10(-3) M)-induced vasodilation. In addition, lipid emulsions attenuated diltiazem-induced vasodilation. Lipid emulsions enhanced norepinephrine-induced contraction in endothelium-denuded aorta without pretreatment with local anesthetics. Taken together, these results suggest that lipid emulsions enhance the norepinephrine-mediated reversal of local anesthetic-induced vasodilation at toxic anesthetic doses and inhibit local anesthetic-induced vasodilation in a manner correlated with the lipid solubility of a particular local anesthetic.

Exercise-mediated vasodilation in human obesity and metabolic syndrome: effect of acute ascorbic acid infusion.

PubMed

Limberg, Jacqueline K; Kellawan, J Mikhail; Harrell, John W; Johansson, Rebecca E; Eldridge, Marlowe W; Proctor, Lester T; Sebranek, Joshua J; Schrage, William G

2014-09-15

We tested the hypothesis that infusion of ascorbic acid (AA), a potent antioxidant, would alter vasodilator responses to exercise in human obesity and metabolic syndrome (MetSyn). Forearm blood flow (FBF, Doppler ultrasound) was measured in lean, obese, and MetSyn adults (n = 39, 32 ± 2 yr). A brachial artery catheter was inserted for blood pressure monitoring and local infusion of AA. FBF was measured during dynamic handgrip exercise (15% maximal effort) with and without AA infusion. To account for group differences in blood pressure and forearm size, and to assess vasodilation, forearm vascular conductance (FVC = FBF/mean arterial blood pressure/lean forearm mass) was calculated. We examined the time to achieve steady-state FVC (mean response time, MRT) and the rise in FVC from rest to steady-state exercise (Δ, exercise - rest) before and during acute AA infusion. The MRT (P = 0.26) and steady-state vasodilator responses to exercise (ΔFVC, P = 0.31) were not different between groups. Intra-arterial infusion of AA resulted in a significant increase in plasma total antioxidant capacity (174 ± 37%). AA infusion did not alter MRT or steady-state FVC in any group (P = 0.90 and P = 0.85, respectively). Interestingly, higher levels of C-reactive protein predicted longer MRT (r = 0.52, P < 0.01) and a greater reduction in MRT with AA infusion (r = -0.43, P = 0.02). We concluded that AA infusion during moderate-intensity, rhythmic forearm exercise does not alter the time course or magnitude of exercise-mediated vasodilation in groups of young lean, obese, or MetSyn adults. However, systemic inflammation may limit the MRT to exercise, which can be improved with AA. Copyright © 2014 the American Physiological Society.

Exercise-mediated vasodilation in human obesity and metabolic syndrome: effect of acute ascorbic acid infusion

PubMed Central

Limberg, Jacqueline K.; Kellawan, J. Mikhail; Harrell, John W.; Johansson, Rebecca E.; Eldridge, Marlowe W.; Proctor, Lester T.; Sebranek, Joshua J.

2014-01-01

We tested the hypothesis that infusion of ascorbic acid (AA), a potent antioxidant, would alter vasodilator responses to exercise in human obesity and metabolic syndrome (MetSyn). Forearm blood flow (FBF, Doppler ultrasound) was measured in lean, obese, and MetSyn adults (n = 39, 32 ± 2 yr). A brachial artery catheter was inserted for blood pressure monitoring and local infusion of AA. FBF was measured during dynamic handgrip exercise (15% maximal effort) with and without AA infusion. To account for group differences in blood pressure and forearm size, and to assess vasodilation, forearm vascular conductance (FVC = FBF/mean arterial blood pressure/lean forearm mass) was calculated. We examined the time to achieve steady-state FVC (mean response time, MRT) and the rise in FVC from rest to steady-state exercise (Δ, exercise − rest) before and during acute AA infusion. The MRT (P = 0.26) and steady-state vasodilator responses to exercise (ΔFVC, P = 0.31) were not different between groups. Intra-arterial infusion of AA resulted in a significant increase in plasma total antioxidant capacity (174 ± 37%). AA infusion did not alter MRT or steady-state FVC in any group (P = 0.90 and P = 0.85, respectively). Interestingly, higher levels of C-reactive protein predicted longer MRT (r = 0.52, P < 0.01) and a greater reduction in MRT with AA infusion (r = −0.43, P = 0.02). We concluded that AA infusion during moderate-intensity, rhythmic forearm exercise does not alter the time course or magnitude of exercise-mediated vasodilation in groups of young lean, obese, or MetSyn adults. However, systemic inflammation may limit the MRT to exercise, which can be improved with AA. PMID:25038148

Cerebrovascular regulation in men and women: stimulus-specific role of cyclooxygenase.

PubMed

Peltonen, Garrett L; Harrell, John W; Rousseau, Cameron L; Ernst, Brady S; Marino, Mariah L; Crain, Meghan K; Schrage, William G

2015-07-01

Greater cerebral artery vasodilation mediated by cyclooxygenase (COX) in female animals is unexplored in humans. We hypothesized that young, healthy women would exhibit greater basal cerebral blood flow (CBF) and greater vasodilation during hypoxia or hypercapnia compared to men, mediated by a larger contribution of COX. We measured middle cerebral artery velocity (MCAv, transcranial Doppler ultrasound) in 42 adults (24 women, 18 men; 24 ± 1 years) during two visits, in a double-blind, placebo-controlled design (COX inhibition, 100 mg oral indomethacin, Indo). Women were studied early in the follicular phase of the menstrual cycle (days 1-5). Two levels of isocapnic hypoxia (SPO2 = 90% and 80%) were induced for 5-min each. Separately, hypercapnia was induced by increasing end-tidal carbon dioxide (PETCO 2) 10 mmHg above baseline. A positive change in MCAv (ΔMCAv) reflected vasodilation. Basal MCAv was greater in women compared to men (P < 0.01) across all conditions. Indo decreased baseline MCAv (P < 0.01) similarly between sexes. Hypoxia increased MCAv (P < 0.01), but ΔMCAv was not different between sexes. Indo did not alter hypoxic vasodilation in either sex. Hypercapnia increased MCAv (P < 0.01), but ΔMCAv was not different between sexes. Indo elicited a large decrease in hypercapnic vasodilation (P < 0.01) that was similar between sexes. During the early follicular phase, women exhibit greater basal CBF than men, but similar vasodilatory responses to hypoxia and hypercapnia. Moreover, COX is not obligatory for hypoxic vasodilation, but plays a vital and similar role in the regulation of basal CBF (~30%) and hypercapnic response (~55%) between sexes. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Cardiovascular dysfunction in symptomatic primary hyperparathyroidism and its reversal after curative parathyroidectomy: results of a prospective case control study.

PubMed

Agarwal, Gaurav; Nanda, Gitika; Kapoor, Aditya; Singh, Kul Ranjan; Chand, Gyan; Mishra, Anjali; Agarwal, Amit; Verma, Ashok K; Mishra, Saroj K; Syal, Sanjeev K

2013-12-01

Cardiovascular mortality in primary hyperparathyroidism (PHPT) is attributed to myocardial and endothelial dysfunction. In this prospective, case-control study we assessed cardiovascular dysfunction in patients with symptomatic PHPT and its reversal after successful parathyroidectomy. Fifty-six patients with symptomatic PHPT underwent two-dimensional echocardiography, tissue Doppler (diastolic function assessment), serum N-terminal pro-brain natriuretic peptide (s-NTproBNP, a myocardial damage marker), and endothelial- and smooth muscle-dependent vasodilatory response (vascular dysfunction) studies before, 3, and 6 months after parathyroidectomy; 25 age-matched controls were studied similarly. Patients had greater left ventricular mass (192 ± 70 vs. 149 ± 44 g; P = .006), interventricular septal thickness (10.8 ± 2.5 vs. 9.0 ± 1.6 mm; P = .001), posterior wall thickness (9.9 ± 2.0 vs. 8.6 ± 2.2 mm; P = .004), and diastolic dysfunction (lower E/A trans-mitral flow velocity ratio [1.0 ± 0.4 vs. 1.3 ± 0.4; P = .01). Patients had greater s-NTproBNP (4,625 ± 1,130 vs. 58 ± 49 pg/mL; P = .002) and lower endothelial-mediated vasodilation (9.3 ± 8.6 vs. 11.7 ± 6.3%; P = .03) and smooth muscle-mediated vasodilation (20.1 ± 17.9 vs. 23.8 ± 11.2%; P = .01). Improvements in left ventricular mass, systolic and diastolic function, and smooth muscle-mediated vasodilation were noted from 3 to 6 months after parathyroidectomy. Endothelial-mediated vasodilation did not improve significantly. S-NTproBNP levels mirrored echocardiographic changes with a substantial, sustained decrease. Results were similar in hypertensive and normotensive patients. Symptomatic PHPT patients have substantial cardiac and vascular dysfunction, which improve by 6 months after parathyroidectomy. Objective cardiovascular evaluation may improve outcomes in symptomatic PHPT patients. Copyright © 2013 Mosby, Inc. All rights reserved.

Vascular effects of aldosterone: sorting out the receptors and the ligands.

PubMed

Feldman, Ross D; Gros, Robert

2013-12-01

Aldosterone has actions far beyond its role as a renal regulator of sodium reabsorption, and broader mechanisms of action than simply a transcriptional regulator. Aldosterone has a number of vascular effects, including regulation of vascular reactivity and vascular growth and/or development. Aldosterone-mediated effects on vascular reactivity reflect a balance between its endothelial-dependent vasodilator effects and its direct smooth muscle vasoconstrictor effects. The endothelial vasodilator effects of aldosterone are mediated by phosphatidylinositol 3-kinase-dependent activation of nitric oxide synthase. G-Protein oestrogen receptor (GPER) is a recently recognized G-protein coupled receptor (GPCR) that is activated by steroid hormones. It was first recognized as the GPCR mediating the rapid effects of oestrogens. Activation of GPER also mediates at least some of the vascular effects of aldosterone in smooth muscle and endothelial cells. In vascular endothelial cells, aldosterone activation of GPER mediates vasodilation. In contrast, activation of endothelial mineralocorticoid receptors has been linked to enhanced vasoconstrictor and/or impaired vasodilator responses. © 2013 Wiley Publishing Asia Pty Ltd.

Oral atorvastatin therapy increases nitric oxide-dependent cutaneous vasodilation in humans by decreasing ascorbate-sensitive oxidants.

PubMed

Holowatz, Lacy A; Kenney, W Larry

2011-09-01

Elevated low-density lipoproteins (LDL) are associated with cutaneous microvascular dysfunction partially mediated by increased arginase activity, which is decreased following a systemic atorvastatin therapy. We hypothesized that increased ascorbate-sensitive oxidant stress, partially mediated through uncoupled nitric oxide synthase (NOS) induced by upregulated arginase, contributes to cutaneous microvascular dysfunction in hypercholesterolemic (HC) humans. Four microdialysis fibers were placed in the skin of nine HC (LDL = 177 ± 6 mg/dl) men and women before and after 3 mo of a systemic atorvastatin intervention and at baseline in nine normocholesterolemic (NC) (LDL = 95 ± 4 mg/dl) subjects. Sites served as control, NOS inhibited, L-ascorbate, and arginase-inhibited+L-ascorbate. Skin blood flow was measured while local skin heating (42°C) induced NO-dependent vasodilation. After the established plateau in all sites, 20 mM ≪ngname≫ was infused to quantify NO-dependent vasodilation. Data were normalized to maximum cutaneous vascular conductance (CVC) (sodium nitroprusside + 43°C). The plateau in vasodilation during local heating (HC: 78 ± 4 vs. NC: 96 ± 2% CVC(max), P < 0.01) and NO-dependent vasodilation (HC: 40 ± 4 vs. NC: 54 ± 4% CVC(max), P < 0.01) was reduced in the HC group. Acute L-ascorbate alone (91 ± 5% CVC(max), P < 0.001) or combined with arginase inhibition (96 ± 3% CVC(max), P < 0.001) augmented the plateau in vasodilation in the HC group but not the NC group (ascorbate: 96 ± 2; combo: 93 ± 4% CVC(max), both P > 0.05). After the atorvastatin intervention NO-dependent vasodilation was augmented in the HC group (HC postatorvastatin: 64 ± 4% CVC(max), P < 0.01), and there was no further effect of ascorbate alone (58 ± 4% CVC(max,) P > 0.05) or combined with arginase inhibition (67 ± 4% CVC(max,) P > 0.05). Increased ascorbate-sensitive oxidants contribute to hypercholesteromic associated cutaneous microvascular dysfunction which is partially reversed with atorvastatin therapy.

Characterizing Methods of Measuring Flow-Mediated Dilation in the Brachial Artery

NASA Technical Reports Server (NTRS)

Callender, Ariane R.

2010-01-01

Regulation of vascular tone is one of the many important functions of the vascular endothelium. Endothelial dysfunction is a critical early event in the pathogenesis of atherosclerosis and occurs in the absence of angiographic disease. Flow-Mediated Dilation (FMD) is a noninvasive technique commonly used to evaluate endothelium-dependent vasodilation in humans and gauge the health of the cardiovascular system. Reductions in brachial artery FMD have been strongly correlated with disease progression and are predictive of future cardiac events. The flow stimulus for brachial artery FMD occurs as a result of the increased shear stress following deflation of an occlusion cuff around the upper arm. Using 2-dimensional ultrasound, changes in arterial diameter up to 5-minutes following cuff deflation are calculated from baseline image measurements. Along with pulsed Doppler measures of flow velocity through the artery, flow-mediated, endothelium-dependent vasodilation can be assessed. There is debate among investigators, however, about the proper positioning of the occlusion cuff during FMD testing. It is thought that placement of the cuff around the upper arm may not accurately reflect the impact of nitric oxide, a critically important molecule released as a result of the increased shear stress created by the FMD technique. Data suggest that the production of other endogenous metabolites may also contribute to FMD-related changes when positioning the cuff around the upper arm. To overcome the potential influence of such molecules, researchers now suggest that the occlusion cuff be placed below the elbow allowing a more precise estimate of nitric oxide mediated dilation. The purpose of this study is to compare the differences in FMD between the two methodologies of occlusion cuff placement. In addition, this study will determine the method that is easier for ultrasound technicians to perform and will produce a low coefficient of variance between technicians. Ultimately, the results of this study will help in tracking any adverse cardiovascular effects of spaceflight.

Phase coherence of 0.1 Hz microvascular tone oscillations during the local heating

NASA Astrophysics Data System (ADS)

Mizeva, I. A.

2017-06-01

The origin of the mechanisms of blood flow oscillations at low frequencies is discussed. It is known that even isolated arteriole demonstrates oscillations with the frequency close to 0.1 Hz, which is caused by the synchronous activity of myocyte cells. On the other hand, oscillations with close frequency are found in the heart rate, which are associated with quite different mechanism. The main purpose of this work is to study phase coherence of the blood flow oscillations in the peripheral vessels under basal and perturbed conditions. Local heating which locally influences the microvascular tone, as one of currently elucidated in sufficient detail physiological test, was chosen. During such provocation blood flow though the small vessels significantly increases because of vasodilation induced by the local synthesis of nitric oxide. In the first part of the paper microvascular response to the local test is quantified in healthy and pathological conditions of diabetes mellitus type 1. It is obtained that regardless of the pathology, subjects with high basal perfusion had lower reserve for vasodilation, which can be caused by the low elasticity of microvascular structure. Further synchronization of pulsations of the heated and undisturbed skin was evaluated on the base of wavelet phase coherency analysis. Being highly synchronised in basal conditions 0.1 Hz pulsations became more independent during heating, especially during NO-mediated vasodilation.

Acute retinal ischemia inhibits endothelium-dependent nitric oxide-mediated dilation of retinal arterioles via enhanced superoxide production.

PubMed

Hein, Travis W; Ren, Yi; Potts, Luke B; Yuan, Zhaoxu; Kuo, Enoch; Rosa, Robert H; Kuo, Lih

2012-01-03

Because retinal vascular disease is associated with ischemia and increased oxidative stress, the vasodilator function of retinal arterioles was examined after retinal ischemia induced by elevated intraocular pressure (IOP). The role of superoxide anions in the development of vascular dysfunction was assessed. IOP was increased and maintained at 80 to 90 mm Hg for 30, 60, or 90 minutes by infusing saline into the anterior chamber of a porcine eye. The fellow eye with normal IOP (10-20 mm Hg) served as control. In some pigs, superoxide dismutase mimetic TEMPOL (1 mM) or vehicle (saline) was injected intravitreally before IOP elevation. After enucleation, retinal arterioles were isolated and pressurized without flow for functional analysis by recording diameter changes using videomicroscopic techniques. Dihydroethidium (DHE) was used to detect superoxide production in isolated retinal arterioles. Isolated retinal arterioles developed stable basal tone and the vasodilations to endothelium-dependent nitric oxide (NO)-mediated agonists bradykinin and L-lactate were significantly reduced only by 90 minutes of ischemia. However, vasodilation to endothelium-independent NO donor sodium nitroprusside was unaffected after all time periods of ischemia. DHE staining showed that 90 minutes of ischemia significantly increased superoxide levels in retinal arterioles. Intravitreal injection of membrane-permeable radical scavenger but not vehicle before ischemia prevented elevation of vascular superoxide and preserved bradykinin-induced dilation. Endothelium-dependent NO-mediated dilation of retinal arterioles is impaired by 90 minutes of ischemia induced by elevated IOP. The inhibitory effect appears to be mediated by the alteration of NO signaling via vascular superoxide.

Parasympathetic reflex vasodilation in the cerebral hemodynamics of rats.

PubMed

Ishii, Hisayoshi; Sato, Toshiya; Izumi, Hiroshi

2014-04-01

We investigated the role of parasympathetic reflex vasodilation in the regulation of the cerebral hemodynamics, and whether GABAA receptors modulate the response. We examined the effects of activation of the parasympathetic fibers through trigeminal afferent inputs on blood flow in the internal carotid artery (ICABF) and the cerebral blood vessels (rCBF) in parietal cortex in urethane-anesthetized rats. Electrical stimulation of the central cut end of the lingual nerve (LN) elicited intensity- and frequency-dependent increases in ICABF that were independent of changes in external carotid artery blood flow. Increases in ICABF were elicited by LN stimulation regardless of the presence or absence of sympathetic innervation. The ICABF increases evoked by LN stimulation were almost abolished by the intravenous administration of hexamethonium (10 mg kg(-1)) and were reduced significantly by atropine administration (0.1 mg kg(-1)). Although the LN stimulation alone had no significant effect on rCBF, LN stimulation in combination with a blocker of the GABAA receptor pentylenetetrazole increased the rCBF markedly. This increase in rCBF was reduced significantly by the administration of hexamethonium and atropine. These observations indicate that the increases in both ICABF and rCBF are evoked by parasympathetic activation via the trigeminal-mediated reflex. The rCBF increase evoked by LN stimulation is thought to be limited by the GABAA receptors in the central nervous system. These results suggest that the parasympathetic reflex vasodilation and its modulation mediated by GABA receptors within synaptic transmission in the brainstem are involved in the regulation of the cerebral hemodynamics during trigeminal afferent inputs.

Roles of nitric oxide synthase isoforms in cutaneous vasodilation induced by local warming of the skin and whole body heat stress in humans

PubMed Central

Zhao, Joan L.; Wu, Yubo

2009-01-01

Nitric oxide (NO) participates in the cutaneous vasodilation caused by increased local skin temperature (Tloc) and whole body heat stress in humans. In forearm skin, endothelial NO synthase (eNOS) participates in vasodilation due to elevated Tloc and neuronal NO synthase (nNOS) participates in vasodilation due to heat stress. To explore the relative roles and interactions of these isoforms, we examined the effects of a relatively specific eNOS inhibitor, Nω-amino-l-arginine (LNAA), and a specific nNOS inhibitor, Nω-propyl-l-arginine (NPLA), both separately and in combination, on skin blood flow (SkBF) responses to increased Tloc and heat stress in two protocols. In each protocol, SkBF was monitored by laser-Doppler flowmetry (LDF) and mean arterial pressure (MAP) by Finapres. Cutaneous vascular conductance (CVC) was calculated (CVC = LDF/MAP). Intradermal microdialysis was used to treat one site with 5 mM LNAA, another with 5 mM NPLA, a third with combined 5 mM LNAA and 5 mM NPLA (Mix), and a fourth site with Ringer only. In protocol 1, Tloc was controlled with combined LDF/local heating units. Tloc was increased from 34°C to 41.5°C to cause local vasodilation. In protocol 2, after a period of normothermia, whole body heat stress was induced (water-perfused suits). At the end of each protocol, all sites were perfused with 58 mM nitroprusside to effect maximal vasodilation for data normalization. In protocol 1, at Tloc = 34°C, CVC did not differ between sites (P > 0.05). LNAA and Mix attenuated CVC increases at Tloc = 41.5°C to similar extents (P < 0.05, LNAA or Mix vs. untreated or NPLA). In protocol 2, in normothermia, CVC did not differ between sites (P > 0.05). During heat stress, NPLA and Mix attenuated CVC increases to similar extents, but no significant attenuation occurred with LNAA (P < 0.05, NPLA or Mix vs. untreated or LNAA). In forearm skin, eNOS mediates the vasodilator response to increased Tloc and nNOS mediates the vasodilator response to heat stress. The two isoforms do not appear to interact during either response. PMID:19745188

Physical training improves flow-mediated dilation in patients with the polymetabolic syndrome.

PubMed

Lavrencic, A; Salobir, B G; Keber, I

2000-02-01

Endothelial dysfunction that can be detected as impaired flow-mediated dilation by ultrasonography is an early event in atherogenesis and has been demonstrated in healthy subjects with risk factors for atherosclerosis many years before the appearance of atheromatous plaques. We examined the influence of physical training on flow-mediated dilation in patients with the polymetabolic syndrome. Twenty-nine asymptomatic men aged 40 to 60 years with the polymetabolic syndrome were randomly divided between the control group and the training group, which trained 3 times a week for 12 weeks. On high-resolution ultrasound images, the diameter of the brachial artery was measured at rest, after reactive hyperemia (causing flow-mediated, endothelium-dependent dilation), and after sublingual glyceryltrinitrate (causing endothelium-independent vasodilation) in all subjects before and after the training period. The training program induced an increase of 18% in physical fitness. Flow-mediated dilation increased from 5.3+/-2.8% to 7.3+/-2.7% (P<0. 05). There was no change in body mass index, blood pressure, insulin resistance, lipids, and big endothelin-1 in either group. Flow-mediated dilation measured before training was negatively correlated with resting heart rate, waist-to-hip ratio, and insulin resistance. Resting heart rate emerged as the only independent determinant, which explained 22% of the variation in flow-mediated dilation. In conclusion, our findings suggest that a 3-month physical training program, which improved maximal exercise capacity, enhances flow-mediated dilation in patients with the polymetabolic syndrome.

Vasodilatory effect of nitroglycerin in Japanese subjects with different aldehyde dehydrogenase 2 (ALDH2) genotypes.

PubMed

Miura, Takeshi; Nishinaka, Toru; Terada, Tomoyuki; Yonezawa, Kazuya

2017-10-01

The functional genetic polymorphism of aldehyde dehydrogenase 2 (ALDH2) influences the enzymatic activities of its wild type (Glu504 encoded by ALDH2*1) and mutant type (Lys504 encoded by ALDH2*2) proteins. The enzymatic activities of mutant-type ALDH2 are limited compared with those of the wild type. ALDH2 has been suggested as a critical factor for nitroglycerin-mediated vasodilation by some human studies and in vitro studies. Currently, there is no research on direct observations of the vasodilatory effect of nitroglycerin sublingual tablets, which is the generally used dosage form. In the present study, the contribution of ALDH2 to the vasodilatory effect of nitroglycerin sublingual tablets was investigated among three genotype groups (ALDH2*1/*1, ALDH2*1/*2, and ALDH2*2/*2) in Japanese. The results by direct assessments of in vivo nitroglycerin-mediated dilation showed no apparent difference in vasodilation among all genotypes of ALDH2. Furthermore, to analyze the effect of other factors (age and flow-mediated dilation), multiple regression analysis and Pearson's correlation coefficient analysis were carried out. These analyses also indicated that the genotypes of ALDH2 were not related to the degree of vasodilation. These results suggest the existence of other predominant pathway(s) for nitroglycerin biotransformation, at least with regard to clinical nitroglycerin (e.g., a sublingual tablet) in Japanese subjects. Copyright © 2017 Elsevier B.V. All rights reserved.

Beneficial Effects of Apelin on Vascular Function in Patients With Central Obesity.

PubMed

Schinzari, Francesca; Veneziani, Augusto; Mores, Nadia; Barini, Angela; Di Daniele, Nicola; Cardillo, Carmine; Tesauro, Manfredi

2017-05-01

Patients with central obesity have impaired insulin-stimulated vasodilation and increased ET-1 (endothelin 1) vasoconstriction, which may contribute to insulin resistance and vascular damage. Apelin enhances insulin sensitivity and glucose disposal but also acts as a nitric oxide (NO)-dependent vasodilator and a counter-regulator of AT 1 (angiotensin [Ang] II type 1) receptor-induced vasoconstriction. We, therefore, examined the effects of exogenous (Pyr 1 )apelin on NO-mediated vasodilation and Ang II- or ET-1-dependent vasoconstrictor tone in obese patients. In the absence of hyperinsulinemia, forearm blood flow responses to graded doses of acetylcholine and sodium nitroprusside were not different during saline or apelin administration (both P >0.05). During intra-arterial infusion of regular insulin, however, apelin enhanced the vasodilation induced by both acetylcholine and nitroprusside (both P <0.05). Interestingly, the vasodilator effect of concurrent blockade of AT 1 (telmisartan) and AT 2 (PD 123,319) receptors was blunted by apelin (3±5% versus 32±9%; P <0.05). Similarly, during apelin administration, blockade of ET A receptors (BQ-123) resulted in lower vasodilator response than during saline (23±10% versus 65±12%; P <0.05). NO synthase inhibition by L-NMMA (l- N -monometylarginine) during the concurrent blockade of either Ang II or ET A receptors resulted in similar vasoconstriction in the absence or presence of apelin ( P >0.05). In conclusion, in patients with central obesity, apelin has favorable effects not only to improve insulin-stimulated endothelium-dependent and endothelium-independent vasodilator responses but also to blunt Ang II- and ET-1-dependent vasoconstriction by a mechanism not involving NO. Taken together, our results suggest that targeting the apelin system might favorably impact some hemodynamic abnormalities of insulin-resistant states like obesity. © 2017 American Heart Association, Inc.

TRPV4 channels: physiological and pathological role in cardiovascular system.

PubMed

Randhawa, Puneet Kaur; Jaggi, Amteshwar Singh

2015-11-01

TRPV4 channels are non-selective cation channels permeable to Ca(2+), Na(+), and Mg(2+) ions. Recently, TRPV4 channels have received considerable attention as these channels are widely expressed in the cardiovascular system including endothelial cells, cardiac fibroblasts, vascular smooth muscles, and peri-vascular nerves. Therefore, these channels possibly play a pivotal role in the maintenance of cardiovascular homeostasis. TRPV4 channels critically regulate flow-induced arteriogenesis, TGF-β1-induced differentiation of cardiac fibroblasts into myofibroblasts, and heart failure-induced pulmonary edema. These channels also mediate hypoxia-induced increase in proliferation and migration of pulmonary artery smooth muscle cells and progression of pulmonary hypertension. These channels also maintain flow-induced vasodilation and preserve vascular function by directly activating Ca(2+)-dependent KCa channels. Furthermore, these may also induce vasodilation and maintain blood pressure indirectly by evoking the release of NO, CGRP, and substance P. The present review discusses the evidences and the potential mechanisms implicated in diverse responses including arteriogenesis, cardiac remodeling, congestive heart failure-induced pulmonary edema, pulmonary hypertension, flow-induced dilation, regulation of blood pressure, and hypoxic preconditioning.

Current concepts of active vasodilation in human skin

PubMed Central

Wong, Brett J.; Hollowed, Casey G.

2017-01-01

ABSTRACT In humans, an increase in internal core temperature elicits large increases in skin blood flow and sweating. The increase in skin blood flow serves to transfer heat via convection from the body core to the skin surface while sweating results in evaporative cooling of the skin. Cutaneous vasodilation and sudomotor activity are controlled by a sympathetic cholinergic active vasodilator system that is hypothesized to operate through a co-transmission mechanism. To date, mechanisms of cutaneous active vasodilation remain equivocal despite many years of research by several productive laboratory groups. The purpose of this review is to highlight recent advancements in the field of cutaneous active vasodilation framed in the context of some of the historical findings that laid the groundwork for our current understanding of cutaneous active vasodilation. PMID:28349094

Atorvastatin Restores Endothelial Function in Normocholesterolemic Smokers Independent of Changes in Low-Density Lipoprotein

PubMed Central

Beckman, Joshua A.; Liao, James K.; Hurley, Shauna; Garrett, Leslie A.; Chui, Daoshan; Mitra, Debi; Creager, Mark A.

2009-01-01

Cigarette smoking impairs endothelial function. Hydroxymethylglutaryl (HMG) CoA reductase inhibitors (statins) may favorably affect endothelial function via nonlipid mechanisms. We tested the hypothesis that statins would improve endothelial function independent of changes in lipids in cigarette smokers. Twenty normocholesterolemic cigarette smokers and 20 matched healthy control subjects were randomized to atorvastatin 40 mg daily or placebo for 4 weeks, washed out for 4 weeks, and then crossed-over to the other treatment. Baseline low-density lipoprotein (LDL) levels were similar in smokers and healthy subjects, 103±22 versus 95±27 mg/dL, respectively (P=NS) and were reduced similarly in smokers and control subjects by atorvastatin, to 55±30 and 58±20 mg/dL, respectively (P=NS). Vascular ultrasonography was used to determine brachial artery, flow-mediated, endothelium-dependent, and nitroglycerin-mediated, endothelium-independent vasodilation. To elucidate potential molecular mechanisms that may account for changes in endothelial function, skin biopsy specimens were assayed for eNOS mRNA, eNOS activity, and nitrotyrosine. Endothelium-dependent vasodilation was less in smokers than nonsmoking control subjects during placebo treatment, 8.0±0.6% versus 12.1±1.1%, (P=0.003). Atorvastatin increased endothelium-dependent vasodilation in smokers to 10.5±1.3% (P=0.017 versus placebo) but did not change endothelium-dependent vasodilation in control subjects (to 11.0±0.8%, P=NS). Endothelium-independent vasodilation did not differ between groups during placebo treatment and was not significantly affected by atorvastatin. Multivariate analysis did not demonstrate any association between baseline lipid levels or the change in lipid levels and endothelium-dependent vasodilation. Cutaneous nitrotyrosine levels and skin microvessel eNOS mRNA, but not ENOS activity, were increased in smokers compared with controls but unaffected by atorvastatin treatment. Atorvastatin restores endothelium-dependent vasodilation in normocholesterolemic cigarette smokers independent of changes in lipids. These results are consistent with a lipid-independent vascular benefit of statins but could not be explained by changes in eNOS message and tissue oxidative stress. These findings implicate a potential role for statin therapy to restore endothelial function and thereby investigate vascular disease in cigarette smokers. PMID:15178637

Evidence for circulatory benefits of resveratrol in humans.

PubMed

Wong, Rachel H X; Coates, Alison M; Buckley, Jonathan D; Howe, Peter R C

2013-07-01

Impairments of endothelial function, which can be assessed noninvasively by flow-mediated dilation (FMD) of the brachial artery, contribute to the development of cardiovascular disease. Associations between FMD and cognition suggest a vascular component in the loss of cognitive function. Certain vasoactive nutrients that have been shown to improve FMD may also have the potential to enhance cerebral perfusion and cognition. Preclinical studies show that trans-resveratrol can enhance nitric oxide bioavailability, thereby increasing endothelium-dependent vasodilation. We have now shown that acute administration of resveratrol elicits dose-dependent increases of FMD with greater potency than other vasoactive nutrients and that this benefit is sustained following regular consumption. We describe the potential implications of this vasodilator benefit of resveratrol and its role in enhancing cerebrovascular and cognitive functions. © 2013 New York Academy of Sciences.

Vascular inward rectifier K+ channels as external K+ sensors in the control of cerebral blood flow.

PubMed

Longden, Thomas A; Nelson, Mark T

2015-04-01

For decades it has been known that external K(+) ions are rapid and potent vasodilators that increase CBF. Recent studies have implicated the local release of K(+) from astrocytic endfeet-which encase the entirety of the parenchymal vasculature-in the dynamic regulation of local CBF during NVC. It has been proposed that the activation of KIR channels in the vascular wall by external K(+) is a central component of these hyperemic responses; however, a number of significant gaps in our knowledge remain. Here, we explore the concept that vascular KIR channels are the major extracellular K(+) sensors in the control of CBF. We propose that K(+) is an ideal mediator of NVC, and discuss KIR channels as effectors that produce rapid hyperpolarization and robust vasodilation of cerebral arterioles. We provide evidence that KIR channels, of the KIR 2 subtype in particular, are present in both the endothelial and SM cells of parenchymal arterioles and propose that this dual positioning of KIR 2 channels increases the robustness of the vasodilation to external K(+), enables the endothelium to be actively engaged in NVC, and permits electrical signaling through the endothelial syncytium to promote upstream vasodilation to modulate CBF. © 2015 John Wiley & Sons Ltd.

Impact of shear rate modulation on vascular function in humans

PubMed Central

Tinken, Toni M.; Thijssen, Dick H.J.; Hopkins, Nicola; Black, Mark A.; Dawson, Ellen A.; Minson, Christopher T.; Newcomer, Sean C.; Laughlin, M. Harold; Cable, N. Timothy; Green, Daniel J.

2010-01-01

Shear stress is an important stimulus to arterial adaptation in response to exercise and training in humans. We recently observed significant reverse arterial flow and shear during exercise and different antegrade/retrograde patterns of shear and flow in response to different types of exercise. The purpose of this study was to simultaneously examine flow mediated dilation (FMD), a largely nitric oxide mediated vasodilator response, in both brachial arteries of healthy young men before and after 30-minute interventions consisting of bilateral forearm heating, recumbent leg cycling and bilateral handgrip exercise. During each intervention, a cuff inflated to 60mmHg was placed on one arm to unilaterally manipulate the shear rate stimulus. In the non-cuffed arm, antegrade flow and shear increased similarly in response to each intervention (ANOVA; P<0.001, no interaction between interventions; P=0.71). Baseline FMD (4.6, 6.9 and 6.7%) increased similarly in response to heating, handgrip and cycling (8.1, 10.4 and 8.9%, ANOVA; P<0.001, no interaction; 0.89). In contrast, cuffed arm antegrade shear rate was lower than in the non-cuffed arm for all conditions (P<0.05) and the increase in FMD was abolished in this arm (4.7, 6.7 and 6.1%) (2-way ANOVA: all conditions interacted P<0.05). These results suggest that differences in the magnitude of antegrade shear rate transduce differences in endothelial vasodilator function in humans, a finding which may have relevance for the impact of different exercise interventions on vascular adaptation in humans. PMID:19546374

Effects of forskolin on cerebral blood flow: implications for a role of adenylate cyclase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wysham, D.G.; Brotherton, A.F.; Heistad, D.D.

1986-11-01

We have studied cerebral vascular effects of forskolin, a drug which stimulates adenylate cyclase and potentiates dilator effects of adenosine in other vascular beds. Our goals were to determine whether forskolin is a cerebral vasodilator and whether it potentiates cerebral vasodilator responses to adenosine. We measured cerebral blood flow with microspheres in anesthetized rabbits. Forskolin (10 micrograms/kg per min) increased blood flow (ml/min per 100 gm) from 39 +/- 5 (mean +/- S.E.) to 56 +/- 9 (p less than 0.05) in cerebrum, and increased flow to myocardium and kidney despite a decrease in mean arterial pressure. Forskolin did notmore » alter cerebral oxygen consumption, which indicates that the increase in cerebral blood flow is a direct vasodilator effect and is not secondary to increased metabolism. We also examined effects of forskolin on the response to infusion of adenosine. Cerebral blood flow was measured during infusion of 1-5 microM/min adenosine into one internal carotid artery, under control conditions and during infusion of forskolin at 3 micrograms/kg per min i.v. Adenosine alone increased ipsilateral cerebral blood flow from 32 +/- 3 to 45 +/- 5 (p less than 0.05). Responses to adenosine were not augmented during infusion of forskolin. We conclude that forskolin is a direct cerebral vasodilator and forskolin does not potentiate cerebral vasodilator responses to adenosine.« less

The effect of bioresorbable vascular scaffold implantation on distal coronary endothelial function in dyslipidemic swine with and without diabetes.

PubMed

van den Heuvel, Mieke; Sorop, Oana; van Ditzhuijzen, Nienke S; de Vries, René; van Duin, Richard W B; Peters, Ilona; van Loon, Janine E; de Maat, Moniek P; van Beusekom, Heleen M; van der Giessen, Wim J; Jan Danser, A H; Duncker, Dirk J

2018-02-01

We studied the effect of bioresorbable vascular scaffold (BVS) implantation on distal coronary endothelial function, in swine on a high fat diet without (HFD) or with diabetes (DM+HFD). Five DM+HFD and five HFD swine underwent BVS implantation on top of coronary plaques, and were studied six months later. Conduit artery segments >5mm proximal and distal to the scaffold and corresponding segments of non-scaffolded coronary arteries, and segments of small arteries within the flow-territory of scaffolded and non-scaffolded arteries were harvested for in vitro vasoreactivity studies. Conduit segments proximal and distal of the BVS edges showed reduced endothelium-dependent vasodilation as compared to control vessels (p≤0.01), with distal segments being most prominently affected(p≤0.01). Endothelial dysfunction was only observed in DM±HFD swine and was principally due to a loss of NO. Endothelium-independent vasodilation and vasoconstriction were unaffected. Surprisingly, segments from the microcirculation distal to the BVS showed enhanced endothelium-dependent vasodilation (p<0.01), whereas endothelium-independent vasodilation and vasoconstriction were unaltered. This enhanced vasorelaxation was only observed in DM+HFD swine, and did not appear to be either NO- or EDHF-mediated. Six months of BVS implantation in DM+HFD swine causes NO-mediated endothelial dysfunction in nearby coronary segments, which is accompanied by a, possibly compensatory, increase in endothelial function of the distal microcirculation. Endothelial dysfunction extending into coronary conduit segments beyond the implantation-site, is in agreement with recent reports expressing concern for late scaffold thrombosis and of early BVS failure in diabetic patients. Copyright © 2017. Published by Elsevier B.V.

Temporal characteristics of nitric oxide-, prostaglandin-, and EDHF-mediated components of endothelium-dependent vasodilation in the kidney.

PubMed

Dautzenberg, Marcel; Just, Armin

2013-11-01

Endothelium-dependent vasodilation is mediated by nitric oxide (NO), prostaglandins (PG), and endothelium-derived hyperpolarizing factor (EDHF). We studied the contributions and temporal characteristics of these components in the renal vasodilator responses to acetylcholine (ACh) and bradykinin (BK) and in the buffering of vasoconstrictor responses to norepinephrine (NE) and angiotensin II (ANG II). Renal blood flow (RBF) and vascular conductance (RVC) were studied in anesthetized rats in response to renal arterial bolus injections before and after inhibition of NO-synthase (N(G)-nitro-L-arginine methyl ester, L-NAME), cyclooxygenase (indomethacin, INDO), or both. ACh increased RVC peaking at maximal time (tmax) = 29 s. L-NAME (n = 8) diminished the integrated response and made it substantially faster (tmax = 18 s). The point-by-point difference caused by L-NAME (= NO component) integrated to 74% of control and was much slower (tmax = 38 s). INDO (n = 9) reduced the response without affecting tmax (36 vs. 30 s). The difference (= PG) reached 21% of the control with tmax = 25 s. L-NAME+INDO (n = 17) reduced the response to 18% and markedly accelerated tmax to 16s (= EDHF). Results were similar for BK with slightly more PG and less NO contribution than for ACh. Constrictor responses to NE and ANG II were augmented and decelerated by L-NAME and L-NAME+INDO. The calculated difference (= buffering by NO or NO+PG) was slower than the constriction. It is concluded that NO, PG, and EDHF contribute >50%, 20-40%, and <20% to the renal vasodilator effect of ACh and BK, respectively. EDHF acts substantially faster and less sustained (tmax = 16 s) than NO and PG (tmax = 30 s). Constrictor buffering by NO and PG is not constant over time, but renders the constriction less sustained.

Relationships of vascular function with measures of ambulatory blood pressure variation.

PubMed

Hodgson, Jonathan M; Woodman, Richard J; Croft, Kevin D; Ward, Natalie C; Bondonno, Catherine P; Puddey, Ian B; Lukoshkova, Elena V; Head, Geoffrey A

2014-03-01

Characteristics of short-term blood pressure (BP) variation may influence cardiovascular disease risk via effects on vascular function. In a cross-sectional study of a group of treated hypertensive and untreated largely normotensive subjects we investigated the relationships of measures of short-term BP variation with brachial artery vasodilator function. A total of 163 treated hypertensive (n = 91) and untreated largely normotensive (n = 72) men and women were recruited from the general population. Measures of systolic and diastolic BP variation were calculated from 24 h ambulatory BP assessments and included: (i) rate of measurement-to-measurement BP variation (SBP-var and DBP-var); and (ii) day-to-night BP dip (SBP-dip and DBP dip). Endothelium-dependent vasodilation was assessed as flow-mediated dilation (FMD) and endothelium-independent vasodilation was assessed in response to glyceryl trinitrate (GTN). Relationships were explored using univariate and multivariate linear regression. The relationships of brachial artery vasodilator function with BP variation were not significantly different between treated hypertensive and untreated subjects, therefore these groups were combined for analysis. In univariate analysis, higher SBP-var (P < 0.001) and lower DBP-dip (P = 0.004) were associated with lower FMD; and higher SBP-var (P = 0.002) and lower SBP-dip (P = 0.003) and DBP-dip (P = 0.001) were associated with lower GTN-mediated dilation. In multivariate analysis, lower SBP-dip (P = 0.007) and DBP-dip (P = 0.03) were independently associated with lower GTN response. Our results indicate that a lower day-to-night BP dip is independently associated with impaired smooth muscle cell function. Although rate of BP variation was associated with measures of endothelial and smooth muscle cell function, relationships were attenuated after accounting for age and BP. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Favorable Vascular Actions of Angiotensin-(1-7) in Human Obesity.

PubMed

Schinzari, Francesca; Tesauro, Manfredi; Veneziani, Augusto; Mores, Nadia; Di Daniele, Nicola; Cardillo, Carmine

2018-01-01

Obese patients have vascular dysfunction related to impaired insulin-stimulated vasodilation and increased endothelin-1-mediated vasoconstriction. In contrast to the harmful vascular actions of angiotensin (Ang) II, the angiotensin-converting enzyme 2 product Ang-(1-7) has shown to exert cardiovascular and metabolic benefits in experimental models through stimulation of the Mas receptor. We, therefore, examined the effects of exogenous Ang-(1-7) on vasodilator tone and endothelin-1-dependent vasoconstriction in obese patients. Intra-arterial infusion of Ang-(1-7) (10 nmol/min) resulted in significant increase in unstimulated forearm flow ( P =0.03), an effect that was not affected by the Mas receptor antagonist A779 (10 nmol/min; P >0.05). In the absence of hyperinsulinemia, however, forearm flow responses to graded doses of acetylcholine and sodium nitroprusside were not different during Ang-(1-7) administration compared with saline (both P >0.05). During infusion of regular insulin (0.15 mU/kg per minute), by contrast, endothelium-dependent vasodilator response to acetylcholine was significantly enhanced by Ang-(1-7) ( P =0.04 versus saline), whereas endothelium-independent response to sodium nitroprusside was not modified ( P =0.91). Finally, Ang-(1-7) decreased the vasodilator response to endothelin A receptor blockade (BQ-123; 10 nmol/min) compared with saline (6±1% versus 93±17%; P <0.001); nitric oxide inhibition by l- N -monomethylarginine (4 µmol/min) during concurrent endothelin A antagonism resulted in similar vasoconstriction in the absence or presence of Ang-(1-7 Ang-(1-7) ( P =0.69). Our findings indicate that in obese patients Ang-(1-7) has favorable effects not only to improve insulin-stimulated endothelium-dependent vasodilation but also to blunt endothelin-1-dependent vasoconstrictor tone. These findings provide support for targeting Ang-(1-7) to counteract the hemodynamic abnormalities of human obesity. © 2017 American Heart Association, Inc.

Myocardial Blood Flow Distribution during Ischemia-Induced Coronary Vasodilation in the Unanesthetized Dog

PubMed Central

Bache, Robert J.; Cobb, Frederick R.; Greenfield, Joseph C.

1974-01-01

This study was designed to determine whether coronary vasodilation distal to a flow-limiting coronary artery stenosis could result in redistribution of myocardial blood flow to produce subendocardial underperfusion. Studies were performed in 10 awake dogs chronically prepared with electromagnetic flow-meters and hydraulic occluders on the left circumflex coronary artery. Regional myocardial blood flow was measured using radionuclide-labeled microspheres, 7-10 μm in diameter, injected into the left atrium. A 5-s coronary artery occlusion was followed by reactive hyperemia with excess inflow of arterial blood effecting 375±20% repayment of the blood flow debt incurred during occlusion. When, after a 5-s occlusion, the occluder was only partially released to hold arterial inflow to the preocclusion level for 20 s before complete release, the delayed reactive hyperemia was augmented (mean blood flow repayment = 610±45%, P < 0.01). This augmentation of the reactive hyperemia suggested that ischemia was continuing during the interval of coronary vasodilation when coronary inflow was at the preocclusion level. Measurements of regional myocardial blood flow demonstrated that endocardial flow slightly exceeded epicardial flow during control conditions. When arterial inflow was limited to the preocclusion rate during vasodilation after a 5-s total coronary artery occlusion, however, flow to the subepicardial myocardium was increased at the expense of underperfusion of the subendocardial myocardium. Thus, in the presence of a flow-limiting proximal coronary artery stenosis, ischemia-induced coronary vasodilation resulted in redistribution of myocardial blood flow with production of subendocardial ischemia in the presence of a net volume of arterial inflow which, if properly distributed, would have been adequate to prevent myocardial ischemia. Images PMID:4279928

Effect of skin temperature on cutaneous vasodilator response to the β-adrenergic agonist isoproterenol

PubMed Central

Hodges, Gary J.; Johnson, John M.

2015-01-01

The vascular response to local skin cooling is dependent in part on a cold-induced translocation of α2C-receptors and an increased α-adrenoreceptor function. To discover whether β-adrenergic function might contribute, we examined whether β-receptor sensitivity to the β-agonist isoproterenol was affected by local skin temperature. In seven healthy volunteers, skin blood flow was measured from the forearm by laser-Doppler flowmetry and blood pressure was measured by finger photoplethysmography. Data were expressed as cutaneous vascular conductance (CVC; laser-Doppler flux/mean arterial blood pressure). Pharmacological agents were administered via intradermal microdialysis. We prepared four skin sites: one site was maintained at a thermoneutral temperature of 34°C (32 ± 10%CVCmax) one site was heated to 39°C (38 ± 11%CVCmax); and two sites were cooled, one to 29°C (22 ± 7%CVCmax) and the other 24°C (16 ± 4%CVCmax). After 20 min at these temperatures to allow stabilization of skin blood flow, isoproterenol was perfused in concentrations of 10, 30, 100, and 300 μM. Each concentration was perfused for 15 min. Relative to the CVC responses to isoproterenol at the thermoneutral skin temperature (34°C) (+21 ± 10%max), low skin temperatures reduced (at 29°C) (+17 ± 6%max) or abolished (at 24°C) (+1 ± 5%max) the vasodilator response, and warm (39°C) skin temperatures enhanced the vasodilator response (+40 ± 9%max) to isoproterenol. These data indicate that β-adrenergic function was influenced by local skin temperature. This finding raises the possibility that a part of the vasoconstrictor response to direct skin cooling could include reduced background β-receptor mediated vasodilation. PMID:25701007

Effect of skin temperature on cutaneous vasodilator response to the β-adrenergic agonist isoproterenol.

PubMed

Hodges, Gary J; Kellogg, Dean L; Johnson, John M

2015-04-01

The vascular response to local skin cooling is dependent in part on a cold-induced translocation of α2C-receptors and an increased α-adrenoreceptor function. To discover whether β-adrenergic function might contribute, we examined whether β-receptor sensitivity to the β-agonist isoproterenol was affected by local skin temperature. In seven healthy volunteers, skin blood flow was measured from the forearm by laser-Doppler flowmetry and blood pressure was measured by finger photoplethysmography. Data were expressed as cutaneous vascular conductance (CVC; laser-Doppler flux/mean arterial blood pressure). Pharmacological agents were administered via intradermal microdialysis. We prepared four skin sites: one site was maintained at a thermoneutral temperature of 34°C (32 ± 10%CVCmax) one site was heated to 39°C (38 ± 11%CVCmax); and two sites were cooled, one to 29°C (22 ± 7%CVCmax) and the other 24°C (16 ± 4%CVCmax). After 20 min at these temperatures to allow stabilization of skin blood flow, isoproterenol was perfused in concentrations of 10, 30, 100, and 300 μM. Each concentration was perfused for 15 min. Relative to the CVC responses to isoproterenol at the thermoneutral skin temperature (34°C) (+21 ± 10%max), low skin temperatures reduced (at 29°C) (+17 ± 6%max) or abolished (at 24°C) (+1 ± 5%max) the vasodilator response, and warm (39°C) skin temperatures enhanced the vasodilator response (+40 ± 9%max) to isoproterenol. These data indicate that β-adrenergic function was influenced by local skin temperature. This finding raises the possibility that a part of the vasoconstrictor response to direct skin cooling could include reduced background β-receptor mediated vasodilation. Copyright © 2015 the American Physiological Society.

Regular aerobic exercise reduces endothelin-1-mediated vasoconstrictor tone in overweight and obese adults.

PubMed

Dow, Caitlin A; Stauffer, Brian L; Brunjes, Danielle L; Greiner, Jared J; DeSouza, Christopher A

2017-09-01

What is the central question of this study? Does aerobic exercise training reduce endothelin-1 (ET-1)-mediated vasoconstrictor tone in overweight/obese adults? And, if so, does lower ET-1 vasoconstriction underlie the exercise-related enhancement in endothelium-dependent vasodilatation in overweight/obese adults? What is the main finding and its importance? Regular aerobic exercise reduces ET-1-mediated vasoconstrictor tone in previously sedentary overweight/obese adults, independent of weight loss. Decreased ET-1 vasoconstriction is an important mechanism underlying the aerobic exercise-induced improvement in endothelium-dependent vasodilator function in overweight/obese adults. Endothelin-1 (ET-1)-mediated vasoconstrictor tone is elevated in overweight and obese adults, contributing to vasomotor dysfunction and increased cardiovascular disease risk. Although the effects of habitual aerobic exercise on endothelium-dependent vasodilatation in overweight/obese adults have been studied, little is known regarding ET-1-mediated vasoconstriction. Accordingly, the aims of the present study were to determine the following: (i) whether regular aerobic exercise training reduces ET-1-mediated vasoconstrictor tone in overweight and obese adults; and, if so, (ii) whether the reduction in ET-1-mediated vasoconstriction contributes to exercise-induced improvement in endothelium-dependent vasodilatation in this population. Forearm blood flow (FBF) in response to intra-arterial infusion of selective ET A receptor blockade (BQ-123, 100 nmol min -1 for 60 min), acetylcholine [4.0, 8.0 and 16.0 μg (100 ml tissue) -1  min -1 ] in the absence and presence of ET A receptor blockade and sodium nitroprusside [1.0, 2.0 and 4.0 μg (100 ml tissue) -1  min -1 ] were determined before and after a 3 month aerobic exercise training intervention in 25 (16 men and nine women) overweight/obese (body mass index 30.1 ± 0.5 kg m -2 ) adults. The vasodilator response to BQ-123 was significantly lower (∼25%) and the FBF responses to acetylcholine were ∼35% higher after exercise training. Before the exercise intervention, the co-infusion of acetylcholine plus BQ-123 resulted in a greater vasodilator response than acetylcholine alone; however, after the exercise intervention the FBF response to acetylcholine was not significantly increased by ET A receptor blockade. These results demonstrate that regular aerobic exercise reduces ET-1-mediated vasoconstrictor tone in previously sedentary overweight and obese adults. Moreover, decreased ET-1-mediated vasoconstriction is an important mechanism underlying the aerobic exercise-induced improvement in endothelium-dependent vasodilator function in overweight/obese adults. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

Critical contribution of Na+-Ca2+ exchanger to the Ca2+-mediated vasodilation activated in endothelial cells of resistance arteries.

PubMed

Lillo, Mauricio A; Gaete, Pablo S; Puebla, Mariela; Ardiles, Nicolás M; Poblete, Inés; Becerra, Alvaro; Simon, Felipe; Figueroa, Xavier F

2018-04-01

Na + -Ca 2+ exchanger (NCX) contributes to control the intracellular free Ca 2+ concentration ([Ca 2+ ] i ), but the functional activation of NCX reverse mode (NCXrm) in endothelial cells is controversial. We evaluated the participation of NCXrm-mediated Ca 2+ uptake in the endothelium-dependent vasodilation of rat isolated mesenteric arterial beds. In phenylephrine-contracted mesenteries, the acetylcholine (ACh)-induced vasodilation was abolished by treatment with the NCXrm blockers SEA0400, KB-R7943, or SN-6. Consistent with that, the ACh-induced hyperpolarization observed in primary cultures of mesenteric endothelial cells and in smooth muscle of isolated mesenteric resistance arteries was attenuated by KB-R7943 and SEA0400, respectively. In addition, both blockers abolished the NO production activated by ACh in intact mesenteric arteries. In contrast, the inhibition of NCXrm did not affect the vasodilator responses induced by the Ca 2+ ionophore, ionomycin, and the NO donor, S-nitroso- N-acetylpenicillamine. Furthermore, SEA0400, KB-R7943, and a small interference RNA directed against NCX1 blunted the increase in [Ca 2+ ] i induced by ACh or ATP in cultured endothelial cells. The analysis by proximity ligation assay showed that the NO-synthesizing enzyme, eNOS, and NCX1 were associated in endothelial cell caveolae of intact mesenteric resistance arteries. These results indicate that the activation of NCXrm has a central role in Ca 2+ -mediated vasodilation initiated by ACh in endothelial cells of resistance arteries.-Lillo, M. A., Gaete, P. S., Puebla, M., Ardiles, N. M., Poblete, I., Becerra, A., Simon, F., Figueroa, X. F. Critical contribution of Na + -Ca 2+ exchanger to the Ca 2+ -mediated vasodilation activated in endothelial cells of resistance arteries.

The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects

PubMed Central

Johns, D G; Behm, D J; Walker, D J; Ao, Z; Shapland, E M; Daniels, D A; Riddick, M; Dowell, S; Staton, P C; Green, P; Shabon, U; Bao, W; Aiyar, N; Yue, T-L; Brown, A J; Morrison, A D; Douglas, S A

2007-01-01

Background and purpose: Atypical cannabinoids are thought to cause vasodilatation through an as-yet unidentified ‘CBx' receptor. Recent reports suggest GPR55 is an atypical cannabinoid receptor, making it a candidate for the vasodilator ‘CBx' receptor. The purpose of the present study was to test the hypothesis that human recombinant GPR55 is activated by atypical cannabinoids and mediates vasodilator responses to these agents. Experimental approach: Human recombinant GPR55 was expressed in HEK293T cells and specific GTPγS activity was monitored as an index of receptor activation. In GPR55-deficient and wild-type littermate control mice, in vivo blood pressure measurement and isolated resistance artery myography were used to determine GPR55 dependence of atypical cannabinoid-induced haemodynamic and vasodilator responses. Key results: Atypical cannabinoids O-1602 and abnormal cannabidiol both stimulated GPR55-dependent GTPγS activity (EC50 approximately 2 nM), whereas the CB1 and CB2-selective agonist WIN 55,212-2 showed no effect in GPR55-expressing HEK293T cell membranes. Baseline mean arterial pressure and heart rate were not different between WT and GPR55 KO mice. The blood pressure-lowering response to abnormal cannabidiol was not different between WT and KO mice (WT 20±2%, KO 26±5% change from baseline), nor was the vasodilator response to abnormal cannabidiol in isolated mesenteric arteries (IC50 approximately 3 μ M for WT and KO). The abnormal cannabidiol vasodilator response was antagonized equivalently by O-1918 in both strains. Conclusions: These results demonstrate that while GPR55 is activated by atypical cannabinoids, it does not appear to mediate the vasodilator effects of these agents. PMID:17704827

Identification of the Muscarinic Acetylcholine Receptor Subtype Mediating Cholinergic Vasodilation in Murine Retinal Arterioles

PubMed Central

Sniatecki, Jan J.; Goloborodko, Evgeny; Steege, Andreas; Zavaritskaya, Olga; Vetter, Jan M.; Grus, Franz H.; Patzak, Andreas; Wess, Jürgen; Pfeiffer, Norbert

2011-01-01

Purpose. To identify the muscarinic acetylcholine receptor subtype that mediates cholinergic vasodilation in murine retinal arterioles. Methods. Muscarinic receptor gene expression was determined in murine retinal arterioles using real-time PCR. To assess the functional relevance of muscarinic receptors for mediating vascular responses, retinal vascular preparations from muscarinic receptor–deficient mice were studied in vitro. Changes in luminal arteriole diameter in response to muscarinic and nonmuscarinic vasoactive substances were measured by video microscopy. Results. Only mRNA for the M3 receptor was detected in retinal arterioles. Thus, M3 receptor–deficient mice (M3R−/−) and respective wild-type controls were used for functional studies. Acetylcholine concentration-dependently dilated retinal arterioles from wild-type mice. In contrast, vasodilation to acetylcholine was almost completely abolished in retinal arterioles from M3R−/− mice, whereas responses to the nitric oxide (NO) donor nitroprusside were retained. Carbachol, an acetylcholinesterase-resistant analog of acetylcholine, also evoked dilation in retinal arterioles from wild-type, but not from M3R−/−, mice. Vasodilation responses from wild-type mice to acetylcholine were negligible after incubation with the non–subtype-selective muscarinic receptor blocker atropine or the NO synthase inhibitor Nω-nitro-l-arginine methyl ester, and were even reversed to contraction after endothelial damage with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate. Conclusions. These findings provide evidence that endothelial M3 receptors mediate cholinergic vasodilation in murine retinal arterioles via activation of NO synthase. PMID:21873683

Dilator and constrictor response of renal vasculature during acute renal hypotension in anesthetized goats. Role of nitric oxide.

PubMed

Diéguez, Godofredo; García-Villalón, Angel Luis

2011-01-01

The relative role of NO derived from endothelium NO synthase (eNOS) and neuronal NO synthase (nNOS) in renovascular reactivity during renal hypotension is unknown. To examine this issue, we recorded the effects of unspecific inhibitor of NO synthase N(w)-nitro-L-arginine methyl esther (L-NAME) and inhibitor of nNOS 7-nitroindazole monosodium salt (7-NINA) on renal vasodilator and vasoconstrictor responses in anesthetized goats during renal hypotension by constricting the abdominal aorta. Intrarenal administration of L-NAME and hypotension, either untreated or treated with L-NAME, decreased resting renal blood flow, and the increases in renal blood flow by acetylcholine but not those by sodium nitroprusside were tempered, and the decreases by norepinephrine and angiotensin II were augmented. Intraperitoneal administration of 7-NINA did not affect, and 7-NINA+hypotension decreased renal blood flow, and under these conditions the increases in renal blood flow by acetylcholine and sodium nitroprusside were not modified, and the decreases by norepinephrine and angiotensin II were slightly (during 7-NINA) or consistently augmented (7-NINA+hypotension). Therefore, NO derived from eNOS plays a significant role, while that derived from nNOS plays a little role, if any, to regulate renal blood flow and to mediate acetylcholine-induced vasodilation, as well to modulate renal vasoconstriction by norepinephrine and angiotensin II. Copyright © 2011 Elsevier Inc. All rights reserved.

Uric acid and endothelial function in elderly community-dwelling subjects.

PubMed

Ticinesi, Andrea; Lauretani, Fulvio; Ceda, Gian Paolo; Ruggiero, Carmelinda; Ferrucci, Luigi; Aloe, Rosalia; Larsson, Anders; Cederholm, Tommy; Lind, Lars; Meschi, Tiziana; Maggio, Marcello

2017-03-01

The role of serum uric acid (SUA), an inflammatory agent and potential mediator of cardiovascular diseases, in endothelial function (EF) has been tested only in middle-aged subjects affected by specific diseases. Our aim was to assess the relationship between SUA and measures of EF in a cohort of elderly community-dwellers. This study involved 424 males and 426 females aged 70years from the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS), having complete data on SUA and EF assessed by flow-mediated vasodilation (FMD) and by intra-arterial infusion of acetylcholine (endothelium-dependent vasodilation, EDV) and sodium nitroprusside (endothelium-independent vasodilation, EIDV). Univariate and multivariate regression models obtained by backward selection from initial fully-adjusted models were built to assess the relationship between SUA and measures of EF in both genders. Cardiovascular risk factors, serum hormonal and metabolic mediators, and body composition were considered as potential confounders. In the univariate model, SUA was inversely associated in both genders with log(EDV) (β±SE males -0.39±0.17, p=0.03; females -0.57±0.19, p=0.003) and log(EIDV) (males -0.23±0.12, p=0.05; females -0.49±0.15, p=0.002), but not with log(FMD). After adjustment for BMI, only the association between SUA and log(EIDV) in females persisted, though attenuated (-0.32±0.16, p=0.049), and was no longer significant in the fully-adjusted multivariate model including waist/hip ratio. In conclusion, in older subjects, especially women, SUA is associated with EF not independently of a list of confounders including BMI and trunk fat mass, suggesting a role as surrogate metabolic marker rather than an active player in EF. Copyright © 2017 Elsevier Inc. All rights reserved.

Uric acid and endothelial function in elderly community-dwelling subjects

PubMed Central

Ticinesi, Andrea; Lauretani, Fulvio; Ceda, Gian Paolo; Ruggiero, Carmelinda; Ferrucci, Luigi; Aloe, Rosalia; Larsson, Anders; Cederholm, Tommy; Lind, Lars; Meschi, Tiziana; Maggio, Marcello

2017-01-01

The role of serum uric acid (SUA), an inflammatory agent and potential mediator of cardiovascular diseases, in endothelial function (EF) has been tested only in middle-aged subjects affected by specific diseases. Our aim was to assess the relationship between SUA and measures of EF in a cohort of elderly community-dwellers. This study involved 424 males and 426 females aged 70 years from the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS), having complete data on SUA and EF assessed by flow-mediated vasodilation (FMD) and by intra-arterial infusion of acetylcholine (endothelium-dependent vasodilation, EDV) and sodium nitroprusside (endothelium-independent vasodilation, EIDV). Univariate and multivariate regression models obtained by backward selection from initial fully-adjusted models were built to assess the relationship between SUA and measures of EF in both genders. Cardiovascular risk factors, serum hormonal and metabolic mediators, and body composition were considered as potential confounders. In the univariate model, SUA was inversely associated in both genders with log(EDV) (β ± SE males −0.39 ± 0.17, p = 0.03; females −0.57 ± 0.19, p = 0.003) and log(EIDV) (males −0.23 ± 0.12, p = 0.05; females −0.49 ± 0.15, p = 0.002), but not with log(FMD). After adjustment for BMI, only the association between SUA and log(EIDV) in females persisted, though attenuated (−0.32 ± 0.16, p = 0.049), and was no longer significant in the fully-adjusted multivariate model including waist/hip ratio. In conclusion, in older subjects, especially women, SUA is associated with EF not independently of a list of confounders including BMI and trunk fat mass, suggesting a role as surrogate metabolic marker rather than an active player in EF. PMID:28057563

Dissociation between neural and vascular responses to sympathetic stimulation : contribution of local adrenergic receptor function

NASA Technical Reports Server (NTRS)

Jacob, G.; Costa, F.; Shannon, J.; Robertson, D.; Biaggioni, I.

2000-01-01

Sympathetic activation produced by various stimuli, eg, mental stress or handgrip, evokes regional vascular responses that are often nonhomogeneous. This phenomenon is believed to be the consequence of the recruitment of differential central neural pathways or of a sympathetically mediated vasodilation. The purpose of this study was to determine whether a similar heterogeneous response occurs with cold pressor stimulation and to test the hypothesis that local differences in adrenergic receptor function could be in part responsible for this diversity. In 8 healthy subjects, local norepinephrine spillover and blood flow were measured in arms and legs at baseline and during sympathetic stimulation induced by baroreflex mechanisms (nitroprusside infusion) or cold pressor stimulation. At baseline, legs had higher vascular resistance (27+/-5 versus 17+/-2 U, P=0.05) despite lower norepinephrine spillover (0.28+/-0.04 versus 0.4+/-0.05 mg. min(-1). dL(-1), P=0.03). Norepinephrine spillover increased similarly in both arms and legs during nitroprusside infusion and cold pressor stimulation. On the other hand, during cold stimulation, vascular resistance increased in arms but not in legs (20+/-9% versus -7+/-4%, P=0.03). Increasing doses of isoproterenol and phenylephrine were infused intra-arterially in arms and legs to estimate beta-mediated vasodilation and alpha-induced vasoconstriction, respectively. beta-Mediated vasodilation was significantly lower in legs compared with arms. Thus, we report a dissociation between norepinephrine spillover and vascular responses to cold stress in lower limbs characterized by a paradoxical decrease in local resistance despite increases in sympathetic activity. The differences observed in adrenergic receptor responses cannot explain this phenomenon.

Impaired arterial smooth muscle cell vasodilatory function in methamphetamine users.

PubMed

Nabaei, Ghaemeh; Oveisgharan, Shahram; Ghorbani, Askar; Fatehi, Farzad

2016-11-15

Methamphetamine use is a strong risk factor for stroke. This study was designed to evaluate arterial function and structure in methamphetamine users ultrasonographically. In a cross-sectional study, 20 methamphetamine users and 21 controls, aged between 20 and 40years, were enrolled. Common carotid artery intima-media thickness (CCA-IMT) marker of early atherogenesis, flow-mediated dilatation (FMD) determinants of endothelium-dependent vasodilation, and nitroglycerine-mediated dilatation (NMD) independent marker of vasodilation were measured in two groups. There were no significant differences between the two groups regarding demographic and metabolic characteristics. The mean (±SD) CCA-IMT in methamphetamine users was 0.58±0.09mm, versus 0.59±0.07mm in the controls (p=0.84). Likewise, FMD% was not significantly different between the two groups [7.6±6.1% in methamphetamine users vs. 8.2±5.1% in the controls; p=0.72], nor were peak flow and shear rate after hyperemia. However, NMD% was considerably decreased in the methamphetamine users [8.5±7.8% in methamphetamine users vs. 13.4±6.2% in controls; p=0.03]. According to our results, NMD is reduced among otherwise healthy methamphetamine users, which represents smooth muscle dysfunction in this group. This may contribute to the high risk of stroke among methamphetamine users. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of supplementation with the fat-soluble vitamins E and D on fasting flow-mediated vasodilation in adults: a meta-analysis of randomized controlled trials.

PubMed

Joris, Peter J; Mensink, Ronald P

2015-03-10

The effects of fat-soluble vitamin supplementation on cardiovascular disease (CVD) risk are not clear. Therefore, we performed a meta-analysis to quantify effects of fat-soluble vitamin supplements on fasting flow-mediated vasodilation (FMD) of the brachial artery, a validated marker to assess CVD risk. Randomized placebo-controlled trials (RCTs) were identified by a systematic search till July 2014. Seven RCTs studying the effects of vitamin E supplements (range: 300 to 1800 IU per day) and nine RCTs examining the effects of vitamin D supplements, that involved, respectively, 303 and 658 adults, were included. No studies with carotenoid or vitamin K supplements were found. Vitamin E supplementation increased FMD vs. control by 2.42% (95% CI: 0.46% to 4.37%; p = 0.015). No effects of vitamin D supplementation were found (0.15%; 95% CI: -0.21% to 0.51%; p = 0.41). These effects did not depend on subject characteristics, treatment characteristics or technical aspects of the FMD measurement. However, no dose-response relationship was evident for vitamin E, statistical significance depended on one study, while the levels of supplement were far above recommended intakes. The current meta-analysis, therefore, does not provide unambiguous evidence to support the use of fat-soluble vitamin supplements to improve fasting FMD in adults.

Effects of Supplementation with the Fat-Soluble Vitamins E and D on Fasting Flow-Mediated Vasodilation in Adults: A Meta-Analysis of Randomized Controlled Trials

PubMed Central

Joris, Peter J.; Mensink, Ronald P.

2015-01-01

The effects of fat-soluble vitamin supplementation on cardiovascular disease (CVD) risk are not clear. Therefore, we performed a meta-analysis to quantify effects of fat-soluble vitamin supplements on fasting flow-mediated vasodilation (FMD) of the brachial artery, a validated marker to assess CVD risk. Randomized placebo-controlled trials (RCTs) were identified by a systematic search till July 2014. Seven RCTs studying the effects of vitamin E supplements (range: 300 to 1800 IU per day) and nine RCTs examining the effects of vitamin D supplements, that involved, respectively, 303 and 658 adults, were included. No studies with carotenoid or vitamin K supplements were found. Vitamin E supplementation increased FMD vs. control by 2.42% (95% CI: 0.46% to 4.37%; p = 0.015). No effects of vitamin D supplementation were found (0.15%; 95% CI: −0.21% to 0.51%; p = 0.41). These effects did not depend on subject characteristics, treatment characteristics or technical aspects of the FMD measurement. However, no dose-response relationship was evident for vitamin E, statistical significance depended on one study, while the levels of supplement were far above recommended intakes. The current meta-analysis, therefore, does not provide unambiguous evidence to support the use of fat-soluble vitamin supplements to improve fasting FMD in adults. PMID:25763531

Histamine response and local cooling in the human skin: involvement of H1- and H2-receptors.

PubMed

Grossmann, M; Jamieson, M J; Kirch, W

1999-08-01

Histamine may contribute locally to cutaneous blood flow control under normal and pathologic conditions. The objective of this study was to observe the influence of skin temperature on histamine vasodilation, and the roles of H1-and H2-receptors using novel noninvasive methods. Eleven healthy subjects received, double-blind, single doses of the H1-receptor antagonist cetirizine (10 mg), cetirizine (10 mg) plus the H2-receptor antagonist cimetidine (400 mg), or placebo on separate occasions. Histamine was dosed cumulatively by iontophoresis to the forearm skin at 34 degrees C and 14 degrees C. Laser-Doppler flux (LDF) was measured at the same sites using customised probeholder/iontophoretic chambers with Peltier cooling elements. Finger mean arterial pressure (MAP) was measured and cutaneous vascular conductance calculated as LDF/MAP. Histamine vasodilation was reduced in cold skin. Cetirizine shifted the histamine dose-response at both temperatures: statistically significantly at 14 degrees C only. Combined H1- and H2-receptor antagonism shifted the response significantly at both temperatures. H1- and H2-receptors mediate histamine-induced skin vasodilation. The sensitivity of these receptors, particularly the H1- receptor, is attenuated at low skin temperature. Whether the reduced effect in cold skin represents specific receptor or postreceptor desensitization, or nonspecific attenuation of cutaneous vasodilation remains to be elucidated.

Autonomic control of body temperature and blood pressure: influences of female sex hormones.

PubMed

Charkoudian, Nisha; Hart, Emma C J; Barnes, Jill N; Joyner, Michael J

2017-06-01

Female reproductive hormones exert important non-reproductive influences on autonomic regulation of body temperature and blood pressure. Estradiol and progesterone influence thermoregulation both centrally and peripherally, where estradiol tends to promote heat dissipation, and progesterone tends to promote heat conservation and higher body temperatures. Changes in thermoregulation over the course of the menstrual cycle and with hot flashes at menopause are mediated by hormonal influences on neural control of skin blood flow and sweating. The influence of estradiol is to promote vasodilation, which, in the skin, results in greater heat dissipation. In the context of blood pressure regulation, both central and peripheral hormonal influences are important as well. Peripherally, the vasodilator influence of estradiol contributes to the lower blood pressures and smaller risk of hypertension seen in young women compared to young men. This is in part due to a mechanism by which estradiol augments beta-adrenergic receptor mediated vasodilation, offsetting alpha-adrenergic vasoconstriction, and resulting in a weak relationship between muscle sympathetic nerve activity and total peripheral resistance, and between muscle sympathetic nerve activity and blood pressure. After menopause, with the loss of reproductive hormones, sympathetic nerve activity, peripheral resistance and blood pressure become more strongly related, and sympathetic nerve activity (which increases with age) becomes a more important contributor to the prevailing level of blood pressure. Continuing to increase our understanding of sex hormone influences on body temperature and blood pressure regulation will provide important insight for optimization of individualized health care for future generations of women.

Endocannabinoids in cerebrovascular regulation

PubMed Central

Ruisanchez, Éva; Leszl-Ishiguro, Miriam; Sándor, Péter; Pacher, Pál

2016-01-01

The cerebral blood flow is tightly regulated by myogenic, endothelial, metabolic, and neural mechanisms under physiological conditions, and a large body of recent evidence indicates that inflammatory pathways have a major influence on the cerebral blood perfusion in certain central nervous system disorders, like hemorrhagic and ischemic stroke, traumatic brain injury, and vascular dementia. All major cell types involved in cerebrovascular control pathways (i.e., smooth muscle, endothelium, neurons, astrocytes, pericytes, microglia, and leukocytes) are capable of synthesizing endocannabinoids and/or express some or several of their target proteins [i.e., the cannabinoid 1 and 2 (CB1 and CB2) receptors and the transient receptor potential vanilloid type 1 ion channel]. Therefore, the endocannabinoid system may importantly modulate the regulation of cerebral circulation under physiological and pathophysiological conditions in a very complex manner. Experimental data accumulated since the late 1990s indicate that the direct effect of cannabinoids on cerebral vessels is vasodilation mediated, at least in part, by CB1 receptors. Cannabinoid-induced cerebrovascular relaxation involves both a direct inhibition of smooth muscle contractility and a release of vasodilator mediator(s) from the endothelium. However, under stress conditions (e.g., in conscious restrained animals or during hypoxia and hypercapnia), cannabinoid receptor activation was shown to induce a reduction of the cerebral blood flow, probably via inhibition of the electrical and/or metabolic activity of neurons. Finally, in certain cerebrovascular pathologies (e.g., subarachnoid hemorrhage, as well as traumatic and ischemic brain injury), activation of CB2 (and probably yet unidentified non-CB1/non-CB2) receptors appear to improve the blood perfusion of the brain via attenuating vascular inflammation. PMID:26825517

Endocannabinoids in cerebrovascular regulation.

PubMed

Benyó, Zoltán; Ruisanchez, Éva; Leszl-Ishiguro, Miriam; Sándor, Péter; Pacher, Pál

2016-04-01

The cerebral blood flow is tightly regulated by myogenic, endothelial, metabolic, and neural mechanisms under physiological conditions, and a large body of recent evidence indicates that inflammatory pathways have a major influence on the cerebral blood perfusion in certain central nervous system disorders, like hemorrhagic and ischemic stroke, traumatic brain injury, and vascular dementia. All major cell types involved in cerebrovascular control pathways (i.e., smooth muscle, endothelium, neurons, astrocytes, pericytes, microglia, and leukocytes) are capable of synthesizing endocannabinoids and/or express some or several of their target proteins [i.e., the cannabinoid 1 and 2 (CB1 and CB2) receptors and the transient receptor potential vanilloid type 1 ion channel]. Therefore, the endocannabinoid system may importantly modulate the regulation of cerebral circulation under physiological and pathophysiological conditions in a very complex manner. Experimental data accumulated since the late 1990s indicate that the direct effect of cannabinoids on cerebral vessels is vasodilation mediated, at least in part, by CB1 receptors. Cannabinoid-induced cerebrovascular relaxation involves both a direct inhibition of smooth muscle contractility and a release of vasodilator mediator(s) from the endothelium. However, under stress conditions (e.g., in conscious restrained animals or during hypoxia and hypercapnia), cannabinoid receptor activation was shown to induce a reduction of the cerebral blood flow, probably via inhibition of the electrical and/or metabolic activity of neurons. Finally, in certain cerebrovascular pathologies (e.g., subarachnoid hemorrhage, as well as traumatic and ischemic brain injury), activation of CB2 (and probably yet unidentified non-CB1/non-CB2) receptors appear to improve the blood perfusion of the brain via attenuating vascular inflammation.

Aortic assessment of bicuspid aortic valve patients and their first-degree relatives.

PubMed

Straneo, Pablo; Parma, Gabriel; Lluberas, Natalia; Marichal, Alvaro; Soca, Gerardo; Cura, Leandro; Paganini, Juan J; Brusich, Daniel; Florio, Lucia; Dayan, Victor

2017-03-01

Background Bicuspid aortic valve patients have an increased risk of aortic dilatation. A deficit of nitric oxide synthase has been proposed as the causative factor. No correlation between flow-mediated dilation and aortic diameter has been performed in patients with bicuspid aortic valves and normal aortic diameters. Being a hereditary disease, we compared echocardiographic features and endothelial function in these patients and their first-degree relatives. Methods Comprehensive physical examinations, routine laboratory tests, transthoracic echocardiography, and measurements of endothelium-dependent and non-dependent flow-mediated vasodilatation were performed in 18 bicuspid aortic valve patients (14 type 1 and 4 type 2) and 19 of their first-degree relatives. Results The first-degree relatives were younger (36.7 ± 18.8 vs. 50.5 ± 13.9 years, p = 0.019) with higher ejection fractions (64.6% ± 1.7% vs. 58.4% ± 9.5%, p = 0.015). Aortic diameters indexed to body surface area were similar in both groups, the except the tubular aorta which was larger in bicuspid aortic valve patients (19.3 ± 2.7 vs. 17.4 ± 2.2 mm·m -2 , p = 0.033). Flow-dependent vasodilation was similar in both groups. A significant inverse correlation was found between non-flow-dependent vasodilation and aortic root diameter in patients with bicuspid aortic valve ( R = -0.57, p = 0.05). Conclusions Bicuspid aortic valve patients without aortopathy have larger ascending aortic diameters than their first-degree relatives. Endothelial function is similar in both groups, and there is no correlation with ascending aorta diameter. Nonetheless, an inverse correlation exists between non-endothelial-dependent dilation and aortic root diameter in bicuspid aortic valve patients.

Short-term therapy with relatively low-dose cerivastatin improves endothelial function independently of its lipid-lowering effect: Evaluation of brachial artery vasodilatation using B-mode ultrasound imaging.

PubMed

Sakabe, Koichi; Fukuda, Nobuo; Nada, Teru; Onose, Yukiko; Soeki, Takeshi; Shinohara, Hisanori; Tamura, Yoshiyuki

2002-12-01

Administration of 0.4 to 0.8 mg of cerivastatin per day for 2 weeks has been reported to have pleiotropic effects and improve endothelial function. Whether low-dose cerivastatin would produce these rapid pleiotropic effects in the clinical setting remains uncertain, however. We investigated the effect of short-term therapy with relatively low-dose cerivastatin (0.15 mg/day) on endothelial function, thrombostatic parameters, and C-reactive protein (CRP) levels in hypercholesterolemic patients. Thirteen patients with LDL-cholesterol>160 mg/dl were treated with daily doses of 0.15 mg of cerivastatin for 2 weeks. Endothelial function, thrombostatic parameters (tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor type 1 [PAI-1], and CRP were estimated at baseline and again after 2 weeks of treatment. Endothelial function was measured as flow-mediated vasodilation. Flow-mediated vasodilatation was assessed by measuring the percent change in the diameter of the brachial artery in response to reactive hyperemia using high-resolution ultrasound. Endothelium-independent vasodilatation was also measured using sublingual nitroglycerin. No major complications developed after the treatment. Total cholesterol decreased significantly, from 258±32 to 211±21 mg/dl, and LDL-cholesterol also decreased from 171±15 to 133±16 mg/dl after the treatment. Flow-mediated vasodilatation increased significantly, from 4.6±1.3 percent to 8.7±3.5 percent after 2 weeks of therapy, although endothelium-independent vasodilatation was not affected (9.5±2.4% vs 8.8±3.1%). No relation was found between percent change in flow-mediated vasodilatation and improvement in levels of LDL-cholesterol after therapy (r=0.07). PAI-1, t-PA, and CRP were not significantly changed by 2 weeks of therapy. (1) Evaluating vasodilation of the brachial artery with B-mode ultrasound imaging was useful in investigating the effect of statin on endothelial function. (2) Although no effect was detected in PAI-1, t-PA, or CRP, relatively low-dose cerivastatin therapy for 2 weeks improved endothelial function and lipid level independently and safely in hypercholesterolemic patients.

Bradykinin Type 2 Receptor BE1 Genotype Influences Bradykinin-Dependent Vasodilation During Angiotensin-Converting Enzyme Inhibition

PubMed Central

Van Guilder, Gary P.; Pretorius, Mias; Luther, James M.; Byrd, J. Brian; Hill, Kevin; Gainer, James V.; Brown, Nancy J.

2008-01-01

To test the hypothesis that the bradykinin receptor 2 (BDKRB2) BE1 +9/−9 polymorphism affects vascular responses to bradykinin, we measured the effect of intra-arterial bradykinin on forearm blood flow and tissue-type plasminogen activator (t-PA) release in 89 normotensive, nonsmoking, white American subjects in whom degradation of bradykinin was blocked by enalaprilat. BE1 genotype frequencies were +9/+9:+9/−9:−9/−9=19:42:28. BE1 genotype was associated with systolic blood pressure (121.4±2.8, 113.8±1.8, and 110.6±1.8 mm Hg in +9/+9, +9/−9, and −9/−9 groups, respectively; P=0.007). In the absence of enalaprilat, bradykinin-stimulated forearm blood flow, forearm vascular resistance, and net t-PA release were similar among genotype groups. Enalaprilat increased basal forearm blood flow (P=0.002) and decreased basal forearm vascular resistance (P=0.01) without affecting blood pressure. Enalaprilat enhanced the effect of bradykinin on forearm blood flow, forearm vascular resistance, and t-PA release (all P<0.001). During enalaprilat, forearm blood flow was significantly lower and forearm vascular resistance was higher in response to bradykinin in the +9/+9 compared with +9/−9 and −9/−9 genotype groups (P=0.04 for both). t-PA release tended to be decreased in response to bradykinin in the +9/+9 group (P=0.08). When analyzed separately by gender, BE1 genotype was associated with bradykinin-stimulated t-PA release in angiotensin-converting enzyme inhibitor–treated men but not women (P=0.02 and P=0.77, respectively), after controlling for body mass index. There was no effect of BE1 genotype on responses to the bradykinin type 2 receptor–independent vasodilator methacholine during enalaprilat. In conclusion, the BDKRB2 BE1 polymorphism influences bradykinin type 2 receptor–mediated vasodilation during angiotensin-converting enzyme inhibition. PMID:18180402

Nitric oxide-mediated vasodilation becomes independent of β-adrenergic receptor activation with increased intensity of hypoxic exercise

PubMed Central

Curry, Timothy B.; Wilkins, Brad W.; Joyner, Michael J.

2011-01-01

Hypoxic vasodilation in skeletal muscle at rest is known to include β-adrenergic receptor-stimulated nitric oxide (NO) release. We previously reported that the augmented skeletal muscle vasodilation during mild hypoxic forearm exercise includes β-adrenergic mechanisms. However, it is unclear whether a β-adrenergic receptor-stimulated NO component exists during hypoxic exercise. We hypothesized that NO-mediated vasodilation becomes independent of β-adrenergic receptor activation with increased exercise intensity during hypoxic exercise. Ten subjects (7 men, 3 women; 23 ± 1 yr) breathed hypoxic gas to titrate arterial O2 saturation to 80% while remaining normocapnic. Subjects performed two consecutive bouts of incremental rhythmic forearm exercise (10% and 20% of maximum) with local administration (via a brachial artery catheter) of propranolol (β-adrenergic receptor inhibition) alone and with the combination of propranolol and nitric oxide synthase inhibition [NG-monomethyl-l-arginine (l-NMMA)] under normoxic and hypoxic conditions. Forearm blood flow (FBF, ml/min; Doppler ultrasound) and blood pressure [mean arterial pressure (MAP), mmHg; brachial artery catheter] were assessed, and forearm vascular conductance (FVC, ml·min−1·100 mmHg−1) was calculated (FBF/MAP). During propranolol alone, the rise in FVC (Δ from normoxic baseline) due to hypoxic exercise was 217 ± 29 and 415 ± 41 ml·min−1·100 mmHg−1 (10% and 20% of maximum, respectively). Combined propranolol-l-NMMA infusion during hypoxic exercise attenuated ΔFVC at 20% (352 ± 44 ml·min−1·100 mmHg−1; P < 0.001) but not at 10% (202 ± 28 ml·min−1·100 mmHg−1; P = 0.08) of maximum compared with propranolol alone. These data, when integrated with earlier findings, demonstrate that NO contributes to the compensatory vasodilation during mild and moderate hypoxic exercise; a β-adrenergic receptor-stimulated NO component exists during low-intensity hypoxic exercise. However, the source of the NO becomes less dependent on β-adrenergic mechanisms as exercise intensity increases. PMID:21193565

Peroxynitrite mediates testosterone-induced vasodilation of microvascular resistance vessels.

PubMed

Puttabyatappa, Yashoda; Stallone, John N; Ergul, Adviye; El-Remessy, Azza B; Kumar, Sanjiv; Black, Stephen; Johnson, Maribeth; Owen, Mary P; White, Richard E

2013-04-01

Our knowledge of how androgens influence the cardiovascular system is far from complete, and this lack of understanding is especially true of how androgens affect resistance vessels. Our aim was to identify the signaling mechanisms stimulated by testosterone (TES) in microvascular arteries and to understand how these mechanisms mediate TES-induced vasodilation. Mesenteric microvessels were isolated from male Sprague-Dawley rats. Tension studies demonstrated a rapid, concentration-dependent, vasodilatory response to TES that did not involve protein synthesis or aromatization to 17β-estradiol. Dichlorofluorescein fluorescence and nitrotyrosine immunoblot experiments indicated that TES stimulated peroxynitrite formation in microvessels, and functional studies demonstrated that TES-induced vasodilation was inhibited by scavenging peroxynitrite. As predicted, TES enhanced the production of both peroxynitrite precursors (i.e., superoxide and nitic oxide), and xanthine oxidase was identified as the likely source of TES-stimulated superoxide production. Functional and biochemical studies indicated that TES signaling involved activity of the phosphoinositide 3 (PI3) kinase-protein kinase B (Akt) cascade initiated by activation of the androgen receptor and culminated in enhanced production of cGMP and microvascular vasodilation. These findings, derived from a variety of analytical and functional approaches, provide evidence for a novel nongenomic signaling mechanism for androgen action in the microvasculature: TES-stimulated vasodilation mediated primarily by peroxynitrite formed from xanthine oxidase-generated superoxide and NO. This response was associated with activation of the PI3 kinase-Akt signaling cascade initiated by activation of the androgen receptor. We propose this mechanism could account for TES-stimulated cGMP production in microvessels and, ultimately, vasodilation.

Peroxynitrite Mediates Testosterone-Induced Vasodilation of Microvascular Resistance Vessels

PubMed Central

Puttabyatappa, Yashoda; Stallone, John N.; Ergul, Adviye; El-Remessy, Azza B.; Kumar, Sanjiv; Black, Stephen; Johnson, Maribeth; Owen, Mary P.

2013-01-01

Our knowledge of how androgens influence the cardiovascular system is far from complete, and this lack of understanding is especially true of how androgens affect resistance vessels. Our aim was to identify the signaling mechanisms stimulated by testosterone (TES) in microvascular arteries and to understand how these mechanisms mediate TES-induced vasodilation. Mesenteric microvessels were isolated from male Sprague-Dawley rats. Tension studies demonstrated a rapid, concentration-dependent, vasodilatory response to TES that did not involve protein synthesis or aromatization to 17β-estradiol. Dichlorofluorescein fluorescence and nitrotyrosine immunoblot experiments indicated that TES stimulated peroxynitrite formation in microvessels, and functional studies demonstrated that TES-induced vasodilation was inhibited by scavenging peroxynitrite. As predicted, TES enhanced the production of both peroxynitrite precursors (i.e., superoxide and nitic oxide), and xanthine oxidase was identified as the likely source of TES-stimulated superoxide production. Functional and biochemical studies indicated that TES signaling involved activity of the phosphoinositide 3 (PI3) kinase-protein kinase B (Akt) cascade initiated by activation of the androgen receptor and culminated in enhanced production of cGMP and microvascular vasodilation. These findings, derived from a variety of analytical and functional approaches, provide evidence for a novel nongenomic signaling mechanism for androgen action in the microvasculature: TES-stimulated vasodilation mediated primarily by peroxynitrite formed from xanthine oxidase-generated superoxide and NO. This response was associated with activation of the PI3 kinase-Akt signaling cascade initiated by activation of the androgen receptor. We propose this mechanism could account for TES-stimulated cGMP production in microvessels and, ultimately, vasodilation. PMID:23318471

Poor oral health, that is, decreased frequency of tooth brushing, is associated with endothelial dysfunction.

PubMed

Kajikawa, Masato; Nakashima, Ayumu; Maruhashi, Tatsuya; Iwamoto, Yumiko; Iwamoto, Akimichi; Matsumoto, Takeshi; Hidaka, Takayuki; Kihara, Yasuki; Chayama, Kazuaki; Goto, Chikara; Taguchi, Akira; Noma, Kensuke; Higashi, Yukihito

2014-01-01

 Poor oral health is an independent predictor of cardiovascular outcome. Endothelial dysfunction is the initial step of atherosclerosis, resulting in cardiovascular outcomes; but there is no information on the association between oral health and endothelial function. The purpose of this study was to determine the relationships between oral health and endothelial function.  A total of 190 subjects who underwent health examinations (mean age, 57±18 years), including patients with cardiovascular disease, completed a questionnaire on oral health and frequency of tooth brushing, and underwent measurement of vascular function, flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation. The subjects were divided into 2 groups according to frequency of tooth brushing (≥twice/day and

Differences in finger skin contact cooling response between an arterial occlusion and a vasodilated condition.

PubMed

Jay, Ollie; Havenith, George

2006-05-01

To assess the presence and magnitude of the effect of skin blood flow on finger skin cooling on contact with cold objects against the background of circulatory disorder risks in occupational exposures, this study investigates the effect of zero vs. close-to-maximal hand blood flow on short-term (< or =180 s) skin contact cooling response at a contact pressure that allows capillary perfusion of the distal pulp of the fingertip. Six male volunteers touched a block of aluminium with a finger contact force of 0.5 N at a temperature of -2 degrees C under a vasodilated and an occluded condition. Before both conditions, participants were required to exercise in a hot room for > or = 30 min for cutaneous vasodilation to occur (increase in rectal temperature of 1 degrees C). Under the vasodilated condition, forearm blood flow rate rose as high as 16.8 ml.100 ml(-1).min(-1). Under the occluded condition, the arm was exsanguinated, after which a blood pressure cuff was secured on the wrist inducing arterial occlusion. Contact temperature of the finger pad during the subsequent cold contact exposure was measured. No significant difference was found between the starting skin temperatures for the two blood flow conditions, but a distinct difference in shape of the contact cooling curve was apparent between the two blood flow conditions, with Newtonian cooling observed under the occluded condition, whereas a rewarming of the finger skin toward the end of the exposure occurred for the vasodilated condition. Blood flow was found to significantly increase contact temperature from 40 s onward (P < 0.01). It is concluded that, at a finger contact force compatible with capillary perfusion of the finger pad ( approximately 0.5 N), circulating blood provides a heat input source that significantly affects finger skin contact cooling during a vasodilated state.

EFFECT OF FREE RADICALS ON CALCITONIN-GENE-RELATED PEPTIDE MEDIATED VASODILATION.

PubMed

Dekanosidze, M; Saganelidze, K; Mitagvaria, N

2018-01-01

It is known that in some pathological conditions, due to the formation of a large number of free oxygen radicals, the cardiovascular system is severely affected. However, the effect of free radicals on CGRP-mediated vasodilation remains unclear. The aim of this work was to study the effect of free radicals on CGRP-mediated neurogenic vasodilation on preparations of an isolated rabbit lingual artery. The experiments were performed on the lingual artery preparations of 6 rabbits of the Chinchilla breed of both sexes. The contractile-relaxation activity of isolated preparations, both with intact endothelial layer and deendotelized, were studied in isometric mode on a strain-gauge unit using mechanotrons of the 6 MX1C type. Our experiments showed that free radicals can disrupt the reactivity of the vascular wall both in the presence and in the absence of endothelium-dependent relaxation factors and that is might be considered as a main conclusion of this study.

Beta-blocking agents in patients with insulin resistance: effects of vasodilating beta-blockers.

PubMed

Jacob, S; Balletshofer, B; Henriksen, E J; Volk, A; Mehnert, B; Löblein, K; Häring, H U; Rett, K

1999-01-01

Essential hypertension is--at least in many subjects--associated with a decrease in insulin sensitivity, while glycaemic control is (still) normal. It seems that in hypertensive patients, two major functions of insulin are impaired: there is insulin resistance of peripheral glucose uptake (primarily skeletal muscle) and insulin resistance of insulin-stimulated vasodilation. In view of some retrospective data and meta-analyses, which showed a less than expected reduction in coronary events (coronary paradox), the metabolic side effects of the antihypertensive treatment have received more attention. Many groups have shown that conventional antihypertensive treatment, both with beta-blockers and/or diuretics, decreases insulin sensitivity by various mechanisms. While low-dose diuretics seem to be free of these metabolic effects, there is no evidence for this in the beta-adrenergic blockers. However, recent metabolic studies evaluated the effects of vasodilating beta-blockers, such as dilevalol, carvedilol and celiprolol, on insulin sensitivity and the atherogenic risk factors. None of them decreased insulin sensitivity, as has been described for the beta-blockers with and without beta1 selectivity. This supports the idea that peripheral vascular resistance and peripheral blood flow play a central role in mediating the metabolic side effects of the beta-blocking agents, as the vasodilating action (either via beta2 stimulation or alpha1-blockade) seems to more than offset the detrimental effects of the blockade of beta (or beta1) receptors. Further studies are needed to elucidate the relevance of the radical scavenging properties of these agents and their connection to their metabolic effects. Therefore, the beneficial characteristics of these newer beta-adrenoreceptor blockers suggest that the vasodilating beta-blocking agents could be advantageous for hypertensive patients with insulin resistance or type 2 diabetes.

VIP/PACAP receptor mediation of cutaneous active vasodilation during heat stress in humans

PubMed Central

Zhao, Joan L.; Wu, Yubo; Johnson, John M.

2010-01-01

Vasoactive intestinal peptide (VIP) is implicated in cutaneous active vasodilation in humans. VIP and the closely related pituitary adenylate cyclase activating peptide (PACAP) act through several receptor types: VIP through VPAC1 and VPAC2 receptors and PACAP through VPAC1, VPAC2, and PAC1 receptors. We examined participation of VPAC2 and/or PAC1 receptors in cutaneous vasodilation during heat stress by testing the effects of their specific blockade with PACAP6–38. PACAP6–38 dissolved in Ringer's was administered by intradermal microdialysis at one forearm site while a control site received Ringer's solution. Skin blood flow was monitored by laser-Doppler flowmetry (LDF). Blood pressure was monitored noninvasively and cutaneous vascular conductance (CVC) calculated. A 5- to 10-min baseline period was followed by ∼70 min of PACAP6–38 (100 μM) perfusion at one site in normothermia and a 3-min period of body cooling. Whole body heating was then performed to engage cutaneous active vasodilation and was maintained until CVC had plateaued at an elevated level at all sites for 5–10 min. Finally, 58 mM sodium nitroprusside was perfused through both microdialysis sites to effect maximal vasodilation. No CVC differences were found between control and PACAP6–38-treated sites during normothermia (19 ± 3%max untreated vs. 20 ± 3%max, PACAP6–38 treated; P > 0.05 between sites) or cold stress (11 ± 2%max untreated vs. 10 ± 2%max, PACAP6–38 treated, P > 0.05 between sites). PACAP6–38 attenuated the increase in CVC during whole body heating when compared with untreated sites (59 ± 3%max untreated vs. 46 ± 3%max, PACAP6–38 treated, P < 0.05). We conclude that VPAC2 and/or PAC1 receptor activation is involved in cutaneous active vasodilation in humans. PMID:20395540

VIP/PACAP receptor mediation of cutaneous active vasodilation during heat stress in humans.

PubMed

Kellogg, Dean L; Zhao, Joan L; Wu, Yubo; Johnson, John M

2010-07-01

Vasoactive intestinal peptide (VIP) is implicated in cutaneous active vasodilation in humans. VIP and the closely related pituitary adenylate cyclase activating peptide (PACAP) act through several receptor types: VIP through VPAC1 and VPAC2 receptors and PACAP through VPAC1, VPAC2, and PAC1 receptors. We examined participation of VPAC2 and/or PAC1 receptors in cutaneous vasodilation during heat stress by testing the effects of their specific blockade with PACAP6-38. PACAP6-38 dissolved in Ringer's was administered by intradermal microdialysis at one forearm site while a control site received Ringer's solution. Skin blood flow was monitored by laser-Doppler flowmetry (LDF). Blood pressure was monitored noninvasively and cutaneous vascular conductance (CVC) calculated. A 5- to 10-min baseline period was followed by approximately 70 min of PACAP6-38 (100 microM) perfusion at one site in normothermia and a 3-min period of body cooling. Whole body heating was then performed to engage cutaneous active vasodilation and was maintained until CVC had plateaued at an elevated level at all sites for 5-10 min. Finally, 58 mM sodium nitroprusside was perfused through both microdialysis sites to effect maximal vasodilation. No CVC differences were found between control and PACAP6-38-treated sites during normothermia (19 +/- 3%max untreated vs. 20 +/- 3%max, PACAP6-38 treated; P > 0.05 between sites) or cold stress (11 +/- 2%max untreated vs. 10 +/- 2%max, PACAP6-38 treated, P > 0.05 between sites). PACAP6-38 attenuated the increase in CVC during whole body heating when compared with untreated sites (59 +/- 3%max untreated vs. 46 +/- 3%max, PACAP6-38 treated, P < 0.05). We conclude that VPAC2 and/or PAC1 receptor activation is involved in cutaneous active vasodilation in humans.

Increasing Muscle Mass Improves Vascular Function in Obese (db/db) Mice

PubMed Central

Qiu, Shuiqing; Mintz, James D.; Salet, Christina D.; Han, Weihong; Giannis, Athanassios; Chen, Feng; Yu, Yanfang; Su, Yunchao; Fulton, David J.; Stepp, David W.

2014-01-01

Background A sedentary lifestyle is an independent risk factor for cardiovascular disease and exercise has been shown to ameliorate this risk. Inactivity is associated with a loss of muscle mass, which is also reversed with isometric exercise training. The relationship between muscle mass and vascular function is poorly defined. The aims of the current study were to determine whether increasing muscle mass by genetic deletion of myostatin, a negative regulator of muscle growth, can influence vascular function in mesenteric arteries from obese db/db mice. Methods and Results Myostatin expression was elevated in skeletal muscle of obese mice and associated with reduced muscle mass (30% to 50%). Myostatin deletion increased muscle mass in lean (40% to 60%) and obese (80% to 115%) mice through increased muscle fiber size (P<0.05). Myostatin deletion decreased adipose tissue in lean mice, but not obese mice. Markers of insulin resistance and glucose tolerance were improved in obese myostatin knockout mice. Obese mice demonstrated an impaired endothelial vasodilation, compared to lean mice. This impairment was improved by superoxide dismutase mimic Tempol. Deletion of myostatin improved endothelial vasodilation in mesenteric arteries in obese, but not in lean, mice. This improvement was blunted by nitric oxide (NO) synthase inhibitor l‐NG‐nitroarginine methyl ester (l‐NAME). Prostacyclin (PGI2)‐ and endothelium‐derived hyperpolarizing factor (EDHF)‐mediated vasodilation were preserved in obese mice and unaffected by myostatin deletion. Reactive oxygen species) was elevated in the mesenteric endothelium of obese mice and down‐regulated by deletion of myostatin in obese mice. Impaired vasodilation in obese mice was improved by NADPH oxidase inhibitor (GKT136901). Treatment with sepiapterin, which increases levels of tetrahydrobiopterin, improved vasodilation in obese mice, an improvement blocked by l‐NAME. Conclusions Increasing muscle mass by genetic deletion of myostatin improves NO‐, but not PGI2‐ or EDHF‐mediated vasodilation in obese mice; this vasodilation improvement is mediated by down‐regulation of superoxide. PMID:24965025

Nitroglycerin fails to lower blood pressure in redox-dead Cys42Ser PKG1α knock-in mouse.

PubMed

Rudyk, Olena; Prysyazhna, Oleksandra; Burgoyne, Joseph R; Eaton, Philip

2012-07-17

Although nitroglycerin has remained in clinical use since 1879, the mechanism by which it relaxes blood vessels to lower blood pressure remains incompletely understood. Nitroglycerin undergoes metabolism that generates several reaction products, including oxidants, and this bioactivation process is essential for vasodilation. Protein kinase G (PKG) mediates classic nitric oxide-dependent vasorelaxation, but the 1α isoform is also independently activated by oxidation that involves interprotein disulfide formation within this homodimeric protein complex. We hypothesized that nitroglycerin-induced vasodilation is mediated by disulfide activation of PKG1α. Treating smooth muscle cells or isolated blood vessels with nitroglycerin caused PKG1α disulfide dimerization. PKG1α disulfide formation was increased in wild-type mouse aortas by in vivo nitroglycerin treatment, but this oxidation was lost as tolerance developed. To establish whether kinase oxidation underlies nitroglycerin-induced vasodilation in vivo, we used a Cys42Ser PKG1α knock-in mouse that cannot transduce oxidant signals because it does not contain the vital redox-sensing thiol. This redox-dead knock-in mouse was substantively deficient in hypotensive response to nitroglycerin compared with wild-type littermates as measured in vivo by radiotelemetry. Resistance blood vessels from knock-ins were markedly less sensitive to nitroglycerin-induced vasodilation (EC(50)=39.2 ± 10.7 μmol/L) than wild-types (EC(50)=12.1 ± 2.9 μmol/L). Furthermore, after ≈24 hours of treatment, wild-type controls stopped vasodilating to nitroglycerin, and the vascular sensitivity to nitroglycerin was decreased, whereas this tolerance phenomenon, which routinely hampers the management of hypertensive patients, was absent in knock-ins. PKG1α disulfide formation is a significant mediator of nitroglycerin-induced vasodilation, and tolerance to nitroglycerin is associated with loss of kinase oxidation.

Neurovascular contributions to migraine: Moving beyond vasodilation.

PubMed

Jacobs, Blaine; Dussor, Gregory

2016-12-03

Migraine is the third most common disease worldwide, the most common neurological disorder, and one of the most common pain conditions. Despite its prevalence, the basic physiology and underlying mechanisms contributing to the development of migraine are still poorly understood and development of new therapeutic targets is long overdue. Until recently, the major contributing pathophysiological event thought to initiate migraine was cerebral and meningeal arterial vasodilation. However, the role of vasodilation in migraine is unclear and recent findings challenge its necessity. While vasodilation itself may not contribute to migraine, it remains possible that vessels play a role in migraine pathophysiology in the absence of vasodilation. Blood vessels consist of a variety of cell types that both release and respond to numerous mediators including growth factors, cytokines, adenosine triphosphate (ATP), and nitric oxide (NO). Many of these mediators have actions on neurons that can contribute to migraine. Conversely, neurons release factors such as norepinephrine and calcitonin gene-related peptide (CGRP) that act on cells native to blood vessels. Both normal and pathological events occurring within and between vascular cells could thus mediate bi-directional communication between vessels and the nervous system, without the need for changes in vascular tone. This review will discuss the potential contribution of the vasculature, specifically endothelial cells, to current neuronal mechanisms hypothesized to play a role in migraine. Hypothalamic activity, cortical spreading depression (CSD), and dural afferent input from the cranial meninges will be reviewed with a focus on how these mechanisms can influence or be impacted by blood vessels. Together, the data discussed will provide a framework by which vessels can be viewed as important potential contributors to migraine pathophysiology, even in light of the current uncertainty over the role of vasodilation in this disorder. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Neurovascular contributions to migraine: moving beyond vasodilation

PubMed Central

Jacobs, Blaine; Dussor, Gregory

2016-01-01

Migraine is the third most common disease worldwide, the most common neurological disorder, and one of the most common pain conditions. Despite its prevalence, the basic physiology and underlying mechanisms contributing to the development of migraine is still poorly understood and development of new therapeutic targets is long overdue. Until recently, the major contributing pathophysiological event thought to initiate migraine was cerebral and meningeal arterial vasodilation. However, the role of vasodilation in migraine is unclear and recent findings challenge its necessity. While vasodilation itself may not contribute to migraine, it remains possible that vessels play a role in migraine pathophysiology in the absence of vasodilation. Blood vessels consist of a variety of cell types that both release and respond to numerous mediators including growth factors, cytokines, adenosine triphosphate (ATP), and nitric oxide (NO). Many of these mediators have actions on neurons that can contribute to migraine. Conversely, neurons release factors such as norepinephrine and calcitonin gene-related peptide (CGRP) that act on cells native to blood vessels. Both normal and pathological events occurring within and between vascular cells could thus mediate bi-directional communication between vessels and the nervous system, without the need for changes in vascular tone. This review will discuss the potential contribution of the vasculature, specifically endothelial cells, to current neuronal mechanisms hypothesized to play a role in migraine. Hypothalamic activity, cortical spreading depression (CSD), and dural afferent input from the cranial meninges will be reviewed with a focus on how these mechanisms can influence or be impacted by blood vessels. Together, the data discussed will provide a framework by which vessels can be viewed as important potential contributors to migraine pathophysiology, even in light of the current uncertainty over the role of vasodilation in this disorder. PMID:27312704

Skin blood flow response in the rat model of wound healing: expression of vasoactive factors.

PubMed

Rendell, Marc S; Johnson, Mark L; Smith, Denae; Finney, David; Capp, Christopher; Lammers, Rebecca; Lancaster, Scott

2002-09-01

Although the microvascular blood flow response to wounding is predominantly vasodilation at skin sites with nutritive capillary perfusion (NUTR), there is a significant vasoconstrictive response at sites with high arteriovenous perfusion (AV). There may be a difference between NUTR and AV sites in the vasoactive factors which mediate the blood flow response to wounding. We measured the levels of mRNA expression of several potential mediators of the blood flow response to assess this possible difference. We measured skin blood flow at wounds placed at the back, a NUTR site, and at the paw, an AV site, in 12 Wistar Kyoto rats. Measurements were performed at baseline and then at 7 days post wounding. There was a significant increase in blood flow at back wound sites, with a rise from 4.1 +/- 0.3 ml/min/100 g to 9.8 +/- 1.9 ml/min/100 g. At the undisturbed wound perimeter, outside the zone of granulation tissue, flow rose to 7.3 +/- 1.1 ml/min/100 g. At the paw wound site, Day 0 flow was 8.8 +/- 0.8 ml/min/100 g. At 7 days, there was a significant decrease in flow at wound center to 5.5 +/- 0.5 ml/min/100 g. We measured the levels of inducible nitric oxide synthetase (iNOS), endothelin, endothelin receptor, vascular endothelial growth factor (VEGF), and keratinocyte growth factor (KGF) gene mRNAs using reverse transcriptase PCR. There was a 10-fold increase in NOS mRNA in granulation tissue of both wounds on Day 7. There was a lesser but still substantial increase in the wound perimeter tissue. Levels of endothelin mRNA in the wound and wound perimeter were significantly lower at the paw than at the back. At baseline, the level of endothelin receptor B (ETrB) mRNA was greater at the back than at the paw. Wounding resulted in a substantial increase in EtrB mRNA levels in granulation tissue, reaching the same level at the back and paw wounds. There was also a substantial rise in EtrB mRNA levels at the paw wound perimeter, so that there was a reversal of the baseline condition, with paw levels actually surpassing the levels at the back perimeter. Thus, we have found significant changes in mediators both of vasoconstriction and vasodilation affecting the healing wound. These changes affect NUTR and AV sites in different ways. These results demonstrate the complexity of the regulatory processes controlling microvascular blood flow in wound healing.

Voluntary wheel running selectively augments insulin-stimulated vasodilation in arterioles from white skeletal muscle of insulin-resistant rats.

PubMed

Mikus, Catherine R; Roseguini, Bruno T; Uptergrove, Grace M; Morris, E Matthew; Rector, Randy Scott; Libla, Jessica L; Oberlin, Douglas J; Borengasser, Sarah J; Taylor, Angelina M; Ibdah, Jamal A; Laughlin, Maurice Harold; Thyfault, John P

2012-11-01

Exercise (RUN) prevents declines in insulin-mediated vasodilation, an important component of insulin-mediated glucose disposal, in rats prone to obesity and insulin resistance. Determine whether RUN (1) improves insulin-stimulated vasodilation after insulin resistance has been established, and (2) differentially affects arterioles from red and white muscle. Insulin signaling and vasoreactivity to insulin (1-1000 μIU/mL) were assessed in 2A from the Gw and Gr of SED OLETF rats at 12 and 20 weeks of age (SED12, SED20) and those undergoing RUN (RUN20) or caloric restriction (CR20; to match body weight of RUN) from 12 to 20 weeks. Glucose and insulin responses to i.p. glucose were reduced in RUN20, elevated in SED20 (p < 0.05 vs. SED12), and maintained in CR20. Insulin-stimulated vasodilation was greater in Gw but not Gr, 2As of RUN20 (p < 0.01 vs. all groups), and was improved by ET-1 receptor inhibition in Gw 2As from SED20 and CR20 (p < 0.05). There were no differences in microvascular insulin signaling among groups or muscle beds. RUN selectively improved insulin-mediated vasodilation in Gw 2As, in part through attenuated ET-1 sensitivity/production, an adaptation that was independent of changes in adiposity and may contribute to enhanced insulin-stimulated glucose disposal. © 2012 John Wiley & Sons Ltd.

Contribution of Kv7 channels to natriuretic peptide mediated vasodilation in normal and hypertensive rats.

PubMed

Stott, Jennifer B; Barrese, Vincenzo; Jepps, Thomas A; Leighton, Emma V; Greenwood, Iain A

2015-03-01

The Kv7 family of voltage-gated potassium channels are expressed within the vasculature where they are key regulators of vascular tone and mediate cAMP-linked endogenous vasodilator responses, a pathway that is compromised in hypertension. However, the role of Kv7 channels in non-cAMP-linked vasodilator pathways has not been investigated. Natriuretic peptides are potent vasodilators, which operate primarily through the activation of a cGMP-dependent signaling pathway. This study investigated the putative role of Kv7 channels in natriuretic peptide-dependent relaxations in the vasculature of normal and hypertensive animals. Relaxant responses of rat aorta to both atrial and C-type natriuretic peptides and the nitric oxide donor sodium nitroprusside were impaired by the Kv7 blocker linopirdine (10 μmol/L) but not by the Kv7.1-specific blocker HMR1556 (10 μmol/L) and other K(+) channel blockers. In contrast, only the atrial natriuretic peptide response was sensitive to linopirdine in the renal artery. These Kv7-mediated responses were attenuated in arteries from hypertensive rats. Quantitative polymerase chain reaction showed that A- and B-type natriuretic peptide receptors were expressed at high levels in the aorta and renal artery from normal and spontaneously hypertensive rats. This study provides the first evidence that natriuretic peptide responses are impaired in hypertension and that recruitment of Kv7 channels is a key component of natriuretic peptide-dependent vasodilations. © 2014 American Heart Association, Inc.

Muscle metaboreceptor modulation of cutaneous active vasodilation

NASA Technical Reports Server (NTRS)

Crandall, C. G.; Stephens, D. P.; Johnson, J. M.

1998-01-01

PURPOSE: Isometric handgrip exercise in hyperthermia has been shown to reduce cutaneous vascular conductance (CVC) by inhibiting the cutaneous active vasodilator system. METHODS: To identify whether this response was initiated by muscle metaboreceptors, in seven subjects two 3-min bouts of isometric handgrip exercise in hyperthermia were performed, followed by 2 min of postexercise ischemia (PEI). An index of forearm skin blood flow (laser-Doppler flowmetry) was measured on the contralateral arm at an unblocked site and at a site at which adrenergic vasoconstrictor function was blocked via bretylium iontophoresis to reveal active cutaneous vasodilator function unambiguously. Sweat rate was measured via capacitance hygrometry, CVC was indexed from the ratio of skin blood flow to mean arterial pressure and was expressed as a percentage of maximal CVC at that site. In normothermia, neither isometric exercise nor PEI affected CVC (P > 0.05). RESULTS: The first bout of isometric handgrip exercise in hyperthermia reduced CVC at control sites and this reduction persisted through PEI (pre-exercise: 59.8 +/- 5.4, exercise: 49.8 +/- 4.9, PEI: 49.7 +/- 5.3% of maximum; both P < 0.05), whereas there were no significant changes in CVC at the bretylium treated sites. The succeeding bout of isometric exercise in hyperthermia significantly reduced CVC at both untreated (pre-exercise: 59.0 +/- 4.8, exercise: 47.3 +/- 4.0, PEI: 50.1 +/- 4.1% of maximum; both P < 0.05) and bretylium treated sites (pre-exercise: 61.4 +/- 7.3, exercise: 50.6 +/- 5.1, PEI: 53.9 +/- 6.0% of maximum, both P < 0.05). At both sites, CVC during PEI was lower than during the pre-exercise period (P < 0.05). Sweat rate rose significantly during both bouts of isometric exercise and remained elevated during PEI. CONCLUSIONS: These data suggest that the reduction in CVC during isometric exercise in hyperthermia, including the inhibition of the active vasodilator system, is primarily mediated by muscle metaboreceptors, whereas central command or muscle mechanoreceptors have less influence.

Estrogen-Mediated Breast Carcinogenesis: The Role of Sulfation Pharmacogenetics

DTIC Science & Technology

2001-05-01

Cipkus, L.A. and Taylor, C.J. Mechanism of action of minoxidil sulfate- induced vasodilation: a role for increased K+ permeability. J. Pharmacol...1993. Meisheri, K.D., Cipkus, L.A. and Taylor, C.J. Mechanism of action of minoxidil sulfate-induced vasodilation: a role for increased K

Regulation of coronary blood flow. Effect of coronary artery stenosis.

PubMed

Duncker, D J; Merkus, D

2004-12-01

The consistently high level of myocardial oxygen extraction requires tight control of coronary blood flow, because an increase in myocardial oxygen demand, as occurs during exercise, cannot be obtained by a further increase in oxygen extraction. Consequently, adequate control of coronary vascular resistance is critical. Coronary resistance vessel tone is the result of a myriad of vasodilator and vasoconstrictor influences, which are exerted by the myocardium, endothelium and neurohumoral status. Unraveling of the integrative mechanisms controlling metabolic vasodilation has been difficult, more than likely due to the redundancy design of vasomotor control. In contrast to the traditional view that myocardial ischemia produced by a coronary artery stenosis causes maximal microvascular dilation, more recent studies have shown that the coronary microvessels retain some degree of vasodilator reserve during ischemia and remain responsive to vasoconstrictor stimuli. These observations raise the question of whether pharmacologic vasodilators acting at the microvascular level might be therapeutically useful. The critical property of effective vasodilator therapy requires selective dilation of small arteries, while avoiding coronary steal by not interfering with metabolic vasoregulation at the level of the arterioles.

Cyclooxygenase-2 Selectively Controls Renal Blood Flow Through a Novel PPARβ/δ-Dependent Vasodilator Pathway.

PubMed

Kirkby, Nicholas S; Sampaio, Walkyria; Etelvino, Gisele; Alves, Daniele T; Anders, Katie L; Temponi, Rafael; Shala, Fisnik; Nair, Anitha S; Ahmetaj-Shala, Blerina; Jiao, Jing; Herschman, Harvey R; Xiaomeng, Wang; Wahli, Walter; Santos, Robson A; Mitchell, Jane A

2018-02-01

Cyclooxygenase-2 (COX-2) is an inducible enzyme expressed in inflammation and cancer targeted by nonsteroidal anti-inflammatory drugs. COX-2 is also expressed constitutively in discreet locations where its inhibition drives gastrointestinal and cardiovascular/renal side effects. Constitutive COX-2 expression in the kidney regulates renal function and blood flow; however, the global relevance of the kidney versus other tissues to COX-2-dependent blood flow regulation is not known. Here, we used a microsphere deposition technique and pharmacological COX-2 inhibition to map the contribution of COX-2 to regional blood flow in mice and compared this to COX-2 expression patterns using luciferase reporter mice. Across all tissues studied, COX-2 inhibition altered blood flow predominantly in the kidney, with some effects also seen in the spleen, adipose, and testes. Of these sites, only the kidney displayed appreciable local COX-2 expression. As the main site where COX-2 regulates blood flow, we next analyzed the pathways involved in kidney vascular responses using a novel technique of video imaging small arteries in living tissue slices. We found that the protective effect of COX-2 on renal vascular function was associated with prostacyclin signaling through PPARβ/δ (peroxisome proliferator-activated receptor-β/δ). These data demonstrate the kidney as the principle site in the body where local COX-2 controls blood flow and identifies a previously unreported PPARβ/δ-mediated renal vasodilator pathway as the mechanism. These findings have direct relevance to the renal and cardiovascular side effects of drugs that inhibit COX-2, as well as the potential of the COX-2/prostacyclin/PPARβ/δ axis as a therapeutic target in renal disease. © 2018 The Authors.

Resveratrol induces acute endothelium-dependent renal vasodilation mediated through nitric oxide and reactive oxygen species scavenging

PubMed Central

Gordish, Kevin L.

2014-01-01

Resveratrol is suggested to have beneficial cardiovascular and renoprotective effects. Resveratrol increases endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) synthesis. We hypothesized resveratrol acts as an acute renal vasodilator, mediated through increased NO production and scavenging of reactive oxygen species (ROS). In anesthetized rats, we found 5.0 mg/kg body weight (bw) of resveratrol increased renal blood flow (RBF) by 8% [from 6.98 ± 0.42 to 7.54 ± 0.17 ml·min−1·gram of kidney weight−1 (gkw); n = 8; P < 0.002] and decreased renal vascular resistance (RVR) by 18% from 15.00 ± 1.65 to 12.32 ± 1.20 arbitrary resistance units (ARU; P < 0.002). To test the participation of NO, we administered 5.0 mg/kg bw resveratrol before and after 10 mg/kg bw of the NOS inhibitor N-nitro-l-arginine methyl ester (l-NAME). l-NAME reduced the increase in RBF to resveratrol by 54% (from 0.59 ± 0.05 to 0.27 ± 0.06 ml·min−1·gkw−1; n = 10; P < 0.001). To test the participation of ROS, we gave 5.0 mg/kg bw resveratrol before and after 1 mg/kg bw tempol, a superoxide dismutase mimetic. Resveratrol increased RBF 7.6% (from 5.91 ± 0.32 to 6.36 ± 0.12 ml·min−1·gkw−1; n = 7; P < 0.001) and decreased RVR 19% (from 18.83 ± 1.37 to 15.27 ± 1.37 ARU). Tempol blocked resveratrol-induced increase in RBF (from 0.45 ± 0.12 to 0.10 ± 0.05 ml·min−1·gkw−1; n = 7; P < 0.03) and the decrease in RVR posttempol was 44% of the control response (3.56 ± 0.34 vs. 1.57 ± 0.21 ARU; n = 7; P < 0.006). We also tested the role of endothelium-derived prostanoids. Two days of 10 mg/kg bw indomethacin pretreatment did not alter basal blood pressure or RBF. Resveratrol-induced vasodilation remained unaffected. We conclude intravenous resveratrol acts as an acute renal vasodilator, partially mediated by increased NO production/NO bioavailability and superoxide scavenging but not by inducing vasodilatory cyclooxygenase products. PMID:24431202

[Vasodilator effect mediated by nitric oxide of the Zea mays L (andean purple corn) hydroalcoholic extract in aortic rings of rat].

PubMed

Moreno-Loaiza, Oscar; Paz-Aliaga, Azael

2010-01-01

To evaluate the vasodilator response of the hydroalcoholic extract of Zea mays L. (Andean purple corn) and to determine if this response is mediated by nitric oxide (NO). We obtained an extract by maceration for eight days of Andean purple corn cobs in 70% ethanol and subsequent concentration of the product. Thoracic aortic rings were evaluated in an isolated organ chamber, bathed with Krebs-Hensleit solution (KH), and vasomotor activity was recorded with an isometric tension transducer. Basal contraction was produced with 120 mM KCl and then, we proceeded to determinate the vasodilator effect of 3 doses of the extract: 0.1, 0.5, and 1.0 mg/mL. We used L-NG-Nitroarginin methyl ester (L-NAME) to verify that the vasodilation depends on nitric oxide sinteasa (NOs). Then we compared the inhibition of vascular contraction after incubation for 30 minutes, with purple corn extract and captopril 10-5 M. We observed a reduction in maximum contraction (100%) to 85.25 ± 2.60%, 77.76 ± 3.23%, and 73.3 ± 4.87% for doses of 0.1, 0.5 and 1,0 mg/mL respectively. The vasodilation was inhibited by prior incubation with L-NAME. Andean purple corn extract did not inhibit vascular contraction as captopril did (reduction to 75.27 ± 8.61%). The hydroalcoholic extract of Zea mays L produces NO dependent vasodilation.

PI3K/Akt-Independent NOS/HO Activation Accounts for the Facilitatory Effect of Nicotine on Acetylcholine Renal Vasodilations: Modulation by Ovarian Hormones

PubMed Central

Gohar, Eman Y.; El-gowilly, Sahar M.; El-Gowelli, Hanan M.; El-Demellawy, Maha A.; El-Mas, Mahmoud M.

2014-01-01

We investigated the effect of chronic nicotine on cholinergically-mediated renal vasodilations in female rats and its modulation by the nitric oxide synthase (NOS)/heme oxygenase (HO) pathways. Dose-vasodilatory response curves of acetylcholine (0.01–2.43 nmol) were established in isolated phenylephrine-preconstricted perfused kidneys obtained from rats treated with or without nicotine (0.5–4.0 mg/kg/day, 2 weeks). Acetylcholine vasodilations were potentiated by low nicotine doses (0.5 and 1 mg/kg/day) in contrast to no effect for higher doses (2 and 4 mg/kg/day). The facilitatory effect of nicotine was acetylcholine specific because it was not observed with other vasodilators such as 5′-N-ethylcarboxamidoadenosine (NECA, adenosine receptor agonist) or papaverine. Increases in NOS and HO-1 activities appear to mediate the nicotine-evoked enhancement of acetylcholine vasodilation because the latter was compromised after pharmacologic inhibition of NOS (L-NAME) or HO-1 (zinc protoporphyrin, ZnPP). The renal protein expression of phosphorylated Akt was not affected by nicotine. We also show that the presence of the two ovarian hormones is necessary for the nicotine augmentation of acetylcholine vasodilations to manifest because nicotine facilitation was lost in kidneys of ovariectomized (OVX) and restored after combined, but not individual, supplementation with medroxyprogesterone acetate (MPA) and estrogen (E2). Together, the data suggests that chronic nicotine potentiates acetylcholine renal vasodilation in female rats via, at least partly, Akt-independent HO-1 upregulation. The facilitatory effect of nicotine is dose dependent and requires the presence of the two ovarian hormones. PMID:24733557

5-HT2 receptor blockade exhibits 5-HT vasodilator effects via nitric oxide, prostacyclin and ATP-sensitive potassium channels in rat renal vasculature.

PubMed

García-Pedraza, J A; García, M; Martín, M L; Rodríguez-Barbero, A; Morán, A

2016-04-01

The aim of this study was to determine whether orally sarpogrelate (selective 5-HT2 antagonist) treatment (30 mg/kg/day; 14 days) could modify 5-HT renal vasoconstrictor responses, characterizing 5-HT receptors and mediator mechanisms involved in serotonergic responses in the in situ autoperfused rat kidney. Intra-arterial (i.a.) injections of 5-HT (0.00000125 to 0.1 μg/kg) decreased renal perfusion pressure (RPP) but did not affect the mean blood pressure (MBP). i.a. agonists 5-CT (5-HT1/7), CGS-12066B (5-HT1B), L-694,247 (5-HT1D) or AS-19 (5-HT7) mimicked renal 5-HT vasodilator effect. However, neither 8-OH-DPAT (5-HT1A) nor 1-phenylbiguanide (5-HT3) modified RPP. Moreover: (i) GR-55562 (5-HT1B antagonist) and L-NAME (nitric oxide synthase [NOS] inhibitor) blocked CGS-12066B-induced vasodilator response, (ii) LY310762 (5-HT1D antagonist) and indomethacin (non-selective cyclooxygenase inhibitor) blocked L-694,247-induced vasodilator response; (iii) SB-258719 (5-HT7 antagonist) and glibenclamide (ATP-sensitive K+ channel blocker) blocked AS-19-induced vasodilator response; and (iv) 5-HT- or 5-CT-elicited renal vasodilation was significantly blocked by the mixture of GR-55562 + LY310762 + SB-258719. Furthermore, eNOS and iNOS proteins and prostacyclin levels are overexpressed in sarpogrelate-treated rats. Our data suggest that 5-HT exerts renal vasodilator effect in the in situ autoperfused sarpogrelate-treated rat kidney, mediated by 5-HT1D, 5-HT1B and 5-HT7 receptors, involving cyclooxygenase-derived prostacyclin, nitric oxide synthesis/release and ATP-sensitive K+ channels, respectively.

Augmentation of limb perfusion and reversal of tissue ischemia produced by ultrasound-mediated microbubble cavitation.

PubMed

Belcik, J Todd; Mott, Brian H; Xie, Aris; Zhao, Yan; Kim, Sajeevani; Lindner, Nathan J; Ammi, Azzdine; Linden, Joel M; Lindner, Jonathan R

2015-04-01

Ultrasound can increase tissue blood flow, in part, through the intravascular shear produced by oscillatory pressure fluctuations. We hypothesized that ultrasound-mediated increases in perfusion can be augmented by microbubble contrast agents that undergo ultrasound-mediated cavitation and sought to characterize the biological mediators. Contrast ultrasound perfusion imaging of hindlimb skeletal muscle and femoral artery diameter measurement were performed in nonischemic mice after unilateral 10-minute exposure to intermittent ultrasound alone (mechanical index, 0.6 or 1.3) or ultrasound with lipid microbubbles (2×10(8) IV). Studies were also performed after inhibiting shear- or pressure-dependent vasodilator pathways, and in mice with hindlimb ischemia. Ultrasound alone produced a 2-fold increase (P<0.05) in muscle perfusion regardless of ultrasound power. Ultrasound-mediated augmentation in flow was greater with microbubbles (3- and 10-fold higher than control for mechanical index 0.6 and 1.3, respectively; P<0.05), as was femoral artery dilation. Inhibition of endothelial nitric oxide synthase attenuated flow augmentation produced by ultrasound and microbubbles by 70% (P<0.01), whereas inhibition of adenosine-A2a receptors and epoxyeicosatrienoic acids had minimal effect. Limb nitric oxide production and muscle phospho-endothelial nitric oxide synthase increased in a stepwise fashion by ultrasound and ultrasound with microbubbles. In mice with unilateral hindlimb ischemia (40%-50% reduction in flow), ultrasound (mechanical index, 1.3) with microbubbles increased perfusion by 2-fold to a degree that was greater than the control nonischemic limb. Increases in muscle blood flow during high-power ultrasound are markedly amplified by the intravascular presence of microbubbles and can reverse tissue ischemia. These effects are most likely mediated by cavitation-related increases in shear and activation of endothelial nitric oxide synthase. © 2015 American Heart Association, Inc.

AUGMENTATION OF LIMB PERFUSION AND REVERSAL OF TISSUE ISCHEMIA PRODUCED BY ULTRASOUND-MEDIATED MICROBUBBLE CAVITATION

PubMed Central

Belcik, J. Todd; Mott, Brian H.; Xie, Aris; Zhao, Yan; Kim, Sajeevani; Lindner, Nathan J.; Ammi, Azzdine; Linden, Joel M.; Lindner, Jonathan R.

2015-01-01

Background Ultrasound can increase tissue blood flow in part through the intravascular shear produced by oscillatory pressure fluctuations. We hypothesized that ultrasound-mediated increases in perfusion can be augmented by microbubble contrast agents that undergo ultrasound-mediated cavitation, and sought to characterize the biologic mediators. Methods and Results Contrast ultrasound perfusion imaging of hindlimb skeletal muscle and femoral artery diameter measurement were performed in non-ischemic mice after unilateral 10 min exposure to intermittent ultrasound alone (mechanical index [MI] 0.6 or 1.3) or ultrasound with lipid microbubbles (2×108 I.V.). Studies were also performed after inhibiting shear- or pressure-dependent vasodilator pathways, and in mice with hindlimb ischemia. Ultrasound alone produced a 2-fold increase (p<0.05) in muscle perfusion regardless of ultrasound power. Ultrasound-mediated augmentation in flow was greater with microbubbles (3-fold and 10-fold higher than control for MI 0.6 and 1.3, respectively; p<0.05), as was femoral artery dilation. Inhibition of endothelial nitric oxide synthase (eNOS) attenuated flow augmentation produced by ultrasound and microbubbles by 70% (p<0.01), whereas inhibition of adenosine-A2a receptors and epoxyeicosatrienoic acids had minimal effect. Limb nitric oxide (NO) production and muscle phospho-eNOS increased in a stepwise fashion by ultrasound and ultrasound with microbubbles. In mice with unilateral hindlimb ischemia (40–50% reduction in flow), ultrasound (MI 1.3) with microbubbles increased perfusion by 2-fold to a degree that was greater than the control non-ischemic limb. Conclusions Increases in muscle blood flow during high-power ultrasound are markedly amplified by the intravascular presence of microbubbles and can reverse tissue ischemia. These effects are most likely mediated by cavitation-related increases in shear and activation of eNOS. PMID:25834183

Arachidonic acid metabolites and endothelial dysfunction of portal hypertension.

PubMed

Sacerdoti, David; Pesce, Paola; Di Pascoli, Marco; Brocco, Silvia; Cecchetto, Lara; Bolognesi, Massimo

2015-07-01

Increased resistance to portal flow and increased portal inflow due to mesenteric vasodilatation represent the main factors causing portal hypertension in cirrhosis. Endothelial cell dysfunction, defined as an imbalance between the synthesis, release, and effect of endothelial mediators of vascular tone, inflammation, thrombosis, and angiogenesis, plays a major role in the increase of resistance in portal circulation, in the decrease in the mesenteric one, in the development of collateral circulation. Reduced response to vasodilators in liver sinusoids and increased response in the mesenteric arterioles, and, viceversa, increased response to vasoconstrictors in the portal-sinusoidal circulation and decreased response in the mesenteric arterioles are also relevant to the pathophysiology of portal hypertension. Arachidonic acid (AA) metabolites through the three pathways, cyclooxygenase (COX), lipoxygenase, and cytochrome P450 monooxygenase and epoxygenase, are involved in endothelial dysfunction of portal hypertension. Increased thromboxane-A2 production by liver sinusoidal endothelial cells (LSECs) via increased COX-1 activity/expression, increased leukotriens, increased epoxyeicosatrienoic acids (EETs) (dilators of the peripheral arterial circulation, but vasoconstrictors of the portal-sinusoidal circulation), represent a major component in the increased portal resistance, in the decreased portal response to vasodilators and in the hyper-response to vasoconstrictors. Increased prostacyclin (PGI2) via COX-1 and COX-2 overexpression, and increased EETs/heme-oxygenase-1/K channels/gap junctions (endothelial derived hyperpolarizing factor system) play a major role in mesenteric vasodilatation, hyporeactivity to vasoconstrictors, and hyper-response to vasodilators. EETs, mediators of liver regeneration after hepatectomy and of angiogenesis, may play a role in the development of regenerative nodules and collateral circulation, through stimulation of vascular endothelial growth factor (VEGF) inside the liver and in the portal circulation. Pharmacological manipulation of AA metabolites may be beneficial for cirrhotic portal hypertension. Copyright © 2015 Elsevier Inc. All rights reserved.

Soya isoflavone-enriched cereal bars affect markers of endothelial function in postmenopausal women.

PubMed

Hallund, J; Bügel, S; Tholstrup, T; Ferrari, M; Talbot, D; Hall, W L; Reimann, M; Williams, C M; Wiinberg, N

2006-06-01

Soya isoflavones are thought to be cardioprotective due to their structural similarity to oestrogen. In order to investigate the effect of soya isoflavones on markers of endothelial function we conducted a randomised, double-blind, placebo-controlled, cross-over study with thirty healthy postmenopausal women. The women consumed cereal bars, with or without soya isoflavones (50 mg/d), for 8 weeks, separated by an 8-week washout period. Systemic arterial compliance (SAC), isobaric arterial compliance (IAC), flow-mediated endothelium-dependent vasodilation (FMD) and nitroglycerine-mediated endothelium-independent vasodilation (NMD) were measured at the beginning of the study and after each intervention period. Blood pressure (BP) and plasma concentrations of nitrite and nitrate (NOx) and endothelin-1 (ET-1) were measured at the beginning and end of each intervention period. NMD was 13.4 (SEM 2.0)% at baseline and 15.5 (SEM 1.1) % after isoflavone treatment compared with 12.4 (SEM 1.0)% after placebo treatment (P=0.03). NOx increased from 27.7 (SEM 2.7) to 31.1 (SEM 3.2) microM after isoflavones treatment compared with 25.4 (SEM 1.5) to 20.4 (SEM 1.1) microM after placebo treatment (P=0.003) and a significant increase in the NOx:ET-1 ratio (P=0.005) was observed after the isoflavone treatment compared with placebo. A significant difference in SAC after the isoflavone and placebo treatment was observed (P=0.04). No significant difference was found in FMD, IAC, BP and ET-1. In conclusion, 8 weeks' consumption of cereals bars enriched with 50 mg soya isoflavones/d increased plasma NOx concentrations and improved endothelium-independent vasodilation in healthy postmenopausal women.

Lack of effect of sodium nitroprusside on insulin-mediated blood flow and glucose disposal in the elderly.

PubMed

Meneilly, G S; Battistini, B; Floras, J S

2000-03-01

Insulin increases skeletal muscle blood flow in healthy young subjects by a nitric oxide (NO)-dependent mechanism. Impairment of this mechanism may contribute to the insulin resistance of normal aging, a state characterized by reduced endothelial production of NO, an attenuated effect of insulin on skeletal muscle blood flow, and resistance to insulin-mediated glucose uptake (IMGU). We tested the hypothesis that the NO donor sodium nitroprusside (SNP) would augment insulin-mediated vasodilation and thus increase IMGU in healthy elderly subjects. Experiments were performed with young (n = 9; age, 25 +/- 1 years; body mass index [BMI], 24 +/- 1 kg/m2) and old (n = 10; age, 78 +/- 2 years; BMI, 25 +/- 1 kg/m2) healthy subjects. Each group underwent two studies in random order. In one study (control), insulin was infused using the euglycemic clamp protocol for 240 minutes at a rate of 40 mU/m2/min (young) and 34 mU/m2/min (old). In the other study (SNP), SNP was coinfused with insulin from 120 to 240 minutes. At regular intervals in each study, blood samples were obtained and calf blood flow was measured using venous occlusion plethysmography. Glucose and insulin values were similar in control and SNP studies in both age groups. In the young, SNP had no effect on blood flow to the calf, but its action in calf resistance vessels augmented insulin-mediated vasodilation, since incremental calf vascular conductance was greater during SNP infusion (control v SNP, 0.027 +/- 0.002 v 0.040 +/- 0.008 mL/100 mL/min/mm Hg, P< .0001). However, SNP had no effect on insulin-mediated glucose disposal. In the elderly, SNP reduced the blood flow to the calf, but this was countered by its effect on calf resistance vessels such that vascular conductance was unaffected (control v SNP, 0.012 +/- 0.003 v 0.011 +/- 0.003 mL/100 mL/min/mm Hg, P = nonsignificant [NS]). Steady-state (180 to 240 minutes) glucose disposal (control v SNP, 7.47 +/- 0.47 v 6.54 +/- 0.56 mg/kg/min, P < .01) rates were significantly lower during SNP infusion. In summary, systemic infusion of SNP did not increase insulin-mediated glucose disposal in either young or old subjects. Thus, the present findings do not support the concept that increasing NO availability will enhance glucose disposal in either age group. However, because the incremental increases in IMGU during SNP infusion paralleled the changes in blood supply to the calf rather than calf vascular conductance, any potential benefits on NO delivery in elderly subjects may have been offset by the direct or reflex effects of systemic hypotension. Other stimuli to NO production that do not cause hypotension must be tested before this therapeutic strategy can be considered as a potential means for enhancing the metabolic actions of insulin in the elderly.

Differential effects of ascorbate on endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilatation in the bovine ciliary vascular bed and coronary artery.

PubMed

McNeish, Alister J; Nelli, Silvia; Wilson, William S; Dowell, Fiona J; Martin, William

2003-03-01

1. The ability of ascorbate to inhibit endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilatation was compared in the bovine perfused ciliary vascular bed and isolated rings of coronary artery. 2. Acetylcholine-induced, EDHF-mediated vasodilatation of the ciliary circulation was blocked following inclusion of ascorbate (50 micro M, 120 min) in the perfusion fluid. The blockade was highly selective since ascorbate had no effect on the vasodilator actions of the K(ATP) channel opener, levcromakalim, nor on the tonic vasodepressor action of basally released nitric oxide. 3. The possibility that concentration of ascorbate by the ciliary body was a prerequisite for blockade to occur was ruled out, since EDHF was still blocked when the anterior and posterior chambers were continuously flushed with Krebs solution or when both the aqueous and vitreous humour were drained. 4. Ascorbate at 50 micro M failed to affect bradykinin- or acetylcholine-induced, EDHF-mediated vasodilatation in rings of bovine coronary artery. Raising the concentration to 3 mM did produce blockade of EDHF, but this was nonselective, since vasodilator responses to endothelium-derived nitric oxide were also inhibited. 5. Thus, ascorbate (50 micro M) is not a universal blocker of EDHF. Whether its ability to block in the bovine ciliary circulation, but not in the coronary artery, is due to differences in the nature of EDHF at the two sites, differences in vessel size (resistance arterioles versus conduit artery), the presence or absence of flow, or to some other factor remains to be determined.

Nitroglycerin fails to lower blood pressure in redox-dead Cys42Ser PKG1α knock-in mouse

PubMed Central

Rudyk, Olena; Prysyazhna, Oleksandra; Burgoyne, Joseph R; Eaton, Philip

2013-01-01

Background Although nitroglycerin has remained in clinical use since 1879 the mechanism by which it relaxes blood vessels to lower blood pressure remains incompletely understood. Nitroglycerin undergoes metabolism generating several reaction products, including oxidants, and this ‘bioactivation’ process is essential for vasodilation. Protein kinase G (PKG) mediates classical nitric oxide-dependent vasorelaxation, but the 1α isoform is also independently activated by oxidation involving interprotein disulfide formation within this homodimeric protein complex. We hypothesised that nitroglycerin-induced vasodilation is mediated by disulfide activation of PKG1α. Methods and Results Treating smooth muscle cells or isolated blood vessels with nitroglycerin caused PKG1α disulfide dimerization. PKG1α disulfide formation was increased in wild-type mouse aortae by in vivo nitroglycerin treatment, but this oxidation was lost as tolerance developed. To establish whether kinase oxidation underlies nitroglycerin-induced vasodilation in vivo we employed a Cys42Ser PKG1α knock-in mouse that cannot transduce oxidant signals as it doesn’t contain the vital redox-sensing thiol. This ‘redox-dead’ knock-in mouse was substantively deficient in hypotensive response to nitroglycerin compared to wild-type littermates as measured in vivo using radiotelemetry. Resistance blood vessels from knock-ins were markedly less sensitive to nitroglycerin-induced vasodilation (EC50=39.2±10.7μM) than wild-types (EC50=12.1±2.9μM). Furthermore, after ~24 hours of treatment wild-type controls stopped vasodilating to nitroglycerin and the vascular sensitivity to nitroglycerin was decreased, whereas this ‘tolerance’ phenomenon that routinely hampers the management of hypertensive patients was absent in knock-ins. Conclusions PKG1α disulfide formation is a significant mediator of nitroglycerin-induced vasodilation and tolerance to nitroglycerin is associated with loss of kinase oxidation. PMID:22685118

Effects of losartan on whole-body, skeletal muscle, and vascular insulin responses in obesity/insulin resistance without hypertension

PubMed Central

Lteif, AA; Chisholm, RL; Gilbert, K; Considine, RV; Mather, KJ

2011-01-01

Aims Renin-angiotensin system antagonists have been found to improve glucose metabolism in obese hypertensive and type 2 diabetic subjects. The mechanism of these effects is not well understood. We hypothesized that the angiotensin receptor antagonist losartan would improve insulin-mediated vasodilation, and thereby improve insulin-stimulated glucose uptake in skeletal muscle of insulin resistant subjects. Materials and Methods We studied subjects with obesity and insulin resistance but without hypertension, hypercholesterolemia or dysglycemia (age 39.0±9.6 yrs [mean±SD], BMI 33.2±5.9 kg/m2, BP 115.8±12.2/70.9±7.2 mmHg, LDL 2.1±0.5 mmol/L). Subjects were randomized to 12 weeks’ double-blind treatment with losartan 100 mg once daily (n=9) or matching placebo (n=8). Before and after treatment, under hyperinsulinemic euglycemic clamp conditions we measured whole-body insulin stimulated glucose disposal, insulin-mediated vasodilation, and insulin-stimulated leg glucose uptake by the limb balance technique. Results Whole-body insulin-stimulated glucose disposal was not significantly increased by losartan. Insulin-mediated vasodilation was augmented following both treatments (increase in leg vascular conductance: pre-treatment 0.7±0.3 L*min−1*mmHg−1[losartan, mean ±SEM] and 0.9±0.3 [placebo], post-treatment 1.0±0.4 [losartan] and 1.3±0.6 [placebo]) but not different between treatment groups (p=0.53). Insulin’s action to augment NO production and to augment endothelium-dependent vasodilation were also not improved. Leg glucose uptake was not significantly changed by treatments, and not different between groups (p=0.11). Conclusions These findings argue against the hypothesis that losartan might improve skeletal muscle glucose metabolism by improving insulin-mediated vasodilation in normotensive insulin resistant obese subjects. The metabolic benefits of angiotensin receptor blockers may require the presence of hypertension in addition to obesity-associated insulin resistance. PMID:22051059

Effect of Red Blood Cell Storage on Cardiac Performance. Improved Myocardial Oxygen Delivery and Function during Constant Flow Coronary Perfusion with Low Oxy-Hemoglobin Affinity Human Red Blood Cells in Normothermic and Hypothermic Rabbit Hearts.

DTIC Science & Technology

1983-02-01

with an isovolumic left ven- tricular balloon. Coronary flow was held constant to simulate the physiolog of coronary atherosclerosis and other...erythrocyte DPG content can potentially benefit patients with coronary atherosclerosis , or other states with a limited coronary vasodilator reserve, who...Coronary flow was held constant to simulate the physiology of coronary atherosclerosis and other conditions of limited coronary vasodilator reserve

Rho-kinase inhibition acutely augments blood flow in focal cerebral ischemia via endothelial mechanisms.

PubMed

Shin, Hwa Kyoung; Salomone, Salvatore; Potts, E Michelle; Lee, Sae-Won; Millican, Eric; Noma, Kensuke; Huang, Paul L; Boas, David A; Liao, James K; Moskowitz, Michael A; Ayata, Cenk

2007-05-01

Rho-kinase is a serine threonine kinase that increases vasomotor tone via its effects on both endothelium and smooth muscle. Rho-kinase inhibition reduces cerebral infarct size in wild type, but not endothelial nitric oxide synthase deficient (eNOS-/-) mice. The mechanism may be related to Rho-kinase activation under hypoxic/ischemic conditions and impaired vasodilation because of downregulation of eNOS activity. To further implicate Rho-kinase in impaired vascular relaxation during hypoxia/ischemia, we exposed isolated vessels from rat and mouse to 60 mins of hypoxia, and showed that hypoxia reversibly abolished acetylcholine-induced eNOS-dependent relaxation, and that Rho-kinase inhibitor hydroxyfasudil partially preserved this relaxation during hypoxia. We, therefore, hypothesized that if hypoxia-induced Rho-kinase activation acutely impairs vasodilation in ischemic cortex, in vivo, then Rho-kinase inhibitors would acutely augment cerebral blood flow (CBF) as a mechanism by which they reduce infarct size. To test this, we studied the acute cerebral hemodynamic effects of Rho-kinase inhibitors in ischemic core and penumbra during distal middle cerebral artery occlusion (dMCAO) in wild-type and eNOS-/- mice using laser speckle flowmetry. When administered 60 mins before or immediately after dMCAO, Rho-kinase inhibitors hydroxyfasudil and Y-27632 reduced the area of severely ischemic cortex. However, hydroxyfasudil did not reduce the area of CBF deficit in eNOS-/- mice, suggesting that its effect on CBF within the ischemic cortex is primarily endothelium-dependent, and not mediated by its direct vasodilator effect on vascular smooth muscle. Our results suggest that Rho-kinase negatively regulates eNOS activity in acutely ischemic brain, thereby worsening the CBF deficit. Therefore, rapid nontranscriptional upregulation of eNOS activity by small molecule inhibitors of Rho-kinase may be a viable therapeutic approach in acute stroke.

Mechanisms of vasodilation in the dorsal aorta of the elephant fish, Callorhinchus milii (Chimaeriformes: Holocephali).

PubMed

Jennings, Brett L; Bell, Justin D; Hyodo, Susumu; Toop, Tes; Donald, John A

2007-07-01

This study investigated vasodilator mechanisms in the dorsal aorta of the elephant fish, Callorhinchus milii, using anatomical and physiological approaches. Nitric oxide synthase could only be located in the perivascular nerve fibres and not the endothelium of the dorsal aorta, using NADPH histochemistry and immunohistochemistry. In vitro organ bath experiments demonstrated that a NO/soluble guanylyl cyclase (GC) system appeared to be absent in the vascular smooth muscle, since the NO donors SNP (10(-4) mol l(-1)) and SIN-1 (10(-5) mol l(-1)) were without effect. Nicotine (3 x 10(-4) mol l(-1)) mediated a vasodilation that was not affected by ODQ (10(-5) mol l(-1)), L-NNA (10(-4) mol l(-1)), indomethacin (10(-5) mol l(-1)), or removal of the endothelium. In contrast, the voltage-gated sodium channel inhibitor, tetrodotoxin (10(-5) mol l(-1)), significantly decreased the dilation induced by nicotine, suggesting that it contained a neural component. Pre-incubation of the dorsal aorta with the calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP(8-37) (10(-6) mol l(-1)) also caused a significant decrease in the nicotine-induced dilation. We propose that nicotine is mediating a neurally-derived vasodilation in the dorsal aorta that is independent of NO, prostaglandins and the endothelium, and partly mediated by CGRP.

Measurement of Flow-Mediated Dilation of Mouse Femoral Artery in vivo by Optical Coherence Tomography.

PubMed

Song, Weiye; Zhou, Libo; Kot, Kevin Liu; Fan, Huijie; Han, Jingyan; Yi, Ji

2018-05-31

Flow-mediated vasodilation (FMD) is used for assessment of vascular endothelial function in humans as a predictor of cardiovascular events. It has been challenging to carry it on preclinical murine models due to the diminutive size of the femoral artery. Here, we present a new approach to accurately measure the blood velocity and femoral artery diameters of mice by acquiring Doppler optical coherence tomography (DOCT) and optical coherence tomography angiography (OCTA) continuously within one single experimental scanning protocol. Using the high precision three-dimensional imaging and new velocity algorithm, the measurement precision of diameter, blood flow, velocity, and wall shear stress are improved to 0.91%, 11.0%, 10.7%, and 14.0%, respectively. FMD of healthy mouse femoral artery measured by this method was 11.96 ± 0.98%, which was blunted to 5.69±0.4% by intravenous administration of eNOS inhibitor (L-NAME), in agreement with that reported in the literature. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Cardiac beta-adrenergic receptors and coronary hemodynamics in the conscious dog during hypoxic hypoxia.

NASA Technical Reports Server (NTRS)

Erickson, H. H.; Stone, H. L.

1972-01-01

The mechanisms by which acute hypoxia (10% and 5% oxygen) mediates changes in coronary blood flow and cardiac function were investigated in the conscious dog. When the dogs breathed hypoxic gas mixtures through a tracheostomy, both arterial and coronary sinus oxygen tensions were significantly decreased. With 5% oxygen, there were significant increases in heart rate (25%), maximum left ventricular dP/dt (39%), left circumflex coronary artery blood flow (163%), and left ventricular oxygen consumption (52%), which were attenuated by beta-adrenergic blockage with propranolol. When electrical pacing was used to keep the ventricular rate constant during hypoxia, there was no significant difference in coronary blood flow before and after beta blockade. Beta-adrenergic receptor activity in the myocardium participates in the integrated response to hypoxia although it may not cause active vasodilation of the coronary vessels.

Monoamine uptake inhibitors block alpha7-nAChR-mediated cerebral nitrergic neurogenic vasodilation.

PubMed

Long, Cheng; Chen, Mei-Fang; Sarwinski, Susan J; Chen, Po-Yi; Si, Minliang; Hoffer, Barry J; Evans, M Steven; Lee, Tony J F

2006-07-01

We have proposed that activation of cerebral perivascular sympathetic alpha7-nicotinic acetylcholine receptors (alpha7-nAChRs) by nicotinic agonists releases norepinephrine, which then acts on parasympathetic nitrergic nerves, resulting in release of nitric oxide and vasodilation. Using patch-clamp electrophysiology, immunohistochemistry, and in vitro tissue bath myography, we tested this axo-axonal interaction hypothesis further by examining whether blocking norepinephrine reuptake enhanced alpha7-nAChR-mediated cerebral nitrergic neurogenic vasodilation. The results indicated that choline- and nicotine-induced alpha7-nAChR-mediated nitrergic neurogenic relaxation in endothelium-denuded isolated porcine basilar artery rings was enhanced by desipramine and imipramine at lower concentrations (0.03-0.1 microM) but inhibited at higher concentrations (0.3-10 microM). In cultured superior cervical ganglion (SCG) neurons of the pig and rat, choline (0.1-30 mM)-evoked inward currents were reversibly blocked by 1-30 microM mecamylamine, 1-30 microM methyllycaconitine, 10-300 nM alpha-bungarotoxin, and 0.1-10 microM desipramine and imipramine, providing electrophysiological evidence for the presence of similar functional alpha7-nAChRs in cerebral perivascular sympathetic neurons of pigs and rats. In alpha7-nAChR-expressing Xenopus oocytes, choline-elicited inward currents were attenuated by alpha-bungarotoxin, imipramine, and desipramine. These monoamine uptake inhibitors appeared to directly block the alpha7-nAChR, resulting in diminished nicotinic agonist-induced cerebral nitrergic vasodilation. The enhanced nitrergic vasodilation by lower concentrations of monoamine uptake inhibitors is likely due to a greater effect on monoamine uptake than on alpha7-nAChR blockade. These results further support the hypothesis of axo-axonal interaction in nitrergic regulation of cerebral vascular tone.

Daily physical activity enhances reactivity to insulin in skeletal muscle arterioles of hyperphagic Otsuka Long-Evans Tokushima Fatty rats.

PubMed

Mikus, Catherine R; Rector, R Scott; Arce-Esquivel, Arturo A; Libla, Jessica L; Booth, Frank W; Ibdah, Jamal A; Laughlin, M Harold; Thyfault, John P

2010-10-01

Insulin-mediated glucose disposal is dependent on the vasodilator effects of insulin. In type 2 diabetes, insulin-stimulated vasodilation is impaired as a result of an imbalance in NO and ET-1 production. We tested the hypothesis that chronic voluntary wheel running (RUN) prevents impairments in insulin-stimulated vasodilation associated with obesity and type 2 diabetes independent of the effects of RUN on adiposity by randomizing Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of hyperphagia-induced obesity and type 2 diabetes, to 1) RUN, 2) caloric restriction (CR; diet adjusted to match body weights of RUN group), or 3) sedentary control (SED) groups (n = 8/group) at 4 wk. At 40 wk, NO- and ET-1-mediated vasoreactivity to insulin (1-1,000 μIU/ml) was assessed in the presence of a nonselective ET-1 receptor blocker (tezosentan) or a NO synthase (NOS) inhibitor [N(G)-nitro-L-arginine methyl ester (L-NAME)], respectively, in second-order arterioles isolated from the white portion of the gastrocnemius muscle. Body weight, fasting plasma glucose, and hemoglobin A1c were lower in RUN and CR than SED (P < 0.05); however, the glucose area under the curve (AUC) following the intraperitoneal glucose tolerance test was lower only in the RUN group (P < 0.05). Vasodilator responses to all doses of insulin were greater in RUN than SED or CR in the presence of a tezosentan (P < 0.05), but group differences in vasoreactivity to insulin with coadministration of L-NAME were not observed. We conclude daily wheel running prevents obesity and type 2 diabetes-associated declines in insulin-stimulated vasodilation in skeletal muscle arterioles through mechanisms that appear to be NO mediated and independent of attenuating excess adiposity in hyperphagic rats.

WNT5A-JNK regulation of vascular insulin resistance in human obesity.

PubMed

Farb, Melissa G; Karki, Shakun; Park, Song-Young; Saggese, Samantha M; Carmine, Brian; Hess, Donald T; Apovian, Caroline; Fetterman, Jessica L; Bretón-Romero, Rosa; Hamburg, Naomi M; Fuster, José J; Zuriaga, María A; Walsh, Kenneth; Gokce, Noyan

2016-12-01

Obesity is associated with the development of vascular insulin resistance; however, pathophysiological mechanisms are poorly understood. We sought to investigate the role of WNT5A-JNK in the regulation of insulin-mediated vasodilator responses in human adipose tissue arterioles prone to endothelial dysfunction. In 43 severely obese (BMI 44±11 kg/m 2 ) and five metabolically normal non-obese (BMI 26±2 kg/m 2 ) subjects, we isolated arterioles from subcutaneous and visceral fat during planned surgeries. Using videomicroscopy, we examined insulin-mediated, endothelium-dependent vasodilator responses and characterized adipose tissue gene and protein expression using real-time polymerase chain reaction and Western blot analyses. Immunofluorescence was used to quantify endothelial nitric oxide synthase (eNOS) phosphorylation. Insulin-mediated vasodilation was markedly impaired in visceral compared to subcutaneous vessels from obese subjects (p<0.001), but preserved in non-obese individuals. Visceral adiposity was associated with increased JNK activation and elevated expression of WNT5A and its non-canonical receptors, which correlated negatively with insulin signaling. Pharmacological JNK antagonism with SP600125 markedly improved insulin-mediated vasodilation by sixfold (p<0.001), while endothelial cells exposed to recombinant WNT5A developed insulin resistance and impaired eNOS phosphorylation (p<0.05). We observed profound vascular insulin resistance in the visceral adipose tissue arterioles of obese subjects that was associated with up-regulated WNT5A-JNK signaling and impaired endothelial eNOS activation. Pharmacological JNK antagonism markedly improved vascular endothelial function, and may represent a potential therapeutic target in obesity-related vascular disease. © The Author(s) 2016.

WNT5A-JNK regulation of vascular insulin resistance in human obesity

PubMed Central

Farb, Melissa G; Karki, Shakun; Park, Song-Young; Saggese, Samantha M; Carmine, Brian; Hess, Donald T; Apovian, Caroline; Fetterman, Jessica L; Bretón-Romero, Rosa; Hamburg, Naomi M; Fuster, José J; Zuriaga, María A; Walsh, Kenneth; Gokce, Noyan

2017-01-01

Obesity is associated with the development of vascular insulin resistance; however, pathophysiological mechanisms are poorly understood. We sought to investigate the role of WNT5A-JNK in the regulation of insulin-mediated vasodilator responses in human adipose tissue arterioles prone to endothelial dysfunction. In 43 severely obese (BMI 44±11 kg/m2) and five metabolically normal non-obese (BMI 26±2 kg/m2) subjects, we isolated arterioles from subcutaneous and visceral fat during planned surgeries. Using videomicroscopy, we examined insulin-mediated, endothelium-dependent vasodilator responses and characterized adipose tissue gene and protein expression using real-time polymerase chain reaction and Western blot analyses. Immunofluorescence was used to quantify endothelial nitric oxide synthase (eNOS) phosphorylation. Insulin-mediated vasodilation was markedly impaired in visceral compared to subcutaneous vessels from obese subjects (p<0.001), but preserved in non-obese individuals. Visceral adiposity was associated with increased JNK activation and elevated expression of WNT5A and its non-canonical receptors, which correlated negatively with insulin signaling. Pharmacological JNK antagonism with SP600125 markedly improved insulin-mediated vasodilation by sixfold (p<0.001), while endothelial cells exposed to recombinant WNT5A developed insulin resistance and impaired eNOS phosphorylation (p<0.05). We observed profound vascular insulin resistance in the visceral adipose tissue arterioles of obese subjects that was associated with up-regulated WNT5A-JNK signaling and impaired endothelial eNOS activation. Pharmacological JNK antagonism markedly improved vascular endothelial function, and may represent a potential therapeutic target in obesity-related vascular disease. PMID:27688298

Influence of nitric oxide-mediated vasodilation on the blood pressure measured with the tail-cuff method in the rat.

PubMed

Fritz, Mariana; Rinaldi, Gustavo

2007-11-01

Systolic blood pressure (SBP) is frequently measured in rats by the tail cuff method, which usually comprises pulse/flow disappearance and reappearance during cuff inflation (Inf) and deflation (Def), separated by an interval between cycles (IBC). Although Def values are habitually used to estimate SBP, in 58 Wistar rats we found (Def-Inf) to be -6 +/- 1 mmHg, indicating that Def < Inf in most cases. When the IBC was lengthened to 2 min, (Def-Inf) was increased to -17 +/- 2 mmHg, indicating the probable accumulation of a vasodilating metabolite. This increase of (Def-Inf) was prevented by papaverine, indicating its relation to smooth muscle contractility. Adrenergic blockade did not prevent the increase of (Def-Inf), but pretreatment with L-NAME decreased it to -5 +/- 2 mmHg (p < 0.05). Simultaneous measurement of SBP by tail-cuff method and carotid cannulation revealed that the Inf value was the most accurate estimation of intravascular SBP. We conclude that: (1) the Inf value should be taken as representative of SBP, since depending on the duration of suprasystolic compression the Def value can underestimate it, and (2) nitric oxide accumulation due to flow deprivation was the main cause of SBP underestimation by Def values.

Nitrite and S-Nitrosohemoglobin Exchange Across the Human Cerebral and Femoral Circulation: Relationship to Basal and Exercise Blood Flow Responses to Hypoxia.

PubMed

Bailey, Damian M; Rasmussen, Peter; Overgaard, Morten; Evans, Kevin A; Bohm, Aske M; Seifert, Thomas; Brassard, Patrice; Zaar, Morten; Nielsen, Henning B; Raven, Peter B; Secher, Niels H

2017-01-10

The mechanisms underlying red blood cell (RBC)-mediated hypoxic vasodilation remain controversial, with separate roles for nitrite () and S-nitrosohemoglobin (SNO-Hb) widely contested given their ability to transduce nitric oxide bioactivity within the microcirculation. To establish their relative contribution in vivo, we quantified arterial-venous concentration gradients across the human cerebral and femoral circulation at rest and during exercise, an ideal model system characterized by physiological extremes of O 2 tension and blood flow. Ten healthy participants (5 men, 5 women) aged 24±4 (mean±SD) years old were randomly assigned to a normoxic (21% O 2 ) and hypoxic (10% O 2 ) trial with measurements performed at rest and after 30 minutes of cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled simultaneously from the brachial artery and internal jugular and femoral veins with plasma and RBC nitric oxide metabolites measured by tri-iodide reductive chemiluminescence. Blood flow was determined by transcranial Doppler ultrasound (cerebral blood flow) and constant infusion thermodilution (femoral blood flow) with net exchange calculated via the Fick principle. Hypoxia was associated with a mild increase in both cerebral blood flow and femoral blood flow (P<0.05 versus normoxia) with further, more pronounced increases observed in femoral blood flow during exercise (P<0.05 versus rest) in proportion to the reduction in RBC oxygenation (r=0.680-0.769, P<0.001). Plasma gradients reflecting consumption (arterial>venous; P<0.05) were accompanied by RBC iron nitrosylhemoglobin formation (venous>arterial; P<0.05) at rest in normoxia, during hypoxia (P<0.05 versus normoxia), and especially during exercise (P<0.05 versus rest), with the most pronounced gradients observed across the bioenergetically more active, hypoxemic, and acidotic femoral circulation (P<0.05 versus cerebral). In contrast, we failed to observe any gradients consistent with RBC SNO-Hb consumption and corresponding delivery of plasma S-nitrosothiols (P>0.05). These findings suggest that hypoxia and, to a far greater extent, exercise independently promote arterial-venous delivery gradients of intravascular nitric oxide, with deoxyhemoglobin-mediated reduction identified as the dominant mechanism underlying hypoxic vasodilation. © 2016 American Heart Association, Inc.

Endothelial dysfunction in normoglycaemic first-degree relatives of type 2 diabetes mellitus complicated with hyperuricaemia.

PubMed

Zhang, Junxia; Xiang, Lin; Zhang, Bilin; Cheng, Yangyang

2017-03-01

To reveal the effect of hyperuricaemia on endothelial function in normoglycaemic first-degree relatives of type 2 diabetes mellitus. In all, 40 first-degree relatives of type 2 diabetes mellitus with hyperuricaemia, 40 first-degree relatives of type 2 diabetes mellitus with normouricaemia and 35 healthy subjects without diabetic family history were recruited in this study. Anthropometric parameters as well as blood pressure, blood lipids, fasting blood glucose, fasting insulin, C-reactive protein, tumour necrosis factor-α and interleukin-6 were measured. Insulin resistance was assessed with homoeostasis model assessment index-insulin resistance index. To assess endothelial function, high-resolution ultrasonography was used for measuring flow- and nitroglycerine-mediated brachial artery vasodilation. When compared with control, flow-mediated dilation was lower in first-degree relatives with or without hyperuricaemia (both p < 0.001). When compared with first-degree relative subjects with normouricaemia, there were lower flow-mediated dilation ( p < 0.001) and higher levels of uric acid ( p < 0.001), fasting blood glucose ( p < 0.001), C-reactive protein ( p = 0.001), tumour necrosis factor-α ( p < 0.001) and interleukin-6 ( p < 0.001) in first-degree relative subjects with hyperuricaemia. Flow-mediated dilation was found to be negatively related to uric acid ( r = -0.597, p < 0.001). Stepwise multiple regressions demonstrated that uric acid was a significant determinant of flow-mediated dilation independent of other variables in first-degree relatives of type 2 diabetes mellitus (β = -0.677, p < 0.001; confidence interval: -0.010 to -0.006). Further endothelial dysfunction is found in normoglycaemic first-degree relatives of type 2 diabetes mellitus complicated with hyperuricaemia.

Role of endothelium-derived relaxing factors in adrenomedullin-induced vasodilation in the rat kidney.

PubMed

Wangensteen, Rosemary; Quesada, Andrés; Sainz, Juan; Duarte, Juan; Vargas, Félix; Osuna, Antonio

2002-05-24

The present study aimed to evaluate the contributions of endothelium-derived hyperpolarizing factor (EDHF), the nitric oxide (NO)-cGMP pathway, and prostaglandins to adrenomedullin-induced vasodilation in isolated rat kidney. Inhibition of the NO-cGMP pathway with N(omega)-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo-[4,3a]quinoxalin-1-one (ODQ) reduced the maximal vasodilator response to adrenomedullin by approximately 50%. Pretreatment of the vessels with the potassium channel inhibitor, tetraethylammonium or increased extracellular K(+), also decreased the maximal response to adrenomedullin by approximately 50%. The simultaneous administration of blockers of both endothelium-derived relaxing factors had a combined effect that almost suppressed adrenomedullin-induced vasodilation. The administration of indomethacin did not modify the renal response to adrenomedullin. Our results suggest that the vasodilator response to adrenomedullin in the isolated perfused kidney of rats is mediated by EDHF and NO to a similar extent. Our data also provide evidence that prostaglandins play no role in the vasodilator response to adrenomedullin in the renal vasculature.

Infrared Imaging of Nitric Oxide-Mediated Blood Flow in Human Sickle Cell Disease

PubMed Central

Gorbach, Alexander M.; Ackerman, Hans C.; Liu, Wei-Min; Meyer, Joseph M.; Littel, Patricia L.; Seamon, Catherine; Footman, Eleni; Chi, Amy; Zorca, Suzana; Krajewski, Megan L.; Cuttica, Michael J.; Machado, Roberto F.; Cannon, Richard O.; Kato, Gregory J.

2012-01-01

Vascular dysfunction is an important pathophysiologic manifestation of sickle cell disease (SCD), a condition that increases risk of pulmonary hypertension and stroke. We hypothesized that infrared (IR) imaging would detect changes in cutaneous blood flow reflective of vascular function. We performed IR imaging and conventional strain gauge plethysmography in twenty-five adults with SCD at baseline and during intra-arterial infusions of an endothelium-dependent vasodilator acetylcholine (ACh), an endothelium-independent vasodilator sodium nitroprusside (SNP), and a NOS inhibitor L-NMMA. Skin temperature measured by IR imaging increased in a dose-dependent manner to graded infusions of ACh (+1.1° C, p < 0.0001) and SNP (+0.9° C, p < 0.0001), and correlated with dose-dependent increases in forearm blood flow (ACh: +19.9 mL/min/100mL, p < 0.0001; rs = 0.57, p = 0.003; SNP: +8.6 mL/min/100mL, p < 0.0001; r = 0.70, p = 0.0002). Although IR measurement of skin temperature accurately reflected agonist-induced increases in blood flow, it was less sensitive to decreases in blood flow caused by NOS inhibition. Baseline forearm skin temperature measured by IR imaging correlated significantly with baseline forearm blood flow (31.8±0.2° C, 6.0±0.4 mL/min/100mL; r = 0.58, p = 0.003), and appeared to represent a novel biomarker of vascular function. It predicted a blunted blood flow response to SNP (r = −0.61, p = 0.002), and was independently associated with a marker of pulmonary artery pressure, as well as hemoglobin level, diastolic blood pressure, homocysteine, and cholesterol (R2 = 0.84, p < 0.0001 for the model). IR imaging of agonist-stimulated cutaneous blood flow represents a less cumbersome alternative to plethysmography methodology. Measurement of baseline skin temperature by IR imaging may be a useful new marker of vascular risk in adults with SCD. PMID:22784510

Coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone improves postprandial endothelial dysfunction in patients with borderline and stage 1 hypertension.

PubMed

Kajikawa, Masato; Maruhashi, Tatsuya; Hidaka, Takayuki; Nakano, Yukiko; Kurisu, Satoshi; Matsumoto, Takeshi; Iwamoto, Yumiko; Kishimoto, Shinji; Matsui, Shogo; Aibara, Yoshiki; Yusoff, Farina Mohamad; Kihara, Yasuki; Chayama, Kazuaki; Goto, Chikara; Noma, Kensuke; Nakashima, Ayumu; Watanabe, Takuya; Tone, Hiroshi; Hibi, Masanobu; Osaki, Noriko; Katsuragi, Yoshihisa; Higashi, Yukihito

2018-01-12

The purpose of this study was to evaluate acute effects of coffee with a high content of chlorogenic acids and different hydroxyhydroquinone contents on postprandial endothelial dysfunction. This was a single-blind, randomized, placebo-controlled, crossover-within-subject clinical trial. A total of 37 patients with borderline or stage 1 hypertension were randomized to two study groups. The participants consumed a test meal with a single intake of the test coffee. Subjects in the Study 1 group were randomized to single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone or coffee with a high content of chlorogenic acids and a high content of hydroxyhydroquinone with crossover. Subjects in the Study 2 group were randomized to single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone or placebo coffee with crossover. Endothelial function assessed by flow-mediated vasodilation and plasma concentration of 8-isoprostanes were measured at baseline and at 1 and 2 h after coffee intake. Compared with baseline values, single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone, but not coffee with a high content of chlorogenic acids and high content of hydroxyhydroquinone or placebo coffee, significantly improved postprandial flow-mediated vasodilation and decreased circulating 8-isoprostane levels. These findings suggest that a single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone is effective for improving postprandial endothelial dysfunction. URL for Clinical Trial: https://upload.umin.ac.jp ; Registration Number for Clinical Trial: UMIN000013283.

Potentiation of the NO-cGMP pathway and blood flow responses during dynamic exercise in healthy humans

PubMed Central

Limberg, Jacqueline K.; Malterer, Katherine R.; Kellawan, J. Mikhail; Schrage, William G.; Wilkins, Brad W.; Nicholson, Wayne T.; Eisenach, John H.; Joyner, Michael J.; Curry, Timothy B.

2017-01-01

Purpose Previous work has shown nitric oxide (NO) contributes to ~15% of the hyperemic response to dynamic exercise in healthy humans. This NO-mediated vasodilation occurs, in part, via increases in intracellular cyclic guanosine monophosphate (cGMP), which is catabolized by phosphodiesterase. We sought to examine the effect of phosphodiesterase-5 (PDE-5) inhibition on forearm blood flow (FBF responses to dynamic handgrip exercise in healthy humans and the role of NO. We hypothesized exercise hyperemia would be augmented by sildenafil citrate (SDF, PDE-5 inhibitor). We further hypothesized any effect of SDF on exercise hyperemia would be abolished with intra-arterial infusion of the NO synthase (NOS) inhibitor L-NG-monomethyl arginine (L-NMMA). Methods FBF (Doppler ultrasound) was assessed at rest and during 5 minutes of dynamic forearm handgrip exercise at 15% of maximal voluntary contraction under control (saline) conditions and during 3 experimental protocols: 1) oral SDF (n=10), 2) intra-arterial L-NMMA (n=20), 3) SDF and L-NMMA (n=10). FBF responses to intra-arterial sodium nitroprusside (NTP, NO donor) were also assessed. Results FBF increased with exercise (p<0.01). Intra-arterial infusion of L-NMMA resulted in a reduction in exercise hyperemia (17±1 to 15±1 mL/dL/min, p<0.01). Although the hyperemic response to NTP was augmented by SDF (Area under the curve: 41±7 vs 61±11 AU, p<0.01), there was no effect of SDF on exercise hyperemia (p=0.33). Conclusions Despite improving NTP-mediated vasodilation, oral SDF failed to augment exercise hyperemia in young, healthy adults. These observations reflect a minor contribution of NO and the cGMP pathway during exercise hyperemia in healthy young humans. PMID:28013386

The action of red wine and purple grape juice on vascular reactivity is independent of plasma lipids in hypercholesterolemic patients.

PubMed

Coimbra, S R; Lage, S H; Brandizzi, L; Yoshida, V; da Luz, P L

2005-09-01

Although red wine (RW) reduces cardiovascular risk, the mechanisms underlying the effect have not been identified. Correction of endothelial dysfunction by RW flavonoids could be one mechanism. We measured brachial artery reactivity by high-resolution ultrasonography, plasma lipids, glucose, adhesion molecules (ICAM-1 and VCAM), and platelet function in 16 hypercholesterolemic individuals (8 men and 8 women; mean age 51.6 +/- 8.1 years) without other risk factors. Twenty-four normal subjects were used as controls for vascular reactivity. Subjects randomly received RW, 250 ml/day, or purple grape juice (GJ), 500 ml/day, for 14 days with an equal wash-out period. At baseline, all 16 subjects were hypercholesterolemic (mean LDL = 181.0 +/- 28.7 mg/dl) but HDL, triglycerides, glucose, adhesion molecules, and platelet function were within normal limits. Brachial artery flow-mediated dilation was significantly decreased compared to controls (9.0 +/- 7.1 vs 12.1 +/- 4.5%; P < 0.05) and increased with both GJ (10.1 +/- 7.1 before vs 16.9 +/- 6.7% after: P < 0.05) and RW (10.1 +/- 6.4 before vs 15.6 +/- 4.6% after; P < 0.05). RW, but not GJ, also significantly increased endothelium-independent vasodilation (17.0 +/- 8.6 before vs 23.0 +/- 12.0% after; P < 0.01). GJ reduced ICAM-1 but not VCAM and RW had no effect on either molecule. No significant alterations were observed in plasma lipids, glucose or platelet aggregability with RW or GJ. Both RW and GJ similarly improved flow-mediated dilation, but RW also enhanced endothelium-independent vasodilation in hypercholesterolemic patients despite the increased plasma cholesterol. Thus, we conclude that GJ may protect against coronary artery disease without the additional negative effects of alcohol despite the gender.

Fractal regional myocardial blood flows pattern according to metabolism, not vascular anatomy

PubMed Central

Yipintsoi, Tada; Kroll, Keith

2015-01-01

Regional myocardial blood flows are markedly heterogeneous. Fractal analysis shows strong near-neighbor correlation. In experiments to distinguish control by vascular anatomy vs. local vasomotion, coronary flows were increased in open-chest dogs by stimulating myocardial metabolism (catecholamines + atropine) with and without adenosine. During control states mean left ventricular (LV) myocardial blood flows (microspheres) were 0.5–1 ml·g−1·min−1 and increased to 2–3 ml·g−1·min−1 with catecholamine infusion and to ∼4 ml·g−1·min−1 with adenosine (Ado). Flow heterogeneity was similar in all states: relative dispersion (RD = SD/mean) was ∼25%, using LV pieces 0.1–0.2% of total. During catecholamine infusion local flows increased in proportion to the mean flows in 45% of the LV, “tracking” closely (increased proportionately to mean flow), while ∼40% trended toward the mean. Near-neighbor regional flows remained strongly spatially correlated, with fractal dimension D near 1.2 (Hurst coefficient 0.8). The spatial patterns remain similar at varied levels of metabolic stimulation inferring metabolic dominance. In contrast, adenosine vasodilation increased flows eightfold times control while destroying correlation with the control state. The Ado-induced spatial patterns differed from control but were self-consistent, inferring that with full vasodilation the relaxed arterial anatomy dominates the distribution. We conclude that vascular anatomy governs flow distributions during adenosine vasodilation but that metabolic vasoregulation dominates in normal physiological states. PMID:26589329

Fractal regional myocardial blood flows pattern according to metabolism, not vascular anatomy.

PubMed

Yipintsoi, Tada; Kroll, Keith; Bassingthwaighte, James B

2016-02-01

Regional myocardial blood flows are markedly heterogeneous. Fractal analysis shows strong near-neighbor correlation. In experiments to distinguish control by vascular anatomy vs. local vasomotion, coronary flows were increased in open-chest dogs by stimulating myocardial metabolism (catecholamines + atropine) with and without adenosine. During control states mean left ventricular (LV) myocardial blood flows (microspheres) were 0.5-1 ml·g(-1)·min(-1) and increased to 2-3 ml·g(-1)·min(-1) with catecholamine infusion and to ∼4 ml·g(-1)·min(-1) with adenosine (Ado). Flow heterogeneity was similar in all states: relative dispersion (RD = SD/mean) was ∼25%, using LV pieces 0.1-0.2% of total. During catecholamine infusion local flows increased in proportion to the mean flows in 45% of the LV, "tracking" closely (increased proportionately to mean flow), while ∼40% trended toward the mean. Near-neighbor regional flows remained strongly spatially correlated, with fractal dimension D near 1.2 (Hurst coefficient 0.8). The spatial patterns remain similar at varied levels of metabolic stimulation inferring metabolic dominance. In contrast, adenosine vasodilation increased flows eightfold times control while destroying correlation with the control state. The Ado-induced spatial patterns differed from control but were self-consistent, inferring that with full vasodilation the relaxed arterial anatomy dominates the distribution. We conclude that vascular anatomy governs flow distributions during adenosine vasodilation but that metabolic vasoregulation dominates in normal physiological states. Copyright © 2016 the American Physiological Society.

High Salt Intake Increases Blood Pressure in Normal Rats: Putative Role of 20-HETE and No Evidence on Changes in Renal Vascular Reactivity

PubMed Central

Walkowska, A.; Kuczeriszka, M.; Sadowski, J.; Olszyński, K.H.; Dobrowolski, L.; Červenka, L.; Hammock, B.D.; Kompanowska-Jezierska, E.

2015-01-01

Background/Aims High salt (HS) intake may elevate blood pressure (BP), also in animals without genetic salt sensitivity. The development of salt-dependent hypertension could be mediated by endogenous vasoactive agents; here we examined the role of vasodilator epoxyeicosatrienoic acids (EETs) and vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). Methods In conscious Wistar rats on HS diet systolic BP (SBP) was examined after chronic elevation of EETs using 4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB), a blocker of soluble epoxide hydrolase, or after inhibition of 20-HETE with 1-aminobenzotriazole (ABT). Thereafter, in acute experiments the responses of renal artery blood flow (Transonic probe) and renal regional perfusion (laser-Doppler) to intrarenal acetylcholine (ACh) or norepinephrine were determined. Results HS diet increased urinary 20-HETE excretion. The SBP increase was not reduced by c-AUCB but prevented by ABT until day 5 of HS exposure. Renal vasomotor responses to ACh or norepinephrine were similar on standard and HS diet. ABT but not c-AUCB abolished the responses to ACh. Conclusions 20-HETE seems to mediate the early-phase HS diet-induced BP increase while EETs are not engaged in the process. Since HS exposure did not alter renal vasodilator responses to Ach, endothelial dysfunction is not a critical factor in the mechanism of salt-induced blood pressure elevation. PMID:26067851

Ketorolac alters blood flow during normothermia but not during hyperthermia in middle-aged human skin

PubMed Central

Jennings, John D.; Lang, James A.; Kenney, W. Larry

2009-01-01

In young healthy humans full expression of reflex cutaneous vasodilation is dependent on cyclooxygenase (COX)- and nitric oxide synthase (NOS)-dependent mechanisms. Chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilation potentially through both platelet and vascular COX-dependent mechanisms. We hypothesized the contribution of COX-dependent vasodilators to reflex cutaneous vasodilation during localized acute COX inhibition would be attenuated in healthy middle-aged humans due to a shift toward COX-dependent vasoconstrictors. Four microdialysis fibers were placed in forearm skin of 13 middle-aged (53 ± 2 yr) normotensive healthy humans, serving as control (Ringer), COX-inhibited (10 mM ketorolac), NOS-inhibited (10 mM NG-nitro-l-arginine methyl ester), and combined NOS- and COX-inhibited sites. Red blood cell flux was measured over each site by laser-Doppler flowmetry as reflex vasodilation was induced by increasing oral temperature (Tor) 1.0°C using a water-perfused suit. Cutaneous vascular conductance was calculated (CVC = flux/mean arterial pressure) and normalized to maximal CVC (CVCmax; 28 mM sodium nitroprusside). CVCmax was not affected by localized microdialysis drug treatment (P > 0.05). Localized COX inhibition increased baseline (18 ± 3%CVCmax; P < 0.001) compared with control (9 ± 1%CVCmax), NOS-inhibited (7 ± 1%CVCmax), and combined sites (10 ± 1%CVCmax). %CVCmax in the COX-inhibited site remained greater than the control site with ΔTor ≤ 0.3°C; however, there was no difference between these sites with ΔTor ≥ 0.4°C. NOS inhibition and combined COX and NOS inhibition attenuated reflex vasodilation compared with control (P < 0.001), but there was no difference between these sites. Localized COX inhibition with ketorolac significantly augments baseline CVC but does not alter the subsequent skin blood flow response to hyperthermia, suggesting a limited role for COX-derived vasodilator prostanoids in reflex cutaneous vasodilation and a shift toward COX-derived vasoconstrictors in middle-aged human skin. PMID:19661446

Association Between the Female Athlete Triad and Endothelial Dysfunction in Dancers

PubMed Central

Hoch, Anne Z.; Papanek, Paula; Szabo, Aniko; Widlansky, Michael E.; Schimke, Jane E.; Gutterman, David D.

2013-01-01

Objective To determine the prevalence of the 3 components of the female athlete triad [disordered eating, menstrual dysfunction, low bone mineral density (BMD)] and their relationships with brachial artery flow-mediated dilation in professional dancers. Design Prospective study. Setting Academic institution in the Midwest. Participants Twenty-two professional ballet dancers volunteered for this study. Interventions The prevalence of the female athlete triad and its relationship to endothelial dysfunction. Main Outcome Measures Subjects completed questionnaires to assess disordered eating and menstrual status/history. They also completed a 3-day food record and wore an accelerometer for 3 days to determine energy availability. Serum baseline thyrotropin, prolactin, and hormonal concentrations were obtained. Bone mineral density and body composition were measured with a GE Lunar Prodigy dual-energy X-ray absorptiometry. Endothelial function was determined as flow-mediated vasodilation measured by high-frequency ultrasound in the brachial artery. An increase in brachial diameter <5% to hyperemic flow stimulus was defined a priori as endothelial dysfunction. Results Seventeen dancers (77%) had evidence of low/negative energy availability. Thirty-two percent had disordered eating (EDE-Q score). Thirty-six percent had menstrual dysfunction and 14% were currently using hormone contraception. Twenty-three percent had evidence of low bone density (Z-score < −1.0). Sixty-four percent had abnormal brachial artery flow-mediated dilation (<5%). Flow-mediated dilation values were significantly correlated with serum estrogen and whole-body and lumbar BMD. All the 3 components of the triad plus endothelial dysfunction were present in 14% of the subjects. Conclusions Endothelial dysfunction was correlated with reduced BMD, menstrual dysfunction, and low serum estrogen. These findings may have profound implications for cardiovascular and bone health in professional women dancers. PMID:21358502

Central Role of eNOS in the Maintenance of Endothelial Homeostasis

PubMed Central

Rodriguez-Mateos, Ana; Kelm, Malte

2015-01-01

Abstract Significance: Disruption of endothelial function is considered a key event in the development and progression of atherosclerosis. Endothelial nitric oxide synthase (eNOS) is a central regulator of cellular function that is important to maintain endothelial homeostasis. Recent Advances: Endothelial homeostasis encompasses acute responses such as adaption of flow to tissue's demand and more sustained responses to injury such as re-endothelialization and sprouting of endothelial cells (ECs) and attraction of circulating angiogenic cells (CAC), both of which support repair of damaged endothelium. The balance and the intensity of endothelial damage and repair might be reflected by changes in circulating endothelial microparticles (EMP) and CAC. Flow-mediated vasodilation (FMD) is a generally accepted clinical read-out of NO-dependent vasodilation, whereas EMP are upcoming prognostically validated markers of endothelial injury and CAC are reflective of the regenerative capacity with both expressing a functional eNOS. These markers can be integrated in a clinical endothelial phenotype, reflecting the net result between damage from risk factors and endogenous repair capacity with NO representing a central signaling molecule. Critical Issues: Improvements of reproducibility and observer independence of FMD measurements and definitions of relevant EMP and CAC subpopulations warrant further research. Future Directions: Endothelial homeostasis may be a clinical therapeutic target for cardiovascular health maintenance. Antioxid. Redox Signal. 22, 1230–1242. PMID:25330054

Sympathetic α₃β₂-nAChRs mediate cerebral neurogenic nitrergic vasodilation in the swine.

PubMed

Lee, Reggie Hui-Chao; Liu, Yi-Qing; Chen, Po-Yi; Liu, Chin-Hung; Chen, Mei-Fang; Lin, Hung-Wen; Kuo, Jon-Son; Premkumar, Louis S; Lee, Tony Jer-Fu

2011-08-01

The α(7)-nicotinic ACh receptor (α(7)-nAChR) on sympathetic neurons innervating basilar arteries of pigs crossed bred between Landrace and Yorkshire (LY) is known to mediate nicotine-induced, β-amyloid (Aβ)-sensitive nitrergic neurogenic vasodilation. Preliminary studies, however, demonstrated that nicotine-induced cerebral vasodilation in pigs crossbred among Landrace, Yorkshire, and Duroc (LYD) was insensitive to Aβ and α-bungarotoxin (α-BGTX). We investigated nAChR subtype on sympathetic neurons innervating LYD basilar arteries. Nicotine-induced relaxation of porcine isolated basilar arteries was examined by tissue bath myography, inward currents on nAChR-expressing oocytes by two-electrode voltage recording, and mRNA and protein expression in the superior cervical ganglion (SCG) and middle cervical ganglion (MCG) by reverse transcription PCR and Western blotting. Nicotine-induced basilar arterial relaxation was not affected by Aβ, α-BGTX, and α-conotoxin IMI (α(7)-nAChR antagonists), or α-conotoxin AuIB (α(3)β(4)-nAChR antagonist) but was inhibited by tropinone and tropane (α(3)-containing nAChR antagonists) and α-conotoxin MII (selective α(3)β(2)-nAChR antagonist). Nicotine-induced inward currents in α(3)β(2)-nAChR-expressing oocytes were inhibited by α-conotoxin MII but not by α-BGTX, Aβ, or α-conotoxin AuIB. mRNAs of α(3)-, α(7)-, β(2)-, and β(4)-subunits were expressed in both SCGs and MCGs with significantly higher mRNAs of α(3)-, β(2)-, and β(4)-subunits than that of α(7)-subunit. The Aβ-insensitive sympathetic α(3)β(2)-nAChR mediates nicotine-induced cerebral nitrergic neurogenic vasodilation in LYD pigs. The different finding from Aβ-sensitive α(7)-nAChR in basilar arteries of LY pigs may offer a partial explanation for different sensitivities of individuals to Aβ in causing diminished cerebral nitrergic vasodilation in diseases involving Aβ.

Hyperinsulinemia fails to augment ET-1 action in the skeletal muscle vascular bed in vivo in humans

PubMed Central

Lteif, Amale A.; Fulford, Angie D.; Considine, Robert V.; Gelfand, Inessa; Baron, Alain D.; Mather, Kieren J.

2008-01-01

Endogenous endothelin action is augmented in human obesity and type 2 diabetes and contributes to endothelial dysfunction and impairs insulin-mediated vasodilation in humans. We hypothesized that insulin resistance-associated hyperinsulinemia could preferentially drive endothelin-mediated vasoconstriction. We applied hyperinsulinemic-euglycemic clamps with higher insulin dosing in obese subjects than lean subjects (30 vs. 10 mU·m−2·min−1, respectively), with the goal of matching insulin's nitric oxide (NO)-mediated vascular effects. We predicted that, under these circumstances, insulin-stimulated endothelin-1 (ET-1) action (assessed with the type A endothelin receptor antagonist BQ-123) would be augmented in proportion to hyperinsulinemia. NO bioactivity was assessed using the nitric oxide synthase inhibitor NG-monomethyl-l-arginine. Insulin-mediated vasodilation and insulin-stimulated NO bioavailability were well matched across groups by this approach. As expected, steady-state insulin levels were approximately threefold higher in obese than lean subjects (109.2 ± 10.2 pmol/l vs. 518.4 ± 84.0, P = 0.03). Despite this, the augmentation of insulin-mediated vasodilation by BQ-123 was not different between groups. ET-1 flux across the leg was not augmented by insulin alone but was increased with the addition of BQ-123 to insulin (P = 0.01 BQ-123 effect, P = not significant comparing groups). Endothelin antagonism augmented insulin-stimulated NO bioavailability and NOx flux, but not differently between groups and not proportional to hyperinsulinemia. These findings do not support the hypothesis that insulin resistance-associated hyperinsulinemia preferentially drives endothelin-mediated vasoconstriction. PMID:18957616

Sildenafil Citrate in Fetal Growth Restriction

PubMed Central

Panda, Subrat; Das, Ananya; Md Nowroz, Hossain

2014-01-01

Background Pregnancies with early onset fetal growth restriction have poor perinatal outcome. Sildenafil citrate (PDE -5 inhibitor) as a vasodilator increases utero-placental blood flow and potentiates fetal growth. Case Presentation In this study, a case was examined and Sildenafil was administered for her. It was found that Sildenafil improved the uterine blood flow with a favorable fetal outcome at delivery. Conclusion Sildenafil, as a vasodilator has emerged as a potential management option in the treatment of Intra Uterine Growth Retardation (IUGR) and preeclampsia by later normalization in velocimetric profile. PMID:25202677

Novel approaches to the treatment of cocaine addiction.

PubMed

Sofuoglu, Mehmet; Kosten, Thomas R

2005-01-01

Cocaine addiction continues to be an important public health problem with over 1.7 million users in the US alone. Although there are no approved pharmacotherapies for cocaine addiction, a number of medications have been tested with some promising results. In this review, we summarise some of the emerging targets for cocaine pharmacotherapy including dopaminergic and GABA medications, adrenoceptor antagonists, vasodilators and immunotherapies. The brain dopamine system plays a significant role in mediating the rewarding effects of cocaine. Among dopaminergic agents tested for cocaine pharmacotherapy, disulfiram has decreased cocaine use in a number of studies. Amantadine, another medication with dopaminergic effects, may also be effective in cocaine users with high withdrawal severity. GABA is the main inhibitory neurotransmitter in the brain, and accumulating evidence suggests that the GABA system modulates the dopaminergic system and cocaine effects. Two anticonvulsant medications with GABAergic effects, tiagabine and topiramate, have yielded positive findings in clinical trials. Baclofen, a GABA(B) receptor agonist, is also promising, especially in those with more severe cocaine use. Some of the physiological and behavioural effects of cocaine are mediated by activation of the adrenergic system. In cocaine users, propranolol, a beta-adrenoceptor antagonist, had promising effects in individuals with more severe cocaine withdrawal symptoms. Cerebral vasodilators are another potential target for cocaine pharmacotherapy. Cocaine users have reduced cerebral blood flow and cortical perfusion deficits. Treatment with the vasodilators amiloride or isradipine has reduced perfusion abnormalities found in cocaine users. The functional significance of these improvements needs to be further investigated. All these proposed pharmacotherapies for cocaine addiction act on neural pathways. In contrast, immunotherapies for cocaine addiction are based on the blockade of cocaine effects peripherally, and as a result, prevent or at least slow the entry of cocaine into the brain. A cocaine vaccine is another promising treatment for cocaine addiction. The efficacy of this vaccine for relapse prevention is under investigation. Many initial promising findings need to be replicated in larger, controlled clinical trials.

Continuously measured renal blood flow does not increase in diabetes if nitric oxide synthesis is blocked.

PubMed

Bell, Tracy D; DiBona, Gerald F; Biemiller, Rachel; Brands, Michael W

2008-11-01

This study used 16 h/day measurement of renal blood flow (RBF) and arterial pressure (AP) to determine the role of nitric oxide (NO) in mediating the renal vasodilation caused by onset of type 1 diabetes. The AP and RBF power spectra were used to determine the autoregulatory efficiency of the renal vasculature. Rats were instrumented with artery and vein catheters and a Transonic flow probe on the left renal artery and were divided randomly into four groups: control (C), diabetes (D), control plus nitro-L-arginine methyl ester (L-NAME; CL), and diabetes plus L-NAME (DL). Mean AP averaged 90 +/- 1 and 121 +/- 1 mmHg in the D and DL groups, respectively, during the control period, and RBF averaged 5.9 +/- 1.2 and 5.7 +/- 0.7 ml/min, respectively. Respective C and CL groups were not different. Onset of diabetes (streptozotocin 40 mg/kg iv) in D rats increased RBF gradually, but it averaged 55% above control by day 14. In DL rats, on the other hand, RBF remained essentially constant, tracking with RBF in the nondiabetic C and CL groups for the 2-wk period. Diabetes did not change mean AP in any group. Transfer function analysis revealed impaired dynamic autoregulation of RBF overall, including the frequency range of tubuloglomerular feedback (TGF), and L-NAME completely prevented those changes as well. These data strongly support a role for NO in causing renal vasodilation in diabetes and suggest that an effect of NO to blunt RBF autoregulation may play an important role.

Continuously measured renal blood flow does not increase in diabetes if nitric oxide synthesis is blocked

PubMed Central

Bell, Tracy D.; DiBona, Gerald F.; Biemiller, Rachel; Brands, Michael W.

2008-01-01

This study used 16 h/day measurement of renal blood flow (RBF) and arterial pressure (AP) to determine the role of nitric oxide (NO) in mediating the renal vasodilation caused by onset of type 1 diabetes. The AP and RBF power spectra were used to determine the autoregulatory efficiency of the renal vasculature. Rats were instrumented with artery and vein catheters and a Transonic flow probe on the left renal artery and were divided randomly into four groups: control (C), diabetes (D), control plus nitro-l-arginine methyl ester (l-NAME; CL), and diabetes plus l-NAME (DL). Mean AP averaged 90 ± 1 and 121 ± 1 mmHg in the D and DL groups, respectively, during the control period, and RBF averaged 5.9 ± 1.2 and 5.7 ± 0.7 ml/min, respectively. Respective C and CL groups were not different. Onset of diabetes (streptozotocin 40 mg/kg iv) in D rats increased RBF gradually, but it averaged 55% above control by day 14. In DL rats, on the other hand, RBF remained essentially constant, tracking with RBF in the nondiabetic C and CL groups for the 2-wk period. Diabetes did not change mean AP in any group. Transfer function analysis revealed impaired dynamic autoregulation of RBF overall, including the frequency range of tubuloglomerular feedback (TGF), and l-NAME completely prevented those changes as well. These data strongly support a role for NO in causing renal vasodilation in diabetes and suggest that an effect of NO to blunt RBF autoregulation may play an important role. PMID:18753304

Lipid Emulsion Inhibits Vasodilation Induced by a Toxic Dose of Bupivacaine via Attenuated Dephosphorylation of Myosin Phosphatase Target Subunit 1 in Isolated Rat Aorta

PubMed Central

Ok, Seong-Ho; Byon, Hyo-Jin; Kwon, Seong-Chun; Park, Jungchul; Lee, Youngju; Hwang, Yeran; Baik, Jiseok; Choi, Mun-Jeoung; Sohn, Ju-Tae

2015-01-01

Lipid emulsions are widely used for the treatment of systemic toxicity that arises from local anesthetics. The goal of this in vitro study was to examine the cellular mechanism associated with the lipid emulsion-mediated attenuation of vasodilation induced by a toxic dose of bupivacaine in isolated endothelium-denuded rat aorta. The effects of lipid emulsion on vasodilation induced by bupivacaine, mepivacaine, and verapamil were assessed in isolated aorta precontracted with phenylephrine, the Rho kinase stimulant NaF, and the protein kinase C activator phorbol 12,13-dibutyrate (PDBu). The effects of Rho kinase inhibitor Y-27632 on contraction induced by phenylephrine or NaF were assessed. The effects of bupivacaine on intracellular calcium concentrations ([Ca2+]i) and tension induced by NaF were simultaneously measured. The effects of bupivacaine alone and lipid emulsion plus bupivacaine on myosin phosphatase target subunit 1 (MYPT1) phosphorylation induced by NaF were examined in rat aortic vascular smooth muscle cells. In precontracted aorta, the lipid emulsion attenuated bupivacaine-induced vasodilation but had no effect on mepivacaine-induced vasodilation. Y-27632 attenuated contraction induced by either phenylephrine or NaF. The lipid emulsion attenuated verapamil-induced vasodilation. Compared with phenylephrine-induced precontracted aorta, bupivacaine-induced vasodilation was slightly attenuated in NaF-induced precontracted aorta. The magnitude of the bupivacaine-induced vasodilation was higher than that of a bupivacaine-induced decrease in [Ca2+]i. Bupivacaine attenuated NaF-induced MYPT1 phosphorylation, whereas lipid emulsion pretreatment attenuated the bupivacaine-induced inhibition of MYPT1 phosphorylation induced by NaF. Taken together, these results suggest that lipid emulsions attenuate bupivacaine-induced vasodilation via the attenuation of inhibition of MYPT1 phosphorylation evoked by NaF. PMID:26664257

Neutral endopeptidase modulates substance P-induced vasodilation in vivo.

PubMed

Gao, X P; Rubinstein, I

1995-02-01

The purpose of this study was to investigate whether neutral endopeptidase (NEP; EC 3.4.24.11) modulates substance P-induced vasodilation in the oral mucosa in vivo. Using intravital microscopy, we measured the diameter of second-order arterioles (44-70 microns) in the hamster cheek pouch during suffusion of capsaicin and substance P. We found that capsaicin (0.1 and 10.0 nM) induced significant concentration-dependent vasodilations (13 +/- 4 and 39 +/- 7% increase from baseline, respectively; P < 0.05) that were significantly potentiated by phosphoramidon (10.0 nM), a selective NEP inhibitor (35 +/- 15 and 61 +/- 12% increase from baseline, respectively; P < 0.05). Substance P (0.1 and 10.0 nM) also induced significant concentration-dependent vasodilations (7 +/- 3 and 25 +/- 8% increase from baseline, respectively; P < 0.05) that were mediated by the COOH-terminal of the molecule. Substance P-induced responses were significantly potentiated by phosphoramidon (34 +/- 9 and 53 +/- 10% increase from baseline, respectively; P < 0.05) and thiorphan (10.0 microM), a selective NEP inhibitor (44 +/- 11 and 53 +/- 10% increase from baseline, respectively; P < 0.05). Substance P-(1-9) had no significant effects on arteriolar diameter. Suffusion of captopril, leupeptin, Bestatin, and DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid together had no significant effects on substance P-induced vasodilation. Phosphoramidon did not potentiate nitroglycerin-induced vasodilation. These data indicate that NEP modulates substance P-induced vasodilation in the hamster cheek pouch in vivo. We suggest that any decrease in tissue NEP activity may amplify neurogenic vasodilation in the oral mucosa.

Regulation of exercise blood flow: Role of free radicals.

PubMed

Trinity, Joel D; Broxterman, Ryan M; Richardson, Russell S

2016-09-01

During exercise, oxygen and nutrient rich blood must be delivered to the active skeletal muscle, heart, skin, and brain through the complex and highly regulated integration of central and peripheral hemodynamic factors. Indeed, even minor alterations in blood flow to these organs have profound consequences on exercise capacity by modifying the development of fatigue. Therefore, the fine-tuning of blood flow is critical for optimal physical performance. At the level of the peripheral circulation, blood flow is regulated by a balance between the mechanisms responsible for vasodilation and vasoconstriction. Once thought of as toxic by-products of in vivo chemistry, free radicals are now recognized as important signaling molecules that exert potent vasoactive responses that are dependent upon the underlying balance between oxidation-reduction reactions or redox balance. Under normal healthy conditions with low levels of oxidative stress, free radicals promote vasodilation, which is attenuated with exogenous antioxidant administration. Conversely, with advancing age and disease where background oxidative stress is elevated, an exercise-induced increase in free radicals can further shift the redox balance to a pro-oxidant state, impairing vasodilation and attenuating blood flow. Under these conditions, exogenous antioxidants improve vasodilatory capacity and augment blood flow by restoring an "optimal" redox balance. Interestingly, while the active skeletal muscle, heart, skin, and brain all have unique functions during exercise, the mechanisms by which free radicals contribute to the regulation of blood flow is remarkably preserved across each of these varied target organs. Published by Elsevier Inc.

Regulation of Exercise Blood Flow: Role of Free Radicals

PubMed Central

Trinity, Joel D.; Broxterman, Ryan M.; Richardson, Russell S.

2016-01-01

During exercise, oxygen and nutrient rich blood must be delivered to the active skeletal muscle, heart, skin, and brain through the complex and highly regulated integration of central and peripheral hemodynamic factors. Indeed, even minor alterations in blood flow to these organs have profound consequences on exercise capacity by modifying the development of fatigue. Therefore, the fine-tuning of blood flow is critical for optimal physical performance. At the level of the peripheral circulation, blood flow is regulated by a balance between the mechanisms responsible for vasodilation and vasoconstriction. Once thought of as toxic by-products of in vivo chemistry, free radicals are now recognized as important signaling molecules that exert potent vasoactive responses that are dependent upon the underlying balance between oxidation-reduction reactions or redox balance. Under normal healthy conditions with low levels of oxidative stress, free radicals promote vasodilation, which is attenuated with exogenous antioxidant administration. Conversely, with advancing age and disease where background oxidative stress is elevated, an exercise-induced increase in free radicals can further shift the redox balance to a pro-oxidant state, impairing vasodilation and attenuating blood flow. Under these conditions, exogenous antioxidants improve vasodilatory capacity and augment blood flow by restoring an “optimal” redox balance. Interestingly, while the active skeletal muscle, heart, skin, and brain all have unique functions during exercise, the mechanisms by which free radicals contribute to the regulation of blood flow is remarkably preserved across each of these varied target organs. PMID:26876648

Observation of vasculature alternation by intense pulsed light combined with physicochemical methods.

PubMed

Son, Taeyoon; Kang, Heesung; Jung, Byungjo

2016-05-01

Intense pulsed light (IPL) with low energy insufficient to completely destroy a vasculature was applied to rabbit ears to investigate vasculature alteration. Glycerol was combined with IPL to enhance the transfer efficacy of IPL energy. Both trans-illumination and laser speckle contrast images were obtained and analyzed after treatment. The application of IPL and glycerol combination induced vasodilation and improvement in blood flow. Moreover, such phenomenon was maintained over time. IPL may be applied to treat blood circulatory diseases by inducing vasodilation and to improve blood flow. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of sympathetic stimulation on cerebral and ocular blood flow. Modification by hypertension, hypercapnia, acetazolamide, PGI2 and papaverine.

PubMed

Beausang-Linder, M

1982-02-01

The effect of unilateral, electrical stimulation of the cervical sympathetic chain in rabbits anesthetized with pentobarbital sodium and vasodilated by hypercapnia, acetazolamide, papaverine or PGI2 was investigated to determine to what extent the sympathetic nerves to the brain and the eye cause vasoconstriction and prevent overperfusion in previously vasodilated animals. Evans blue was given as a tracer for protein leakage. Blood flow determinations were made with the labelled microsphere method during normotension and acute arterial hypertension. Hypertension was induced by ligation of the thoracic aorta and in some animals metaraminol or angiotensin was also used. Acetazolamide caused a two to threefold increase in cerebral blood flow (CBF) and hypercapnia resulted in a fivefold increase. CBF was not markedly affected by papaverine or PGI2. In the choroid plexus, the ciliary body and choroid, papaverine and hypercapnia caused significant blood flow increases on the control side. Sympathetic stimulation induced a 12% blood flow reduction in the brain in normotensive, hypercapnic animals. Marked effects of sympathetic stimulation at normotension were obtained under all conditions in the eye. In the hypertensive state the CBF reduction during sympathetic stimulation was moderate, but highly significant in hypercapnic or papaverine-treated animals as well as in controls. Leakage of Evans blue was more frequently seen on the nonstimulated side of the brain. In the eye there was leakage only on the control side except in PGI2-treated animals where 2 rabbits had bilateral leakage. The effect of sympathetic stimulation on the blood flow in the cerebrum and cerebellum in vasodilated animals seems to be small or absent if the blood pressure is normal. In the eye pronounced vasoconstriction occurs under these conditions. In acute arterial hypertension sympathetic stimulation protects both the cerebral and ocular barriers even under conditions of marked vasodilation.

Exercise ameliorates endoplasmic reticulum stress-mediated vascular dysfunction in mesenteric arteries in atherosclerosis.

PubMed

Hong, Junyoung; Kim, Kwangchan; Park, Eunkyung; Lee, Jonghae; Markofski, Melissa M; Marrelli, Sean P; Park, Yoonjung

2018-05-21

Endoplasmic reticulum (ER) stress is closely associated with atherosclerosis, but the effects of exercise on ER stress-mediated endothelial dysfunction in atherosclerosis is not yet fully understood. We assessed endothelium-dependent vasodilation in isolated mesenteric arteries from wild type (WT), WT with exercise (WT-EX), ApoE knockout (ApoE KO), and ApoE KO mice with exercise (ApoE KO-EX). Vasodilation to acetylcholine (ACh) was elicited in the presence of inhibitors of ER stress, eNOS, caspase-1, and UCP-2 (Tudca, L-NAME, AC-YVARD-cmk, and Genipin, respectively) and the ER stress inducer (Tunicamycin). Immunofluorescence was used to visualize the expression of CHOP, as an indicator of ER stress, in superior mesenteric arteries (SMA). Dilation to ACh was attenuated in ApoE KO but was improved in ApoE KO-EX. Incubation of Tudca and AC-YVARD-cmk improved ACh-induced vasodilation in ApoE KO. L-NAME, tunicamycin, and Genipin attenuated vasodilation in WT, WT-EX and ApoE KO-EX, but not in ApoE KO. Exercise training reversed the increase in CHOP expression in the endothelium of SMA of ApoE KO mice. We conclude that ER stress plays a significant role in endothelial dysfunction of resistance arteries in atherosclerosis and that exercise attenuates ER stress and regulates its critical downstream signaling pathways including eNOS, UCP-2 and caspase-1.

Dietary nitrate restores compensatory vasodilation and exercise capacity in response to a compromise in oxygen delivery in the noncompensator phenotype.

PubMed

Bentley, Robert F; Walsh, Jeremy J; Drouin, Patrick J; Velickovic, Aleksandra; Kitner, Sarah J; Fenuta, Alyssa M; Tschakovsky, Michael E

2017-09-01

Recently, dietary nitrate supplementation has been shown to improve exercise capacity in healthy individuals through a potential nitrate-nitrite-nitric oxide pathway. Nitric oxide has been shown to play an important role in compensatory vasodilation during exercise under hypoperfusion. Previously, we established that certain individuals lack a vasodilation response when perfusion pressure reductions compromise exercising muscle blood flow. Whether this lack of compensatory vasodilation in healthy, young individuals can be restored with dietary nitrate supplementation is unknown. Six healthy (21 ± 2 yr), recreationally active men completed a rhythmic forearm exercise. During steady-state exercise, the exercising arm was rapidly transitioned from an uncompromised (below heart) to a compromised (above heart) position, resulting in a reduction in local pressure of -31 ± 1 mmHg. Exercise was completed following 5 days of nitrate-rich (70 ml, 0.4 g nitrate) and nitrate-depleted (70 ml, ~0 g nitrate) beetroot juice consumption. Forearm blood flow (in milliliters per minute; brachial artery Doppler and echo ultrasound), mean arterial blood pressure (in millimeters of mercury; finger photoplethysmography), exercising forearm venous effluent (ante-cubital vein catheter), and plasma nitrite concentrations (chemiluminescence) revealed two distinct vasodilatory responses: nitrate supplementation increased (plasma nitrite) compared with placebo (245 ± 60 vs. 39 ± 9 nmol/l; P < 0.001), and compensatory vasodilation was present following nitrate supplementation (568 ± 117 vs. 714 ± 139 ml ⋅ min -1 ⋅ 100 mmHg -1 ; P = 0.005) but not in placebo (687 ± 166 vs. 697 ± 171 min -1 ⋅ 100 mmHg -1 ; P = 0.42). As such, peak exercise capacity was reduced to a lesser degree (-4 ± 39 vs. -39 ± 27 N; P = 0.01). In conclusion, dietary nitrate supplementation during a perfusion pressure challenge is an effective means of restoring exercise capacity and enabling compensatory vasodilation. NEW & NOTEWORTHY Previously, we identified young, healthy persons who suffer compromised exercise tolerance when exercising muscle perfusion pressure is reduced as a result of a lack of compensatory vasodilation. The ability of nitrate supplementation to restore compensatory vasodilation in such noncompensators is unknown. We demonstrated that beetroot juice supplementation led to compensatory vasodilation and restored perfusion and exercise capacity. Elevated plasma nitrite is an effective intervention for correcting the absence of compensatory vasodilation in the noncompensator phenotype. Copyright © 2017 the American Physiological Society.

Role of CYP1A1 in modulating the vascular and blood pressure benefits of omega-3 polyunsaturated fatty acids.

PubMed

Agbor, Larry N; Wiest, Elani F; Rothe, Michael; Schunck, Wolf-Hagen; Walker, Mary K

2014-12-01

The mechanisms that mediate the cardiovascular protective effects of omega 3 (n-3) polyunsaturated fatty acids (PUFAs) have not been fully elucidated. Cytochrome P450 1A1 efficiently metabolizes n-3 PUFAs to potent vasodilators. Thus, we hypothesized that dietary n-3 PUFAs increase nitric oxide (NO)-dependent blood pressure regulation and vasodilation in a CYP1A1-dependent manner. CYP1A1 wild-type (WT) and knockout (KO) mice were fed an n-3 or n-6 PUFA-enriched diet for 8 weeks and were analyzed for tissue fatty acids and metabolites, NO-dependent blood pressure regulation, NO-dependent vasodilation of acetylcholine (ACh) in mesenteric resistance arterioles, and endothelial NO synthase (eNOS) and phospho-Ser1177-eNOS expression in the aorta. All mice fed the n-3 PUFA diet showed significantly higher levels of n-3 PUFAs and their metabolites, and significantly lower levels of n-6 PUFAs and their metabolites. In addition, KO mice on the n-3 PUFA diet accumulated significantly higher levels of n-3 PUFAs in the aorta and kidney without a parallel increase in the levels of their metabolites. Moreover, KO mice exhibited significantly less NO-dependent regulation of blood pressure on the n-3 PUFA diet and significantly less NO-dependent, ACh-mediated vasodilation in mesenteric arterioles on both diets. Finally, the n-3 PUFA diet significantly increased aortic phospho-Ser1177-eNOS/eNOS ratio in the WT compared with KO mice. These data demonstrate that CYP1A1 contributes to eNOS activation, NO bioavailability, and NO-dependent blood pressure regulation mediated by dietary n-3 PUFAs. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Exercise-induced brachial artery vasodilation: effects of antioxidants and exercise training in elderly men

PubMed Central

Donato, Anthony J.; Uberoi, Abhimanyu; Bailey, Damian M.; Walter Wray, D.

2010-01-01

Aging, vascular function, and exercise are thought to have a common link in oxidative stress. Of the 28 subjects studied (young, 26 ± 2 yr; old, 71 ± 6 yr), 12 took part in a study to validate an antioxidant cocktail (AOC: vitamins C, E, and α-lipoic acid), while the remaining 8 young and 8 old subjects performed submaximal forearm handgrip exercise with placebo or AOC. Old subjects repeated forearm exercise with placebo or AOC following knee-extensor (KE) exercise training. Brachial arterial diameter and blood velocity (Doppler ultrasound) were measured at rest and during exercise. During handgrip exercise, brachial artery vasodilation in the old subjects was attenuated compared with that in young subjects following placebo (maximum = ∼3.0 and ∼6.0%, respectively). In contrast to the previously documented attenuation in exercise-induced brachial artery vasodilation in the young group with AOC, in the old subjects the AOC restored vasodilation (maximum = ∼7.0%) to match the young. KE training also improved exercise-induced brachial artery vasodilation. However, in the trained state, AOC administration no longer augmented brachial artery vasodilation in the elderly, but rather attenuated it. These data reveal an age-related pro-/antioxidant imbalance that impacts vascular function and show that exercise training is capable of restoring equilibrium such that vascular function is improved and the AOC-mediated reduction in free radicals now negatively impacts brachial artery vasodilation, as seen in the young. PMID:19966056

Colforsin-induced vasodilation in chronic hypoxic pulmonary hypertension in rats.

PubMed

Yokochi, Ayumu; Itoh, Hiroo; Maruyama, Junko; Zhang, Erquan; Jiang, Baohua; Mitani, Yoshihide; Hamada, Chikuma; Maruyama, Kazuo

2010-06-01

Colforsin, a water-soluble forskolin derivative, directly activates adenylate cyclase and thereby increases the 3',5'-cyclic adenosine monophosphate (cAMP) level in vascular smooth muscle cells. In this study, we investigated the vasodilatory action of colforsin on structurally remodeled pulmonary arteries from rats with pulmonary hypertension (PH). A total of 32 rats were subjected to hypobaric hypoxia (380 mmHg, 10% oxygen) for 10 days to induce chronic hypoxic PH, while 39 rats were kept in room air. Changes in isometric force were recorded in endothelium-intact (+E) and -denuded (-E) pulmonary arteries from the PH and control (non-PH) rats. Colforsin-induced vasodilation was impaired in both +E and -E arteries from PH rats compared with their respective controls. Endothelial removal did not influence colforsin-induced vasodilation in the arteries from control rats, but attenuated it in arteries from PH rats. The inhibition of nitric oxide (NO) synthase did not influence colforsin-induced vasodilation in +E arteries from controls, but attenuated it in +E arteries from PH rats, shifting its concentration-response curve closer to that of -E arteries from PH rats. Vasodilation induced by 8-bromo-cAMP (a cell-permeable cAMP analog) was also impaired in -E arteries from PH rats, but not in +E arteries from PH rats, compared with their respective controls. cAMP-mediated vasodilatory responses without beta-adrenergic receptor activation are impaired in structurally remodeled pulmonary arteries from PH rats. In these arteries, endothelial cells presumably play a compensatory role against the impaired cAMP-mediated vasodilatory response by releasing NO (and thereby attenuating the impairment). The results suggest that colforsin could be effective in the treatment of PH.

Pregnancy Augments G Protein Estrogen Receptor (GPER) Induced Vasodilation in Rat Uterine Arteries via the Nitric Oxide - cGMP Signaling Pathway.

PubMed

Tropea, Teresa; De Francesco, Ernestina Marianna; Rigiracciolo, Damiano; Maggiolini, Marcello; Wareing, Mark; Osol, George; Mandalà, Maurizio

2015-01-01

The regulation of vascular tone in the uterine circulation is a key determinant of appropriate uteroplacental blood perfusion and successful pregnancy outcome. Estrogens, which increase in the maternal circulation throughout pregnancy, can exert acute vasodilatory actions. Recently a third estrogen receptor named GPER (G protein-coupled estrogen receptor) was identified and, although several studies have shown vasodilatory effects in several vascular beds, nothing is known about its role in the uterine vasculature. The aim of this study was to determine the function of GPER in uterine arteries mainly during pregnancy. Uterine arteries were isolated from nonpregnant and pregnant rats. Vessels were contracted with phenylephrine and then incubated with incremental doses (10-12-10-5 M) of the selective GPER agonist G1. G1 induced a dose-dependent vasodilation which was: 1) significantly increased in pregnancy, 2) endothelium-dependent, 3) primarily mediated by NO/cGMP pathway and 4) unaffected by BKca channel inhibition. This is the first study to show the potential importance of GPER signaling in reducing uterine vascular tone during pregnancy. GPER may therefore play a previously unrecognized role in the regulation of uteroplacental blood flow and normal fetus growth.

Vasodilatory responsiveness to adenosine triphosphate in ageing humans.

PubMed

Kirby, Brett S; Crecelius, Anne R; Voyles, Wyatt F; Dinenno, Frank A

2010-10-15

Endothelium-dependent vasodilatation is reduced with advancing age in humans, as evidenced by blunted vasodilator responsiveness to acetylcholine (ACh). Circulating adenosine triphosphate (ATP) has been implicated in the control of skeletal muscle vascular tone during mismatches in oxygen delivery and demand (e.g. exercise) via binding to purinergic receptors (P2Y) on the endothelium evoking subsequent vasodilatation, and ageing is typically associated with reductions in muscle blood flow under such conditions. Therefore, we tested the hypothesis that ATP-mediated vasodilatation is impaired with age in healthy humans. We measured forearm blood flow (venous occlusion plethysmography) and calculated vascular conductance (FVC) responses to local intra-arterial infusions of ACh, ATP, and sodium nitroprusside (SNP) before and during ascorbic acid (AA) infusion in 13 young and 13 older adults. The peak increase in FVC to ACh was significantly impaired in older compared with young adults (262 ± 71% vs. 618 ± 97%; P < 0.05), and this difference was abolished during AA infusion (510 ± 82% vs. 556 ± 71%; not significant, NS). In contrast, peak FVC responses were not different between older and young adults to either ATP (675 ± 105% vs. 734 ± 126%) or SNP (1116 ± 111% vs. 1138 ± 148%) and AA infusion did not alter these responses in either age group (both NS). In another group of six young and six older adults, we determined whether vasodilator responses to adenosine and ATP were influenced by P1-receptor blockade via aminophylline. The peak FVC responses to adenosine were not different in young (350 ± 65%) versus older adults (360 ± 80%), and aminophylline blunted these responses by ∼50% in both groups. The peak FVC responses to ATP were again not different in young and older adults, and aminophylline did not impact the vasodilatation in either group. Thus, in contrast to the observed impairments in ACh responses, the vasodilatory response to exogenous ATP is not reduced with age in healthy humans. Further, our data also indicate that adenosine mediated vasodilatation is not reduced with age, and that ATP-mediated vasodilatation is independent of P1-receptor stimulation in both young and older adults.

Metoprolol impairs resistance artery function in mice

PubMed Central

El Beheiry, Mostafa H.; Heximer, Scott P.; Voigtlaender-Bolz, Julia; Mazer, C. David; Connelly, Kim A.; Wilson, David F.; Beattie, W. Scott; Tsui, Albert K. Y.; Zhang, Hangjun; Golam, Kabir; Hu, Tina; Liu, Elaine; Lidington, Darcy; Bolz, Steffen-Sebastian

2011-01-01

Acute β-blockade with metoprolol has been associated with increased mortality by undefined mechanisms. Since metoprolol is a relatively high affinity blocker of β2-adrenoreceptors, we hypothesized that some of the increased mortality associated with its use may be due to its abrogation of β2-adrenoreceptor-mediated vasodilation of microvessels in different vascular beds. Cardiac output (CO; pressure volume loops), mean arterial pressure (MAP), relative cerebral blood flow (rCBF; laser Doppler), and microvascular brain tissue Po2 (G2 oxyphor) were measured in anesthetized mice before and after acute treatment with metoprolol (3 mg/kg iv). The vasodilatory dose responses to β-adrenergic agonists (isoproterenol and clenbuterol), and the myogenic response, were assessed in isolated mesenteric resistance arteries (MRAs; ∼200-μm diameter) and posterior cerebral arteries (PCAs ∼150-μm diameter). Data are presented as means ± SE with statistical significance applied at P < 0.05. Metoprolol treatment did not effect MAP but reduced heart rate and stroke volume, CO, rCBF, and brain microvascular Po2, while concurrently increasing systemic vascular resistance (P < 0.05 for all). In isolated MRAs, metoprolol did not affect basal artery tone or the myogenic response, but it did cause a dose-dependent impairment of isoproterenol- and clenbuterol-induced vasodilation. In isolated PCAs, metoprolol (50 μM) impaired maximal vasodilation in response to isoproterenol. These data support the hypothesis that acute administration of metoprolol can reduce tissue oxygen delivery by impairing the vasodilatory response to β2-adrenergic agonists. This mechanism may contribute to the observed increase in mortality associated with acute administration of metoprolol in perioperative patients. PMID:21799135

Lactate dilates cochlear capillaries via type V fibrocyte-vessel coupling signaled by nNOS.

PubMed

Dai, Min; Yang, Yue; Shi, Xiaorui

2011-10-01

Transduction of sound in the inner ear demands tight control over delivery of oxygen and glucose. However, the mechanisms underlying the control of regional blood flow are not yet fully understood. In this study, we report a novel local control mechanism that regulates cochlear blood flow to the stria vascularis, a high energy-consuming region of the inner ear. We found that extracellular lactate had a vasodilatory effect on the capillaries of the spiral ligament under both in vitro and in vivo conditions. The lactate, acting through monocarboxylate transporter 1 (MCT1), initiated neuronal nitric oxide (NO) synthase (nNOS) and catalyzed production of NO for the vasodilation. Blocking MCT1 with the MCT blocker, α-cyano-4-hydroxycinnamate (CHC), or a suppressing NO production with either the nonspecific inhibitor of NO synthase, N(G)-nitro-L-arginine methyl ester (L-NAME), or either of two selective nNOS inhibitors, 3-bromo-7-nitroindazole or (4S)-N-(4-amino-5[aminoethyl]aminopentyl)-N'-nitroguanidine (TFA), totally abolished the lactate-induced vasodilation. Pretreatment with the selective endothelial NO synthase inhibitor, L-N(5)-(1-iminoethyl)ornithine (L-NIO), eliminated the inhibition of lactate-induced vessel dilation. With immunohistochemical labeling, we found the expression of MCT1 and nNOS in capillary-coupled type V fibrocytes. The data suggest that type V fibrocytes are the source of the lactate-induced NO. Cochlear microvessel tone, regulated by lactate, is mediated by an NO-signaled coupling of fibrocytes and capillaries.

Microcirculatory responses of sacral tissue in healthy individuals and inpatients on different pressure-redistribution mattresses.

PubMed

Bergstrand, S; Källman, U; Ek, A-C; Engström, M; Lindgren, M

2015-08-01

The aim of this study was to explore the interaction between interface pressure, pressure-induced vasodilation, and reactive hyperaemia with different pressure-redistribution mattresses. A cross-sectional study was performed with a convenience sample of healthy young individuals, and healthy older individuals and inpatients, at a university hospital in Sweden. Blood flow was measured at depths of 1mm, 2mm, and 10mm using laser Doppler flowmetry and photoplethysmography. The blood flow, interface pressure and skin temperature were measured in the sacral tissue before, during, and after load while lying on one standard hospital mattress and three different pressure-redistribution mattresses. There were significant differences between the average sacral pressure, peak sacral pressure, and local probe pressure on the three pressure-redistribution mattresses, the lowest values found were with the visco-elastic foam/air mattress (23.5 ± 2.5mmHg, 49.3 ± 11.1mmHg, 29.2 ± 14.0mmHg, respectively). Blood flow, measured as pressure-induced vasodilation, was most affected in the visco-elastic foam/air group compared to the alternating pressure mattress group at tissue depths of 2mm (39.0% and 20.0%, respectively), and 10mm (56.9 % and 35.1%, respectively). Subjects in all three groups, including healthy 18-65 year olds, were identified with no pressure-induced vasodilation or reactive hyperaemia on any mattress (n=11), which is considered a high-risk blood flow response. Interface pressure magnitudes considered not harmful during pressure-exposure on different pressure-redistribution mattresses can affect the microcirculation in different tissue structures. Despite having the lowest pressure values compared with the other mattresses, the visco-elastic foam/air mattress had the highest proportion of subjects with decreased blood flow. Healthy young individuals were identified with the high-risk blood flow response, suggesting an innate vulnerability to pressure exposure. Furthermore, the evaluation of pressure-redistribution support surfaces in terms of mean blood flow during and after tissue exposure is not feasible, but assessment of pressure-induced vasodilation and reactive hyperaemia could be a new way to assess individualised physiological measurements of mechanisms known to be related to pressure ulcer development.

Cardiovascular and adenylate cyclase stimulating effects of colforsin daropate, a water-soluble forskolin derivative, compared with those of isoproterenol, dopamine and dobutamine.

PubMed

Yoneyama, Masahiko; Sugiyama, Atsushi; Satoh, Yoshioki; Takahara, Akira; Nakamura, Yuji; Hashimoto, Keitaro

2002-12-01

Colforsin daropate is a recently developed water-soluble derivative of forskolin that directly stimulates adenylate cyclase, unlike the catecholamines. The chronotropic, inotropic and coronary vasodilator actions of colforsin daropate were compared with those of isoproterenol, dopamine and dobutamine, using canine isolated, blood-perfused heart preparations. The stimulating effect of each drug on adenylate cyclase activity was also assessed. Colforsin daropate, as well as each of the catecholamines, exerted positive chronotropic, inotropic and coronary vasodilator actions. The order of selectivity for the cardiovascular variables of colforsin daropate was coronary vasodilation > positive inotropy > positive chronotropy; whereas that of isoproterenol, dopamine and dobutamine was positive inotropy > coronary vasodilation > positive chronotropy. Thus, a marked characteristic of colforsin daropate is its potent coronary vasodilator action. On the other hand, each drug significantly increased the adenylate cyclase activity in a dose-related manner: colforsin daropate > isoproterenol > dopamine = dobutamine. These results suggest that colforsin daropate may be preferable in the treatment of severe heart failure where the coronary blood flow is reduced and beta-adrenoceptor-dependent signal transduction pathway is down-regulated.

Endogenous calcitonin gene-related peptide (CGRP) mediates adrenergic-dependent vasodilation induced by nicotine in mesenteric resistance arteries of the rat

PubMed Central

Shiraki, Hinako; Kawasaki, Hiromu; Tezuka, Satoko; Nakatsuma, Akira; Kurosaki, Yuji

2000-01-01

The mechanisms underlying vasodilator effect of nicotine on mesenteric resistance blood vessels and the role of calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves were studied in the rat. Mesenteric vascular beds isolated from Wistar rats were perfused with Krebs solution, and perfusion pressure was measured with a pressure transducer. In preparations with intact endothelium and contracted by perfusion with Krebs solution containing methoxamine, perfusion of nicotine (1–100 μM) for 1 min caused a concentration-dependent vasodilator response without vasoconstriction. The nicotine-induced vasodilation was markedly inhibited by hexamethonium (nicotinic cholinoceptor antagonist, 10 μM) and blocked by guanethidine (adrenergic neuron blocker, 5 μM). Either denervation by cold storage (4°C for 72 h) or adrenergic denervation by 6-hydroxydopamine (toxin for adrenergic neurons, 2 mM for 20 min incubation, twice) blocked the nicotine-induced vasodilation. Neither endothelium removal with perfusion of sodium deoxycholate (1.80 mg ml−1, for 30 s) nor treatment with Nω-nitro-L-arginine (nitric oxide synthase inhibitor, 100 μM), atropine (muscarinic cholinoceptor antagonist, 10 nM) or propranolol (β-adrenoceptor antagonist, 100 nM) affected the nicotine-induced vasodilation. In preparations without endothelium, treatment with capsaicin (depleting CGRP-containing sensory nerves, 1 μM) or human CGRP[8–37] (CGRP receptor antagonist, 0.5 μM) markedly inhibited the nicotine-induced vasodilation. These results suggest that, in the mesenteric resistance artery of the rat, nicotine induces vasodilation, which is independent of the function of the endothelium and is involved in activation of CGRPergic nerves. It is also suggested that nicotine stimulates presynaptic nicotinic cholinoceptors on adrenergic nerves to release adrenergic neurotransmitters, which then act on CGRPergic nerves to release endogenous CGRP from the nerve. PMID:10882393

Endothelial and kidney function in women with a history of preeclampsia and healthy parous controls: A case control study.

PubMed

Lopes van Balen, Veronica A; Spaan, Julia J; Cornelis, Tom; Heidema, Wieteke M; Scholten, Ralph R; Spaanderman, Marc E A

2018-03-01

Preeclampsia (PE) is a pregnancy related endothelial disease characterized by hypertension and albuminuria. Postpartum endothelial dysfunction often persists in these women. We postulate that in women with a history of PE reduced endothelial dependent vasodilation coincides with attenuated kidney function, as both reflect endothelial dysfunction. We assessed endothelial and kidney function in women with a history of PE (n=79) and uncomplicated pregnancies (n=49) at least 4years postpartum. Women with hypertension, diabetes or kidney disease prior to pregnancy were excluded. Brachial artery flow mediated dilatation (FMD) was measured and analysed by a custom designed edge-detection and wall-tracking software. We measured albumin and creatinine levels in a 24-h urine sample and calculated glomerular filtration rate (GFR) by CKD-EPI. Women with a history of PE had lower FMD but comparable GFR and albumin creatinine ratio (ACR) compared with controls. Independent of obstetric history, in both controls and women with a history of PE respectively, GFR (r=0.19, p=0.17 and r=0.12, p=0.29) and albumin creatinine ratio (r=0.07, p=0.62 and r=0.06 p=0.57) did not correlate with FMD. At least 4years after pregnancy, women with a history of PE demonstrated decreased flow mediated dilatation when compared to healthy parous controls. In this study, decreased flow mediated dilation however did not coincide with decreased kidney function. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Exercise training in adults with repaired tetralogy of Fallot: A randomized controlled pilot study of continuous versus interval training.

PubMed

Novaković, Marko; Prokšelj, Katja; Rajkovič, Uroš; Vižintin Cuderman, Tjaša; Janša Trontelj, Katja; Fras, Zlatko; Jug, Borut

2018-03-15

Adults with repaired tetralogy of Fallot (ToF) have impaired exercise capacity, vascular and cardiac autonomic function, and quality of life (QoL). Specific effects of high-intensity interval or moderate continuous exercise training on these parameters in adults with repaired ToF remain unknown. Thirty adults with repaired ToF were randomized to either high-intensity interval, moderate intensity continuous training (36 sessions, 2-3 times a week) or usual care (no supervised exercise). Exercise capacity, flow-mediated vasodilation, pulse wave velocity, NT-proBNP and fibrinogen levels, heart rate variability and recovery, and QoL (SF-36 questionnaire) were determined at baseline and after the intervention period. Twenty-seven patients (mean age 39±9years, 63% females, 9 from each group) completed this pilot study. Both training groups improved in at least some parameters of cardiovascular health compared to no exercise. Interval-but not continuous-training improved VO2peak (21.2 to 22.9ml/kg/min, p=0.004), flow-mediated vasodilation (8.4 to 12.9%, p=0.019), pulse wave velocity (5.4 to 4.8m/s, p=0.028), NT-proBNP (202 to 190ng/L, p=0.032) and fibrinogen levels (2.67 to 2.46g/L, p=0.018). Conversely, continuous-but not interval-training improved heart rate variability (low-frequency domain, 0.32 to 0.22, p=0.039), heart rate recovery after 2min post-exercise (40 to 47 beats, p=0.023) and mental domain of SF-36 (87 to 95, p=0.028). Both interval and continuous exercise training modalities were safe. Interval training seems more efficacious in improving exercise capacity, vascular function, NT-proBNP and fibrinogen levels, while continuous training seems more efficacious in improving cardiac autonomic function and QoL. (Clinicaltrials.gov, NCT02643810). Copyright © 2018 Elsevier Ireland Ltd. All rights reserved.

Characterisation of the vasodilation effects of DHA and EPA, n-3 PUFAs (fish oils), in rat aorta and mesenteric resistance arteries.

PubMed

Limbu, Roshan; Cottrell, Graeme S; McNeish, Alister J

2018-01-01

Increasing evidence suggests that the omega-3 polyunsaturated acids (n-3 PUFA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are beneficial to cardiovascular health, promoting relaxation of vascular smooth muscle cells and vasodilation. Numerous studies have attempted to study these responses, but to date there has not been a systematic characterisation of both DHA and EPA mediated vasodilation in conduit and resistance arteries. Therefore, we aimed to fully characterise the n-3 PUFA-induced vasodilation pathways in rat aorta and mesenteric artery. Wire myography was used to measure the vasomotor responses of freshly dissected rat mesenteric artery and aorta. Arteries were pre-constricted with U46619 and cumulative concentrations of either DHA or EPA (10 nM-30 μM) were added. The mechanisms by which n-3 PUFA relaxed arteries were investigated using inhibitors of vasodilator pathways, which include: nitric oxide synthase (NOS; L-NAME), cycloxygenase (COX; indomethacin), cytochrome P450 epoxygenase (CYP450; clotrimazole); and calcium-activated potassium channels (KCa), SKCa (apamin), IKCa (TRAM-34) and BKCa (paxilline). Both DHA- and EPA-induced relaxations were partially inhibited following endothelium removal in rat mesenteric arteries. Similarly, in aorta EPA-induced relaxation was partially suppressed due to endothelium removal. CYP450 also contributed to EPA-induced relaxation in mesenteric artery. Inhibition of IKCa partially attenuated DHA-induced relaxation in aorta and mesenteric artery along with EPA-induced relaxation in mesenteric artery. Furthermore, this inhibition of DHA- and EPA-induced relaxation was increased following the additional blockade of BKCa in these arteries. This study provides evidence of heterogeneity in the vasodilation mechanisms of DHA and EPA in different vascular beds. Our data also demonstrates that endothelium removal has little effect on relaxations produced by either PUFA. We demonstrate IKCa and BKCa are involved in DHA-induced relaxation in rat aorta and mesenteric artery; and EPA-induced relaxation in rat mesenteric artery only. CYP450 derived metabolites of EPA may also be involved in BKCa dependent relaxation. To our knowledge this is the first study indicating the involvement of IKCa in n-3 PUFA mediated relaxation.

Characterisation of the vasodilation effects of DHA and EPA, n-3 PUFAs (fish oils), in rat aorta and mesenteric resistance arteries

PubMed Central

Limbu, Roshan; Cottrell, Graeme S.

2018-01-01

Background and purpose Increasing evidence suggests that the omega-3 polyunsaturated acids (n-3 PUFA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are beneficial to cardiovascular health, promoting relaxation of vascular smooth muscle cells and vasodilation. Numerous studies have attempted to study these responses, but to date there has not been a systematic characterisation of both DHA and EPA mediated vasodilation in conduit and resistance arteries. Therefore, we aimed to fully characterise the n-3 PUFA-induced vasodilation pathways in rat aorta and mesenteric artery. Methods Wire myography was used to measure the vasomotor responses of freshly dissected rat mesenteric artery and aorta. Arteries were pre-constricted with U46619 and cumulative concentrations of either DHA or EPA (10 nM-30 μM) were added. The mechanisms by which n-3 PUFA relaxed arteries were investigated using inhibitors of vasodilator pathways, which include: nitric oxide synthase (NOS; L-NAME), cycloxygenase (COX; indomethacin), cytochrome P450 epoxygenase (CYP450; clotrimazole); and calcium-activated potassium channels (KCa), SKCa (apamin), IKCa (TRAM-34) and BKCa (paxilline). Results Both DHA- and EPA-induced relaxations were partially inhibited following endothelium removal in rat mesenteric arteries. Similarly, in aorta EPA-induced relaxation was partially suppressed due to endothelium removal. CYP450 also contributed to EPA-induced relaxation in mesenteric artery. Inhibition of IKCa partially attenuated DHA-induced relaxation in aorta and mesenteric artery along with EPA-induced relaxation in mesenteric artery. Furthermore, this inhibition of DHA- and EPA-induced relaxation was increased following the additional blockade of BKCa in these arteries. Conclusions This study provides evidence of heterogeneity in the vasodilation mechanisms of DHA and EPA in different vascular beds. Our data also demonstrates that endothelium removal has little effect on relaxations produced by either PUFA. We demonstrate IKCa and BKCa are involved in DHA-induced relaxation in rat aorta and mesenteric artery; and EPA-induced relaxation in rat mesenteric artery only. CYP450 derived metabolites of EPA may also be involved in BKCa dependent relaxation. To our knowledge this is the first study indicating the involvement of IKCa in n-3 PUFA mediated relaxation. PMID:29394279

Endothelial dysfunction in patients with chronic heart failure is independently associated with increased incidence of hospitalization, cardiac transplantation, or death.

PubMed

Fischer, D; Rossa, S; Landmesser, U; Spiekermann, S; Engberding, N; Hornig, B; Drexler, H

2005-01-01

Endothelial dysfunction of coronary and peripheral arteries has been demonstrated in patients with chronic heart failure (CHF) and appears to be associated with functional implications. However, it is unknown whether endothelial dysfunction in CHF is independently associated with impaired outcome or progression of the disease. We assessed the follow-up of 67 consecutive patients with CHF [New York Heart Association (NYHA) functional class II-III] in which flow-dependent, endothelium-mediated vasodilation (FDD) of the radial artery was assessed by high resolution ultrasound. The primary endpoint was defined by cardiac death, hospitalization due to worsening of heart failure (NYHA class IV, pulmonary oedema), or heart transplantation. Cox regression analysis was used to determine whether FDD was associated with these heart failure-related events. During a median follow-up of 45.7 months 24 patients had an event: 18 patients were hospitalized due to worsening of heart failure or heart transplantation, six patients died for cardiac reasons. Cox regression analysis demonstrated that FDD (P<0.01), diabetes mellitus (P<0.01), and ejection fraction (P<0.01) were independent predictive factors for the occurrence of the primary endpoint. The Kaplan-Meier survival curve revealed a significantly better clinical outcome in patients with FDD above the median (6.2%) compared with those with FDD below the median (P<0.013). These observations suggest that endothelium-mediated vasodilation represents an independent predictor of cardiac death and hospitalization in patients with CHF, consistent with the notion that endothelium-derived nitric oxide may play a protective role in heart failure.

Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans

PubMed Central

Arif, Sayqa; Borgognone, Alessandra; Lin, Erica Lai-Sze; O'Sullivan, Aine G; Sharma, Vishal; Drury, Nigel E; Menon, Ashvini; Nightingale, Peter; Mascaro, Jorge; Bonser, Robert S; Horowitz, John D; Feelisch, Martin; Frenneaux, Michael P; Madhani, Melanie

2015-01-01

Background and Purpose Hypoxic conditions favour the reduction of nitrite to nitric oxide (NO) to elicit vasodilatation, but the mechanism(s) responsible for bioconversion remains ill defined. In the present study, we assess the role of aldehyde dehydrogenase 2 (ALDH2) in nitrite bioactivation under normoxia and hypoxia in the rat and human vasculature. Experimental Approach The role of ALDH2 in vascular responses to nitrite was studied using rat thoracic aorta and gluteal subcutaneous fat resistance vessels from patients with heart failure (HF; 16 patients) in vitro and by measurement of changes in forearm blood flow (FBF) during intra-arterial nitrite infusion (21 patients) in vivo. Specifically, we investigated the effects of (i) ALDH2 inhibition by cyanamide or propionaldehyde and the (ii) tolerance-independent inactivation of ALDH2 by glyceryl trinitrate (GTN) on the vasodilator activity of nitrite. In each setting, nitrite effects were measured via evaluation of the concentration–response relationship under normoxic and hypoxic conditions in the absence or presence of ALDH2 inhibitors. Key Results Both in rat aorta and human resistance vessels, dilatation to nitrite was diminished following ALDH2 inhibition, in particular under hypoxia. In humans there was a non-significant trend towards attenuation of nitrite-mediated increases in FBF. Conclusions and Implications In human and rat vascular tissue in vitro, hypoxic nitrite-mediated vasodilatation involves ALDH2. In patients with HF in vivo, the role of this enzyme in nitrite bioactivation is at the most, modest, suggesting the involvement of other more important mechanisms. PMID:25754766

Peroxynitrite Disrupts Endothelial Caveolae Leading to eNOS Uncoupling and Diminished Flow-Mediated Dilation in Coronary Arterioles of Diabetic Patients

PubMed Central

Cassuto, James; Dou, Huijuan; Czikora, Istvan; Szabo, Andras; Patel, Vijay S.; Kamath, Vinayak; Belin de Chantemele, Eric; Feher, Attila; Romero, Maritza J.; Bagi, Zsolt

2014-01-01

Peroxynitrite (ONOO−) contributes to coronary microvascular dysfunction in diabetes mellitus (DM). We hypothesized that in DM, ONOO− interferes with the function of coronary endothelial caveolae, which plays an important role in nitric oxide (NO)-dependent vasomotor regulation. Flow-mediated dilation (FMD) of coronary arterioles was investigated in DM (n = 41) and non-DM (n = 37) patients undergoing heart surgery. NO-mediated coronary FMD was significantly reduced in DM patients, which was restored by ONOO− scavenger, iron-(III)-tetrakis(N-methyl-4'pyridyl)porphyrin-pentachloride, or uric acid, whereas exogenous ONOO− reduced FMD in non-DM subjects. Immunoelectron microscopy demonstrated an increased 3-nitrotyrosine formation (ONOO−-specific protein nitration) in endothelial plasma membrane in DM, which colocalized with caveolin-1 (Cav-1), the key structural protein of caveolae. The membrane-localized Cav-1 was significantly reduced in DM and also in high glucose–exposed coronary endothelial cells. We also found that DM patients exhibited a decreased number of endothelial caveolae, whereas exogenous ONOO− reduced caveolae number. Correspondingly, pharmacological (methyl-β-cyclodextrin) or genetic disruption of caveolae (Cav-1 knockout mice) abolished coronary FMD, which was rescued by sepiapterin, the stable precursor of NO synthase (NOS) cofactor, tetrahydrobiopterin. Sepiapterin also restored coronary FMD in DM patients. Thus, we propose that ONOO− selectively targets and disrupts endothelial caveolae, which contributes to NOS uncoupling, and, hence, reduced NO-mediated coronary vasodilation in DM patients. PMID:24353182

Acetylcholine released by endothelial cells facilitates flow‐mediated dilatation

PubMed Central

Wilson, Calum; Lee, Matthew D.

2016-01-01

Key points The endothelium plays a pivotal role in the vascular response to chemical and mechanical stimuli.The endothelium is exquisitely sensitive to ACh, although the physiological significance of ACh‐induced activation of the endothelium is unknown.In the present study, we investigated the mechanisms of flow‐mediated endothelial calcium signalling.Our data establish that flow‐mediated endothelial calcium responses arise from the autocrine action of non‐neuronal ACh released by the endothelium. Abstract Circulating blood generates frictional forces (shear stress) on the walls of blood vessels. These frictional forces critically regulate vascular function. The endothelium senses these frictional forces and, in response, releases various vasodilators that relax smooth muscle cells in a process termed flow‐mediated dilatation. Although some elements of the signalling mechanisms have been identified, precisely how flow is sensed and transduced to cause the release of relaxing factors is poorly understood. By imaging signalling in large areas of the endothelium of intact arteries, we show that the endothelium responds to flow by releasing ACh. Once liberated, ACh acts to trigger calcium release from the internal store in endothelial cells, nitric oxide production and artery relaxation. Flow‐activated release of ACh from the endothelium is non‐vesicular and occurs via organic cation transporters. ACh is generated following mitochondrial production of acetylCoA. Thus, we show ACh is an autocrine signalling molecule released from endothelial cells, and identify a new role for the classical neurotransmitter in endothelial mechanotransduction. PMID:27730645

Improvement of Acetylcholine-Induced Vasodilation by Acute Exercise in Ovariectomized Hypertensive Rats.

PubMed

Cheng, Tsung-Lin; Lin, Yi-Yuan; Su, Chia-Ting; Hu, Chun-Che; Yang, Ai-Lun

2016-06-30

Postmenopause is associated with the development of cardiovascular disease, such as hypertension. However, limited information is available regarding effects of exercise on cardiovascular responses and its underlying mechanisms in the simultaneous postmenopausal and hypertensive status. We aimed to investigate whether acute exercise could enhance vasodilation mediated by acetylcholine (ACh) and sodium nitroprusside (SNP) in ovariectomized hypertensive rats. The fifteen-week-old female spontaneously hypertensive rats (SHR) were bilaterally ovariectomized, at the age of twenty-four weeks, and randomly divided into sedentary (SHR-O) and acute exercise (SHR-OE) groups. Age-matched WKY rats were used as the normotensive control group. The SHR-OE group ran on a motor-driven treadmill at a speed of 24 m/min for one hour in a moderate-intensity program. Following a single bout of exercise, rat aortas were isolated for the evaluation of the endothelium-dependent (ACh-induced) and endothelium-independent (SNP-induced) vasodilation by the organ bath system. Also, the serum levels of oxidative stress and antioxidant activities, including malondialdehyde (MDA), superoxide dismutase (SOD), and catalase, were measured after acute exercise among the three groups. We found that acute exercise significantly enhanced the ACh-induced vasodilation, but not the SNP-induced vasodilation, in ovariectomized hypertensive rats. This increased vasodilation was eliminated after the inhibition of nitric oxide synthase (NOS). Also, the activities of SOD and catalase were significantly increased after acute exercise, whereas the level of MDA was comparable among the three groups. These results indicated that acute exercise improved the endothelium-dependent vasodilating response to ACh through the NOS-related pathway in ovariectomized hypertensive rats, which might be associated with increased serum antioxidant activities.

Ratio of serum levels of AGEs to soluble form of RAGE is a predictor of endothelial function.

PubMed

Kajikawa, Masato; Nakashima, Ayumu; Fujimura, Noritaka; Maruhashi, Tatsuya; Iwamoto, Yumiko; Iwamoto, Akimichi; Matsumoto, Takeshi; Oda, Nozomu; Hidaka, Takayuki; Kihara, Yasuki; Chayama, Kazuaki; Goto, Chikara; Aibara, Yoshiki; Noma, Kensuke; Takeuchi, Masayoshi; Matsui, Takanori; Yamagishi, Sho-Ichi; Higashi, Yukihito

2015-01-01

Advanced glycation end products (AGEs) and their specific receptor, the receptor for AGEs (RAGE), play an important role in atherosclerosis. Recently, a soluble form of RAGE (sRAGE) has been identified in human serum. However, the role of sRAGE in cardiovascular disease is still controversial. There is no information on the association between simultaneous measurements of AGEs and sRAGE and vascular function. In this study, we evaluated the associations between serum levels of AGEs and sRAGE, ratio of AGEs to sRAGE, and vascular function. We measured serum levels of AGEs and sRAGE and assessed vascular function by measurement of flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation in 110 subjects who underwent health examinations. Multivariate regression analyses were performed to identify factors associated with vascular function. Univariate regression analysis revealed that FMD correlated with age, BMI, systolic blood pressure, diastolic blood pressure, heart rate, triglycerides, HDL cholesterol, glucose, smoking pack-years, nitroglycerine-induced vasodilation, serum levels of AGEs and sRAGE, and ratio of AGEs to sRAGE. Multivariate analysis revealed that the ratio of AGEs to sRAGE remained an independent predictor of FMD, while serum level of AGEs alone or sRAGE alone was not associated with FMD. These findings suggest that sRAGE may have a counterregulatory mechanism that is activated to counteract the vasotoxic effect of the AGE-RAGE axis. The ratio of AGEs to sRAGE may be a new chemical biomarker of endothelial function. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Effects of nitric oxide synthase inhibition with or without cyclooxygenase-2 inhibition on resting haemodynamics and responses to exendin-4

PubMed Central

Gardiner, S M; March, J E; Kemp, P A; Bennett, T

2006-01-01

Background and purpose: Interactions between the NO system and the cyclooxygenase systems may be important in cardiovascular regulation. Here we measured the effects of acute cyclooxygenase-2 inhibition (with parecoxib), alone and in combination with NOS inhibition (with N G-nitro-L-arginine methyl ester (L-NAME)), on resting cardiovascular variables and on responses to the glucagon-like peptide 1 agonist, exendin-4, which causes regionally-selective vasoconstriction and vasodilatation. Experimental approach: Rats were instrumented with flow probes and intravascular catheters to measure regional haemodynamics in the conscious, freely moving state. L-NAME was administered as a primed infusion 180 min after administration of parecoxib or vehicle, and exendin-4 was given 60 min after the onset of L-NAME infusion. Key results: Parecoxib had no effect on resting cardiovascular variables or on responses to L-NAME. Exendin-4 caused a pressor response accompanied by tachycardia, mesenteric vasoconstriction and hindquarters vasodilatation. Parecoxib did not affect haemodynamic responses to exendin-4, but L-NAME inhibited its hindquarters vasodilator and tachycardic effects. When combined, L-NAME and parecoxib almost abolished the hindquarters vasodilatation while enhancing the pressor response. Conclusions and implications: Cyclooxygenase-2-derived products do not affect basal haemodynamic status in conscious normotensive rats, or influence the NO system acutely. The inhibitory effects of L-NAME on the hindquarters vasodilator and tachycardic effects of exendin-4 are consistent with a previous study that showed those events to be β-adrenoceptor mediated. The additional effect of parecoxib on responses to exendin-4 in the presence of L-NAME, is consistent with other evidence for enhanced involvement of vasodilator prostanoids when NO production is reduced. PMID:17016494

Purple grape juice improves endothelial function and reduces the susceptibility of LDL cholesterol to oxidation in patients with coronary artery disease.

PubMed

Stein, J H; Keevil, J G; Wiebe, D A; Aeschlimann, S; Folts, J D

1999-09-07

In vitro, the flavonoid components of red wine and purple grape juice are powerful antioxidants that induce endothelium-dependent vasodilation of vascular rings derived from rat aortas and human coronary arteries. Although improved endothelial function and inhibition of LDL oxidation may be potential mechanisms by which red wine and flavonoids reduce cardiovascular risk, the in vivo effects of grape products on endothelial function and LDL oxidation have not been investigated. This study assessed the effects of ingesting purple grape juice on endothelial function and LDL susceptibility to oxidation in patients with coronary artery disease (CAD). Fifteen adults with angiographically documented CAD ingested 7.7+/-1.2 mL. kg(-1). d(-1) of purple grape juice for 14 days. Flow-mediated vasodilation (FMD) was measured using high-resolution brachial artery ultrasonography. Susceptibility of LDL particles to oxidation was determined from the rate of conjugated diene formation after exposure to copper chloride. At baseline, FMD was impaired (2.2+/-2. 9%). After ingestion of grape juice, FMD increased to 6.4+/-4.7% (P=0.003). In a linear regression model that included age, artery diameter, lipid values, and use of lipid-lowering and antioxidant therapies, the effect of grape juice on FMD remained significant (mean change 4.2+/-4.4%, P<0.001). After ingestion of grape juice, lag time increased by 34.5% (P=0.015). Short-term ingestion of purple grape juice improves FMD and reduces LDL susceptibility to oxidation in CAD patients. Improved endothelium-dependent vasodilation and prevention of LDL oxidation are potential mechanisms by which flavonoids in purple grape products may prevent cardiovascular events, independent of alcohol content.

Decreased frequency and duration of tooth brushing is a risk factor for endothelial dysfunction.

PubMed

Matsui, Shogo; Kajikawa, Masato; Maruhashi, Tatsuya; Iwamoto, Yumiko; Iwamoto, Akimichi; Oda, Nozomu; Kishimoto, Shinji; Hidaka, Takayuki; Kihara, Yasuki; Chayama, Kazuaki; Goto, Chikara; Aibara, Yoshiki; Nakashima, Ayumu; Noma, Kensuke; Taguchi, Akira; Higashi, Yukihito

2017-08-15

Periodontal disease is associated with endothelial dysfunction, leading to cardiovascular disease. The effect of detailed tooth brushing behavior, not only frequency but also duration of tooth brushing, on endothelial function is unclear. The purpose of this study was to evaluate the relationships of detailed methods of tooth brushing with vascular function. We evaluated flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation, and frequency and duration of tooth brushing in 896 subjects. We divided the subjects into three groups according to the frequency and duration of tooth brushing: low frequency and short duration group (

The nicorandil-induced vasodilation in humans is inhibited by miconazole.

PubMed

Ueda, Keiko; Goto, Chikara; Jitsuiki, Daisuke; Umemura, Takashi; Nishioka, Kenji; Kimura, Masashi; Noma, Kensuke; Nakagawa, Keigo; Oshima, Tetsuya; Yoshizumi, Masao; Chayama, Kazuaki; Higashi, Yukihito

2005-04-01

Nicorandil, N-(2-hydroxyethyl)-nicotinamide nitrate, exerts its vasodilatory effects by opening ATP-sensitive potassium (K-ATP) channels and by acting as the exogenous nitric oxide (NO). It is not clear, however, whether the actions of other endothelium-dependent vasodilators, such as NO, endothelium-derived hyperpolarizing factor (EDHF), and prostaglandins, contribute to nicorandil-induced vasodilation in the vasculature in humans. We evaluated forearm blood flow (FBF) response to intraarterial infusion of nicorandil alone and in the presence of glibenclamide, a K-ATP channel inhibitor, N(G)-monomethyl-L-arginine, an NO synthase inhibitor, indomethacin, a cyclooxygenase inhibitor, or miconazol, a cytochrome P-450 inhibitor, in 24 healthy male subjects. FBF was measured using strain-gauge plethysmography. Infusion of nicorandil significantly increased the FBF response in a dose-dependent manner. Intraarterial infusion of glibenclamide attenuated nicorandil-induced vasodilation (160.9 +/- 21.2% versus 90.2 +/- 19.4%, P < 0.01), and miconazole also attenuated the FBF response to nicorandil (160.9 +/- 21.2% versus 66.1 +/- 9.2%, P < 0.001). N-monomethyl-L-arginine or indomethacin did not alter the FBF response to nicorandil. These findings suggest that nicorandil causes vasodilation in forearm circulation in humans, at least in part through a pathway that is dependent on K-ATP channels and cytochrome P-450, but not on endogenous NO and prostaglandins. EDHF may contribute to nicorandil-induced vasodilation in humans.

Effects of Buddhism walking meditation on depression, functional fitness, and endothelium-dependent vasodilation in depressed elderly.

PubMed

Prakhinkit, Susaree; Suppapitiporn, Siriluck; Tanaka, Hirofumi; Suksom, Daroonwan

2014-05-01

The objectives of this study were to determine the effects of the novel Buddhism-based walking meditation (BWM) and the traditional walking exercise (TWE) on depression, functional fitness, and vascular reactivity. This was a randomized exercise intervention study. The study was conducted in a university hospital setting. Forty-five elderly participants aged 60-90 years with mild-to-moderate depressive symptoms were randomly allocated to the sedentary control, TWE, and BWM groups. The BWM program was based on aerobic walking exercise incorporating the Buddhist meditations performed 3 times/week for 12 weeks. Depression score, functional fitness, and endothelium-dependent vasodilation as measured by the flow-mediated dilation (FMD) were the outcome measures used. Muscle strength, flexibility, agility, dynamic balance, and cardiorespiratory endurance increased in both exercise groups (p<0.05). Depression score decreased (p<0.05) only in the BWM group. FMD improved (p<0.05) in both exercise groups. Significant reduction in plasma cholesterol, triglyceride, high-density lipoprotein cholesterol, and C-reactive protein were found in both exercise groups, whereas low-density lipoprotein cholesterol, cortisol, and interleukin-6 concentrations decreased only in the BWM group. Buddhist walking meditation was effective in reducing depression, improving functional fitness and vascular reactivity, and appears to confer greater overall improvements than the traditional walking program.

Hypoxemia, oxygen content, and the regulation of cerebral blood flow

PubMed Central

Bain, Anthony R.; Rieger, Mathew G.; Bailey, Damian M; Ainslie, Philip N.

2015-01-01

This review highlights the influence of oxygen (O2) availability on cerebral blood flow (CBF). Evidence for reductions in O2 content (CaO2) rather than arterial O2 tension (PaO2) as the chief regulator of cerebral vasodilation, with deoxyhemoglobin as the primary O2 sensor and upstream response effector, is discussed. We review in vitro and in vivo data to summarize the molecular mechanisms underpinning CBF responses during changes in CaO2. We surmise that 1) during hypoxemic hypoxia in healthy humans (e.g., conditions of acute and chronic exposure to normobaric and hypobaric hypoxia), elevations in CBF compensate for reductions in CaO2 and thus maintain cerebral O2 delivery; 2) evidence from studies implementing iso- and hypervolumic hemodilution, anemia, and polycythemia indicate that CaO2 has an independent influence on CBF; however, the increase in CBF does not fully compensate for the lower CaO2 during hemodilution, and delivery is reduced; and 3) the mechanisms underpinning CBF regulation during changes in O2 content are multifactorial, involving deoxyhemoglobin-mediated release of nitric oxide metabolites and ATP, deoxyhemoglobin nitrite reductase activity, and the downstream interplay of several vasoactive factors including adenosine and epoxyeicosatrienoic acids. The emerging picture supports the role of deoxyhemoglobin (associated with changes in CaO2) as the primary biological regulator of CBF. The mechanisms for vasodilation therefore appear more robust during hypoxemic hypoxia than during changes in CaO2 via hemodilution. Clinical implications (e.g., disorders associated with anemia and polycythemia) and future study directions are considered. PMID:26676248

Age-related endothelial dysfunction in human skeletal muscle feed arteries: the role of free radicals derived from mitochondria in the vasculature.

PubMed

Park, S-Y; Kwon, O S; Andtbacka, R H I; Hyngstrom, J R; Reese, V; Murphy, M P; Richardson, R S

2018-01-01

This study sought to determine the role of free radicals derived from mitochondria in the vasculature in the recognized age-related endothelial dysfunction of human skeletal muscle feed arteries (SMFAs). A total of 44 SMFAs were studied with and without acute exposure to the mitochondria-targeted antioxidant MitoQ and nitric oxide synthase (NOS) blockade. The relative abundance of proteins from the electron transport chain, phosphorylated (p-) to endothelial (e) NOS ratio, manganese superoxide dismutase (MnSOD) and the mitochondria-derived superoxide (O2-) levels were assessed in SMFA. Endothelium-dependent and endothelium-independent SMFA vasodilation was assessed in response to flow-induced shear stress, acetylcholine (ACh) and sodium nitroprusside (SNP). MitoQ restored endothelium-dependent vasodilation in the old to that of the young when stimulated by both flow (young: 68 ± 5; old: 25 ± 7; old + MitoQ 65 ± 9%) and ACh (young: 97 ± 4; old: 59 ± 10; old + MitoQ: 98 ± 5%), but did not alter the initially uncompromised, endothelium-independent vasodilation (SNP). Compared to the young, MitoQ in the old diminished the initially elevated mitochondria-derived O2- levels and appeared to attenuate the breakdown of MnSOD. Furthermore, MitoQ increased the ratio of p-eNOS to NOS and the restoration of endothelium-dependent vasodilation in the old by MitoQ was ablated by NOS blockade. This study demonstrated that MitoQ reverses age-related vascular dysfunction by what appears to be an NO-dependent mechanism in human SMFAs. These findings suggest that mitochondria-targeted antioxidants may have utility in terms of counteracting the attenuated blood flow and vascular dysfunction associated with advancing age. © 2017 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Acute Cutaneous Microvascular Flow Responses to Whole-Body Tilting in Humans

NASA Technical Reports Server (NTRS)

Breit, Gregory A.; Watenpaugh, Donald E.; Ballard, Richard E.; Hargens, Alan R.

1993-01-01

The transition from upright to head-down tilt (HDT) posture in humans increases blood pressure superior to the heart and decreases pressure inferior to the heart. Consequently, above heart level, myogenic arteriolar tone probably increases with HDT, in opposition to the withdrawal of baroreceptor-mediated sympathetic tone. We hypothesized that due to antagonism between central and local controls, the response of the facial cutaneous micro- circulation to acute postural change will be weaker than that in the leg, where these two mechanisms reinforce each other. Cutaneous microvascular flow was measured by laser Doppler flowmetry simultaneously at the shin and the neck of 7 male and 3 female subjects. Subjects underwent a stepwise tilt protocol from standing control to 54 deg head-up tilt (HUT), 30 deg, 12 deg, 0 deg, -6 deg (HDT), -12 deg, -6 deg, 0 deg, 12 deg, 30 deg, 54 deg, and standing, for 30-sec periods with 10-sec transitions between postures. Flows at the shin and the neck increased significantly (P < 0.05) from standing baseline to 12 deg HUT (252 +/- 55 and 126 +/- 9% (bar-X +/- SE) of baseline, respectively). From 12 deg to -12 deg tilt, flows continued to increase at the shin (509 +/- 71% of baseline) but decreased at the neck to baseline levels (100 +/- 15% of baseline). Cutaneous microvascular flow recovered at both sites during the return to standing posture with significant hysteresis. Flow increases from standing to near-supine posture are attributed at both sites to baroreceptor-mediated vasodilation. The great dissimilarity in flow response magnitudes at the two measurement sites may be indicative of central/local regulatory antagonism above heart level and reinforcement below heart level.

Acute Cutaneous Microvascular Flow Responses to Whole-Body Tilting in Humans

NASA Technical Reports Server (NTRS)

Breit, Gregory A.; Watenpaugh, Donald E.; Ballard, Richard E.; Hargens, Alan R.

1993-01-01

The transition from upright to head-down tilt (HDT) posture in humans increases blood pressure superior to the heart and decreases pressure inferior to the heart. Consequently, above heart level, myogenic arteriolar tone probably increases with HDT, in opposition to the withdrawal of baroreceptor-mediated sympathetic tone. We hypothesized that due to antagonism between central and local controls, the response of the facial cutaneous microcirculation to acute postural change will be weaker than that in the leg, where these two mechanisms reinforce each other. Cutaneous microvascular flow was measured by laser Doppler flowmetry simultaneously at the shin and the neck of 7 male and 3 female subjects. Subjects underwent a stepwise tilt protocol from standing control to 54 deg head-up tilt (HUT), 30 deg, 12 deg, O deg, -6 deg (HDT), -12 deg, -6 deg, O deg, 12 deg, 30 deg, 54 deg, and standing, for 30-sec periods with 10-sec transitions between postures. Flows at the shin and the neck increased significantly (P less than 0.05) from standing baseline to 12 deg HUT (252 +/- 55 and 126 +/- 9% (bar X +/- SE) of baseline, respectively). From 12 deg to -12 deg tilt, flows continued to increase at the shin (509 +/- 71% of baseline) but decreased at the neck to baseline levels (100 +/- 15% of baseline). Cutaneous microvascular flow recovered at both sites during the return to standing posture with significant hysteresis. Flow increases from standing to near-supine posture are attributed at both sites to baroreceptor-mediated vasodilation. The great dissimilarity in flow response magnitudes at the two measurement sites may be indicative of central/local regulatory antagonism above heart level and reinforcement below heart level.

Dietary restriction but not angiotensin II type 1 receptor blockade improves DNA damage-related vasodilator dysfunction in rapidly aging Ercc1Δ/- mice.

PubMed

Wu, Haiyan; van Thiel, Bibi S; Bautista-Niño, Paula K; Reiling, Erwin; Durik, Matej; Leijten, Frank P J; Ridwan, Yanto; Brandt, Renata M C; van Steeg, Harry; Dollé, Martijn E T; Vermeij, Wilbert P; Hoeijmakers, Jan H J; Essers, Jeroen; van der Pluijm, Ingrid; Danser, A H Jan; Roks, Anton J M

2017-08-01

DNA damage is an important contributor to endothelial dysfunction and age-related vascular disease. Recently, we demonstrated in a DNA repair-deficient, prematurely aging mouse model ( Ercc1 Δ/- mice) that dietary restriction (DR) strongly increases life- and health span, including ameliorating endothelial dysfunction, by preserving genomic integrity. In this mouse mutant displaying prominent accelerated, age-dependent endothelial dysfunction we investigated the signaling pathways involved in improved endothelium-mediated vasodilation by DR, and explore the potential role of the renin-angiotensin system (RAS). Ercc1 Δ/- mice showed increased blood pressure and decreased aortic relaxations to acetylcholine (ACh) in organ bath experiments. Nitric oxide (NO) signaling and phospho-Ser 1177 -eNOS were compromised in Ercc1 Δ / - DR improved relaxations by increasing prostaglandin-mediated responses. Increase of cyclo-oxygenase 2 and decrease of phosphodiesterase 4B were identified as potential mechanisms. DR also prevented loss of NO signaling in vascular smooth muscle cells and normalized angiotensin II (Ang II) vasoconstrictions, which were increased in Ercc1 Δ/- mice. Ercc1 Δ/ - mutants showed a loss of Ang II type 2 receptor-mediated counter-regulation of Ang II type 1 receptor-induced vasoconstrictions. Chronic losartan treatment effectively decreased blood pressure, but did not improve endothelium-dependent relaxations. This result might relate to the aging-associated loss of treatment efficacy of RAS blockade with respect to endothelial function improvement. In summary, DR effectively prevents endothelium-dependent vasodilator dysfunction by augmenting prostaglandin-mediated responses, whereas chronic Ang II type 1 receptor blockade is ineffective. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Antihypertensive mechanisms of chronic captopril or N-acetylcysteine treatment in L-NAME hypertensive rats.

PubMed

Zicha, Josef; Dobesová, Zdenka; Kunes, Jaroslav

2006-12-01

Hypertension due to chronic inhibition of NO synthase (NOS) by Nomega-nitro-L-arginine methyl ester (L-NAME) administration is characterized by both impaired NO-dependent vasodilation and enhanced sympathetic vasoconstriction. The aim of our study was to evaluate changes in the participation of major vasoactive systems in L-NAME-treated rats which were subjected to simultaneous antihypertensive (captopril) or antioxidant (N-acetylcysteine, NAC) treatment. Three-month-old Wistar males treated with L-NAME (60 mg/kg/day) for 5 weeks were compared to rats in which L-NAME treatment was combined with simultaneous chronic administration of captopril or NAC. Basal blood pressure (BP) and its acute responses to consecutive i.v. injections of captopril (10 mg/kg), pentolinium (5 mg/kg), L-NAME (30 mg/kg), tetraethylammonium (TEA, 16 mg/kg) and nitroprusside (NP, 20 microg/kg) were determined in conscious rats at the end of the study. The development of L-NAME hypertension was prevented by captopril treatment, whereas NAC treatment caused only a moderate BP reduction. Captopril treatment normalized the sympathetic BP component and significantly reduced residual BP (measured at full NP-induced vasodilation). In contrast, chronic NAC treatment did not modify the sympathetic BP component or residual BP, but significantly enhanced NO-dependent vasodilation. Neither captopril nor NAC treatment influenced the compensatory increase of TEA-sensitive vasodilation mediated by endothelium-derived hyperpolarizing factor in L-NAME-treated rats. Chronic captopril treatment prevented L-NAME hypertension by lowering of sympathetic tone, whereas chronic NAC treatment attenuated L-NAME hypertension by reduction in the vasodilator deficit due to enhanced NO-dependent vasodilation.

Regulation of coronary blood flow during exercise.

PubMed

Duncker, Dirk J; Bache, Robert J

2008-07-01

Exercise is the most important physiological stimulus for increased myocardial oxygen demand. The requirement of exercising muscle for increased blood flow necessitates an increase in cardiac output that results in increases in the three main determinants of myocardial oxygen demand: heart rate, myocardial contractility, and ventricular work. The approximately sixfold increase in oxygen demands of the left ventricle during heavy exercise is met principally by augmenting coronary blood flow (~5-fold), as hemoglobin concentration and oxygen extraction (which is already 70-80% at rest) increase only modestly in most species. In contrast, in the right ventricle, oxygen extraction is lower at rest and increases substantially during exercise, similar to skeletal muscle, suggesting fundamental differences in blood flow regulation between these two cardiac chambers. The increase in heart rate also increases the relative time spent in systole, thereby increasing the net extravascular compressive forces acting on the microvasculature within the wall of the left ventricle, in particular in its subendocardial layers. Hence, appropriate adjustment of coronary vascular resistance is critical for the cardiac response to exercise. Coronary resistance vessel tone results from the culmination of myriad vasodilator and vasoconstrictors influences, including neurohormones and endothelial and myocardial factors. Unraveling of the integrative mechanisms controlling coronary vasodilation in response to exercise has been difficult, in part due to the redundancies in coronary vasomotor control and differences between animal species. Exercise training is associated with adaptations in the coronary microvasculature including increased arteriolar densities and/or diameters, which provide a morphometric basis for the observed increase in peak coronary blood flow rates in exercise-trained animals. In larger animals trained by treadmill exercise, the formation of new capillaries maintains capillary density at a level commensurate with the degree of exercise-induced physiological myocardial hypertrophy. Nevertheless, training alters the distribution of coronary vascular resistance so that more capillaries are recruited, resulting in an increase in the permeability-surface area product without a change in capillary numerical density. Maintenance of alpha- and ss-adrenergic tone in the presence of lower circulating catecholamine levels appears to be due to increased receptor responsiveness to adrenergic stimulation. Exercise training also alters local control of coronary resistance vessels. Thus arterioles exhibit increased myogenic tone, likely due to a calcium-dependent protein kinase C signaling-mediated alteration in voltage-gated calcium channel activity in response to stretch. Conversely, training augments endothelium-dependent vasodilation throughout the coronary microcirculation. This enhanced responsiveness appears to result principally from an increased expression of nitric oxide (NO) synthase. Finally, physical conditioning decreases extravascular compressive forces at rest and at comparable levels of exercise, mainly because of a decrease in heart rate. Impedance to coronary inflow due to an epicardial coronary artery stenosis results in marked redistribution of myocardial blood flow during exercise away from the subendocardium towards the subepicardium. However, in contrast to the traditional view that myocardial ischemia causes maximal microvascular dilation, more recent studies have shown that the coronary microvessels retain some degree of vasodilator reserve during exercise-induced ischemia and remain responsive to vasoconstrictor stimuli. These observations have required reassessment of the principal sites of resistance to blood flow in the microcirculation. A significant fraction of resistance is located in small arteries that are outside the metabolic control of the myocardium but are sensitive to shear and nitrovasodilators. The coronary collateral system embodies a dynamic network of interarterial vessels that can undergo both long- and short-term adjustments that can modulate blood flow to the dependent myocardium. Long-term adjustments including recruitment and growth of collateral vessels in response to arterial occlusion are time dependent and determine the maximum blood flow rates available to the collateral-dependent vascular bed during exercise. Rapid short-term adjustments result from active vasomotor activity of the collateral vessels. Mature coronary collateral vessels are responsive to vasodilators such as nitroglycerin and atrial natriuretic peptide, and to vasoconstrictors such as vasopressin, angiotensin II, and the platelet products serotonin and thromboxane A(2). During exercise, ss-adrenergic activity and endothelium-derived NO and prostanoids exert vasodilator influences on coronary collateral vessels. Importantly, alterations in collateral vasomotor tone, e.g., by exogenous vasopressin, inhibition of endogenous NO or prostanoid production, or increasing local adenosine production can modify collateral conductance, thereby influencing the blood supply to the dependent myocardium. In addition, vasomotor activity in the resistance vessels of the collateral perfused vascular bed can influence the volume and distribution of blood flow within the collateral zone. Finally, there is evidence that vasomotor control of resistance vessels in the normally perfused regions of collateralized hearts is altered, indicating that the vascular adaptations in hearts with a flow-limiting coronary obstruction occur at a global as well as a regional level. Exercise training does not stimulate growth of coronary collateral vessels in the normal heart. However, if exercise produces ischemia, which would be absent or minimal under resting conditions, there is evidence that collateral growth can be enhanced. In addition to ischemia, the pressure gradient between vascular beds, which is a determinant of the flow rate and therefore the shear stress on the collateral vessel endothelium, may also be important in stimulating growth of collateral vessels.

Electron spin resonance characterization of vascular xanthine and NAD(P)H oxidase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation.

PubMed

Spiekermann, Stephan; Landmesser, Ulf; Dikalov, Sergey; Bredt, Martin; Gamez, Graciela; Tatge, Helma; Reepschläger, Nina; Hornig, Burkhard; Drexler, Helmut; Harrison, David G

2003-03-18

Increased inactivation of nitric oxide by superoxide (O2*-) contributes to endothelial dysfunction in patients with coronary disease (CAD). We therefore characterized the vascular activities of xanthine oxidase and NAD(P)H oxidase, 2 major O2*--producing enzyme systems, and their relationship with flow-dependent, endothelium-mediated vasodilation (FDD) in patients with CAD. Xanthine- and NAD(P)H-mediated O*.- formation was determined in coronary arteries from 10 patients with CAD and 10 controls by using electron spin resonance spectroscopy. Furthermore, activity of endothelium-bound xanthine oxidase in vivo and FDD of the radial artery were determined in 21 patients with CAD and 10 controls. FDD was measured before and after infusion of the antioxidant vitamin C (25 mg/min i.a.) to determine the portion of FDD inhibited by radicals. In coronary arteries from patients with CAD, xanthine- and NAD(P)H-mediated O2*- formation was increased compared with controls (xanthine: 12+/-2 versus 7+/-1 nmol O2*-/ microg protein; NADH: 11+/-1 versus 7+/-1 nmol O2*-/ microg protein; and NADPH: 12+/-2 versus 9+/-1 nmol O2*-/ microg protein; each P<0.05). Endothelium-bound xanthine oxidase activity was increased by >200% in patients with CAD (25+/-4 versus 9+/-1 nmol O2*-/ microL plasma per min; P<0.05) and correlated inversely with FDD (r=-0.55; P<0.05) and positively with the effect of vitamin C on FDD (r=0.54; P<0.05). The present study represents the first electron spin resonance measurements of xanthine and NAD(P)H oxidase activity in human coronary arteries and supports the concept that increased activities of both enzymes contribute to increased vascular oxidant stress in patients with CAD. Furthermore, the present study suggests that increased xanthine oxidase activity contributes to endothelial dysfunction in patients with CAD and may thereby promote the atherosclerotic process.

A Lipid Emulsion Reverses Toxic-Dose Bupivacaine-Induced Vasodilation during Tyrosine Phosphorylation-Evoked Contraction in Isolated Rat Aortae.

PubMed

Ok, Seong-Ho; Lee, Soo Hee; Kwon, Seong-Chun; Choi, Mun Hwan; Shin, Il-Woo; Kang, Sebin; Park, Miyeong; Hong, Jeong-Min; Sohn, Ju-Tae

2017-02-13

The goal of this in vitro study was to examine the effect of a lipid emulsion on toxic-dose bupivacaine-induced vasodilation in a model of tyrosine phosphatase inhibitor sodium orthovanadate-induced contraction in endothelium-denuded rat aortae and to elucidate the associated cellular mechanism. The effect of a lipid emulsion on vasodilation induced by a toxic dose of a local anesthetic during sodium orthovanadate-induced contraction was examined. In addition, the effects of various inhibitors, either bupivacaine alone or a lipid emulsion plus bupivacaine, on protein kinase phosphorylation induced by sodium orthovanadate in rat aortic vascular smooth muscle cells was examined. A lipid emulsion reversed the vasodilation induced by bupivacaine during sodium orthovanadate-induced contraction. The lipid emulsion attenuated the bupivacaine-mediated inhibition of the sodium orthovanadate-induced phosphorylation of protein tyrosine, c-Jun NH₂-terminal kinase (JNK), myosin phosphatase target subunit 1 (MYPT1), phospholipase C (PLC) γ-1 and extracellular signal-regulated kinase (ERK). These results suggest that a lipid emulsion reverses toxic-dose bupivacaine-induced vasodilation during sodium orthovanadate-induced contraction via the activation of a pathway involving either tyrosine kinase, JNK, Rho-kinase and MYPT1 or tyrosine kinase, PLC γ-1 and ERK, and this reversal is associated with the lipid solubility of the local anesthetic and the induction of calcium sensitization.

A Lipid Emulsion Reverses Toxic-Dose Bupivacaine-Induced Vasodilation during Tyrosine Phosphorylation-Evoked Contraction in Isolated Rat Aortae

PubMed Central

Ok, Seong-Ho; Lee, Soo Hee; Kwon, Seong-Chun; Choi, Mun Hwan; Shin, Il-Woo; Kang, Sebin; Park, Miyeong; Hong, Jeong-Min; Sohn, Ju-Tae

2017-01-01

The goal of this in vitro study was to examine the effect of a lipid emulsion on toxic-dose bupivacaine-induced vasodilation in a model of tyrosine phosphatase inhibitor sodium orthovanadate-induced contraction in endothelium-denuded rat aortae and to elucidate the associated cellular mechanism. The effect of a lipid emulsion on vasodilation induced by a toxic dose of a local anesthetic during sodium orthovanadate-induced contraction was examined. In addition, the effects of various inhibitors, either bupivacaine alone or a lipid emulsion plus bupivacaine, on protein kinase phosphorylation induced by sodium orthovanadate in rat aortic vascular smooth muscle cells was examined. A lipid emulsion reversed the vasodilation induced by bupivacaine during sodium orthovanadate-induced contraction. The lipid emulsion attenuated the bupivacaine-mediated inhibition of the sodium orthovanadate-induced phosphorylation of protein tyrosine, c-Jun NH2-terminal kinase (JNK), myosin phosphatase target subunit 1 (MYPT1), phospholipase C (PLC) γ-1 and extracellular signal-regulated kinase (ERK). These results suggest that a lipid emulsion reverses toxic-dose bupivacaine-induced vasodilation during sodium orthovanadate-induced contraction via the activation of a pathway involving either tyrosine kinase, JNK, Rho-kinase and MYPT1 or tyrosine kinase, PLC γ-1 and ERK, and this reversal is associated with the lipid solubility of the local anesthetic and the induction of calcium sensitization. PMID:28208809

Calycosin and Formononetin Induce Endothelium-Dependent Vasodilation by the Activation of Large-Conductance Ca2+-Activated K+ Channels (BKCa).

PubMed

Tseng, Hisa Hui Ling; Vong, Chi Teng; Leung, George Pak-Heng; Seto, Sai Wang; Kwan, Yiu Wa; Lee, Simon Ming-Yuen; Hoi, Maggie Pui Man

2016-01-01

Calycosin and formononetin are two structurally similar isoflavonoids that have been shown to induce vasodilation in aorta and conduit arteries, but study of their actions on endothelial functions is lacking. Here, we demonstrated that both isoflavonoids relaxed rat mesenteric resistance arteries in a concentration-dependent manner, which was reduced by endothelial disruption and nitric oxide synthase (NOS) inhibition, indicating the involvement of both endothelium and vascular smooth muscle. In addition, the endothelium-dependent vasodilation, but not the endothelium-independent vasodilation, was blocked by BK Ca inhibitor iberiotoxin (IbTX). Using human umbilical vein endothelial cells (HUVECs) as a model, we showed calycosin and formononetin induced dose-dependent outwardly rectifying K + currents using whole cell patch clamp. These currents were blocked by tetraethylammonium chloride (TEACl), charybdotoxin (ChTX), or IbTX, but not apamin. We further demonstrated that both isoflavonoids significantly increased nitric oxide (NO) production and upregulated the activities and expressions of endothelial NOS (eNOS) and neuronal NOS (nNOS). These results suggested that calycosin and formononetin act as endothelial BK Ca activators for mediating endothelium-dependent vasodilation through enhancing endothelium hyperpolarization and NO production. Since activation of BK Ca plays a role in improving behavioral and cognitive disorders, we suggested that these two isoflavonoids could provide beneficial effects to cognitive disorders through vascular regulation.

Calycosin and Formononetin Induce Endothelium-Dependent Vasodilation by the Activation of Large-Conductance Ca2+-Activated K+ Channels (BKCa)

PubMed Central

Tseng, Hisa Hui Ling; Vong, Chi Teng; Leung, George Pak-Heng; Seto, Sai Wang; Lee, Simon Ming-Yuen

2016-01-01

Calycosin and formononetin are two structurally similar isoflavonoids that have been shown to induce vasodilation in aorta and conduit arteries, but study of their actions on endothelial functions is lacking. Here, we demonstrated that both isoflavonoids relaxed rat mesenteric resistance arteries in a concentration-dependent manner, which was reduced by endothelial disruption and nitric oxide synthase (NOS) inhibition, indicating the involvement of both endothelium and vascular smooth muscle. In addition, the endothelium-dependent vasodilation, but not the endothelium-independent vasodilation, was blocked by BKCa inhibitor iberiotoxin (IbTX). Using human umbilical vein endothelial cells (HUVECs) as a model, we showed calycosin and formononetin induced dose-dependent outwardly rectifying K+ currents using whole cell patch clamp. These currents were blocked by tetraethylammonium chloride (TEACl), charybdotoxin (ChTX), or IbTX, but not apamin. We further demonstrated that both isoflavonoids significantly increased nitric oxide (NO) production and upregulated the activities and expressions of endothelial NOS (eNOS) and neuronal NOS (nNOS). These results suggested that calycosin and formononetin act as endothelial BKCa activators for mediating endothelium-dependent vasodilation through enhancing endothelium hyperpolarization and NO production. Since activation of BKCa plays a role in improving behavioral and cognitive disorders, we suggested that these two isoflavonoids could provide beneficial effects to cognitive disorders through vascular regulation. PMID:27994632

The cardiovascular pharmacology of ICI 170777 ((6RS)-6-methyl-5-(pyrid-4-yl)-3H,6H-1,3,4- thiadiazin-2-one) a novel compound with positive inotropic and vasodilator effects.

PubMed Central

Collis, M. G.; Keddie, J. R.; Rouse, W.

1989-01-01

1. This paper describes the cardiovascular effects of ICI 170777, a novel compound which enhances cardiac contractility and causes arterial and venous dilatation. 2. The positive inotropic effects of ICI 170777 on the heart were demonstrated by an increase in left ventricular dP/dtmax in the anaesthetized and conscious dog, and by an increase in tension development in isolated papillary muscles from the cat. 3. In the anaesthetized dog, the positive inotropic effects of ICI 170777 and of isoprenaline were attenuated by atenolol (5 mg kg-1, i.v.). Atenolol displaced the dose-response curve to ICI 170777 to the right by 4 fold but displaced the isoprenaline dose-response curve to the right by 247 fold. In vitro, however, atenolol (10 microM) had no significant effect on the positive inotropic response to ICI 170777. In the ganglion-blocked anaesthetized dog, infusion of a low dose of ICI 170777 which had no effect on the basal left ventricular dP/dtmax, selectively potentiated the positive inotropic effects of isoprenaline. These results indicate that ICI 170777 has both a non-adrenoceptor-mediated positive inotropic effect on the heart and also facilitates the beta-adrenoceptor-mediated control of contractility. 4. In the denervated and perfused hind-limb of the dog, ICI 170777 reduced arterial perfusion pressure and increased limb circumference at a constant arterial flow and venous pressure. This indicates that ICI 170777 has direct dilator actions on both arterial and venous vessels. In this preparation, diazoxide exerted an arterial selective vasodilator effect and sodium nitroprusside was a relatively selective venous dilator.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2758224

Relationship of visit-to-visit and ambulatory blood pressure variability to vascular function in African Americans.

PubMed

Diaz, Keith M; Veerabhadrappa, Praveen; Kashem, Mohammed A; Feairheller, Deborah L; Sturgeon, Kathleen M; Williamson, Sheara T; Crabbe, Deborah L; Brown, Michael D

2012-01-01

Visit-to-visit clinic blood pressure variability (BPV) and 24-h BPV have both been identified as independent risk factors for cardiovascular (CV) morbidity and mortality; however, the mechanisms contributing to the increased CV risk as yet are unclear. The purpose of this study was to assess the relationship between BPV and endothelial function in a cohort of putatively healthy African Americans. A total of 36 African Americans who were sedentary, non-diabetic, non-smoking, free of CV and renal disease and not on antihypertensive medication followed an American Heart Association low fat, low salt diet for 6 weeks. Upon completion of the 6-week dietary stabilization period, participants underwent 24-h ambulatory BP monitoring and had their office blood pressure (BP) measured on 3 separate days. Right brachial artery diameter was assessed at rest, during reactive hyperemia (flow-mediated vasodilation: FMD), and after nitroglycerin administration (nitroglycerin-mediated vasodilation: NMD). Participants classified as having decreased endothelial function according to either %FMD or the FMD/NMD ratio had significantly higher 24-h BPV and a trend for higher visit-to-visit BPV when compared with participants with normal endothelial function. Continuous variable analyses revealed a significant positive association between NMD and 24-h diastolic BPV (DBPV). Visit-to-visit systolic BPV (SBPV), 24-h SBPV and 24-h DBPV were all negatively associated with the FMD/NMD ratio. All relationships remained significant after adjustment for age, body mass index and mean BP levels. These results may suggest that BPV is increased in African Americans with decreased endothelial function and is associated with the vascular smooth muscle response to nitric oxide.

Acute dietary nitrate supplementation enhances compensatory vasodilation during hypoxic exercise in older adults.

PubMed

Casey, Darren P; Treichler, David P; Ganger, Charles T; Schneider, Aaron C; Ueda, Kenichi

2015-01-15

We have previously demonstrated that aging reduces the compensatory vasodilator response during hypoxic exercise due to blunted nitric oxide (NO) signaling. Recent evidence suggests that NO bioavailability can be augmented by dietary nitrate through the nitrate-nitrite pathway. Thus we tested the hypothesis that acute dietary nitrate supplementation increases the compensatory vasodilator response to hypoxic exercise, particularly in older adults. Thirteen young (25 ± 1 yr) and 12 older (64 ± 2 yr) adults performed rhythmic forearm exercise at 20% of maximum voluntary contraction during normoxia and hypoxia (∼80% O2 saturation); both before (control) and 3 h after beetroot juice (BR) consumption. Forearm vascular conductance (FVC; ml·min(-1)·100 mmHg(-1)) was calculated from forearm blood flow (ml/min) and blood pressure (mmHg). Compensatory vasodilation was defined as the relative increase in FVC due to hypoxic exercise (i.e., % increase compared with respective normoxic exercise trial). Plasma nitrite was determined from venous blood samples obtained before the control trials and each of the exercise trials (normoxia and hypoxia) after BR. Consumption of BR increased plasma nitrite in both young and older adults (P < 0.001). During the control condition, the compensatory vasodilator response to hypoxic exercise was attenuated in older compared with young adults (3.8 ± 1.7% vs. 14.2 ± 1.2%, P < 0.001). Following BR consumption, compensatory vasodilation did not change in young (13.7 ± 3.3%, P = 0.81) adults but was substantially augmented in older adults (11.4 ± 2.1%, P < 0.01). Our data suggest that acute dietary nitrate supplementation increases the compensatory vasodilator response to hypoxic exercise in older but not young adults. Copyright © 2015 the American Physiological Society.

Identification of a salivary vasodilator in the primary North American vector of bluetongue viruses, Culicoides variipennis.

PubMed

Perez de Leon, A A; Ribeiro, J M; Tabachnick, W J; Valenzuela, J G

1997-09-01

Several species of Culicoides biting midges are important pests and vectors of pathogens affecting humans and other animals. Bluetongue is the most economically important arthropod-borne animal disease in the United States. Culicoides variipennis is the primary North American vector of the bluetongue viruses. A reddish halo surrounding a petechial hemorrhage was noticed at the site of C. variipennis blood feeding in previously unexposed sheep and rabbits. Salivary gland extracts of nonblood-fed C. variipennis injected intradermally into sheep and rabbits induced cutaneous vasodilation in the form of erythema. A local, dose-dependent erythema, without edema or pruritus, was noted 30 min after injection. Erythema was inapparent with salivary gland extracts obtained after blood feeding. This observation suggested that the vasodilatory activity was inoculated into the host skin at the feeding site. The vasodilatory activity was insoluble in ethanol and destroyed by trypsin or chymotrypsin, which indicated that vasodilation was due to a protein. The association of cutaneous vasodilation with a salivary protein was corroborated by reversed-phase, high-performance liquid chromatography (HPLC). Fractionation of salivary gland extracts by molecular sieving HPLC resulted in maximal vasodilatory activity that coeluted with a protein having a relative molecular weight (MWr) of 22.45 kD. The C. variipennis vasodilator appears to be biologically active at the nanogram level. This vasodilator likely assists C. variipennis during feeding by increasing blood flow from host superficial blood vessels surrounding the bite site. The identification of a salivary vasodilator in C. variipennis may have implications for the transmission of Culicoides-borne pathogens and in the development of dermatitis resulting from the sensitization of humans and animals to Culicoides salivary antigens.

Repeated cycles of electrical stimulation decrease vasoconstriction and axon-reflex vasodilation to noradrenaline in the human forearm

PubMed Central

Drummond, Peter D

2007-01-01

What is already known about this subject Repeated cycles of electrical stimulation inhibit cutaneous vasoconstriction to noradrenaline, but the mechanism is unknown. Investigating this is important because peripheral electrical stimulation is useful for pain modulation and appears to assist cutaneous wound healing. What this study adds Intermittent, brief electrical stimulation of the forearm over a 10-day period inhibited vasoconstriction and axon-reflex vasodilation to noradrenaline, but did not affect vasoconstriction to vasopressin or axon-reflex vasodilation to histamine. Thus, electrical stimulation may evoke a specific reduction in responsiveness to noradrenaline. Aim To investigate whether desensitization to the vasomotor effects of noradrenaline is a specific effect of electrical stimulation. Methods Three sites on the forearm of 10 healthy volunteers were stimulated with 0.2 mA direct current for 2 min twice daily for 10 days. Noradrenaline and histamine were then displaced from ring-shaped iontophoresis chambers into two of the pretreated sites and two untreated sites on the contralateral forearm. Axon-reflex vasodilation was measured from the centre of the ring described by the iontophoresis chamber with a laser Doppler flowmeter. One or two days later, noradrenaline and vasopressin were introduced into pretreated and untreated sites by iontophoresis, and vasoconstriction at sites of administration was measured in the heated forearm. Results The pretreatment blocked vasoconstriction to noradrenaline [median increase in flow 1%, interquartile range (IR) −41 to 52%; median decrease at the untreated site 53%, IR. −70 to −10%; P < 0.05], but did not block vasoconstriction to vasopressin (median decrease 42% at the untreated site and 45% at the pretreated site). Axon-reflex vasodilation to noradrenaline was diminished at the pretreated site (median increase in flow 33%, IR 2–321%; untreated site 247%, IR 31–1087%; P < 0.05). However, axon-reflex vasodilation to histamine did not differ significantly between the pretreated site (median increase 1085%) and the untreated site (median increase 1345%). Conclusions The conditioning pretreatment appears to evoke a specific decrease in responsiveness to noradrenaline. Repeated cycles of electrical stimulation may downregulate neural and vascular responses to noradrenaline by repetitively activating cutaneous sympathetic nerve fibres. PMID:17441931

Apixaban Enhances Vasodilatation Mediated by Protease-Activated Receptor 2 in Isolated Rat Arteries

PubMed Central

Villari, Ambra; Giurdanella, Giovanni; Bucolo, Claudio; Drago, Filippo; Salomone, Salvatore

2017-01-01

Apixaban (APX) is a direct inhibitor of factor X (FXa) approved for prophylaxis and treatment of deep venous thrombosis and atrial fibrillation. Because FXa activates protease-activated receptor 2 (PAR-2) in endothelium and vascular smooth muscle, inhibition of FXa by APX may affect vasomotor function. The effect of APX was assessed in vitro, by wire myography, in rat mesenteric resistance arteries (MRAs) and basilar arteries challenged with vasoconstrictors [phenylephrine (PE); 5-hydroxytryptamine (5-HT)], vasodilators [acetylcholine (ACh); sodium nitroprusside (SNP)] or with the PAR-2 peptide agonist SLIGRL. APX (10 μM) reduced the vasoconstriction to PE and 5-HT while did not change the vasodilatation to ACh or SNP. SLIGRL induced concentration-dependent vasodilation in pre-constricted arteries, that was reduced by incubation with the NO inhibitor NG-nitro-L-arginine (L-NNA) and abolished by endothelium removal. APX enhanced vasodilation to SLIGRL either in the presence or in the absence of L-NNA, but was ineffective in endothelium-denuded vessels. In preparations from heparin-treated rats (to inhibit FXa) APX did not change the vasodilation to SLIGRL. FXa enzymatic activity, detected in mesentery homogenates from controls, was inhibited by APX, whereas APX-sensitive enzymatic activity was undetectable in homogenates from heparin-treated rats. Immunoblot analysis showed that incubation of MRA or aorta with APX increased the abundance of PAR-2, an effect not seen in MRA from heparin-treated rats or in endothelium-denuded aortas. In conclusion, inhibition of FXa by APX increases vasodilatation mediated by PAR-2. APX may act by inhibiting PAR-2 desensitization induced by endogenous FXa. This effect could be useful in the context of endothelial dysfunction associated to cardiovascular diseases. PMID:28769809

Vasodilator therapy with hydralazine induces angiotensin AT2 receptor-mediated cardiomyocyte growth in mice lacking guanylyl cyclase-A

PubMed Central

Li, Y; Saito, Y; Kuwahara, K; Rong, X; Kishimoto, I; Harada, M; Horiuchi, M; Murray, M; Nakao, K

2010-01-01

Background and purpose: Recent clinical guidelines advocate the use of the isosorbide dinitrate/hydralazine combination in treatment for heart failure. However, clinical and laboratory evidence suggest that some vasodilators may induce cardiac hypertrophy under uncertain conditions. This study investigated the effects and underlying mechanism of action of the vasodilator hydralazine on cardiac growth. Experimental approach: Wild-type mice and animals deficient in guanylyl cyclase-A (GCA) and/or angiotensin receptors (AT1 and AT2 subtypes) were treated with hydralazine (≈24 mg·kg−1·day−1 in drinking water) for 5 weeks. Cardiac mass and/or cardiomyocyte cross-sectional area, fibrosis (van Giessen-staining) and cardiac gene expression (real-time RT-PCR) were measured. Key results: Hydralazine lowered blood pressure in mice of all genotypes. However, this treatment increased the heart and left ventricular to body weight ratios, as well as cardiomyocyte cross-sectional area, and cardiac expression of atrial natriuretic peptide mRNA in mice lacking GCA. Hydralazine did not affect cardiac hypertrophy in wild-type mice and mice lacking either AT1 or AT2 receptors alone. However, the pro-hypertrophic effect of hydralazine was prevented in mice lacking both GCA and AT2, but not GCA and AT1 receptors. However, hydralazine did decrease cardiac collagen deposition and collagen I mRNA (signs of cardiac fibrosis) in mice that were deficient in GCA, or both GCA and AT2 receptors. Conclusions and implications: The vasodilator hydralazine induced AT2 receptor-mediated cardiomyocyte growth under conditions of GCA deficiency. However, attenuation of cardiac fibrosis by hydralazine could be beneficial in the management of cardiac diseases. PMID:20136844

Interaction of calcitonin gene related peptide (CGRP) and substance P (SP) in human skin.

PubMed

Schlereth, Tanja; Schukraft, Jonas; Krämer-Best, Heidrun H; Geber, Christian; Ackermann, Tatiana; Birklein, Frank

2016-10-01

Calcitonin gene related peptide (CGRP) and substance P (SP) are neuropeptides that are simultaneously released from nociceptive C-fibers. CGRP is a potent vasodilator, inducing a long-lasting increase in superficial skin blood flow, whereas SP induces only a brief vasodilation but a significant plasma extravasation. CGRP and SP may play important roles in the pathophysiology of various pain states but little is known about their interaction. Different concentrations of SP (ranging from 10 -5 M to 10 -9 M) were applied to the volar forearm of 24 healthy subjects via dermal microdialysis. SP was applied either alone or in combination with CGRP10 -9 M and CGRP 10 -6 M. As expected, SP induced a transient increase in skin blood flow that decayed shortly after application. This transient blood flow peak was blunted with co-application of CGRP 10 -9 M and inhibited with co-application of CGRP10 -6 M. SP alone induced plasma protein extravasation (PPE). However, when CGRP10 -6 M was added, the PPE significantly increased. Our results demonstrate a complex interaction of the neuropeptides CGRP and SP. CGRP10 -6 M prevented SP-induced early vasodilation but augmented SP-induced PPE. These interactions might explain why vascular symptoms in chronic pain can differ strikingly between individuals. Copyright © 2016 Elsevier Ltd. All rights reserved.

Periodontal treatment improves endothelial dysfunction in patients with severe periodontitis.

PubMed

Seinost, Gerald; Wimmer, Gernot; Skerget, Martina; Thaller, Erik; Brodmann, Marianne; Gasser, Robert; Bratschko, Rudolf O; Pilger, Ernst

2005-06-01

Because epidemiological studies provide evidence that periodontal infections are associated with an increased risk of progression of cardiovascular and cerebrovascular disease, we postulated that endothelial dysfunction, a critical element in the pathogenesis of atherosclerosis, would be present in patients with periodontal disease. We tested endothelial function in 30 patients with severe periodontitis and 31 control subjects using flow-mediated dilation (FMD) of the brachial artery. The groups were matched for age, sex, and cardiovascular risk factors. Three months after periodontal treatment, including both mechanical and pharmacological therapy, endothelial function was reassessed by brachial artery FMD. Markers of systemic inflammation were measured at baseline and at follow up. Flow-mediated dilation was significantly lower in patients with periodontitis than in control subjects (6.1% +/- 4.4% vs 8.5% +/- 3.4%, P = .002). Successful periodontal treatment resulted in a significant improvement in FMD (9.8% +/- 5.7%; P = .003 compared to baseline) accompanied by a significant decrease in C-reactive protein concentrations (1.1 +/- 1.9 vs 0.8 +/- 0.8 at baseline, P = .026). Endothelium-independent nitro-induced vasodilation did not differ between the study groups at baseline or after periodontal therapy. These results indicate that treatment of severe periodontitis reverses endothelial dysfunction. Whether improved endothelial function will translate into a beneficial effect on atherogenesis and cardiovascular events needs further investigation.

iNOS-dependent sweating and eNOS-dependent cutaneous vasodilation are evident in younger adults, but are diminished in older adults exercising in the heat

PubMed Central

Fujii, Naoto; Meade, Robert D.; Alexander, Lacy M.; Akbari, Pegah; Foudil-bey, Imane; Louie, Jeffrey C.; Boulay, Pierre

2015-01-01

Nitric oxide synthase (NOS) contributes to sweating and cutaneous vasodilation during exercise in younger adults. We hypothesized that endothelial NOS (eNOS) and neuronal NOS (nNOS) mediate NOS-dependent sweating, whereas eNOS induces NOS-dependent cutaneous vasodilation in younger adults exercising in the heat. Further, aging may upregulate inducible NOS (iNOS), which may attenuate sweating and cutaneous vasodilator responses. We hypothesized that iNOS inhibition would augment sweating and cutaneous vasodilation in exercising older adults. Physically active younger (n = 12, 23 ± 4 yr) and older (n = 12, 60 ± 6 yr) adults performed two 30-min bouts of cycling at a fixed rate of metabolic heat production (400 W) in the heat (35°C). Sweat rate and cutaneous vascular conductance (CVC) were evaluated at four intradermal microdialysis sites with: 1) lactated Ringer (control), 2) nNOS inhibitor (nNOS-I, NPLA), 3) iNOS inhibitor (iNOS-I, 1400W), or 4) eNOS inhibitor (eNOS-I, LNAA). In younger adults during both exercise bouts, all inhibitors decreased sweating relative to control, albeit a lower sweat rate was observed at iNOS-I compared with eNOS-I and nNOS-I sites (all P < 0.05). CVC at the eNOS-I site was lower than control in younger adults throughout the intermittent exercise protocol (all P < 0.05). In older adults, there were no differences between control and iNOS-I sites for sweating and CVC during both exercise bouts (all P > 0.05). We show that iNOS and eNOS are the main contributors to NOS-dependent sweating and cutaneous vasodilation, respectively, in physically active younger adults exercising in the heat, and that iNOS inhibition does not alter sweating or cutaneous vasodilation in exercising physically active older adults. PMID:26586908

iNOS-dependent sweating and eNOS-dependent cutaneous vasodilation are evident in younger adults, but are diminished in older adults exercising in the heat.

PubMed

Fujii, Naoto; Meade, Robert D; Alexander, Lacy M; Akbari, Pegah; Foudil-Bey, Imane; Louie, Jeffrey C; Boulay, Pierre; Kenny, Glen P

2016-02-01

Nitric oxide synthase (NOS) contributes to sweating and cutaneous vasodilation during exercise in younger adults. We hypothesized that endothelial NOS (eNOS) and neuronal NOS (nNOS) mediate NOS-dependent sweating, whereas eNOS induces NOS-dependent cutaneous vasodilation in younger adults exercising in the heat. Further, aging may upregulate inducible NOS (iNOS), which may attenuate sweating and cutaneous vasodilator responses. We hypothesized that iNOS inhibition would augment sweating and cutaneous vasodilation in exercising older adults. Physically active younger (n = 12, 23 ± 4 yr) and older (n = 12, 60 ± 6 yr) adults performed two 30-min bouts of cycling at a fixed rate of metabolic heat production (400 W) in the heat (35°C). Sweat rate and cutaneous vascular conductance (CVC) were evaluated at four intradermal microdialysis sites with: 1) lactated Ringer (control), 2) nNOS inhibitor (nNOS-I, NPLA), 3) iNOS inhibitor (iNOS-I, 1400W), or 4) eNOS inhibitor (eNOS-I, LNAA). In younger adults during both exercise bouts, all inhibitors decreased sweating relative to control, albeit a lower sweat rate was observed at iNOS-I compared with eNOS-I and nNOS-I sites (all P < 0.05). CVC at the eNOS-I site was lower than control in younger adults throughout the intermittent exercise protocol (all P < 0.05). In older adults, there were no differences between control and iNOS-I sites for sweating and CVC during both exercise bouts (all P > 0.05). We show that iNOS and eNOS are the main contributors to NOS-dependent sweating and cutaneous vasodilation, respectively, in physically active younger adults exercising in the heat, and that iNOS inhibition does not alter sweating or cutaneous vasodilation in exercising physically active older adults. Copyright © 2016 the American Physiological Society.

Role of GPER in estrogen-dependent nitric oxide formation and vasodilation.

PubMed

Fredette, Natalie C; Meyer, Matthias R; Prossnitz, Eric R

2018-02-01

Estrogens are potent regulators of vasomotor tone, yet underlying receptor- and ligand-specific signaling pathways remain poorly characterized. The primary physiological estrogen 17β-estradiol (E2), a non-selective agonist of classical nuclear estrogen receptors (ERα and ERβ) as well as the G protein-coupled estrogen receptor (GPER), stimulates formation of the vasodilator nitric oxide (NO) in endothelial cells. Here, we studied the contribution of GPER signaling in E2-dependent activation of endothelial NO formation and subsequent vasodilation. Employing E2 and the GPER-selective agonist G-1, we investigated eNOS phosphorylation and NO formation in human endothelial cells, and endothelium-dependent vasodilation in the aortae of wild-type and Gper-deficient mice. Both E2 and G-1 induced phosphorylation of eNOS at the activation site Ser1177 to similar extents. Endothelial NO production to E2 was comparable to that of G-1, and was substantially reduced after pharmacological inhibition of GPER. Similarly, the clinically used ER-targeting drugs 4OH-tamoxifen, raloxifene, and ICI182,780 (faslodex, fulvestrant™) induced NO formation in part via GPER. We identified c-Src, EGFR, PI3K and ERK signaling pathways to be involved in GPER-dependent NO formation. In line with activation of NO formation in cells, E2 and G-1 induced equally potent vasodilation in the aorta of wild-type mice. Gper deletion completely abrogated the vasodilator response to G-1, while reducing the response to E2 by ∼50%. These findings indicate that a substantial portion of E2-induced endothelium-dependent vasodilation and NO formation is mediated by GPER. Thus, selective targeting of vascular GPER may be a suitable approach to activate the endothelial NO pathway, possibly leading to reduced vasomotor tone and inhibition of atherosclerotic vascular disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

Modulating Vascular Hemodynamics With an Alpha Globin Mimetic Peptide (HbαX).

PubMed

Keller, T C Stevenson; Butcher, Joshua T; Broseghini-Filho, Gilson Brás; Marziano, Corina; DeLalio, Leon J; Rogers, Stephen; Ning, Bo; Martin, Jennifer N; Chechova, Sylvia; Cabot, Maya; Shu, Xiahong; Best, Angela K; Good, Miranda E; Simão Padilha, Alessandra; Purdy, Michael; Yeager, Mark; Peirce, Shayn M; Hu, Song; Doctor, Allan; Barrett, Eugene; Le, Thu H; Columbus, Linda; Isakson, Brant E

2016-12-01

The ability of hemoglobin to scavenge the potent vasodilator nitric oxide (NO) in the blood has been well established as a mechanism of vascular tone homeostasis. In endothelial cells, the alpha chain of hemoglobin (hereafter, alpha globin) and endothelial NO synthase form a macromolecular complex, providing a sink for NO directly adjacent to the production source. We have developed an alpha globin mimetic peptide (named HbαX) that displaces endogenous alpha globin and increases bioavailable NO for vasodilation. Here we show that, in vivo, HbαX administration increases capillary oxygenation and blood flow in arterioles acutely and produces a sustained decrease in systolic blood pressure in normal and angiotensin II-induced hypertensive states. HbαX acts with high specificity and affinity to endothelial NO synthase, without toxicity to liver and kidney and no effect on p50 of O 2 binding in red blood cells. In human vasculature, HbαX blunts vasoconstrictive response to cumulative doses of phenylephrine, a potent constricting agent. By binding to endothelial NO synthase and displacing endogenous alpha globin, HbαX modulates important metrics of vascular function, increasing vasodilation and flow in the resistance vasculature. © 2016 American Heart Association, Inc.

Agonistic autoantibodies as vasodilators in orthostatic hypotension: a new mechanism.

PubMed

Li, Hongliang; Kem, David C; Reim, Sean; Khan, Muneer; Vanderlinde-Wood, Megan; Zillner, Caitlin; Collier, Daniel; Liles, Campbell; Hill, Michael A; Cunningham, Madeleine W; Aston, Christopher E; Yu, Xichun

2012-02-01

Agonistic autoantibodies to the β-adrenergic and muscarinic receptors are a novel investigative and therapeutic target for certain orthostatic disorders. We have identified the presence of autoantibodies to β2-adrenergic and/or M3 muscarinic receptors by ELISA in 75% (15 of 20) of patients with significant orthostatic hypotension. Purified serum IgG from all 20 of the patients and 10 healthy control subjects were examined in a receptor-transfected cell-based cAMP assay for β2 receptor activation and β-arrestin assay for M3 receptor activation. There was a significant increase in IgG-induced activation of β2 and M3 receptors in the patient group compared with controls. A dose response was observed for both IgG activation of β2 and M3 receptors and inhibition of their activation with the nonselective β blocker propranolol and muscarinic blocker atropine. The antibody effects on β2 and/or M3 (via production of NO) receptor-mediated vasodilation were studied in a rat cremaster resistance arteriole assay. Infusion of IgG from patients with documented β2 and/or M3 receptor agonistic activity produced a dose-dependent vasodilation. Sequential addition of the β-blocker propranolol and the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester partially inhibited IgG-induced vasodilation (percentage of maximal dilatory response: from 57.7±10.4 to 35.3±4.6 and 24.3±5.8, respectively; P<0.01; n=3), indicating that antibody activation of vascular β2 and/or M3 receptors may contribute to systemic vasodilation. These data support the concept that circulating agonistic autoantibodies serve as vasodilators and may cause or exacerbate orthostatic hypotension.

Loss of Female Sex Hormones Exacerbates Cerebrovascular and Cognitive Dysfunction in Aortic Banded Miniswine Through a Neuropeptide Y-Ca2+-Activated Potassium Channel-Nitric Oxide Mediated Mechanism.

PubMed

Olver, T Dylan; Hiemstra, Jessica A; Edwards, Jenna C; Schachtman, Todd R; Heesch, Cheryl M; Fadel, Paul J; Laughlin, M Harold; Emter, Craig A

2017-10-31

Postmenopausal women represent the largest cohort of patients with heart failure with preserved ejection fraction, and vascular dementia represents the most common form of dementia in patients with heart failure with preserved ejection fraction. Therefore, we tested the hypotheses that the combination of cardiac pressure overload (aortic banding [AB]) and the loss of female sex hormones (ovariectomy [OVX]) impairs cerebrovascular control and spatial memory. Female Yucatan miniswine were separated into 4 groups (n=7 per group): (1) control, (2) AB, (3) OVX, and (4) AB-OVX. Pigs underwent OVX and AB at 7 and 8 months of age, respectively. At 14 months, cerebral blood flow velocity and spatial memory (spatial hole-board task) were lower in the OVX groups ( P <0.05), with significant impairments in the AB-OVX group ( P <0.05). Resting carotid artery β stiffness and vascular resistance during central hypovolemia were increased in the AB-OVX group ( P <0.05), and blood flow recovery after central hypovolemia was reduced in both OVX groups ( P <0.05). Isolated pial artery (pressure myography) vasoconstriction to neuropeptide Y was greatest in the AB-OVX group ( P <0.05), and vasodilation to the Ca 2+ -activated potassium channel α-subunit agonist NS-1619 was impaired in both AB groups ( P <0.05). The ratio of phosphorylated endothelial nitric oxide synthase:total endothelial nitric oxide synthase was depressed and Ca 2+ -activated potassium channel α-subunit protein was increased in AB groups ( P <0.05). Mechanistically, impaired cerebral blood flow control in experimental heart failure may be the result of heightened neuropeptide Y-induced vasoconstriction along with reduced vasodilation associated with decreased Ca 2+ -activated potassium channel function and impaired nitric oxide signaling, the effects of which are exacerbated in the absence of female sex hormones. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Depletion of NADP(H) due to CD38 activation triggers endothelial dysfunction in the postischemic heart.

PubMed

Reyes, Levy A; Boslett, James; Varadharaj, Saradhadevi; De Pascali, Francesco; Hemann, Craig; Druhan, Lawrence J; Ambrosio, Giuseppe; El-Mahdy, Mohamed; Zweier, Jay L

2015-09-15

In the postischemic heart, coronary vasodilation is impaired due to loss of endothelial nitric oxide synthase (eNOS) function. Although the eNOS cofactor tetrahydrobiopterin (BH4) is depleted, its repletion only partially restores eNOS-mediated coronary vasodilation, indicating that other critical factors trigger endothelial dysfunction. Therefore, studies were performed to characterize the unidentified factor(s) that trigger endothelial dysfunction in the postischemic heart. We observed that depletion of the eNOS substrate NADPH occurs in the postischemic heart with near total depletion from the endothelium, triggering impaired eNOS function and limiting BH4 rescue through NADPH-dependent salvage pathways. In isolated rat hearts subjected to 30 min of ischemia and reperfusion (I/R), depletion of the NADP(H) pool occurred and was most marked in the endothelium, with >85% depletion. Repletion of NADPH after I/R increased NOS-dependent coronary flow well above that with BH4 alone. With combined NADPH and BH4 repletion, full restoration of NOS-dependent coronary flow occurred. Profound endothelial NADPH depletion was identified to be due to marked activation of the NAD(P)ase-activity of CD38 and could be prevented by inhibition or specific knockdown of this protein. Depletion of the NADPH precursor, NADP(+), coincided with formation of 2'-phospho-ADP ribose, a CD38-derived signaling molecule. Inhibition of CD38 prevented NADP(H) depletion and preserved endothelium-dependent relaxation and NO generation with increased recovery of contractile function and decreased infarction in the postischemic heart. Thus, CD38 activation is an important cause of postischemic endothelial dysfunction and presents a novel therapeutic target for prevention of this dysfunction in unstable coronary syndromes.

Endothelial dysfunction assessment by flow-mediated dilation in a high-altitude population.

PubMed

Calderón-Gerstein, Walter S; López-Peña, Antonio; Macha-Ramírez, Raúl; Bruno-Huamán, Astrid; Espejo-Ramos, Roxana; Vílchez-Bravo, Stephany; Ramírez-Breña, María; Damián-Mucha, Milagros; Matos-Mucha, Adriana

2017-01-01

Endothelial function at high altitude has been measured only in populations that are genetically adapted to chronic hypoxia. The objective of this study was to evaluate endothelial dysfunction (ED) in a nongenetically adapted high-altitude population of the Andes mountains, in Huancayo, Peru (3,250 meters above sea level). Participants included 61 patients: 28 cases and 33 controls. The cases were subjects with hypertension, diabetes mellitus, obesity, or a history of stroke or coronary artery disease. Flow-mediated vasodilation (FMD) of the brachial artery was measured in the supine position, at noon, after 5 minutes of resting. The brachial artery was identified above the elbow. Its basal diameter was measured during diastole, and FMD was tested after 5 minutes of forearm ischemia. Intima-media complex in the right carotid artery was also determined. An increase in the artery's baseline diameter <10% indicated a positive test. Endothelium-independent vasodilation was evaluated with sublingual nitrate administration. The intima-media complex in the right carotid artery was also measured. 100% of diabetics had ED; ED was also found in 68.8% of obese individuals, 55% of hypertensive patients, and 46.5% of controls. Age, height, body mass index, and waist diameter were higher in the cases as compared with the controls. A total of 57.9% (n=11) of the cases and 45.2% (n=19) of the controls presented ED. Patients without ED had a mean increase in brachial artery diameter of 23.16%, while in those with ED it was only 3.84%. Individuals with diabetes or hypertension had a greater thickness of the carotid artery intima media layer (1.092 versus 0.664 cm) ( p =0.037). A positive test for ED was associated with a greater basal diameter of the brachial artery (4.66±0.62 versus 4.23±0.59 cm) ( p =0.02). A total of 7 patients presented paradoxical response, developing posthyperemia vasoconstriction. The proportion of ED was high among controls and among patients with risk factors. Controls showed better FMD profiles than subjects studied in Tibet and the Himalayas.

[The two faces of veno-arteriolar reflex: cutaneous vasodilatation and vasoconstriction to raise and to lower the arm].

PubMed

Estanol-Vidal, B; Gutierrez-Manjarrez, F; Martinez-Memije, R; Senties-Madrid, H; Berenguer-Sanchez, M J; Magana-Zamora, L; Delgado-Garcia, G; Chiquete-Anaya, E

2016-05-01

The veno-arteriolar reflex (VAR) is triggered by an increase in the transmural venous pressure on placing a part of the body in the same direction as the gravitational acceleration below the heart. To assess the VAR in healthy subjects on raising a part of the body above the level of the heart. VAR was studied in 16 healthy subjects (20-65 years old) by means of changes in the blood flow in the skin detected using a digital infrared photoplethysmograph attached to the fingertip under the following conditions: right arm at the height of the heart, right arm below the heart and right arm below the level of the heart. The variables measured were: amplitude of the blood flow in the skin with the arm raised to the height of the heart (baseline amplitude), percentage decrease of the blood flow in the skin with the arm below the heart and percentage increase in blood flow with the arm above the heart. The percentage of vasoconstriction with the right arm below the heart was 35%, and that of vasodilation, 50%. Evaluation of the VAR with the arm below the heart causes vasoconstriction, and elevation of the arm causes an important degree of vasodilation. Vasoconstriction and vasodilation are maintained while the limb is kept above or below the heart. This is an economical and potentially very useful way of studying the innervation of the microcirculation in a number of different peripheral neuropathies of thin and mixed fibres.

Vasodilator responses to nitric oxide are enhanced in mesenteric arteries of portal hypertensive rats.

PubMed

Heinemann, A; Stauber, R E

1996-09-01

Nitric oxide (NO) is discussed as a mediator of the splanchnic hyperaemia in portal hypertension. We assessed the vasorelaxation by the NO-dependent vasodilator acetylcholine, the NO donor 3-morpholino-sydnonimine (SIN-1) and forskolin, a stimulator of the adenylate cyclase pathway in potassium-preconstricted isolated perfused mesenteric arteries of portal vein-ligated and sham-operated rats. Dilator responses to acetylcholine and SIN-1 were significantly enhanced in vessels of portal vein-ligated rats as compared to sham-operated rats, whereas no difference was found in forskolin-induced vasodilatation. This suggests enhanced reactivity of the vasculature to NO in experimental portal hypertension.

Skin grafting impairs postsynaptic cutaneous vasodilator and sweating responses.

PubMed

Davis, Scott L; Shibasaki, Manabu; Low, David A; Cui, Jian; Keller, David M; Purdue, Gary F; Hunt, John L; Arnoldo, Brett D; Kowalske, Karen J; Crandall, Craig G

2007-01-01

This study tested the hypothesis that postsynaptic cutaneous vascular responses to endothelial-dependent and -independent vasodilators, as well as sweat gland function, are impaired in split-thickness grafted skin 5 to 9 months after surgery. Intradermal microdialysis membranes were placed in grafted and adjacent control skin, thereby allowing local delivery of the endothelial-dependent vasodilator, acetylcholine (ACh; 1 x 10(-7) to 1 x 10(-1) M at 10-fold increments) and the endothelial-independent nitric oxide donor, sodium nitroprusside (SNP; 5 x 10(-8) to 5 x 10(-2) M at 10-fold increments). Skin blood flow and sweat rate were simultaneously assessed over the semipermeable portion of the membrane. Cutaneous vascular conductance (CVC) was calculated from the ratio of laser Doppler-derived skin blood flow to mean arterial blood pressure. deltaCVC responses from baseline to these drugs were modeled via nonlinear regression curve fitting to identify the dose of ACh and SNP causing 50% of the maximal vasodilator response (EC50). A rightward shift in the CVC dose response curve for ACh was observed in grafted (EC50 = -2.61 +/- 0.44 log M) compared to adjacent control skin (EC50 = -3.34 +/- 0.46 log M; P = .003), whereas the mean EC50 for SNP was similar between grafted (EC50 = -4.21 +/- 0.94 log M) and adjacent control skin (EC50 = -3.87 +/- 0.65 log M; P = 0.332). Only minimal sweating to exogenous ACh was observed in grafted skin whereas normal sweating was observed in control skin. Increased EC50 and decreased maximal CVC responses to the exogenous administration of ACh suggest impairment of endothelial-dependent cutaneous vasodilator responses in grafted skin 5 to 9 months after surgery. Greatly attenuated sweating responses to ACh suggests either abnormal or an absence of functional sweat glands in the grafted skin.

Inhaled carbon monoxide does not cause pulmonary vasodilation in the late-gestation fetal lamb.

PubMed

Grover, T R; Rairigh, R L; Zenge, J P; Abman, S H; Kinsella, J P

2000-04-01

As observed with nitric oxide (NO), carbon monoxide (CO) binds and may activate soluble guanylate cyclase and increase cGMP levels in smooth muscle cells in vitro. Because inhaled NO (I(NO)) causes potent and sustained pulmonary vasodilation, we hypothesized that inhaled CO (I(CO)) may have similar effects on the perinatal lung. To determine whether I(CO) can lower pulmonary vascular resistance (PVR) during the perinatal period, we studied the effects of I(CO) on late-gestation fetal lambs. Catheters were placed in the main pulmonary artery, left pulmonary artery (LPA), aorta, and left atrium to measure pressure. An ultrasonic flow transducer was placed on the LPA to measure blood flow to the left lung. After baseline measurements, fetal lambs were mechanically ventilated with a hypoxic gas mixture (inspired O(2) fraction < 0.10) to maintain a constant fetal arterial PO(2). After 60 min (baseline), the lambs were treated with I(CO) [5-2,500 parts/million (ppm)]. Comparisons were made with I(NO) (5 and 20 ppm) and combined I(NO) (5 ppm) and I(CO) (100 and 2,500 ppm). We found that I(CO) did not alter left lung blood flow or PVR at any of the study doses. In contrast, low-dose I(NO) decreased PVR by 47% (P < 0.005). The combination of I(NO) and I(CO) did not enhance the vasodilator response to I(NO). To determine whether endogenous CO contributes to vascular tone in the fetal lung, zinc protoporphyrin IX, an inhibitor of heme oxygenase, was infused into the LPA in three lambs. Zinc protoporphyrin IX had no effect on baseline PVR, aortic pressure, or the pressure gradient across the ductus arteriosus. We conclude that I(CO) does not cause vasodilation in the near-term ovine transitional circulation, and endogenous CO does not contribute significantly to baseline pulmonary vascular tone or ductus arteriosus tone in the late-gestation ovine fetus.

Nitric Oxide Contributes to Vasomotor Tone in Hypertensive African Americans Treated With Nebivolol and Metoprolol.

PubMed

Neuman, Robert B; Hayek, Salim S; Poole, Joseph C; Rahman, Ayaz; Menon, Vivek; Kavtaradze, Nino; Polhemus, David; Veledar, Emir; Lefer, David J; Quyyumi, Arshed A

2016-03-01

Endothelial dysfunction is more prevalent in African Americans (AAs) compared with whites. The authors hypothesized that nebivolol, a selective β1 -antagonist that stimulates nitric oxide (NO), will improve endothelial function in AAs with hypertension when compared with metoprolol. In a double-blind, randomized, crossover study, 19 AA hypertensive patients were randomized to a 12-week treatment period with either nebivolol 10 mg or metoprolol succinate 100 mg daily. Forearm blood flow (FBF) was measured using plethysmography at rest and after intra-arterial infusion of acetylcholine and sodium nitroprusside to estimate endothelium-dependent and independent vasodilation, respectively. Physiologic vasodilation was assessed during hand-grip exercise. Measurements were repeated after NO blockade with L-N(G) -monomethylarginine (L-NMMA) and after inhibition of endothelium-derived hyperpolarizing factor (EDHF) with tetraethylammonium chloride (TEA). NO blockade with L-NMMA produced a trend toward greater vasoconstriction during nebivolol compared with metoprolol treatment (21% vs 12% reduction in FBF, P=.06, respectively). This difference was more significant after combined administration of L-NMMA and TEA (P<.001). Similarly, there was a contribution of NO to exercise-induced vasodilation during nebivolol but not during metoprolol treatment. There were significantly greater contributions of NO and EDHF to resting vasodilator tone and of NO to exercise-induced vasodilation with nebivolol compared with metoprolol in AAs with hypertension. © 2015 Wiley Periodicals, Inc.

Nitric Oxide Contributes to Vasomotor Tone in Hypertensive African Americans Treated With Nebivolol and Metoprolol

PubMed Central

Neuman, Robert B.; Hayek, Salim; Poole, Joseph C.; Rahman, Ayaz; Menon, Vivek; Kavtaradze, Nino; Polhemus, David; Veledar, Emir; Lefer, David J.; Quyyumi, Arshed A.

2015-01-01

Endothelial dysfunction is more prevalent in African Americans (AA) compared to whites. We hypothesized that nebivolol, a selective β-1 antagonist that stimulates NO, will improve endothelial function in AA with hypertension when compared to metoprolol. In a double-blind, randomized, cross-over study, 19 AA hypertensive subjects were randomized to a 12-week treatment period with either nebivolol 10mg or metoprolol succinate 100mg daily. Forearm blood flow (FBF) was measured using plethysmography at rest and after intra-arterial infusion of acetylcholine, and sodium nitroprusside to estimate endothelium-dependent and independent vasodilation, respectively. Physiologic vasodilation was assessed during hand-grip exercise. Measurements were repeated after NO blockade with L-NG-monomethylarginine (L-NMMA), and after inhibition of endothelium-derived hyperpolarizing factor (EDHF) with tetraethylammonium chloride (TEA). NO blockade with L-NMMA produced a trend toward greater vasoconstriction during nebivolol compared to metoprolol treatment period (21% vs 12% reduction in FBF, p=0.06, respectively). This difference was more significant after combined administration of L-NMMA and TEA (p<0.001). Similarly, there was a contribution of NO to exercise-induced vasodilation during nebivolol but not during metoprolol treatment. There were significantly greater contributions of NO and EDHF to resting vasodilator tone and of NO to exercise-induced vasodilation with nebivolol compared to metoprolol in AA with hypertension. PMID:26285691

Time course of vasodilatory responses in skeletal muscle arterioles: role in hyperemia at onset of exercise

NASA Technical Reports Server (NTRS)

Wunsch, S. A.; Muller-Delp, J.; Delp, M. D.

2000-01-01

At the onset of dynamic exercise, muscle blood flow increases within 1-2 s. It has been postulated that local vasodilatory agents produced by the vascular endothelium or the muscle itself contribute to this response. We hypothesized that only vasodilators that act directly on the vascular smooth muscle could produce vasodilation of skeletal muscle arterioles in <2 s. To test this hypothesis, we determined the time course of the vasodilatory response of isolated skeletal muscle arterioles to direct application of potassium chloride, adenosine, acetylcholine, and sodium nitroprusside. Soleus and gastrocnemius muscles were dissected from the hindlimbs of male Sprague-Dawley rats. First-order arterioles (100-200 microm) were isolated, cannulated on micropipettes, and pressurized to 60 cmH(2)O in an organ bath. Vasodilatory agents were added directly to the bath, and diameter responses of the arterioles were recorded in real time on a videotape recorder. Frame-by-frame analysis of the diameter responses indicated that none of the vasodilator agents tested produced significant diameter increases in <4 s in either soleus or gastrocnemius muscle arterioles. These results indicate that, although these local vasodilators produce significant vasodilation of skeletal muscle resistance arterioles, these responses are not rapid enough (within 1-2 s) to contribute to the initiation of the exercise hyperemic response at the onset of dynamic exercise.

Intestinal trophic effect of enteral arginine is independent of blood flow in neonatal piglets

USDA-ARS?s Scientific Manuscript database

Arginine (ARG) is an indispensable amino acid (AA) in neonates and is required for growth. ARG is synthesized by gut epithelial cells and is a precursor for nitric oxide, which stimulates vasodilation and blood flow. Moreover, evidence indicates that ARG may have a protective role in prevention of n...

Antioxidant and Vasodilator Activity of Ugni molinae Turcz. (Murtilla) and Its Modulatory Mechanism in Hypotensive Response

PubMed Central

Jofré, Ignacio; Pezoa, Cesar; Scheuermann, Erick; Rosalen, Pedro Luiz; Romero, Fernando

2016-01-01

Hypertension is a systemic condition with high morbidity and mortality rates worldwide, which poses an increased risk for cardiovascular diseases. In this study, we demonstrated the antioxidant and vasodilator activity of Ugni molinae Turcz. (Murtilla) fruit, a berry native to Chile and proposed models to explain its modulatory mechanism in hypotensive response. Murtilla fruits were cultivated in a germplasm bank and submitted to chemical and biological analyses. The phenolic compounds gallic acid, Catechin, Quercetin-3-β-D-glucoside, Myricetin, Quercetin, and Kaempferol were identified. Murtilla extract did not generate toxic effects on human endothelial cells and had significant antioxidant activity against ROS production, lipid peroxidation, and superoxide anion production. Furthermore, it showed dose-dependent vasodilator activity in aortic rings in the presence of endothelium, whose hypotensive mechanism is partially mediated by nitric oxide synthase/guanylate cyclase and large-conductance calcium-dependent potassium channels. Murtilla fruits might potentially have beneficial effects on the management of cardiovascular diseases. PMID:27688827

Control of cerebral cortical blood flow by stimulation of basal forebrain cholinergic areas in mice.

PubMed

Hotta, Harumi; Uchida, Sae; Kagitani, Fusako; Maruyama, Naoki

2011-05-01

We examined whether activity of the nucleus basalis of Meynert (NBM) regulates regional cerebral cortical blood flow (rCBF) in mice, using laser speckle and laser Doppler flowmetry. In anesthetized mice, unilateral focal stimulation, either electrical or chemical, of the NBM increased rCBF of the ipsilateral cerebral cortex in the frontal, parietal and occipital lobes, independent of changes in systemic blood pressure. Most of vasodilative responses to low intensity stimuli (2 times threshold intensity: 2T) were abolished by atropine (a muscarinic cholinergic blocker), whereas responses to higher intensity stimuli (3T) were abolished by atropine and mecamylamine (a nicotinic cholinergic blocker). Blood flow changes were largest when the tip of the electrode was located within the area containing cholinergic neurons shown by choline acetyltransferase-immunocytochemistry. These results suggest that cholinergic projections from basal forebrain neurons in mice cause vasodilation in the ipsilateral cerebral cortex by a combination of muscarinic and nicotinic mechanisms, as previously found in rats and cats.

Shaker-related voltage-gated K+ channel expression and vasomotor function in human coronary resistance arteries.

PubMed

Nishijima, Yoshinori; Korishettar, Ankush; Chabowski, Dawid S; Cao, Sheng; Zheng, Xiaodong; Gutterman, David D; Zhang, David X

2018-01-01

K V channels are important regulators of vascular tone, but the identity of specific K V channels involved and their regulation in disease remain less well understood. We determined the expression of K V 1 channel subunits and their role in cAMP-mediated dilation in coronary resistance arteries from subjects with and without CAD. HCAs from patients with and without CAD were assessed for mRNA and protein expression of K V 1 channel subunits with molecular techniques and for vasodilator response with isolated arterial myography. Assays of mRNA transcripts, membrane protein expression, and vascular cell-specific localization revealed abundant expression of K V 1.5 in vascular smooth muscle cells of non-CAD HCAs. Isoproterenol and forskolin, two distinct cAMP-mediated vasodilators, induced potent dilation of non-CAD arterioles, which was inhibited by both the general K V blocker 4-AP and the selective K V 1.5 blocker DPO-1. The cAMP-mediated dilation was reduced in CAD and was accompanied by a loss of or reduced contribution of 4-AP-sensitive K V channels. K V 1.5, as a major 4-AP-sensitive K V 1 channel expressed in coronary VSMCs, mediates cAMP-mediated dilation in non-CAD arterioles. The cAMP-mediated dilation is reduced in CAD coronary arterioles, which is associated with impaired 4-AP-sensitive K V channel function. © 2017 John Wiley & Sons Ltd.

Acetylcholine released from cholinergic nerves contributes to cutaneous vasodilation during heat stress

NASA Technical Reports Server (NTRS)

Shibasaki, Manabu; Wilson, Thad E.; Cui, Jian; Crandall, Craig G.

2002-01-01

Nitric oxide (NO) contributes to active cutaneous vasodilation during a heat stress in humans. Given that acetylcholine is released from cholinergic nerves during whole body heating, coupled with evidence that acetylcholine causes vasodilation via NO mechanisms, it is possible that release of acetylcholine in the dermal space contributes to cutaneous vasodilation during a heat stress. To test this hypothesis, in seven subjects skin blood flow (SkBF) and sweat rate were simultaneously monitored over three microdialysis membranes placed in the dermal space of dorsal forearm skin. One membrane was perfused with the acetylcholinesterase inhibitor neostigmine (10 microM), the second membrane was perfused with the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME; 10 mM) dissolved in the aforementioned neostigmine solution (l-NAME(Neo)), and the third membrane was perfused with Ringer solution as a control site. Each subject was exposed to approximately 20 min of whole body heating via a water-perfused suit, which increased mean body temperature from 36.4 +/- 0.1 to 37.5 +/- 0.1 degrees C (P < 0.05). After the heat stress, SkBF at each site was normalized to its maximum value, identified by administration of 28 mM sodium nitroprusside. Mean body temperature threshold for cutaneous vasodilation was significantly lower at the neostigmine-treated site relative to the other sites (neostigmine: 36.6 +/- 0.1 degrees C, l-NAME(Neo): 37.1 +/- 0.1 degrees C, control: 36.9 +/- 0.1 degrees C), whereas no significant threshold difference was observed between the l-NAME(Neo)-treated and control sites. At the end of the heat stress, SkBF was not different between the neostigmine-treated and control sites, whereas SkBF at the l-NAME(Neo)-treated site was significantly lower than the other sites. These results suggest that acetylcholine released from cholinergic nerves is capable of modulating cutaneous vasodilation via NO synthase mechanisms early in the heat stress but not after substantial cutaneous vasodilation.

Neural vasodilator control in the rectum of the cat and its possible mediation by vasoactive intestinal polypeptide.

PubMed Central

Andersson, P O; Bloom, S R; Edwards, A V; Järhult, J; Mellander, S

1983-01-01

Vascular and motor responses in the rectum to pelvic nerve stimulation are described in the anaesthetized cat and compared with corresponding effects observed in the colon. The responses comprise a cholinergic and a non-cholinergic component, and an attempt has been made to elucidate the latter. Pelvic nerve stimulation evoked a pronounced and well maintained vasodilator response in the rectum whereas that in the colon was transient. Maximal vasodilatation occurred at much lower stimulus frequencies in the rectum (2-4 Hz) than it did in the colon (8-16 Hz) and maximal blood flow under these conditions was also greater in the rectum (greater than 200 ml 100 g-1 min-1) than the colon (less than 150 ml 100 g-1 min-1). Muscarinic blockade further curtailed the colonic vasodilator response to pelvic nerve stimulation, whereas the rectal dilatation was only slightly reduced in the presence of atropine. Pelvic nerve stimulation caused a substantial release of vasoactive intestinal polypeptide (VIP) from the rectum, which was related both in magnitude and duration to the vasodilatation. Intra-arterial infusions of VIP, which reproduced this rise in rectal venous VIP concentration, caused a rectal vasodilator response which closely resembled that during pelvic nerve stimulation after cholinergic blockade. The rectal vasculature was estimated to be 50-100 times more sensitive to VIP than the colonic vasculature. VIP therefore seems to be the most likely putative neurotransmitter responsible for non-cholinergic rectal vasodilatation. Stimulation of the pelvic nerves also caused rapid contractile motor responses before, and more gradual motor responses after, muscarinic blockade in both the colon and rectum, in the latter preceded by a non-cholinergic relaxation. These patterns of motor activity largely confirm previous results. Infusions of substance P effectively mimicked the non-cholinergic contractile motor responses but failed to demonstrate significant release of this peptide during pelvic nerve stimulation in the present experiments. However, substance P is rapidly inactivated and might possibly be involved in these responses. Stimulation of the pelvic nerves in bursts at high frequencies (up to 80 Hz), simulating a discharge pattern observed electrophysiologically in vivo, was effective in eliciting all the above responses, with the exception of the colonic contraction. PMID:6197521

Effect of nicergoline on cerebral blood flow

PubMed Central

Iliff, L. D.; Boulay, G. H. Du; Marshall, John; Russell, R. W. Ross; Symon, Lindsay

1977-01-01

Cerebral blood flow (CBF) was measured before and after intravenous injection of the cerebral vasodilator nicergoline in 13 patients with cerebrovascular disease. CBF increased in seven. The possibility that the effect of the drug in the remainder may have been masked by a fall of CBF which occurs during sequential measurement of patients at rest is discussed. PMID:925694

Effects of pressure applied during standardized spinal mobilizations on peripheral skin blood flow: A randomised cross-over study.

PubMed

Zegarra-Parodi, Rafael; Pazdernik, Vanessa K; Roustit, Matthieu; Park, Peter Yong Soo; Degenhardt, Brian F

2016-02-01

Peripheral skin blood flow (SBF) changes during and after spinal mobilization (SM), evaluated with laser Doppler flowmetry, may document physiological responses associated with SM. To document variations in SBF during and after application of an SM and evaluate influence of pressure on SBF by applying the same standardized SM with 3 different nonnoxious pressures. Cross-over design with 4 interventions on 4 different days: control (no touch) and 3 SMs applied rhythmically at 5%, 40%, or 80% of pain pressure threshold (sham SM, low-pressure SM, or high-pressure SM, respectively). Thirty-two individuals participated. The inspiratory gasp (IG) test was our positive control of vasoconstriction through excitation of the skin sympathetic nervous activity (SSNA). Each session comprised 5 phases: (1) baseline at the end of a 20-min acclimatization, (2) IG test, (3) post-IG phase, (4) SM phase or no manual contact for control, and (5) post-SM phase. A Biopac MP36 system collected SBF data, and a Novel Pliance-X system recorded pressure data. Equal and significant bilateral vasodilation occurred during application of unilateral sham SM, low-pressure SM, and high-pressure SM. Post-SM significant vasodilation persisted after high-pressure SM. The current study is the first to describe bilateral peripheral SBF changes occurring during and 5 min after application of standardized SMs. Our post-SM vasodilation suggests involvement of mechanisms other than the putative SSNA-excitatory mechanism proposed with skin conductance measurements. Persistence of post-SM vasodilation following only high-pressure SM suggests possible pressure-dependent mechanisms. However, further research is warranted to clarify our findings. Copyright © 2015 Elsevier Ltd. All rights reserved.

The actions of two sensory neuropeptides, substance P and calcitonin gene-related peptide, on the canine hepatic arterial and portal vascular beds.

PubMed Central

Withrington, P. G.

1992-01-01

1. The two peptides, calcitonin gene-related peptide (CGRP) and substance P (SP) were administered individually as bolus injections into the separately perfused hepatic arterial and portal vascular beds of the anaesthetized dog to assess their actions and relative molar potencies at these sites. 2. CGRP caused an immediate dose-related increase in hepatic arterial flow when injected close-arterially, reflecting a fall in resistance. This vasodilator effect was slightly increased by the prior administration of the selective beta 2-adrenoceptor antagonist, ICI 118,551. 3. On a molar basis, CGRP was more potent as an hepatic arterial vasodilator than the non-selective beta-adrenoceptor agonist, isoprenaline (Iso). 4. Intra-portal injection of CGRP also evoked hepatic arterial vasodilatation unaccompanied by other cardiovascular changes. 5. CGRP in doses up to 10 nmol had no effect on portal vascular resistance when administered intra-portally. 6. SP evoked a rapid, dose-related increase in hepatic arterial flow when injected intra-arterially. The molar ED50 for this hepatic vasodilatation was 40.2 fmol, significantly less than the ED50 for either CGRP or Iso. SP was the most potent hepatic arterial vasodilator yet examined. The vasodilator effect of SP was slightly potentiated by prior beta 2-adrenoceptor blockade. 7. SP caused hepatic arterial vasodilatation when administered by intra-portal injection; its absolute and relative potency was much reduced. 8. SP when injected intra-portally caused a graded increase in hepatic portal inflow resistance. The molar potency for this portal vasoconstriction was significantly greater than that for noradrenaline (NA); however, the maximum increase in portal resistance was significantly less to SP than to NA.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1384909

Cigarette smoking impairs nitric oxide-mediated cerebral blood flow increase: Implications for Alzheimer's disease.

PubMed

Toda, Noboru; Okamura, Tomio

2016-08-01

Cerebral blood flow is mainly regulated by nitrergic (parasympathetic, postganglionic) nerves and nitric oxide (NO) liberated from endothelial cells in response to shear stress and stretch of vasculature, whereas sympathetic vasoconstrictor control is quite weak. On the other hand, peripheral vascular resistance and blood flow are mainly controlled by adrenergic vasoconstrictor nerves; endothelium-derived NO and nitrergic nerves play some roles as vasodilator factors. Cigarette smoking impairs NO synthesis in cerebral vascular endothelial cells and nitrergic nerves leading to interference with cerebral blood flow and glucose metabolism in the brain. Smoking-induced cerebral hypoperfusion is induced by impairment of synthesis and actions of NO via endothelial nitric oxide synthase (eNOS)/neuronal NOS (nNOS) inhibition and by increased production of oxygen radicals, resulting in decreased actions of NO on vascular smooth muscle. Nicotine acutely and chronically impairs the action of endothelial NO and also inhibits nitrergic nerve function in chronic use. Impaired cerebral blood supply promotes the synthesis of amyloid β that accelerates blood flow decrease. This vicious cycle is thought to be one of the important factors involving in Alzheimer's disease (AD). Quitting smoking is undoubtedly one of the important ways to prevent and delay the genesis or slow the progress of impaired cognitive function and AD. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Exogenous NO administration and alpha-adrenergic vasoconstriction in human limbs.

PubMed

Rosenmeier, Jaya B; Fritzlar, Sandy J; Dinenno, Frank A; Joyner, Michael J

2003-12-01

Nitric oxide (NO) is capable of blunting alpha-adrenergic vasoconstriction in contracting skeletal muscles of experimental animals (functional sympatholysis). We therefore tested the hypothesis that exogenous NO administration can blunt alpha-adrenergic vasoconstriction in resting human limbs by measuring forearm blood flow (FBF; Doppler ultrasound) and blood pressure in eight healthy males during brachial artery infusions of three alpha-adrenergic constrictors (tyramine, which evokes endogenous norepinephrine release; phenylephrine, an alpha1-agonist; and clonidine, an alpha2-agonist). To simulate exercise hyperemia, the vasoconstriction caused by the alpha-agonists was compared during adenosine-mediated (>50% NO independent) and sodium nitroprusside-mediated (SNP; NO donor) vasodilation of the forearm. Both adenosine and SNP increased FBF from approximately 35-40 to approximately 200-250 ml/min. All three alpha-adrenergic constrictor drugs caused marked reductions in FBF and calculated forearm vascular conductance (P < 0.05). The relative reductions in forearm vascular conductance caused by the alpha-adrenergic constrictors during SNP infusion were similar (tyramine, -74 +/- 3 vs. -65 +/- 2%; clonidine, -44 +/- 6 vs. -44 +/- 6%; P > 0.05) or slightly greater (phenylephrine, -47 +/- 6 vs. -33 +/- 6%; P < 0.05) compared with the responses during adenosine. In conclusion, these results indicate that exogenous NO sufficient to raise blood flow to levels simulating those seen during exercise does not blunt alpha-adrenergic vasoconstriction in the resting human forearm.

Medications for Heart Valve Symptoms

MedlinePlus

... on the heart Vasodilators Can lower the heart's work by opening and relaxing the blood vessels; reduced pressure may encourage blood to flow in a forward direction, rather than being forced backward through a leaky valve Additional resources: Print ...

Vasoactivity of rucaparib, a PARP-1 inhibitor, is a complex process that involves myosin light chain kinase, P2 receptors, and PARP itself.

PubMed

McCrudden, Cian M; O'Rourke, Martin G; Cherry, Kim E; Yuen, Hiu-Fung; O'Rourke, Declan; Babur, Muhammad; Telfer, Brian A; Thomas, Huw D; Keane, Patrick; Nambirajan, Thiagarajan; Hagan, Chris; O'Sullivan, Joe M; Shaw, Chris; Williams, Kaye J; Curtin, Nicola J; Hirst, David G; Robson, Tracy

2015-01-01

Therapeutic inhibition of poly(ADP-ribose) polymerase (PARP), as monotherapy or to supplement the potencies of other agents, is a promising strategy in cancer treatment. We previously reported that the first PARP inhibitor to enter clinical trial, rucaparib (AG014699), induced vasodilation in vivo in xenografts, potentiating response to temozolomide. We now report that rucaparib inhibits the activity of the muscle contraction mediator myosin light chain kinase (MLCK) 10-fold more potently than its commercially available inhibitor ML-9. Moreover, rucaparib produces additive relaxation above the maximal degree achievable with ML-9, suggesting that MLCK inhibition is not solely responsible for dilation. Inhibition of nitric oxide synthesis using L-NMMA also failed to impact rucaparib's activity. Rucaparib contains the nicotinamide pharmacophore, suggesting it may inhibit other NAD+-dependent processes. NAD+ exerts P2 purinergic receptor-dependent inhibition of smooth muscle contraction. Indiscriminate blockade of the P2 purinergic receptors with suramin abrogated rucaparib-induced vasodilation in rat arterial tissue without affecting ML-9-evoked dilation, although the specific receptor subtypes responsible have not been unequivocally identified. Furthermore, dorsal window chamber and real time tumor vessel perfusion analyses in PARP-1-/- mice indicate a potential role for PARP in dilation of tumor-recruited vessels. Finally, rucaparib provoked relaxation in 70% of patient-derived tumor-associated vessels. These data provide tantalising evidence of the complexity of the mechanism underlying rucaparib-mediated vasodilation.

Cerebrovascular response to acute hypocapnic and eucapnic hypoxia in normal man

PubMed Central

Shapiro, William; Wasserman, Albert J.; Baker, James P.; Patterson, John L.

1970-01-01

Alterations in human cerebral blood flow and related blood constituents were studied during exposure to acute hypoxia. Observations were made during serial inhalation of decreasing O2 concentrations with and without maintenance of normocarbia, during 8 min inhalation of 10% O2, and after hyperventilation at an arterial PO2 of about 40 mm Hg. In the range of hypoxemia studied, from normal down to arterial PO2 of about 40 mm Hg, the magnitude of the cerebral vasodilator response to hypoxia appeared to be largely dependent upon the coexisting arterial CO2 tension. The mean slope of the increase in cerebral blood flow with decreasing arterial O2 tension rose more quickly (P < 0.05) when eucapnia was maintained when compared with the slope derived under similar hypoxic conditions without maintenance of eucapnia. When 12 subjects inhaled 10% oxygen, cerebral blood flow rose to more than 135% of control in four whose mean decrease in arterial CO2 tension was - 2.0 mm Hg. The remaining eight had flows ranging from 97 to 120% of control, and their mean decrease in CO2 tension was - 5.1 mm Hg. When mean arterial PO2 was 37 mm Hg, hyperventilation was carried out in 10 subjects. Arterial PO2 increased insignificantly, arterial PCO2 declined from 34 to 27 mm Hg (P < 0.05), and cerebral blood flow which had been 143% of control decreased to 109%, a figure not significantly different from control. These data demonstrate the powerful counterbalancing constrictor effects of modest reductions in CO2 tension on the vasodilator influence of hypoxia represented by arterial PO2 reductions to about 40 mm Hg. Indeed, mild hyperventilation completely overcame the vasodilator effect provided by an arterial O2 tension as low as 40 mm Hg. The effects of hypoxia on the control of the cerebral circulation must be analyzed in terms of the effects of any associated changes in CO2 tension. PMID:5480859

Constitutive nitric oxide synthase activation is a significant route for nitroglycerin-mediated vasodilation

PubMed Central

Bonini, Marcelo G.; Stadler, Krisztian; de Oliveira Silva, Sueli; Corbett, Jean; Dore, Michael; Petranka, John; Fernandes, Denise C.; Tanaka, Leonardo Y.; Duma, Danielle; Laurindo, Francisco R. M.; Mason, Ronald P.

2008-01-01

The physiological effects of nitroglycerin as a potent vasodilator have long been documented. However, the molecular mechanisms by which nitroglycerin exerts its biological functions are still a matter of intense debate. Enzymatic pathways converting nitroglycerin to vasoactive compounds have been identified, but none of them seems to fully account for the reported clinical observations. Here, we demonstrate that nitroglycerin triggers constitutive nitric oxide synthase (NOS) activation, which is a major source of NO responsible for low-dose (1–10 nM) nitroglycerin-induced vasorelaxation. Our studies in cell cultures, isolated vessels, and whole animals identified endothelial NOS activation as a fundamental requirement for nitroglycerin action at pharmacologically relevant concentrations in WT animals. PMID:18562300

Finite-element simulation of blood perfusion in muscle tissue during compression and sustained contraction.

PubMed

Vankan, W J; Huyghe, J M; Slaaf, D W; van Donkelaar, C C; Drost, M R; Janssen, J D; Huson, A

1997-09-01

Mechanical interaction between tissue stress and blood perfusion in skeletal muscles plays an important role in blood flow impediment during sustained contraction. The exact mechanism of this interaction is not clear, and experimental investigation of this mechanism is difficult. We developed a finite-element model of the mechanical behavior of blood-perfused muscle tissue, which accounts for mechanical blood-tissue interaction in maximally vasodilated vasculature. Verification of the model was performed by comparing finite-element results of blood pressure and flow with experimental measurements in a muscle that is subject to well-controlled mechanical loading conditions. In addition, we performed simulations of blood perfusion during tetanic, isometric contraction and maximal vasodilation in a simplified, two-dimensional finite-element model of a rat calf muscle. A vascular waterfall in the venous compartment was identified as the main cause for blood flow impediment both in the experiment and in the finite-element simulations. The validated finite-element model offers possibilities for detailed analysis of blood perfusion in three-dimensional muscle models under complicated loading conditions.

Modulatory Effect of 2-(4-Hydroxyphenyl)amino-1,4-naphthoquinone on Endothelial Vasodilation in Rat Aorta.

PubMed

Palacios, Javier; Cifuentes, Fredi; Valderrama, Jaime A; Benites, Julio; Ríos, David; González, Constanza; Chiong, Mario; Cartes-Saavedra, Benjamín; Lafourcade, Carlos; Wyneken, Ursula; González, Pamela; Owen, Gareth I; Pardo, Fabián; Sobrevia, Luis; Buc Calderon, Pedro

The vascular endothelium plays an essential role in the control of the blood flow. Pharmacological agents like quinone (menadione) at various doses modulate this process in a variety of ways. In this study, Q7 , a 2-phenylamino-1,4-naphthoquinone derivative, significantly increased oxidative stress and induced vascular dysfunction at concentrations that were not cytotoxic to endothelial or vascular smooth muscle cells. Q7 reduced nitric oxide (NO) levels and endothelial vasodilation to acetylcholine in rat aorta. It also blunted the calcium release from intracellular stores by increasing the phenylephrine-induced vasoconstriction when CaCl 2 was added to a calcium-free medium but did not affect the influx of calcium from extracellular space. Q7 increased the vasoconstriction to BaCl 2 (10 -3  M), an inward rectifying K + channels blocker, and blocked the vasodilation to KCl (10 -2  M) in aortic rings precontracted with BaCl 2 . This was recovered with sodium nitroprusside (10 -8  M), a NO donor. In conclusion, Q7 induced vasoconstriction was through a modulation of cellular mechanisms involving calcium fluxes through K + channels, and oxidative stress induced endothelium damage. These findings contribute to the characterization of new quinone derivatives with low cytotoxicity able to pharmacologically modulate vasodilation.

Beer elicits vasculoprotective effects through Akt/eNOS activation.

PubMed

Vilahur, Gemma; Casani, Laura; Mendieta, Guiomar; Lamuela-Raventos, Rosa M; Estruch, Ramon; Badimon, Lina

2014-12-01

There is controversy regarding the effect of alcohol beverage intake in vascular vasodilatory function in peripheral arteries. The effects of beer intake in coronary vasodilation remain unknown. We investigated whether regular beer intake (alcohol and alcohol-free) protects against hypercholesterolaemia-induced coronary endothelial dysfunction and the mechanisms behind this effect. Pigs were fed 10 days: (i) a Western-type hypercholesterolaemic diet (WD); (ii) WD+low-dose beer (12·5 g alcohol/day); (iii) WD+moderate-dose beer (25 g alcohol/day); or (iv) WD+moderate-dose alcohol-free-beer (0·0 g alcohol/day). Coronary responses to endothelium-dependent vasoactive drugs (acetylcholine: receptor mediated; calcium ionophore-A23189: nonreceptor mediated), endothelium-independent vasoactive drug (SNP) and L-NMMA (NOS-antagonist) were evaluated in the LAD coronary artery by flow Doppler. Coronary Akt/eNOS activation, MCP-1 expression, oxidative DNA damage and superoxide production were assessed. Lipid profile, lipoproteins resistance to oxidation and urinary isoxanthohumol concentration were evaluated. Alcoholic and nonalcoholic beer intake prevented WD-induced impairment of receptor- and non-receptor-operated endothelial-dependent coronary vasodilation. All animals displayed a similar vasodilatory response to SNP and L-NMMA blunted all endothelial-dependent vasorelaxation responses. Haemodynamic parameters remained unchanged. Coronary arteries showed lower DNA damage and increased Akt/eNOS axis activation in beer-fed animals. Animals taking beer showed HDL with higher antioxidant capacity, higher LDL resistance to oxidation and increased isoxanthohumol levels. Weight, lipids levels, liver enzymes and MCP-1 expression were not affected by beer intake. Non-alcoholic-related beer components protect against hyperlipemia-induced coronary endothelial dysfunction by counteracting vascular oxidative damage and preserving the Akt/eNOS pathway. Light-to-moderate beer consumption prevents and/or reduces the endothelial dysfunction associated with cardiovascular risk factors. © 2014 Stichting European Society for Clinical Investigation Journal Foundation.

Increased Notch3 Activity Mediates pathological Changes in Structure of Cerebral arteries

PubMed Central

Baron-Menguy, Celine; Domenga-Denier, Valérie; Ghezali, Lamia; Faraci, Frank; Joutel, Anne

2016-01-01

CADASIL, the most frequent genetic cause of stroke and vascular dementia, is caused by highly stereotyped mutations in the NOTCH3 receptor, which is predominantly expressed in vascular smooth muscle. The well-established TgNotch3R169C mouse model develops characteristic features of the human disease, with deposition of NOTCH3 and other proteins, including TIMP3 (tissue inhibitor of metalloproteinase 3), on brain vessels as well as reduced maximal dilation, and attenuated myogenic tone of cerebral arteries, but without elevated blood pressure. Increased TIMP3 levels were recently shown to be a major determinant of altered myogenic tone. In this study, we investigated the contribution of TIMP3 and Notch3 signaling to the impairment of maximal vasodilator capacity caused by the archetypal R169C mutation. Maximally dilated cerebral arteries in TgNotch3R169C mice exhibited a decrease in lumen diameter over a range of physiological pressures that occurred prior to myogenic tone deficits. This defect was not prevented by genetic reduction of TIMP3 in TgNotch3R169C mice and was not observed in mice overexpressing TIMP3. Knock-in mice with the R169C mutation (Notch3R170C/R170C) exhibited similar reductions in arterial lumen, and both TgNotch3R169C and Notch3R170C/R170C mice showed increased cerebral artery expression of Notch3 target genes. Reduced maximal vasodilation was prevented by conditional reduction of Notch activity in smooth muscle of TgNotch3R169C mice and mimicked by conditional activation of Notch3 in smooth muscle, an effect that was blood pressure-independent. We conclude that increased Notch3 activity mediates reduction in maximal dilator capacity of cerebral arteries in CADASIL and may contribute to reductions in cerebral blood flow. PMID:27821617

Increased Notch3 Activity Mediates Pathological Changes in Structure of Cerebral Arteries.

PubMed

Baron-Menguy, Celine; Domenga-Denier, Valérie; Ghezali, Lamia; Faraci, Frank M; Joutel, Anne

2017-01-01

CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy), the most frequent genetic cause of stroke and vascular dementia, is caused by highly stereotyped mutations in the NOTCH3 receptor, which is predominantly expressed in vascular smooth muscle. The well-established TgNotch3 R169C mouse model develops characteristic features of the human disease, with deposition of NOTCH3 and other proteins, including TIMP3 (tissue inhibitor of metalloproteinase 3), on brain vessels, as well as reduced maximal dilation, and attenuated myogenic tone of cerebral arteries, but without elevated blood pressure. Increased TIMP3 levels were recently shown to be a major determinant of altered myogenic tone. In this study, we investigated the contribution of TIMP3 and Notch3 signaling to the impairment of maximal vasodilator capacity caused by the archetypal R169C mutation. Maximally dilated cerebral arteries in TgNotch3 R169C mice exhibited a decrease in lumen diameter over a range of physiological pressures that occurred before myogenic tone deficits. This defect was not prevented by genetic reduction of TIMP3 in TgNotch3 R169C mice and was not observed in mice overexpressing TIMP3. Knock-in mice with the R169C mutation (Notch3 R170C/R170C ) exhibited similar reductions in arterial lumen, and both TgNotch3 R169C and Notch3 R170C/R170C mice showed increased cerebral artery expression of Notch3 target genes. Reduced maximal vasodilation was prevented by conditional reduction of Notch activity in smooth muscle of TgNotch3 R169C mice and mimicked by conditional activation of Notch3 in smooth muscle, an effect that was blood pressure-independent. We conclude that increased Notch3 activity mediates reduction in maximal dilator capacity of cerebral arteries in CADASIL and may contribute to reductions in cerebral blood flow. © 2016 American Heart Association, Inc.

Nanoparticle inhalation impairs endothelium-dependent vasodilation in subepicardial arterioles

PubMed Central

LeBlanc, AJ; Cumpston, JL; Chen, BT; Frazer, D; Castranova, V; Nurkiewicz, TR

2009-01-01

Exposure to fine particulate matter (PM, mean aerodynamic diameter ≤ 2.5 μm) has been shown to be a risk factor for cardiovascular disease mortality and may contribute to acute coronary events such as myocardial infarction (MI). There is sufficient reason to believe that smaller particles, such as nanoparticles, might be even more detrimental than larger-sized particles due to their increased surface area and higher pulmonary deposition. Our lab showed that nanoparticle inhalation impairs endothelium-dependent arteriolar vasodilation in skeletal muscle. However, it is not known if coronary microvascular endothelial function is affected in a similar manner. Rats were exposed to filtered air (control) or TiO2 nanoparticles (primary particle diameter, ~21 nm) via inhalation at concentrations that produced measured depositions (10 μg) relevant to ambient air pollution. Subepicardial arterioles (~150 μm in diameter) were isolated and responses to transmural pressure, flow-induced dilation (FID), acetylcholine, the Ca2+ ionophore A23187, and sodium nitroprusside (SNP) assessed. Myogenic responsiveness was preserved between groups. In addition, there was no difference in the vasodilation to SNP, signifying that smooth muscle sensitivity to nitric oxide (NO) is unaffected by nano-TiO2 exposure. However, inhalation of nano-TiO2 produced an increase in spontaneous tone in coronary arterioles and also impaired endothelium-dependent FID. In addition, ACh- and A23187-induced vasodilation was also blunted in arterioles after inhalation of nano-TiO2. Data showed that nanoparticle exposure significantly impairs endothelium-dependent vasodilation in subepicardial arterioles. Such disturbances in coronary microvascular function are consistent with the cardiac events associated with particle pollution exposure. PMID:20077232

Role of Hydrogen Sulfide in Early Blood-Brain Barrier Disruption following Transient Focal Cerebral Ischemia

PubMed Central

Jiang, Zheng; Li, Chun; Manuel, Morganne L.; Yuan, Shuai; Kevil, Christopher G.; McCarter, Kimberly D.; Lu, Wei; Sun, Hong

2015-01-01

We determined the role of endogenous hydrogen sulfide (H₂S) in cerebral vasodilation/hyperemia and early BBB disruption following ischemic stroke. A cranial window was prepared over the left frontal, parietal and temporal cortex in mice. Transient focal cerebral Ischemia was induced by directly ligating the middle cerebral artery (MCA) for two hours. Regional vascular response and cerebral blood flow (CBF) during ischemia and reperfusion were measured in real time. Early BBB disruption was assessed by Evans Blue (EB) and sodium fluorescein (Na-F) extravasation at 3 hours of reperfusion. Topical treatment with DL-propargylglycine (PAG, an inhibitor for cystathionine γ-lyase (CSE)) and aspartate (ASP, inhibitor for cysteine aminotransferase/3-mercaptopyruvate sulfurtransferase (CAT/3-MST)), but not O-(Carboxymethyl)hydroxylamine hemihydrochloride (CHH, an inhibitor for cystathionine β-synthase (CBS)), abolished postischemic cerebral vasodilation/hyperemia and prevented EB and Na-F extravasation. CSE knockout (CSE-/-) reduced postischemic cerebral vasodilation/hyperemia but only inhibited Na-F extravasation. An upregulated CBS was found in cerebral cortex of CSE-/- mice. Topical treatment with CHH didn’t further alter postischemic cerebral vasodilation/hyperemia, but prevented EB extravasation in CSE-/- mice. In addition, L-cysteine-induced hydrogen sulfide (H2S) production similarly increased in ischemic side cerebral cortex of control and CSE-/- mice. Our findings suggest that endogenous production of H2S by CSE and CAT/3-MST during reperfusion may be involved in postischemic cerebral vasodilation/hyperemia and play an important role in early BBB disruption following transient focal cerebral ischemia. PMID:25695633

TRPV3 expression and vasodilator function in isolated uterine radial arteries from non-pregnant and pregnant rats.

PubMed

Murphy, Timothy V; Kanagarajah, Arjna; Toemoe, Sianne; Bertrand, Paul P; Grayson, T Hilton; Britton, Fiona C; Leader, Leo; Senadheera, Sevvandi; Sandow, Shaun L

2016-08-01

This study investigated the expression and function of transient receptor potential vanilloid type-3 ion channels (TRPV3) in uterine radial arteries isolated from non-pregnant and twenty-day pregnant rats. Immunohistochemistry (IHC) suggested TRPV3 is primarily localized to the smooth muscle in arteries from both non-pregnant and pregnant rats. IHC using C' targeted antibody, and qPCR of TRPV3 mRNA, suggested pregnancy increased arterial TRPV3 expression. The TRPV3 activator carvacrol caused endothelium-independent dilation of phenylephrine-constricted radial arteries, with no difference between vessels from non-pregnant and pregnant animals. Carvacrol-induced dilation was reduced by the TRPV3-blockers isopentenyl pyrophosphate and ruthenium red, but not by the TRPA1 or TRPV4 inhibitors HC-030031 or HC-067047, respectively. In radial arteries from non-pregnant rats only, inhibition of NOS and sGC, or PKG, enhanced carvacrol-mediated vasodilation. Carvacrol-induced dilation of arteries from both non-pregnant and pregnant rats was prevented by the IKCa blocker TRAM-34. TRPV3 caused an endothelium-independent, IKCa-mediated dilation of the uterine radial artery. NO-PKG-mediated modulation of TRPV3 activity is lost in pregnancy, but this did not alter the response to carvacrol. Copyright © 2016 Elsevier Inc. All rights reserved.

In vivo effects of CB2 receptor-selective cannabinoids on the vasculature of normal and arthritic rat knee joints

PubMed Central

McDougall, J J; Yu, V; Thomson, J

2007-01-01

Background and purpose: Cannabinoids (CBs) are known to be vasoactive and to regulate tissue inflammation. The present study examined the in vivo vasomotor effects of the CB2 receptor agonists JWH015 and JWH133 in rat knee joints. The effect of acute and chronic joint inflammation on CB2 receptor-mediated responses was also tested. Experimental approach: Blood flow was assessed in rat knee joints by laser Doppler imaging both before and following topical administration of CB2 receptor agonists. Vasoactivity was measured in normal, acute kaolin/carrageenan inflamed and Freund's complete adjuvant chronically inflamed knees. Key results: In normal animals, JWH015 and JWH133 caused a concentration-dependent increase in synovial blood flow which in the case of JWH133 was blocked by the selective CB2 receptor antagonist AM630 as well as the transient receptor potential vanilloid-1 (TRPV1) antagonist SB366791. The vasodilator effect of JWH133 was significantly attenuated in both acute and chronically inflamed knees. Given alone, AM630 had no effect on joint blood flow. Conclusion and implications: In normal joints, the cannabinomimetic JWH133 causes hyperaemia via a CB2 and TRPV1 receptor mechanism. During acute and chronic inflammation, however, this vasodilatatory response is significantly attenuated. PMID:17982474

Habitual exercise training in older adults offsets the age-related prolongation in leg vasodilator kinetics during single limb lower body exercise.

PubMed

Hughes, William E; Kruse, Nicholas T; Ueda, Kenichi; Casey, Darren P

2018-06-01

We tested the hypothesis that aging is associated with prolonged leg vasodilator kinetics and habitual exercise training in older adults improves these responses relative to untrained older adults. Additionally, we examined the relationship between contraction-induced rapid onset vasodilation (ROV) and vasodilator kinetics. Young (n=10), older untrained (n=13) and older trained (n=14) adults performed single and rhythmic knee-extension contractions at 20% and 40% work-rate maximum (WR max ). Femoral artery diameter and mean blood velocity were measured by Doppler ultrasound. Vascular conductance (VC; ml·min -1 ·mmHg-1) was calculated using blood flow (ml·min -1 ) and mean arterial pressure (mmHg). The primary outcome was the kinetic response (mean response time; MRT), modeled using an exponential model, expressed as the number of duty cycles to change 63% of the steady-state amplitude. There was no age or training related differences in VC MRT between the groups at 20% WR max . Older untrained adults exhibited prolonged VC MRT at 40% WR max relative to young (37{plus minus}16 vs. 24{plus minus}10 duty-cycles; P<0.05) and older trained adults (37{plus minus}16 vs. 23{plus minus}14 duty-cycles; P<0.05). There were no differences in VC MRT between young and older trained adults at 40% WR max (P=0.96). There were no associations between peak ROV and VC MRT at 20% or 40% WR max (r=-0.08 and 0.22; P=0.67 and 0.20, respectively) in the group as a whole. Our data suggest 1) advancing age prolongs leg vasodilator kinetics; 2) habitual exercise training in older adults offsets this age-related prolongation; and 3) contraction-induced ROV is not related to vasodilator kinetics within a group of young and older adults.

Elevated blood pressure in cytochrome P4501A1 knockout mice is associated with reduced vasodilation to omega − 3 polyunsaturated fatty acids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Agbor, Larry N.; Walsh, Mary T.; Boberg, Jason R.

In vitro cytochrome P4501A1 (CYP1A1) metabolizes omega − 3 polyunsaturated fatty acids (n − 3 PUFAs); eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), primarily to 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP), respectively. These metabolites have been shown to mediate vasodilation via increases in nitric oxide (NO) and activation of potassium channels. We hypothesized that genetic deletion of CYP1A1 would reduce vasodilatory responses to n − 3 PUFAs, but not the metabolites, and increase blood pressure (BP) due to decreases in NO. We assessed BP by radiotelemetry in CYP1A1 wildtype (WT) and knockout (KO) mice ± NO synthase (NOS) inhibitor.more » We also assessed vasodilation to acetylcholine (ACh), EPA, DHA, 17,18-EEQ and 19,20-EDP in aorta and mesenteric arterioles. Further, we assessed vasodilation to an NO donor and to DHA ± inhibitors of potassium channels. CYP1A1 KO mice were hypertensive, compared to WT, (mean BP in mm Hg, WT 103 ± 1, KO 116 ± 1, n = 5/genotype, p < 0.05), and exhibited a reduced heart rate (beats per minute, WT 575 ± 5; KO 530 ± 7; p < 0.05). However, BP responses to NOS inhibition and vasorelaxation responses to ACh and an NO donor were normal in CYP1A1 KO mice, suggesting that NO bioavailability was not reduced. In contrast, CYP1A1 KO mice exhibited significantly attenuated vasorelaxation responses to EPA and DHA in both the aorta and mesenteric arterioles, but normal vasorelaxation responses to the CYP1A1 metabolites, 17,18-EEQ and 19,20-EDP, and normal responses to potassium channel inhibition. Taken together these data suggest that CYP1A1 metabolizes n − 3 PUFAs to vasodilators in vivo and the loss of these vasodilators may lead to increases in BP. -- Highlights: ► CYP1A1 KO mice are hypertensive. ► CYP1A1 KO mice exhibit reduced vasodilation responses to n-3 PUFAs. ► Constitutive CYP1A1 expression regulates blood pressure and vascular function.« less

Downregulation of BK Channel Function and Protein Expression in Coronary Arteriolar Smooth Muscle Cells of Type 2 Diabetic Patients.

PubMed

Lu, Tong; Chai, Qiang; Jiao, Guoqing; Wang, Xiao-Li; Sun, Xiaojing; Furuseth, Jonathan D; Stulak, John M; Daly, Richard C; Greason, Kevin L; Cha, Yong-Mei; Lee, Hon-Chi

2018-05-30

Type 2 diabetes (T2D) is strongly associated with cardiovascular morbidity and mortality in patients. Vascular large conductance Ca2+-activated potassium (BK) channels, composed of four pore-forming α subunits (BK-α) and four regulatory β1 subunits (BK-β1), are densely expressed in coronary arterial smooth muscle cells (SMCs) and play an important role in regulating vascular tone and myocardial perfusion. However, the role of BK channels in coronary microvascular dysfunction of human subjects with diabetes is unclear. In this study, we examined BK channel function and protein expression, and BK channel-mediated vasodilation in freshly isolated coronary arterioles from T2D patients. Atrial tissues were obtained from 25 patients with T2D and 16 matched non-diabetic subjects during cardiopulmonary bypass procedure. Microvessel videomicroscopy and immunoblot analysis were performed in freshly dissected coronary arterioles and inside-out single BK channel currents was recorded in enzymatically isolated coronary arteriolar SMCs. We found that BK channel sensitivity to physiological Ca2+ concentration and voltage was downregulated in the coronary arteriolar SMCs of diabetic patients, compared with non-diabetic controls. BK channel kinetics analysis revealed that there was significant shortening of the mean open time and prolongation of the mean closed time in diabetic patients, resulting in a remarkable reduction of the channel open probability. Functional studies showed that BK channel activation by dehydrosoyasaponin-1 was diminished and that BK channel-mediated vasodilation in response to shear stress was impaired in diabetic coronary arterioles. Immunoblot experiments confirmed that the protein expressions of BK-α and BK-β1 subunits were significantly downregulated, but the ratio of BK-α/BK-β1 was unchanged in the coronary arterioles of T2D patients. Our results demonstrated for the first time that BK channel function and BK channel-mediated vasodilation were abnormal in the coronary microvasculature of diabetic patients, due to decreased protein expression and altered intrinsic properties of BK channels.

Increased Angiotensin II Sensitivity Contributes to Microvascular Dysfunction in Women Who Have Had Preeclampsia.

PubMed

Stanhewicz, Anna E; Jandu, Sandeep; Santhanam, Lakshmi; Alexander, Lacy M

2017-08-01

Women who have had preeclampsia have increased cardiovascular disease risk; however, the mechanism(s) responsible for this association remain unclear. Microvascular damage sustained during a preeclamptic pregnancy may persist postpartum. The putative mechanisms mediating this dysfunction include a reduction in NO-dependent dilation and an increased sensitivity to angiotensin II. In this study, we evaluated endothelium-dependent dilation, angiotensin II sensitivity, and the therapeutic effect of angiotensin II receptor blockade (losartan) on endothelium-dependent dilation in vivo in the microvasculature of women with a history of preeclampsia (n=12) and control women who had a healthy pregnancy (n=12). We hypothesized that preeclampsia would have (1) reduced endothelium-dependent dilation, (2) reduced NO-mediated dilation, and (3) increased sensitivity to angiotensin II. We further hypothesized that localized losartan would increase endothelium-dependent vasodilation in preeclampsia. We assessed microvascular endothelium-dependent vasodilator function by measurement of cutaneous vascular conductance responses to graded infusion of acetylcholine (acetylcholine; 10 -7 -102 mmol/L) and a standardized local heating protocol in control sites and sites treated with 15 mmol/L L-NAME ( N G -nitro-l-arginine methyl ester; NO-synthase inhibitor) or 43 µmol/L losartan. Further, we assessed microvascular vasoconstrictor sensitivity to angiotensin II (10 -20 -10 -4 mol/L). Preeclampsia had significantly reduced endothelium-dependent dilation (-0.3±0.5 versus -1.0±0.4 log EC50 ; P <0.001) and NO-dependent dilation (16±3% versus 39±6%; P =0.006). Preeclampsia also had augmented vasoconstrictor sensitivity to angiotensin II (-10.2±1.3 versus -8.3±0.5; P =0.006). Angiotensin II type I receptor inhibition augmented endothelium-dependent vasodilation and NO-dependent dilation in preeclampsia but had no effect in healthy pregnancy. These data suggest that women who have had preeclampsia have persistent microvascular dysfunction postpartum, mediated, in part, by increased sensitivity to angiotensin II. © 2017 American Heart Association, Inc.

Gap Junction Regulation of Vascular Tone: Implications of Modulatory Intercellular Communication During Gestation

PubMed Central

Ampey, Bryan C.; Morschauser, Timothy J.; Lampe, Paul D.

2017-01-01

In the vasculature, gap junctions (GJ) play a multifaceted role by serving as direct conduits for cell–cell intercellular communication via the facilitated diffusion of signaling molecules. GJs are essential for the control of gene expression and coordinated vascular development in addition to vascular function. The coupling of endothelial cells to each other, as well as with vascular smooth muscle cells via GJs, plays a relevant role in the control of vasomotor tone, tissue perfusion and arterial blood pressure. The regulation of cell-signaling is paramount to cardiovascular adaptations of pregnancy. Pregnancy requires highly developed cell-to-cell coupling, which is affected partly through the formation of intercellular GJs by Cx43, a gap junction protein, within adjacent cell membranes to help facilitate the increase of uterine blood flow (UBF) in order to ensure adequate perfusion for nutrient and oxygen delivery to the placenta and thus the fetus. One mode of communication that plays a critical role in regulating Cx43 is the release of endothelial-derived vasodilators such as prostacyclin (PGI2) and nitric oxide (NO) and their respective signaling mechanisms involving second messengers (cAMP and cGMP, respectively) that are likely to be important in maintaining UBF. Therefore, the assertion we present in this review is that GJs play an integral if not a central role in maintaining UBF by controlling rises in vasodilators (PGI2 and NO) via cyclic nucleotides. In this review, we discuss: (1) GJ structure and regulation; (2) second messenger regulation of GJ phosphorylation and formation; (3) pregnancy-induced changes in cell-signaling; and (4) the role of uterine arterial endothelial GJs during gestation. These topics integrate the current knowledge of this scientific field with interpretations and hypotheses regarding the vascular effects that are mediated by GJs and their relationship with vasodilatory vascular adaptations required for modulating the dramatic physiological rises in uteroplacental perfusion and blood flow observed during normal pregnancy. PMID:25015806

Flicker-induced retinal vasodilatation is not dependent on complement factor H polymorphism in healthy young subjects.

PubMed

Told, Reinhard; Palkovits, Stefan; Boltz, Agnes; Schmidl, Doreen; Napora, Katarzyna J; Werkmeister, René M; Haslacher, Helmuth; Frantal, Sophie; Popa-Cherecheanu, Alina; Schmetterer, Leopold; Garhöfer, Gerhard

2014-11-01

The complement factor H (CFH) tyrosine 402 histidine (Y402H, rs1061170) variant is known to be significantly associated with age-related macular degeneration (AMD). Whether this genetic variant may impact retinal blood flow regulation is largely unknown. This study investigated whether flicker-induced vasodilation, an indicator for the coupling between neural activity and blood flow, is altered in subjects carrying the rs1061170 risk allele. One hundred healthy subjects (aged between 18 and 45 years) were included in this study. Retinal blood flow regulation was tested by assessing retinal vessel calibres in response to stimulation with diffuse flicker light. Retinal vascular flicker responses were determined with a Dynamic Vessel Analyzer (DVA). In addition, genotyping for rs1061170 was performed. Eighteen subjects were homozygous for the risk allele C, 50 were homozygous for the ancestral allele T, and 31 subjects were heterozygous (CT). One subject had to be excluded from data evaluation, as no genetic analysis could be performed due to technical difficulties. Baseline diameters of retinal arteries (p = 0.39) and veins (p = 0.64) were comparable between the three groups. Flicker-induced vasodilation in both retinal arteries (p = 0.38) and retinal veins (p = 0.62) was also comparable between the three studied groups. Our data indicate that homozygous healthy young carriers of the C risk allele at rs1061170 do not show abnormal flicker-induced vasodilation in the retina. This suggests that the high-risk genetic variant of CFH polymorphism does not impact neuro-vascular coupling in healthy subjects. © 2014 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.

Epoetin beta pegol ameliorates flow-mediated dilation with improving endothelial nitric oxide synthase coupling state in nonobese diabetic rats.

PubMed

Serizawa, Kenichi; Yogo, Kenji; Tashiro, Yoshihito; Kawasaki, Ryohei; Endo, Koichi; Shimonaka, Yasushi; Hirata, Michinori

2017-04-01

Patients with diabetic nephropathy have a high cardiovascular mortality. Epoetin beta pegol (continuous erythropoietin receptor activator, C.E.R.A.) is a drug for the treatment of renal anemia. In this study, we investigated the effect of C.E.R.A. on vascular endothelial function as evaluated by flow-mediated dilation (FMD) and the relationship between hematopoiesis and FMD in diabetic nephropathy rats. Male Spontaneously Diabetic Torii rats (SDT, 22 weeks old) were used. C.E.R.A. (0.6, 1.2 μg/kg) was administered subcutaneously once every 2 weeks for 8 weeks. At 1 week after last administration (31 weeks old), we assessed FMD in the femoral arteries of anesthetized rats using a high-resolution ultrasound system. FMD was also measured 1 week after single C.E.R.A. treatment (5.0 μg/kg) to examine the influence of hematopoiesis. Flow-mediated dilation was significantly decreased in SDT rats before the start of C.E.R.A. treatment (22 weeks old). Repeated administration of C.E.R.A. dose-dependently improved FMD in SDT rats (31 weeks old) without changing blood glucose, nitroglycerin-induced vasodilation, or kidney function. Long-term administration of C.E.R.A. improved the state of endothelial nitric oxide synthase uncoupling in the femoral arteries of SDT rats, which showed a positive correlation with FMD. On the other hand, there was no correlation between FMD and Hb or Hct in SDT rats. Furthermore, at 1 week after single administration of C.E.R.A., FMD was not significantly improved although hemoglobin levels were comparable with levels following long-term C.E.R.A. Long-term treatment with C.E.R.A. improved FMD in SDT rats even after onset of endothelial dysfunction. © 2017 The Authors. Cardiovascular Therapeutics Published by John Wiley & Sons Ltd.

Activity restriction, impaired capillary function, and the development of insulin resistance in lean primates.

PubMed

Chadderdon, Scott M; Belcik, J Todd; Smith, Elise; Pranger, Lindsay; Kievit, Paul; Grove, Kevin L; Lindner, Jonathan R

2012-09-01

Insulin produces capillary recruitment in skeletal muscle through a nitric oxide (NO)-dependent mechanism. Capillary recruitment is blunted in obese and diabetic subjects and contributes to impaired glucose uptake. This study's objective was to define whether inactivity, in the absence of obesity, leads to impaired capillary recruitment and contributes to insulin resistance (IR). A comprehensive metabolic and vascular assessment was performed on 19 adult male rhesus macaques (Macaca mulatta) after sedation with ketamine and during maintenance anesthesia with isoflurane. Thirteen normal-activity (NA) and six activity-restricted (AR) primates underwent contrast-enhanced ultrasound to determine skeletal muscle capillary blood volume (CBV) during an intravenous glucose tolerance test (IVGTT) and during contractile exercise. NO bioactivity was assessed by flow-mediated vasodilation. Although there were no differences in weight, basal glucose, basal insulin, or truncal fat, AR primates were insulin resistant compared with NA primates during an IVGTT (2,225 ± 734 vs. 5,171 ± 3,431 μg·ml⁻¹·min⁻¹, P < 0.05). Peak CBV was lower in AR compared with NA primates during IVGTT (0.06 ± 0.01 vs. 0.12 ± 0.02 ml/g, P < 0.01) and exercise (0.10 ± 0.02 vs. 0.20 ± 0.02 ml/g, P < 0.01), resulting in a lower peak skeletal muscle blood flow in both circumstances. The insulin-mediated changes in CBV correlated inversely with the degree of IR and directly with activity. Flow-mediated dilation was lower in the AR primates (4.6 ± 1.0 vs. 9.8 ± 2.3%, P = 0.01). Thus, activity restriction produces impaired skeletal muscle capillary recruitment during a carbohydrate challenge and contributes to IR in the absence of obesity. Reduced NO bioactivity may be a pathological link between inactivity and impaired capillary function.

Exercise-induced brachial artery vasodilation: role of free radicals.

PubMed

Richardson, Russell S; Donato, Anthony J; Uberoi, Abhimanyu; Wray, D Walter; Lawrenson, Lesley; Nishiyama, Steven; Bailey, Damian M

2007-03-01

Originally thought of as simply damaging or toxic "accidents" of in vivo chemistry, free radicals are becoming increasingly recognized as redox signaling molecules implicit in cellular homeostasis. Indeed, at the vascular level, it is plausible that oxidative stress plays a regulatory role in normal vascular function. Using electron paramagnetic resonance (EPR) spectroscopy, we sought to document the ability of an oral antioxidant cocktail (vitamins C, E, and alpha-lipoic acid) to reduce circulating free radicals, and we employed Doppler ultrasound to examine the consequence of an antioxidant-mediated reduction in oxidative stress on exercise-induced vasodilation. A total of 25 young (18-31 yr) healthy male subjects partook in these studies. EPR spectroscopy revealed a reduction in circulating free radicals following antioxidant administration at rest ( approximately 98%) and as a consequence of exercise ( approximately 85%). Plasma total antioxidant capacity and vitamin C both increased following the ingestion of the antioxidant cocktail, whereas vitamin E levels were not influenced by the ingestion of the antioxidants. Brachial artery vasodilation during submaximal forearm handgrip exercise was greater with the placebo (7.4 +/- 1.8%) than with the antioxidant cocktail (2.3 +/- 0.7%). These data document the efficacy of an oral antioxidant cocktail in reducing free radicals and suggest that, in a healthy state, the aggressive disruption of the delicate balance between pro- and antioxidant forces can negatively impact vascular function. These findings implicate an exercise-induced reliance upon pro-oxidant-stimulated vasodilation, thereby revealing an important and positive vascular role for free radicals.

[Focal cerebral ischemia in rats with estrogen deficiency and endothelial dysfunction].

PubMed

Litvinov, A A; Volotova, E V; Kurkin, D V; Logvinova, E O; Darmanyan, A P; Tyurenkov, I N

2017-01-01

To assess an effect of ovariectomy (OE) on the cerebral blood flow, endothelium-dependent vasodilation, neurological, cognitive and locomotor deficit as markers of brain damage after focal ischemia in rats. The study was conducted in 48 female Wistar rats. Ovariectomy was performed with ovaries and uterine body extirpation, cerebral ischemia was performed by middle cerebral artery occlusion (MCAO) in rats. To assess brain damage, Combs and Garcia scores, 'open field' test (OFT), 'extrapolatory escape test' (EET), 'passive avoidance test' (PAT), 'beam-walking test' were used. Cerebral blood flow was measured using ultrasonic flowmetry. After 7 days of MCAO, the cerebral blood flow in ovarioectomized animals was reduced by 20% compared to sham-ovariectomized animals. Ovariectomized animals with MCAO showed a three-fold endothelium-dependent vasodilation reduction (the reaction of cerebral vessels to the introduction of acetylcholine and N-L-arginine), indicating the presence of severe endothelial dysfunction. In ovarioectomized animals, the cerebral blood flow was reduced by 34% compared to sham-operated animals. MCAO and OE taken together resulted in more than 2-fold increase in neurological, motor disturbances, 3-fold decrease in motor activity of the animals in the OP test. Focal ischemia in ovarioectomized animals with endothelial dysfunction led to memory decrease by 1/5 fold in PAT and by 2-fold in EET.

Insulin resistance adds to endothelial dysfunction in hypertensive patients and in normotensive offspring of subjects with essential hypertension.

PubMed

Zizek, B; Poredos, P

2001-02-01

To evaluate whether endothelium-dependent (nitric oxide-mediated) dilation of the brachial artery (BA) is impaired in patients being treated for essential hypertension (EH), and whether this abnormality can be detected in normotensive offspring of subjects with EH (familial trait, FT); and to investigate the interrelationship between flow-mediated vasodilation (FMD) and hyperinsulinaemia/insulin resistance. Cross-sectional study. Angiology department at a teaching hospital. The study encompassed 172 subjects, of whom 46 were treated hypertonics aged 40-55 (49) years, and 44 age-matched, normotensive volunteers as controls. We also investigated 41 normotonics with FT aged 20-30 (25) years and 41 age-and sex-matched controls without FT. Using high-resolution ultrasound, BA diameters at rest, during reactive hyperaemia (endothelium-dependent dilation) and after sublingual glyceryl trinitrate (GTN) application (endothelium-independent dilation) were measured. In hypertonics FMD was significantly lower than in controls [2.4 (2.9) vs. 7.4 (2.5)%; P < 0.00005], as was GTN-induced dilation [12.1 (4.3) vs. 16.1 (4.6)%; P=0.0007]. In subjects with FT, FMD was also decreased compared with the control group [5.8 (4.1) vs. 10.0 (3.0)%; P < 0.00005]. The response to GTN was comparable in both groups of young subjects. FMD was negatively related to insulin concentration in all subjects studied (P < 0.00005). In treated patients with EH, flow-mediated dilation of the BA as well as endothelium-independent dilation are decreased. In individuals with FT the endothelial function of the peripheral arteries is also altered in the absence of elevated blood pressure. Endothelial dysfunction is related to hyperinsulinaemia/insulin resistance, which could be one of the pathogenetic determinants of EH and its complications.

Leptin is an endothelial-independent vasodilator in humans with coronary artery disease: Evidence for tissue specificity of leptin resistance.

PubMed

Momin, Aziz U; Melikian, Narbeh; Shah, Ajay M; Grieve, David J; Wheatcroft, Stephen B; John, Lindsay; El Gamel, Ahmed; Desai, Jatin B; Nelson, Toby; Driver, Catherine; Sherwood, Roy A; Kearney, Mark T

2006-10-01

We sought to define the mechanisms and correlates of leptin's vascular actions in humans with coronary artery disease. In 131 patients (age 65.7+/-0.7 years mean+/-SEM), ex vivo vascular reactivity to leptin (10(-13)-10(-7) M) was assessed in saphenous vein (SV) rings. Leptin led to SV relaxation (maximal relaxation 24.5+/-1.6%). In separate experiments, relaxation to leptin was unaffected by L-NMMA (17.4+/-3.4 vs.17.8+/-3.3%, P = 0.9) or endothelial denudation (17.4+/-4.4 vs. 22.5+/-3.0%, P = 0.4). We explored the possibility that leptin's vascular effects are mediated via smooth muscle hyperpolarization. In the presence of KCl (30 mmol/L) to inhibit hyperpolarization, the vasodilator effect of leptin was completely blocked (0.08+/-4.1%, P < 0.001 vs. control). Similar results were demonstrated in internal mammary artery rings. The only independent correlate of leptin-mediated vasodilatation was plasma TNF-alpha (r = 0.25, P < 0.05). Neither body mass index nor waist circumference correlated with leptin-mediated vasorelaxation. This lack of a correlation with markers of total body fat/fat distribution suggests that leptin resistance may not extend to the vasculature. Leptin is a vasoactive peptide in human SV and internal mammary artery. Its action is not nitric oxide or endothelial-dependent. Markers of body fat did not correlate with leptin-mediated vasodilatation, raising the intriguing possibility of selective resistance to leptin's actions.

Cysteinyl leukotrienes C4 and D4 downregulate human mast cell expression of toll-like receptors 1 through 7.

PubMed

Karpov, V; Ilarraza, R; Catalli, A; Kulka, M

2018-01-01

Cysteinyl leukotrienes (CysLT) are potent inflammatory lipid molecules that mediate some of the pathophysiological responses associated with asthma such as bronchoconstriction, vasodilation and increased microvascular permeability. As a result, CysLT receptor antagonists (LRA), such as montelukast, have been used to effectively treat patients with asthma. We have recently shown that mast cells are necessary modulators of innate immune responses to bacterial infection and an important component of this innate immune response may involve the production of CysLT. However, the effect of LRA on innate immune receptors, particularly on allergic effector cells, is unknown. This study determined the effect of CysLT on toll-like receptor (TLR) expression by the human mast cell line LAD2. Real-time PCR analysis determined that LTC4, LTD4 and LTE4 downregulated mRNA expression of several TLR. Specifically in human CD34+-derived human mast cells (HuMC), LTC4 inhibited expression of TLR1, 2, 4, 5, 6 and 7 while LTD4 inhibited expression of TLR1-7. Montelukast blocked LTC4-mediated downregulation of all TLR, suggesting that these effects were mediated by activation of the CysLT1 receptor (CysLT1R). Flow cytometry analysis confirmed that LTC4 downregulated surface expression of TLR2 which was blocked by montelukast. These data show that CysLT can modulate human mast cell expression of TLR and that montelukast may be beneficial for innate immune responses mediated by mast cells.

Exercise limits the production of endothelin in the coronary vasculature

PubMed Central

de Beer, Vincent J.; Bender, Shawn B.; Taverne, Yannick J.; Gao, Fen; Duncker, Dirk J.; Laughlin, M. Harold

2011-01-01

We previously demonstrated that endothelin (ET)-mediated coronary vasoconstriction wanes with increasing exercise intensity via a nitric oxide- and prostacyclin-dependent mechanism (Ref. 23). Therefore, we hypothesized that the waning of ET coronary vasoconstriction during exercise is the result of decreased production of ET and/or decreased ET receptor sensitivity. We investigated coronary ET receptor sensitivity using intravenous infusion of ET and coronary ET production using intravenous infusion of the ET precursor Big ET, at rest and during continuous treadmill exercise at 3 km/h in 16 chronically instrumented swine. In the systemic vasculature, Big ET and ET induced similar changes in hemodynamic parameters at rest and during continuous exercise at 3 km/h, indicating that exercise does not alter ET production or receptor sensitivity in the systemic vasculature. In the coronary vasculature, infusion of ET resulted in similar dose-dependent decreases in coronary blood flow and coronary venous oxygen tension and saturation at rest and during exercise. In contrast, administration of Big ET resulted in dose-dependent decreases in coronary blood flow, as well as coronary venous oxygen tension and saturation at rest. These effects of Big ET were significantly reduced during exercise. Altogether, our data indicate that continuous exercise at 3 km/h attenuates ET-mediated coronary vasoconstriction through reduced production of ET from Big ET rather than through reduced ET sensitivity of the coronary vasculature. The decreased ET production during exercise likely contributes to metabolic coronary vasodilation. PMID:21317308

Simulated Microgravity Increases Cutaneous Blood Flow in the Head and Leg of Humans

NASA Technical Reports Server (NTRS)

Stout, M. Shannon; Watenpaugh, Donald E.; Breit, Gregory A.; Hargens, Alan R.

1995-01-01

The cutaneous microcirculation vasodilates during acute 6 degree head-down tilt (HDT, simulated microgravity) relative to upright conditions, more in the lower body than in the upper body. Cutaneous microvascular blood flow was measured with laser-Doppler flowmetry at the leg (over the distal tibia) and cheek (over the zygomatic arch) of eight healthy men before, during, and after 24 h of HDT. Results were calculated as a percentage of baseline value (100% measured during pre-tilt upright sitting). Cutaneous blood flow in the cheek increased significantly to 165 +/- 37% (mean +/- SE, p less than 0.05) at 9-12 h HDT, then returned to near baseline values by 24 h HDT (114 +/- 29%, NSD), despite increased local arterial pressure. Microvascular flow in the leg remained significantly elevated above baseline througout 24 h HDT (427 +/- 85% at 3 h HDT and 215 +/- 142% at 24 h HDT, p less than 0.05). During the 6-h upright sitting recovery period, cheek and leg blood flow levels returned to near pre-tilt baseline values. Because hydrostatic effects of HDT increase local arterial pressure at the carotid sinus, baroreflex-mediated withdrawal of sympathetic tone probably contributed to increased microvascular flows at the head and leg during HDT. In the leg baroreflex effects combined with minimal stimulation of local veno-arteriolar and myogenic autoregulatory vasoconstriction to elicit relatively larger and more sustained increases in cutaneous flow during HDT. In the cheek, delayed myogenic vasoconstriction and/or hurmonal effects apparently compensated for flow elevation by 24 h of HDT. Therefore, localized vascular adaptations to gravity probably explain differences in acclimation of lower and upper body blood flow to HDT and actual microgravity.

Antagonism of soluble guanylyl cyclase attenuates cutaneous vasodilation during whole body heat stress and local warming in humans

PubMed Central

Zhao, Joan L.; Wu, Yubo; Johnson, John M.

2011-01-01

We hypothesized that nitric oxide activation of soluble guanylyl cyclase (sGC) participates in cutaneous vasodilation during whole body heat stress and local skin warming. We examined the effects of the sGC inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), on reflex skin blood flow responses to whole body heat stress and on nonreflex responses to increased local skin temperature. Blood flow was monitored by laser-Doppler flowmetry, and blood pressure by Finapres to calculate cutaneous vascular conductance (CVC). Intradermal microdialysis was used to treat one site with 1 mM ODQ in 2% DMSO and Ringer, a second site with 2% DMSO in Ringer, and a third site received Ringer. In protocol 1, after a period of normothermia, whole body heat stress was induced. In protocol 2, local heating units warmed local skin temperature from 34 to 41°C to cause local vasodilation. In protocol 1, in normothermia, CVC did not differ among sites [ODQ, 15 ± 3% maximum CVC (CVCmax); DMSO, 14 ± 3% CVCmax; Ringer, 17 ± 6% CVCmax; P > 0.05]. During heat stress, ODQ attenuated CVC increases (ODQ, 54 ± 4% CVCmax; DMSO, 64 ± 4% CVCmax; Ringer, 63 ± 4% CVCmax; P < 0.05, ODQ vs. DMSO or Ringer). In protocol 2, at 34°C local temperature, CVC did not differ among sites (ODQ, 17 ± 2% CVCmax; DMSO, 18 ± 4% CVCmax; Ringer, 18 ± 3% CVCmax; P > 0.05). ODQ attenuated CVC increases at 41°C local temperature (ODQ, 54 ± 5% CVCmax; DMSO, 86 ± 4% CVCmax; Ringer, 90 ± 2% CVCmax; P < 0.05 ODQ vs. DMSO or Ringer). sGC participates in neurogenic active vasodilation during heat stress and in the local response to direct skin warming. PMID:21292837

Effects of perilymphatic pressure, sodium nitroprusside, and bupivacaine on cochlear fluid pH of guinea pigs.

PubMed

Suzuki, Masaaki; Kotani, Ryosuke

2015-01-01

Hydrostatic positive pressure and vasoconstrictor acidified the cochlear fluids, whereas the vasodilator made the fluids alkaline. CBF might play a role in regulating cochlea fluid pH. Cochlea fluid pH is highly dependent on the HCO3(-)/CO2 buffer system. Cochlear blood flow (CBF) supplies O2 and removes CO2. It is speculated that cochlear blood flow changes might affect the balance of the HCO3(-)/CO2 buffer system in the cochlea. It is known that the elevation of inner ear pressure decreases the CBF, and local application of vasodilating or vasoconstricting agents directly to the cochlea changes the CBF. The purpose of this study was to elucidate the effect of positive hydrostatic inner ear pressure and application of a vasodilator and vasoconstrictor of cochlear vessels on the pH of the endolymph and perilymph. The authors performed animal physiological experiments on 30 guinea pigs. Hydrostatic positive pressure was infused through a glass capillary tube inserted into the scala tympani of the basal turn. The vasodilator, nitric oxide donor (sodium nitroprusside; SNP), and the vasoconstrictor, bupivacaine, were placed topically onto the round window of the guinea pig cochlea. Endolymph pH (pHe) and endocochlear potential (EP) were monitored by double-barreled ion-selective microelectrodes in the second turn of the guinea pig cochlea. During the topical application study, scala vestibuli perilymph pH (pHv) was also measured simultaneously in the second turn. The application of hydrostatic positive pressure caused a decrease in pHe and EP. Positive perilymphatic pressure caused the endolymph to become acidic pressure-dependently. Application of 3.0% SNP evoked an increase in both the pHe and pHv, following by a gradual recovery to baseline levels. On the other hand, 0.5% bupivacaine caused a decrease in both the pHe and pHv. The EP during topical application showed slight, non-significant changes.

Contributions of endothelial nitric oxide synthase, noradrenaline, and neuropeptide Y to local warming-induced cutaneous vasodilatation in men.

PubMed

Hodges, Gary J; Sparks, Paul A

2013-11-01

We performed a two-part study to determine the roles of endothelial nitric oxide synthase (eNOS) and the vasoconstrictor nerves neurotransmitters noradrenaline (NA) and neuropeptide Y (NPY) in the cutaneous vasodilator response to local skin warming. Forearm skin sites were instrumented with intradermal microdialysis fibres, local heaters, and laser-Doppler flow (LDF) probes. Sites were locally heated from 34 to 42°C. LDF was expressed as cutaneous vascular conductance (CVC; LDF/mean arterial pressure). In Part I, we tested whether sympathetic noradrenergic nerves acted via eNOS. In 8 male participants, treatments were as follows: 1) untreated; 2) bretylium tosylate (BT), preventing sympathetic neurotransmitter release; 3) l-NAA to inhibit eNOS; and 4) combined BT+l-NAA. At treated sites, the initial peak response was markedly reduced, and the plateau phase response to 35min of local warming was also reduced (P<0.05), which was not different among those sites (P>0.05). In Part II, we tested whether NA and NPY were involved in the vasodilator response to local warming. In Part IIa, treatments were: 1) untreated; 2) propranolol and yohimbine to antagonize α- and β-receptors; 3) l-NAA; and 4) combined propranolol, yohimbine, and l-NAA. In Part IIb, conditions were: 1) untreated; 2) BIBP to antagonize Y1-receptors; 3) l-NAA; and 4) combined BIBP and l-NAA. All treatments caused a reduction in the initial peak and plateau responses to local skin warming (P<0.05). The results of Part II indicate that both NA and NPY play roles in the cutaneous vasodilator response and their actions are achieved via eNOS. These data indicate that NA and NPY are involved in the initial, rapid rise in skin blood flow at the onset of local skin warming. However, their vasodilator actions in response to local skin warming appears to be manifested through eNOS. © 2013.

Vasodilator factors in the systemic and local adaptations to pregnancy

PubMed Central

Valdes, Gloria; Kaufmann, Peter; Corthorn, Jenny; Erices, Rafaela; Brosnihan, K Bridget; Joyner-Grantham, JaNae

2009-01-01

We postulate that an orchestrated network composed of various vasodilatory systems participates in the systemic and local hemodynamic adaptations in pregnancy. The temporal patterns of increase in the circulating and urinary levels of five vasodilator factors/systems, prostacyclin, nitric oxide, kallikrein, angiotensin-(1–7) and VEGF, in normal pregnant women and animals, as well as the changes observed in preeclamptic pregnancies support their functional role in maintaining normotension by opposing the vasoconstrictor systems. In addition, the expression of these vasodilators in the different trophoblastic subtypes in various species supports their role in the transformation of the uterine arteries. Moreover, their expression in the fetal endothelium and in the syncytiotrophoblast in humans, rats and guinea-pigs, favour their participation in maintaining the uteroplacental circulation. The findings that sustain the functional associations of the various vasodilators, and their participation by endocrine, paracrine and autocrine regulation of the systemic and local vasoactive changes of pregnancy are abundant and compelling. However, further elucidation of the role of the various players is hampered by methodological problems. Among these difficulties is the complexity of the interactions between the different factors, the likelihood that experimental alterations induced in one system may be compensated by the other players of the network, and the possibility that data obtained by manipulating single factors in vitro or in animal studies may be difficult to translate to the human. In addition, the impossibility of sampling the uteroplacental interface along normal pregnancy precludes obtaining longitudinal profiles of the various players. Nevertheless, the possibility of improving maternal blood pressure regulation, trophoblast invasion and uteroplacental flow by enhancing vasodilation (e.g. L-arginine, NO donors, VEGF transfection) deserves unravelling the intricate association of vasoactive factors and the systemic and local adaptations to pregnancy. PMID:19646248

Regulation of coronary resistance vessel tone in response to exercise.

PubMed

Duncker, Dirk J; Bache, Robert J; Merkus, Daphne

2012-04-01

Exercise is a primary stimulus for increased myocardial oxygen demand. The ~6-fold increase in oxygen demand of the left ventricle during heavy exercise is met principally by augmenting coronary blood flow (~5-fold), as hemoglobin concentration and oxygen extraction (which is already ~70% at rest) increase only modestly in most species. As a result, coronary blood flow is tightly coupled to myocardial oxygen consumption over a wide range of physical activity. This tight coupling has been proposed to depend on periarteriolar oxygen tension, signals released from cardiomyocytes and the endothelium as well as neurohumoral influences, but the contribution of each of these regulatory pathways, and their interactions, to exercise hyperemia in the heart remain incompletely understood. In humans, nitric oxide, adenosine and K(ATP) channels each appear to contribute to resting coronary resistance vessel tone, but evidence for a critical contribution to exercise hyperemia is lacking. In dogs K(ATP)-channel activation together with adenosine and nitric oxide contribute to exercise hyperemia in a non-linear redundant fashion. In contrast, in swine nitric oxide, adenosine and K(ATP) channels contribute to resting coronary resistance vessel tone control in a linear additive manner, but do not appear to be mandatory for exercise hyperemia. Rather, exercise hyperemia in swine appears to involve β-adrenergic activation in conjunction with exercise-induced blunting of an endothelin-mediated vasoconstrictor influence. In view of these remarkable species differences in coronary vasomotor control during exercise, future studies are required to determine the system of vasodilator components that mediate exercise hyperemia in humans. This article is part of a Special Issue entitled "Coronary Blood Flow". Copyright © 2011 Elsevier Ltd. All rights reserved.

Short-term increases in pressure and shear stress attenuate age-related declines in endothelial function in skeletal muscle feed arteries.

PubMed

Seawright, John W; Luttrell, Meredith; Trache, Andreea; Woodman, Christopher R

2016-07-01

We tested the hypothesis that exposure to a short-term (1 h) increase in intraluminal pressure and shear stress (SS), to mimic two mechanical signals associated with a bout of exercise, improves nitric oxide (NO)-mediated endothelium-dependent dilation in aged soleus muscle feed arteries (SFA). In addition, we hypothesized that pressure and SS would interact to produce greater improvements in endothelial function than pressure alone. SFA from young (4 months) and old (24 months) Fischer 344 rats were cannulated and pressurized at 90 (P90) or 130 (P130) cmH2O and exposed to no SS (0 dyn/cm(2)) or high SS (~65 dyn/cm(2)) for 1 h. At the end of the 1 h treatment period, pressure in all P130 SFA was set to 90 cmH2O and no SS (0 dyn/cm(2)) for examination of endothelium-dependent [flow and acetylcholine (ACh)] and endothelium-independent [sodium nitroprusside (SNP)] dilation. To evaluate the contribution of NO, vasodilator responses were assessed in the presence of N(ω)-nitro- l -arginine (L-NNA). Flow- and ACh-induced dilations were impaired in Old P90 SFA. Treatment with increased pressure + SS for 1 h improved flow- and ACh-induced dilations in old SFA. The beneficial effect of pressure + SS was abolished in the presence of L-NNA and was not greater than treatment with increased pressure alone. These results indicate that short-duration increases in pressure + SS improve NO-mediated endothelium-dependent dilation in aged SFA; however, pressure and SS do not interact to produce greater improvements in endothelial function than pressure alone.

SHBG and endothelial function in older subjects.

PubMed

Maggio, Marcello; Cattabiani, Chiara; Lauretani, Fulvio; Mantovani, Marco; Buttò, Valeria; De Vita, Francesca; Volpi, Riccardo; Artoni, Andrea; Giallauria, Francesco; Zuliani, Giovanni; Aloe, Rosalia; Lippi, Giuseppe; Ceresini, Graziano; Cederholm, Tommy; Ceda, Gian Paolo; Lind, Lars

2013-10-03

Endothelial dysfunction is predictor of cardiovascular diseases that have different prevalence in men and women before menopause. Sex hormones and sex hormone binding globulin (SHBG), novel risk factors for diabetes and cardiovascular diseases even in older individuals, might explain this difference. However, the relationship between these hormones and endothelial function has never been addressed in the elderly. 430 men and,424 women 70 years older of Prospective Study of the Vasculature in Uppsala Seniors study, with complete data on SHBG, testosterone(T), estradiol(E2), endothelium-independent vasodilation (EIDV), endothelium-dependent vasodilation(EDV), flow-mediated vasodilation (FMD) and the pulse wave analysis (reflection index, RI) were evaluated. Multivariate regression analysis adjusted for confounders was used to assess the relationship between T, E2, SHBG and endothelial function. In men we found a positive relationship between SHBG and EDV (β ± SE 3.60 ± 0.83, p<0.0001), EIDV (2.42 ± 0.58, p<0.0001) but not with FMD. The relationship between SHBG and EDV and EIDV was maintained after adjustment for sex (1.64 ± 0.47, p<0.001 and 1.79 ± 0.35, p<0.0006, respectively). After adjustment for confounders, the relationship between SHBG and EDV and EIDV was still statistically significant (2.63 ± 0.90 and 1.86 ± 0.63, p = 0.004 for both). In women SHBG and EIDV were positively associated (1.58 ± 0.46; p = 0.0007), and this relationship was independent of sex (1.79 ± 0.35; p<0.001). No significant interaction SHBG * SEX was found for EIDV (p = 0.72). In a combined analysis in two sexes, SHBG and EIDV were positively associated (1.13 ± 0.45; p = 0.01). SHBG was not associated with EDV, FMD and RI. No significant relationship was found between T or E2 and EDV, EIDV, FMD or RI in both sexes. In older men SHBG, but not T and E2, is positively and independently associated with EDV in resistance arteries. In both sexes, SHBG was positively and independently associated with EIDV. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

OPC-28326, a selective femoral arterial vasodilator, augments ischemia induced angiogenesis.

PubMed

Sumi, Makoto; Sata, Masataka; Hashimoto, Ayako; Imaizumi, Takashi; Yanaga, Katsuhiko; Ohki, Takao; Mori, Toyoki; Nagai, Ryozo

2007-05-01

OPC-28326, 4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionyl-aminobenzoyl) piperidine hydrochloride monohydrate, is a newly developed selective peripheral vasodilator and increases blood flow to lower extremities with alpha2-adrenergic antagonist property. Here, we investigated the effect of OPC-28326 on ischemia-induced angiogenesis. OPC-28326 enhanced tube formation by human aortic endothelial cells (HAECs). Moreover, OPC-28326 enhanced the number of microvessels sprouting from aortic rings embedded in collagen gel. OPC-28326 markedly induced phosphorylation of endothelial nitric oxide synthase (eNOS) in HAECs via phosphatidylinositol-3 kinase PI3K/Akt (PI3K/Akt) pathway. Next, the angiogenic effect of OPC-28326 was evaluated in a mouse hindlimb ischemia model. Blood flow recovery to the ischemic leg was significantly enhanced by OPC-28326. Furthermore, anti-CD31 immunostaining revealed that OPC-28326 increased capillary density in the ischemic muscle. However, OPC-28326 failed to promote blood flow recovery in ischemic hindlimb in eNOS-deficient mice. These results suggest that OPC-28326 promotes angiogenesis, which was associated with activation of eNOS via PI3K/Akt pathway. OPC-28326 might be promising to treat patients with ischemic vascular diseases.

Characterization of mechano-sensitive nano-containers for targeted vasodilation

NASA Astrophysics Data System (ADS)

Buscema, Marzia; Deyhle, Hans; Pfohl, Thomas; Hieber, Simone E.; Zumbuehl, Andreas; Müller, Bert

2016-04-01

Cardiovascular diseases are the worldwide number one cause of mortality. The blood flow in diseased human coronary arteries differs from the blood flow in the healthy vessels. This fact should be used for designing targeted localized delivery of vasodilators with a purely physical drug release trigger. Thus, we have proposed mechano-sensitive liposomes as mechano-sensitive containers. One has to tailor the liposome's properties, so that containers are stable under physiological conditions in health, but release their cargo near the constricted vessels at body temperature. In order to determine the shear stress threshold for release, both the morphology of the healthy and diseased human arteries and the mechanical property of the liposomes have to be known. We have shown that micro computed tomography (μCT) techniques allow visualizing the lumen of human coronary arteries and provide the basis for flow simulations to extract the wall shear stress of healthy and stenosed regions in human coronary arteries. The behavior of the mechano-sensitive liposomes is currently investigated by means of microfluidics and spatially resolved small-angle X-ray scattering. The liposomes are injected into micro-channels mimicking in vivo situation. The scattering signal from the liposomes reveals information about their size, shape, and wall thickness.

Resistin impairs endothelium-dependent dilation to bradykinin, but not acetylcholine, in the coronary circulation.

PubMed

Dick, Gregory M; Katz, Paige S; Farias, Martin; Morris, Michael; James, Jeremy; Knudson, Jarrod D; Tune, Johnathan D

2006-12-01

Elevated plasma levels of fat-derived signaling molecules are associated with obesity, vascular endothelial dysfunction, and coronary heart disease; however, little is known about their direct coronary vascular effects. Accordingly, we examined mechanisms by which one adipokine, resistin, affects coronary vascular tone and endothelial function. Studies were conducted in anesthetized dogs and isolated coronary artery rings. Resistin did not change coronary blood flow, mean arterial pressure, or heart rate. Resistin had no effect on acetylcholine-induced relaxation of artery rings; however, resistin did impair bradykinin-induced relaxation. Selective impairment was also observed in vivo, as resistin attenuated vasodilation to bradykinin but not to acetylcholine. Resistin had no effect on dihydroethidium fluorescence, an indicator of superoxide (O(2)(-)) production, and the inhibitory effect of resistin on bradykinin-induced relaxation persisted in the presence of Tempol, a superoxide dismutase mimetic. To determine whether resistin impaired production of and/or responses to nitric oxide (NO) or prostaglandins (e.g., prostacyclin; PGI(2)), we performed experiments with N(omega)-nitro-L-arginine methyl ester (L-NAME) and indomethacin. The effect of resistin to attenuate bradykinin-induced vasodilation persisted in the presence of L-NAME or indomethacin, suggesting resistin may act at a cell signaling point upstream of NO or PGI(2) production. Resistin-induced endothelial dysfunction is not generalized, and it is not consistent with effects mediated by O(2)(-) or interference with NO or PGI(2) signaling. The site of the resistin-induced impairment is unknown but may be at the bradykinin receptor or a closely associated signal transduction machinery proximal to NO synthase or cyclooxygenase.

Inhaled whole exhaust and its effect on exercise performance and vascular function.

PubMed

Cutrufello, Paul T; Rundell, Kenneth W; Smoliga, James M; Stylianides, Georgios A

2011-09-01

Internal combustion engines are a major source of particulate matter (PM) which has been shown to result in vasoconstriction, yet no present study to our knowledge has investigated the effect of exhaust emissions on both exercise performance and the vasculature. To examine the effect of freshly generated whole exhaust on exercise performance, pulmonary arterial pressure (PP), and flow-mediated vasodilation (FMD) of the brachial artery. Sixteen male, collegiate athletes (age: 20.8±1.28 years) were randomly assigned to submaximal exercise for 20 min followed by a 6 min maximal work accumulation exercise test in either high PM (HPM) or low PM (LPM) conditions on two consecutive days. After a 7-day washout period, subjects completed identical exercise trials in the alternate condition. HPM conditions were generated from a 4-cycle gasoline engine. The participants' PP and FMD were assessed before and after each exercise trial by tricuspid regurgitant velocity and brachial artery imaging, respectively. Total work (LPM: 108.0±14.8 kJ; HPM: 104.9±15.2 kJ, p=0.019) and FMD (LPM: 8.17±6.41%; HPM: 6.59±2.53%; p=0.034) significantly decreased in HPM while PP was significantly increased (LPM: 16.9±1.13 mmHg; HPM: 17.9±1.70 mmHg; p=0.004). A significant correlation was identified between the change in exercise performance and the change in FMD (r=0.494; p=0.026) after the first HPM trial. Exercise performance declined in HPM conditions in part due to impaired vasodilation in the peripheral vasculature.

Oxidative stress activates endothelial innate immunity via sterol regulatory element binding protein 2 (SREBP2) transactivation of microRNA-92a.

PubMed

Chen, Zhen; Wen, Liang; Martin, Marcy; Hsu, Chien-Yi; Fang, Longhou; Lin, Feng-Mao; Lin, Ting-Yang; Geary, McKenna J; Geary, Greg G; Zhao, Yongli; Johnson, David A; Chen, Jaw-Wen; Lin, Shing-Jong; Chien, Shu; Huang, Hsien-Da; Miller, Yury I; Huang, Po-Hsun; Shyy, John Y-J

2015-03-03

Oxidative stress activates endothelial innate immunity and disrupts endothelial functions, including endothelial nitric oxide synthase-derived nitric oxide bioavailability. Here, we postulated that oxidative stress induces sterol regulatory element-binding protein 2 (SREBP2) and microRNA-92a (miR-92a), which in turn activate endothelial innate immune response, leading to dysfunctional endothelium. Using cultured endothelial cells challenged by diverse oxidative stresses, hypercholesterolemic zebrafish, and angiotensin II-infused or aged mice, we demonstrated that SREBP2 transactivation of microRNA-92a (miR-92a) is oxidative stress inducible. The SREBP2-induced miR-92a targets key molecules in endothelial homeostasis, including sirtuin 1, Krüppel-like factor 2, and Krüppel-like factor 4, leading to NOD-like receptor family pyrin domain-containing 3 inflammasome activation and endothelial nitric oxide synthase inhibition. In endothelial cell-specific SREBP2 transgenic mice, locked nucleic acid-modified antisense miR-92a attenuates inflammasome, improves vasodilation, and ameliorates angiotensin II-induced and aging-related atherogenesis. In patients with coronary artery disease, the level of circulating miR-92a is inversely correlated with endothelial cell-dependent, flow-mediated vasodilation and is positively correlated with serum level of interleukin-1β. Our findings suggest that SREBP2-miR-92a-inflammasome exacerbates endothelial dysfunction during oxidative stress. Identification of this mechanism may help in the diagnosis or treatment of disorders associated with oxidative stress, innate immune activation, and endothelial dysfunction. © 2014 American Heart Association, Inc.

TRPV4 channels stimulate Ca2+-induced Ca2+ release in astrocytic endfeet and amplify neurovascular coupling responses.

PubMed

Dunn, Kathryn M; Hill-Eubanks, David C; Liedtke, Wolfgang B; Nelson, Mark T

2013-04-09

In the CNS, astrocytes are sensory and regulatory hubs that play important roles in cerebral homeostatic processes, including matching local cerebral blood flow to neuronal metabolism (neurovascular coupling). These cells possess a highly branched network of processes that project from the soma to neuronal synapses as well as to arterioles and capillaries, where they terminate in "endfeet" that encase the blood vessels. Ca(2+) signaling within the endfoot mediates neurovascular coupling; thus, these functional microdomains control vascular tone and local perfusion in the brain. Transient receptor potential vanilloid 4 (TRPV4) channels--nonselective cation channels with considerable Ca(2+) conductance--have been identified in astrocytes, but their function is largely unknown. We sought to characterize the influence of TRPV4 channels on Ca(2+) dynamics in the astrocytic endfoot microdomain and assess their role in neurovascular coupling. We identified local TRPV4-mediated Ca(2+) oscillations in endfeet and further found that TRPV4 Ca(2+) signals are amplified and propagated by Ca(2+)-induced Ca(2+) release from inositol trisphosphate receptors (IP3Rs). Moreover, TRPV4-mediated Ca(2+) influx contributes to the endfoot Ca(2+) response to neuronal activation, enhancing the accompanying vasodilation. Our results identify a dynamic synergy between TRPV4 channels and IP3Rs in astrocyte endfeet and demonstrate that TRPV4 channels are engaged in and contribute to neurovascular coupling.

Aldosterone mediates its rapid effects in vascular endothelial cells through GPER activation.

PubMed

Gros, Robert; Ding, Qingming; Liu, Bonan; Chorazyczewski, Jozef; Feldman, Ross D

2013-03-01

The importance of the rapid vascular effects of aldosterone is increasingly appreciated. Through these rapid pathways, aldosterone has been shown to regulate vascular contractility, cell growth, and apoptosis. In our most recent studies, we demonstrated the effects of aldosterone on cell growth and contractility in vascular smooth muscle cells. We showed that these effects could occur via activation of the classic mineralocorticoid receptor, as well the recently characterized G protein-coupled estrogen receptor (GPER), initially characterized as an estrogen-specific receptor. However, the mechanisms underlying aldosterone's endothelium-dependent actions are unknown. Furthermore, the ERK regulatory and proapoptotic effects of aldosterone mediated by GPER activation in cultured vascular smooth muscle cells were only apparent when GPER was reintroduced into these cells by gene transfer. Whether GPER activation via aldosterone might be an important regulator in native vascular cells has been questioned. Therefore, to determine the role of GPER in mediating aldosterone's effects on cell growth and vascular reactivity in native cells, we examined rat aortic vascular endothelial cells, a model characterized by persistent robust expression of GPER, but without detectable mineralocorticoid receptor expression. In these endothelial cells, the GPER agonist G1 mediates a rapid increase in ERK phosphorylation that is wholly GPER-dependent, paralleling the actions of aldosterone. The effects of G1 and aldosterone to stimulate ERK phosphorylation paralleled their proapoptotic and antiproliferative effects. In previous studies, we reported that aldosterone mediates a rapid endothelium-dependent vasodilatory effect, antagonistic to its direct vasoconstrictor effect in endothelium-denuded preparations. Using a rat aortic ring/organ bath preparation to determine the GPER dependence of aldosterone's endothelium-dependent vasodilator effects, we demonstrate that aldosterone inhibits phenylephrine-mediated contraction. This vasodilator effect parallels the actions of the GPER agonist G1. Furthermore, the effects of aldosterone were completely ablated by the GPER antagonist G15. These data support an important role of GPER activation in aldosterone-mediated regulation of endothelial cell growth, as well as in aldosterone's endothelium-mediated regulation of vasoreactivity.

Water immersion in preeclampsia.

PubMed

Elvan-Taşpinar, Ayten; Franx, Arie; Delprat, Constance C; Bruinse, Hein W; Koomans, Hein A

2006-12-01

Preeclampsia is associated with profound vasoconstriction in most organ systems and reduced plasma volume. Because water immersion produces a marked central redistribution of blood volume and suppresses the renin-angiotensin system response and sympathetic activity, we hypothesized that water immersion might be useful in the treatment of preeclampsia. The effects of thermoneutral water immersion for 3 hours on central and peripheral hemodynamics were evaluated in 7 preeclamptic patients, 7 normal pregnant control patients, and 7 nonpregnant women. Finger plethysmography was used to determine hemodynamic measurements (cardiac output and total peripheral resistance), and forearm blood flow was measured by strain gauge plethysmography. Postischemic hyperemia was used to determine endothelium-dependent vasodilation. Analysis was by analysis of variance for repeated measurements. During water immersion cardiac output increased while diastolic blood pressure and heart rate decreased, although systolic blood pressure remained unchanged in each group. Forearm blood flow increased significantly in the normal pregnant and preeclamptic subjects. Total peripheral resistance decreased in all groups, but values in preeclamptic patients remained above those of normotensive pregnant women. Water immersion had no effect on endothelium-dependent vasodilation in the preeclamptic group, and most hemodynamic changes that were observed reversed to baseline within 2 hours of completion of the procedure. Although water immersion results in hemodynamic alterations in a manner that is theoretically therapeutic for women with preeclampsia, the effect was limited and short-lived. In addition water immersion had no effect on endothelium-dependent vasodilation in women with preeclampsia. The therapeutic potential for water immersion in preeclampsia appears to be limited.

Bidirectional Control of Blood Flow by Astrocytes: A Role for Tissue Oxygen and Other Metabolic Factors.

PubMed

Gordon, Grant R J; Howarth, Clare; MacVicar, Brian A

2016-01-01

Altering cerebral blood flow through the control of cerebral vessel diameter is critical so that the delivery of molecules important for proper brain functioning is matched to the activity level of neurons. Although the close relationship of brain glia known as astrocytes with cerebral blood vessels has long been recognized, it is only recently that these cells have been demonstrated to translate information on the activity level and energy demands of neurons to the vasculature. In particular, astrocytes respond to elevations in extracellular glutamate as a consequence of synaptic transmission through the activation of group 1 metabotropic glutamate receptors. These Gq-protein coupled receptors elevate intracellular calcium via IP3 signaling. A close examination of astrocyte endfeet calcium signals has been shown to cause either vasoconstriction or vasodilation. Common to both vasomotor responses is the generation of arachidonic acid in astrocytes by calcium sensitive phospholipase A2. Vasoconstriction ensues from the conversion of arachidonic acid to 20-hydroxyeicosatetraenoic acid, while vasodilation ensues from the production of epoxyeicosatrienoic acids or prostaglandins. Factors that determine whether constrictor or dilatory pathways predominate include brain oxygen, lactate, adenosine as well as nitric oxide. Changing the oxygen level itself leads to many downstream changes that facilitate the switch from vasoconstriction at high oxygen to vasodilation at low oxygen. These findings highlight the importance of astrocytes as sensors of neural activity and metabolism to coordinate the delivery of essential nutrients via the blood to the working cells.

Targeting the Nociceptin/Orphanin FQ Receptor for Scleroderma Therapy

DTIC Science & Technology

2016-08-01

quantified by flow cytometry. In the aortic ring assay, freshly isolated thoracic aorta rings will be harvested and mounted in a small- vessel...ring assay, freshly isolated thoracic aorta rings will be harvested and mounted in a small-vessel myograph. Vasodilation will be determined by

Selective Methylmagnesium Chloride Mediated Acetylations of Isosorbide: A Route to Powerful Nitric Oxide Donor Furoxans.

PubMed

Kielty, Patrick; Smith, Dennis A; Cannon, Peter; Carty, Michael P; Kennedy, Michael; McArdle, Patrick; Singer, Richard J; Aldabbagh, Fawaz

2018-04-26

Isosorbide was functionalized with furoxan for the first time to give adducts that release nitric oxide up to 7.5 times faster than the commercial vasodilator, isosorbide-5-mononitrate (Is5N). The synthesis was facilitated by MeMgCl-mediated selective acetylation of isosorbide or selective deacetylation of isosorbide-2,5-diacetate, which was rationalized in terms of a more stable 5-alkoxide magnesium salt using DFT. Isosorbide-furoxans are safer to handle than Is5N due to greater thermal stability.

Effect of hawthorn standardized extract on flow mediated dilation in prehypertensive and mildly hypertensive adults: a randomized, controlled cross-over trial.

PubMed

Asher, Gary N; Viera, Anthony J; Weaver, Mark A; Dominik, Rosalie; Caughey, Melissa; Hinderliter, Alan L

2012-03-29

Hawthorn extract has been used for cardiovascular diseases for centuries. Recent trials have demonstrated its efficacy for the treatment of heart failure, and the results of several small trials suggest it may lower blood pressure. However, there is little published evidence to guide its dosing. The blood pressure lowering effect of hawthorn has been linked to nitric oxide-mediated vasodilation. The aim of this study was to investigate the relationship between hawthorn extract dose and brachial artery flow mediated dilation (FMD), an indirect measure of nitric oxide release. We used a four-period cross-over design to evaluate brachial artery FMD in response to placebo or hawthorn extract (standardized to 50 mg oligomeric procyanidin per 250 mg extract). Randomly sequenced doses of hawthorn extract (1000 mg, 1500 mg, and 2500 mg) and placebo were assigned to each participant. Doses were taken twice daily for 3 1/2 days followed by FMD and a 4-day washout before proceeding to the next dosing period. Twenty-one prehypertensive or mildly hypertensive adults completed the study. There was no evidence of a dose-response effect for our main outcome (FMD percent) or any of our secondary outcomes (absolute change in brachial artery diameter and blood pressure). Most participants indicated that if given evidence that hawthorn could lower their blood pressure, they would be likely to use it either in conjunction with or instead of lifestyle modification or anti-hypertensive medications. We found no evidence of a dose-response effect of hawthorn extract on FMD. If hawthorn has a blood pressure lowering effect, it is likely to be mediated via an NO-independent mechanism. This trial has been registered with ClinicalTrials.gov, a service of the U.S. National Institutes of Health: NCT01331486.

Effect of hawthorn standardized extract on flow mediated dilation in prehypertensive and mildly hypertensive adults: a randomized, controlled cross-over trial

PubMed Central

2012-01-01

Background Hawthorn extract has been used for cardiovascular diseases for centuries. Recent trials have demonstrated its efficacy for the treatment of heart failure, and the results of several small trials suggest it may lower blood pressure. However, there is little published evidence to guide its dosing. The blood pressure lowering effect of hawthorn has been linked to nitric oxide-mediated vasodilation. The aim of this study was to investigate the relationship between hawthorn extract dose and brachial artery flow mediated dilation (FMD), an indirect measure of nitric oxide release. Methods We used a four-period cross-over design to evaluate brachial artery FMD in response to placebo or hawthorn extract (standardized to 50 mg oligomeric procyanidin per 250 mg extract). Randomly sequenced doses of hawthorn extract (1000 mg, 1500 mg, and 2500 mg) and placebo were assigned to each participant. Doses were taken twice daily for 3 1/2 days followed by FMD and a 4-day washout before proceeding to the next dosing period. Results Twenty-one prehypertensive or mildly hypertensive adults completed the study. There was no evidence of a dose-response effect for our main outcome (FMD percent) or any of our secondary outcomes (absolute change in brachial artery diameter and blood pressure). Most participants indicated that if given evidence that hawthorn could lower their blood pressure, they would be likely to use it either in conjunction with or instead of lifestyle modification or anti-hypertensive medications. Conclusion We found no evidence of a dose-response effect of hawthorn extract on FMD. If hawthorn has a blood pressure lowering effect, it is likely to be mediated via an NO-independent mechanism. Trial Registration This trial has been registered with ClinicalTrials.gov, a service of the U.S. National Institutes of Health: NCT01331486. PMID:22458601

Hemodynamic actions of systemically injected pituitary adenylate cyclase activating polypeptide-27 in the rat

NASA Technical Reports Server (NTRS)

Whalen, E. J.; Johnson, A. K.; Lewis, S. J.

1999-01-01

The aims of this study were (1) to characterize the hemodynamic mechanisms underlying the hypotensive effects of pituitary adenylate cyclase activating polypeptide-27 (PACAP-27 0.1-2.0 nmol/kg, i.v.) in pentobarbital-anesthetized rats, and (2) to determine the roles of the autonomic nervous system, adrenal catecholamines and endothelium-derived nitric oxide (NO) in the expression of PACAP-27-mediated effects on hemodynamic function. PACAP-27 produced dose-dependent decreases in mean arterial blood pressure and hindquarter and mesenteric vascular resistances in saline-treated rats. PACAP-27 also produced pronounced falls in mean arterial blood pressure in rats treated with the ganglion blocker, chlorisondamine (5 mg/kg, i.v.). The hypotensive and vasodilator actions of PACAP-27 were not attenuated by the beta-adrenoceptor antagonist, propranolol (1 mg/kg, i.v.), or the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME 50 micromol/kg, i.v.). PACAP-27 produced dose-dependent increases in heart rate whereas the hypotensive response produced by the nitrovasodilator, sodium nitroprusside (10 microg/kg, i.v.), was associated with a minimal tachycardia. The PACAP-27-induced tachycardia was unaffected by chlorisondamine, but was virtually abolished by propranolol. These results suggest that the vasodilator effects of PACAP-27 are due to actions in the microcirculation rather than to the release of adrenal catecholamines and that this vasodilation may not involve the release of endothelium-derived NO. These results also suggest that PACAP-27 produces tachycardia by directly releasing norepinephrine from cardiac sympathetic nerve terminals rather than by direct or baroreceptor reflex-mediated increases in sympathetic nerve activity.

Treatment of spontaneously hypertensive rats with rosiglitazone and/or enalapril restores balance between vasodilator and vasoconstrictor actions of insulin with simultaneous improvement in hypertension and insulin resistance.

PubMed

Potenza, Maria A; Marasciulo, Flora L; Tarquinio, Mariela; Quon, Michael J; Montagnani, Monica

2006-12-01

Spontaneously hypertensive rats (SHRs) exhibit endothelial dysfunction and insulin resistance. Reciprocal relationships between endothelial dysfunction and insulin resistance may contribute to hypertension by causing imbalanced regulation of endothelial-derived vasodilators (e.g., nitric oxide) and vasoconstrictors (e.g., endothelin-1 [ET-1]). Treatment of SHRs with rosiglitazone (insulin sensitizer) and/or enalapril (ACE inhibitor) may simultaneously improve hypertension, insulin resistance, and endothelial dysfunction by rebalancing insulin-stimulated production of vasoactive mediators. When compared with WKY control rats, 12-week-old vehicle-treated SHRs were hypertensive, overweight, and insulin resistant, with elevated fasting levels of insulin and ET-1 and reduced serum adiponectin levels. In mesenteric vascular beds (MVBs) isolated from vehicle-treated SHRs and preconstricted with norepinephrine (NE) ex vivo, vasodilator responses to insulin were significantly impaired, whereas the ability of insulin to oppose vasoconstrictor actions of NE was absent (versus WKY controls). Three-week treatment of SHRs with rosiglitazone and/or enalapril significantly reduced blood pressure, insulin resistance, fasting insulin, and ET-1 levels and increased adiponectin levels to values comparable with those observed in vehicle-treated WKY controls. By restoring phosphatidylinositol 3-kinase-dependent effects, rosiglitazone and/or enalapril therapy of SHRs also significantly improved vasodilator responses to insulin in MVB preconstricted with NE ex vivo. Taken together, our data provide strong support for the existence of reciprocal relationships between endothelial dysfunction and insulin resistance that may be relevant for developing novel therapeutic strategies for the metabolic syndrome.

[A comparative study on efficacy of glucocorticoids, mineralocorticoids and vasoactive drugs on reversing hearing loss in patients suffering idiopathic sensorineural cochlear hypoacusis. A preliminary clinical trial].

PubMed

Campos-Bañales, Eugenia María; López-Campos, Daniel; de Serdio-Arias, José Luis; Esteban-Rodriguez, J; García-Sáinz, Mar; Muñoz-Cortés, Álvaro; López-Aguado, Daniel

2015-01-01

Sensory neural hearing loss (SNHL) is a disorder characterised by an important deterioration of the auditory function. Re-establishing normal ion homeostasis of the endolymph could be related to hearing recovery and it might be mediated by mineralocorticoids. The main purpose of this preliminary, randomized controlled clinical trial was assessing the recovery of idiopathic sensory neural cochlear hearing loss (SNHL) by comparing the efficacy of 2 types of steroids versus vasodilators. The 3-month intervention involved 70 patients, allocated into 4 different groups: a control with no medication, consisting of 14 patients (8 men and 6 women); a vasodilator group of 21 patients (11 men and 10 women); a glucocorticoid group with 16 patients (10 men and 6 women); and a mineralocorticoid therapy group, consisting of 19 patients (11 men and 8 women). The level of hearing loss and its topography were estimated using Liminal Tone Audiometry (LTA) and Auditory Brainstem Response (ABR). Our research found overall greater efficacy of mineralocorticoids versus glucocorticoids and vasodilators. There was better response in women than in men and it was higher from the left ear, regardless of patient gender. The hearing gain was significantly superior in the mineralocorticoid group, followed by the glucocorticoid group. However, the responses to vasodilators were lesser and of low statistical significance. Copyright © 2014 Elsevier España, S.L.U. and Sociedad Española de Otorrinolaringología y Patología Cérvico-Facial. All rights reserved.

Fibro-vascular coupling in the control of cochlear blood flow.

PubMed

Dai, Min; Shi, Xiaorui

2011-01-01

Transduction of sound in the cochlea is metabolically demanding. The lateral wall and hair cells are critically vulnerable to hypoxia, especially at high sound levels, and tight control over cochlear blood flow (CBF) is a physiological necessity. Yet despite the importance of CBF for hearing, consensus on what mechanisms are involved has not been obtained. We report on a local control mechanism for regulating inner ear blood flow involving fibrocyte signaling. Fibrocytes in the super-strial region are spatially distributed near pre-capillaries of the spiral ligament of the albino guinea pig cochlear lateral wall, as demonstrably shown in transmission electron microscope and confocal images. Immunohistochemical techniques reveal the inter-connected fibrocytes to be positive for Na+/K+ ATPase β1 and S100. The connected fibrocytes display more Ca(2+) signaling than other cells in the cochlear lateral wall as indicated by fluorescence of a Ca(2+) sensor, fluo-4. Elevation of Ca(2+) in fibrocytes, induced by photolytic uncaging of the divalent ion chelator o-nitrophenyl EGTA, results in propagation of a Ca(2+) signal to neighboring vascular cells and vasodilation in capillaries. Of more physiological significance, fibrocyte to vascular cell coupled signaling was found to mediate the sound stimulated increase in cochlear blood flow (CBF). Cyclooxygenase-1 (COX-1) was required for capillary dilation. The findings provide the first evidence that signaling between fibrocytes and vascular cells modulates CBF and is a key mechanism for meeting the cellular metabolic demand of increased sound activity.

Oxygen dependence of endothelium-dependent vasodilation: importance in chronic obstructive pulmonary disease.

PubMed

Keymel, Stefanie; Schueller, Benedikt; Sansone, Roberto; Wagstaff, Rabea; Steiner, Stephan; Kelm, Malte; Heiss, Christian

2018-03-01

Epidemiological studies have shown increased morbidity and mortality in patients with coronary artery disease (CAD) and chronic obstructive pulmonary disease (COPD). We aimed to characterize the oxygen dependence of endothelial function in patients with CAD and coexisting COPD. In CAD patients with and without COPD ( n = 33), we non-invasively measured flow-mediated dilation (FMD) and intima-media thickness (IMT) of the brachial artery (BA), forearm blood flow (FBF), and perfusion of the cutaneous microcirculation with laser Doppler perfusion imaging (LDPI). In an experimental setup, vascular function was assessed in healthy volunteers ( n = 5) breathing 12% oxygen or 100% oxygen in comparison to room air. COPD was associated with impaired FMD (3.4 ±0.5 vs. 4.2 ±0.6%; p < 0.001) and increased IMT (0.49 ±0.04 vs. 0.44 ±0.04 mm; p <0.01), indicating functional and structural alterations of the BA in COPD. Forearm blood flow and LDPI were comparable between the groups. Flow-mediated dilation correlated with capillary oxygen pressure (pO 2 , r = 0.608). Subgroup analysis in COPD patients with pO 2 > 65 mm Hg and pO 2 ≤ 65 mm Hg revealed even lower FMD in patients with lower pO 2 (3.0 ±0.5 vs. 3.7 ±0.4%; p < 0.01). Multivariate analysis showed that pO 2 was a predictor of FMD independent of the forced expiratory volume and pack years. Exposure to hypoxic air led to an acute decrease in FMD, whereby exposure to 100% oxygen did not change vascular function. Our data suggest that in CAD patients with COPD, decreased systemic oxygen levels lead to endothelial dysfunction, underlining the relevance of cardiopulmonary interaction and the potential importance of pulmonary treatment in secondary prevention of vascular disease.

Acute microcirculatory response to nicotine in frog web.

PubMed

Horimoto, M; Koyama, T

1982-01-01

Acute effects of nicotine (NC) on the microcirculation of frog webs were studied by measuring the blood flow velocity in arterioles, and by determining the diameter of both arterioles and venules. Simultaneous recordings of the ventricular pressure and heart rate were obtained in order to compute the vascular resistance and to interpret the changes in microcirculation. The web of right hindlimb was immersed in a solution of NC (2.6 to 3.4 mg/ml) for 4 min. Blood flow velocity in web arterioles of left hindlimb was measured by means of a laser Doppler microscope. Internal diameters of web microvessels were determined using a micrometer on the ocular lens of the microscope. Mean flow velocity (MV) and pulsatile amplitude (PA) were calculated from the pulsatile flow-velocity contour for each vessel. Both MV and PA were increased after the immersion of the web in NC solution. Although the magnitude of the increment in MV was proportional to that in ventricular pressure, the vasodilation of both arterioles and venules and the flow rate in arterioles higher than the initial state continued even after the ventricular pressure had returned to the initial control value. Calculation of the relative change in vascular resistance in web arterioles following NC administration suggested a vasodilator response to NC. Furthermore, our results indicate that sufficient NC can be absorbed across the web epithelium to produce a systemic vascular response when the concentration of NC in the bathing solution is 2.6 mg/ml.

Folic Acid Supplementation Improves Vascular Function in Professional Dancers With Endothelial Dysfunction

PubMed Central

Hoch, Anne Z.; Papanek, Paula; Szabo, Aniko; Widlansky, Michael E.; Gutterman, David D.

2012-01-01

Objective To determine if folic acid supplementation improves vascular function (brachial artery flow-mediated dilation [FMD]) in professional dancers with known endothelial dysfunction. Design Prospective cross-sectional study. Setting Academic institution in the Midwestern United States. Subjects Twenty-two professional ballet dancers volunteered for this study. Main Outcome Measures Subjects completed a 3-day food record to determine caloric and micronutrient intake. Menstrual status was determined by interview and questionnaire. Endothelial function was determined as flow-induced vasodilation measured by high-frequency ultrasound of the brachial artery. A change in brachial diameter of <5% to hyperemic flow stimulus was defined a priori as endothelial dysfunction. Subjects with abnormal FMD took 10 mg of folic acid daily for 4 weeks, and FMD testing was then repeated. Serum whole blood was measured for folic acid levels before and after supplementation. Results Sixty-four percent of dancers (n = 14) had abnormal brachial artery FMD (<5%) (mean ± standard deviation, 2.9% ± 1.5%). After 4 weeks of folic acid supplementation (10 mg/day), FMD improved in all the subjects (7.1% ± 2.3%; P < .0001). Conclusions This study reveals that vascular endothelial function improves in dancers after supplementation with folic acid (10 mg/day) for at least 4 weeks. This finding may have clinically important implications for future cardiovascular disease risk prevention. PMID:21715240

The Role of Vasodilator Receptors of Renin-angiotensin System on Nitric Oxide Formation and Kidney Circulation after Angiotensin II Infusion in Renal Ischemia/Reperfusion Rats.

PubMed

Maleki, Maryam; Hasanshahi, Jalal; Moslemi, Fatemeh

2018-01-01

Nitric oxide (NO) as a vasodilator factor has renoprotective effect against renal ischemia. The balance between angiotensin II (Ang II) and NO can affect kidney homeostasis. The aim of this study was to determine NO alteration in response to renin-Ang system vasodilator receptors antagonists (PD123319; Ang II type 2 receptor antagonist and A779; Mas receptor antagonist) in renal ischemia/reperfusion injury (IRI) in rats. Sixty-three Wistar male and female rats were used. Animals from each gender were divided into four groups received saline, Ang II, PD123319 + Ang II, and A779 + Ang II after renal IRI. Renal IRI induced with an adjustable hook. Blood pressure and renal blood flow (RBF) measured continuously. The nitrite levels were measured in serum, kidney, and urine samples. In female rats, the serum and kidney nitrite levels increased significantly by Ang II ( P < 0.05) and decreased significantly ( P < 0.05) when PD123319 was accompanied with Ang II. Such observation was not seen in male. Ang II decreased RBF significantly in all groups ( P < 0.05), while PD + Ang II group showed significant decrease in RBF in comparison with the other groups in female rats ( P < 0.05). Males show more sensibility to Ang II infusion; in fact, it is suggested that there is gender dimorphism in the Ang II and NO production associated with vasodilator receptors.

Wearing graduated compression stockings augments cutaneous vasodilation in heat-stressed resting humans.

PubMed

Fujii, Naoto; Nikawa, Toshiya; Tsuji, Bun; Kondo, Narihiko; Kenny, Glen P; Nishiyasu, Takeshi

2017-05-01

We investigated whether graduated compression induced by stockings enhances cutaneous vasodilation in passively heated resting humans. Nine habitually active young men were heated at rest using water-perfusable suits, resulting in a 1.0 °C increase in body core temperature. Heating was repeated twice on separate occasions while wearing either (1) stockings that cause graduated compression (pressures of 26.4 ± 5.3, 17.5 ± 4.4, and 6.1 ± 2.0 mmHg at the ankle, calf, and thigh, respectively), or (2) loose-fitting stockings without causing compression (Control). Forearm vascular conductance during heating was evaluated by forearm blood flow (venous occlusion plethysmography) divided by mean arterial pressure to estimate heat-induced cutaneous vasodilation. Body core (esophageal), skin, and mean body temperatures were measured continuously. Compared to the Control, forearm vascular conductance during heating was higher with graduated compression stockings (e.g., 23.2 ± 5.5 vs. 28.6 ± 5.8 units at 45 min into heating, P = 0.001). In line with this, graduated compression stockings resulted in a greater sensitivity (27.5 ± 8.3 vs. 34.0 ± 9.4 units °C -1 , P = 0.02) and peak level (25.5 ± 5.8 vs. 29.7 ± 5.8 units, P = 0.004) of cutaneous vasodilation as evaluated from the relationship between forearm vascular conductance with mean body temperature. In contrast, the mean body temperature threshold for increases in forearm vascular conductance did not differ between the Control and graduated compression stockings (36.5 ± 0.1 vs. 36.5 ± 0.2 °C, P = 0.85). Our results show that graduated compression associated with the use of stockings augments cutaneous vasodilation by modulating sensitivity and peak level of cutaneous vasodilation in relation to mean body temperature. However, the effect of these changes on whole-body heat loss remains unclear.

Inhaled nitric oxide, oxygen, and alkalosis: dose-response interactions in a lamb model of pulmonary hypertension.

PubMed

Heidersbach, R S; Johengen, M J; Bekker, J M; Fineman, J R

1999-07-01

Inhaled nitric oxide (NO) is currently used as an adjuvant therapy for a variety of pulmonary hypertensive disorders. In both animal and human studies, inhaled NO induces selective, dose-dependent pulmonary vasodilation. However, its potential interactions with other simultaneously used pulmonary vasodilator therapies have not been studied. Therefore, the objective of this study was to determine the potential dose-response interactions of inhaled NO, oxygen, and alkalosis therapies. Fourteen newborn lambs (age 1-6 days) were instrumented to measure vascular pressures and left pulmonary artery blood flow. After recovery, the lambs were sedated and mechanically ventilated. During steady-state pulmonary hypertension induced by U46619 (a thromboxane A2 mimic), the lambs were exposed to the following conditions: Protocol A, inhaled NO (0, 5, 40, and 80 ppm) and inspired oxygen concentrations (FiO2) of 0.21, 0.50, and 1.00; and Protocol B, inhaled NO (0, 5, 40, and 80 ppm) and arterial pH levels of 7.30, 7.40, 7.50, and 7.60. Each condition (in randomly chosen order) was maintained for 10 min, and all variables were allowed to return to baseline between conditions. Inhaled NO, oxygen, and alkalosis produced dose-dependent decreases in mean pulmonary arterial pressures (P < 0.05). Systemic arterial pressure remained unchanged. At 5 ppm of inhaled NO, alkalosis and oxygen induced further dose-dependent decreases in mean pulmonary arterial pressures (P < 0.05). At inhaled NO doses > 5 ppm, alkalosis induced further dose-independent decreases in mean pulmonary arterial pressure, while oxygen did not. We conclude that in this animal model, oxygen, alkalosis, and inhaled NO induced selective, dose-dependent pulmonary vasodilation. However, when combined, a systemic arterial pH > 7.40 augmented inhaled NO-induced pulmonary vasodilation, while an FiO2 > 0.5 did not. Therefore, weaning high FiO2 during inhaled NO therapy should be considered, since it may not diminish the pulmonary vasodilating effects. Further studies are warranted to guide the clinical weaning strategies of these pulmonary vasodilator therapies.

Relationship between regional myocardial blood flow and thallium-201 distribution in the presence of coronary artery stenosis and dipyridamole-induced vasodilation.

PubMed Central

Mays, A E; Cobb, F R

1984-01-01

This study assesses the relationship between the distribution of thallium-201 and myocardial blood flow during coronary vasodilation induced by intravenous dipyridamole in canine models of partial and complete coronary artery stenosis. 10 dogs were chronically instrumented with catheters in the left atrium and aorta and with a balloon occluder and electromagnetic flow probe on the proximal left circumflex coronary artery. Regional myocardial blood flow was measured during control conditions with radioisotope-labeled microspheres, and the phasic reactive hyperemic response to a 20-s transient occlusion was then recorded. Dipyridamole was then infused intravenously until phasic coronary blood flow increased to match peak hyperemic values. The left circumflex coronary artery was either partially occluded to reduce phasic blood flow to control values (group 1) or it was completely occluded (group 2), and thallium-201 and a second microsphere label were injected. 5 min later, the animals were sacrificed, the left ventricle was sectioned into 1-2-g samples, and thallium-201 activity and regional myocardial blood flow were measured. Curvilinear regression analyses between thallium-201 localization and myocardial blood flow during dipyridamole infusion demonstrated a slightly better fit to a second- as compared with a first-order model, indicating a slight roll-off of thallium activity as myocardial blood flow increases. During the dipyridamole infusion, the increases in phasic blood flow, the distributions of regional myocardial blood flow, and the relationships between thallium-201 localization and regional blood flow were comparable to values previously observed in exercising dogs with similar occlusions. These data provide basic validation that supports the use of intravenous dipyridamole and thallium-201 as an alternative to exercise stress and thallium-201 for evaluating the effects of coronary occlusive lesions on the distribution of regional myocardial blood flow. PMID:6715540

Role of blood and vascular smooth muscle in the vasoactivity of nitrite.

PubMed

Liu, Taiming; Schroeder, Hobe J; Barcelo, Lisa; Bragg, Shannon L; Terry, Michael H; Wilson, Sean M; Power, Gordon G; Blood, Arlin B

2014-10-01

Recent evidence from humans and rats indicates that nitrite is a vasodilator under hypoxic conditions by reacting with metal-containing proteins to produce nitric oxide (NO). We tested the hypothesis that near-physiological concentrations of nitrite would produce vasodilation in a hypoxia- and concentration-dependent manner in the hind limb of sheep. Anesthetized sheep were instrumented to measure arterial blood pressure and femoral blood flows continuously in both hind limbs. Nitrite was infused into one femoral artery to raise the nitrite concentration in the femoral vein by 10 to 15-fold while the sheep breathed 50%, 14% or 12% oxygen in inspired air. In contrast to reports in humans and rats, the nitrite infusion had no measurable effect on mean femoral blood flows or vascular conductances, regardless of inspired O2 levels. In vitro experiments showed no significant difference in the release of NO from nitrite in sheep and human red blood cells. Further experiments demonstrated nitrite is converted to NO in rat artery homogenates faster than sheep arteries, and that this source of NO production is attenuated in the presence of a heme oxidizer. Finally, western blots indicate that concentrations of the heme-containing protein cytoglobin, but not myoglobin, are markedly lower in sheep arteries compared with rats. Overall, the results demonstrate that nitrite is not a physiological vasodilator in sheep. This is likely due to a lack of conversion of nitrite to NO within the vascular smooth muscle, perhaps due to deficient amounts of the heme-containing protein cytoglobin. Copyright © 2014 the American Physiological Society.

Role of blood and vascular smooth muscle in the vasoactivity of nitrite

PubMed Central

Liu, Taiming; Schroeder, Hobe J.; Barcelo, Lisa; Bragg, Shannon L.; Terry, Michael H.; Wilson, Sean M.; Power, Gordon G.

2014-01-01

Recent evidence from humans and rats indicates that nitrite is a vasodilator under hypoxic conditions by reacting with metal-containing proteins to produce nitric oxide (NO). We tested the hypothesis that near-physiological concentrations of nitrite would produce vasodilation in a hypoxia- and concentration-dependent manner in the hind limb of sheep. Anesthetized sheep were instrumented to measure arterial blood pressure and femoral blood flows continuously in both hind limbs. Nitrite was infused into one femoral artery to raise the nitrite concentration in the femoral vein by 10 to 15-fold while the sheep breathed 50%, 14% or 12% oxygen in inspired air. In contrast to reports in humans and rats, the nitrite infusion had no measurable effect on mean femoral blood flows or vascular conductances, regardless of inspired O2 levels. In vitro experiments showed no significant difference in the release of NO from nitrite in sheep and human red blood cells. Further experiments demonstrated nitrite is converted to NO in rat artery homogenates faster than sheep arteries, and that this source of NO production is attenuated in the presence of a heme oxidizer. Finally, western blots indicate that concentrations of the heme-containing protein cytoglobin, but not myoglobin, are markedly lower in sheep arteries compared with rats. Overall, the results demonstrate that nitrite is not a physiological vasodilator in sheep. This is likely due to a lack of conversion of nitrite to NO within the vascular smooth muscle, perhaps due to deficient amounts of the heme-containing protein cytoglobin. PMID:25108012

Effect of fluoroquinolone on the enhanced nitric oxide-induced peripheral vasodilation seen in cirrhosis.

PubMed

Chin-Dusting, J P; Rasaratnam, B; Jennings, G L; Dudley, F J

1997-12-01

In patients with cirrhosis, portosystemic shunts allow intestinal bacteria and endotoxin to enter the systemic circulation. Endotoxemia may induce increased synthesis of nitric oxide, thereby contributing to arterial vasodilation. To test the hypothesis that the antibiotic norfloxacin blocks the effects of nitric oxide. Placebo-controlled, double-blind, crossover study. Alfred Hospital, Melbourne, Australia. 9 patients with alcohol-related cirrhosis and 10 healthy controls. Norfloxacin, 400 mg twice daily, for 4 weeks. Peripheral blood flow was measured by using forearm venous occlusion plethysmography. Basal forearm blood flow was higher in patients with cirrhosis than in controls (3.69 +/- 0.27 mL/100 mL per minute and 2.47 +/- 0.40 mL/100 mL per minute; P = 0.014) but returned toward normal after norfloxacin was given (2.64 +/- 0.31 mL/100 mL of tissue per minute in patients with cirrhosis). Responses to NG-monomethyl-L-arginine were greater in patients with cirrhosis but returned to normal after norfloxacin was given. Bacterial endotoxemia in patients with cirrhosis induces increased synthesis of nitric oxide that can be corrected with norfloxacin.

Agonist and antagonist effects of diadenosine tetraphosphate, a platelet dense granule constituent, on platelet P2Y1, P2Y12 and P2X1 receptors.

PubMed

Chang, Hung; Yanachkov, Ivan B; Michelson, Alan D; Li, YouFu; Barnard, M R; Wright, George E; Frelinger, Andrew L

2010-02-01

Diadenosine 5',5'''-P(1),P(4)- tetraphosphate (Ap(4)A) is stored in platelet dense granules, but its effects on platelet function are not well understood. We examined the effects of Ap(4)A on platelet purinergic receptors P2Y(1), P2Y(12) and P2X(1). Flow cytometry was used to measure the effects of Ap(4)A in the presence or absence of ADP on: a) P2Y(12)-mediated decrease in intraplatelet phosphorylated vasodilator stimulated phosphoprotein (VASP), b) P2Y(1)-mediated increase in platelet cytosolic Ca(2+), and c) P2X(1)-mediated intraplatelet entry of extracellular Ca(2+). ADP-stimulated platelet shape change (P2Y(1)-mediated) and aggregation (P2Y(1)- and P2Y(12)-mediated) were measured optically. Ap(4)A inhibited 3 microM ADP-induced: a) platelet aggregation (IC(50) 9.8+/-2.8 microM), b) P2Y(1)-mediated shape change, c) P2Y(1)-mediated increase in platelet cytosolic Ca(2+) (IC(50) 40.8+/-12.3 microM), and d) P2Y(12)-mediated decrease in VASP phosphorylation (IC(50)>250 microM). In the absence of added ADP, Ap(4)A had agonist effects on platelet P2X(1) and P2Y(12), but not P2Y(1), receptors. Ap(4)A, a constituent of platelet dense granules, is a) an antagonist of platelet P2Y(1) and P2Y(12) receptors, where it inhibits the effects of ADP, and b) an agonist of platelet P2X(1) and P2Y(12) receptors. Copyright 2009 Elsevier Ltd. All rights reserved.

Agonist and Antagonist Effects of Diadenosine Tetraphosphate, a Platelet Dense Granule Constituent, on Platelet P2Y1, P2Y12 and P2X1 Receptors

PubMed Central

Chang, Hung; Yanachkov, Ivan B.; Michelson, Alan D.; Li, YouFu; Barnard, M.R.; Wright, George E.; Frelinger, Andrew L.

2010-01-01

Introduction Diadenosine 5',5"'-P1,P4-tetraphosphate (Ap4A) is stored in platelet dense granules, but its effects on platelet function are not well understood. Methods and Results We examined the effects of Ap4A on platelet purinergic receptors P2Y1, P2Y12 and P2X1. Flow cytometry was used to measure the effects of Ap4A in the presence or absence of ADP on: a) P2Y12-mediated decrease in intraplatelet phosphorylated vasodilator stimulated phosphoprotein (VASP), b) P2Y1-mediated increase in platelet cytosolic Ca2+, and c) P2X1-mediated intraplatelet entry of extracellular Ca2+. ADP-stimulated platelet shape change (P2Y1-mediated) and aggregation (P2Y1- and P2Y12-mediated) were measured optically. Ap4A inhibited 3 µM ADP-induced: a) platelet aggregation (IC50 9.8 ± 2.8 µM), b) P2Y1-mediated shape change, c) P2Y1-mediated increase in platelet cytosolic Ca2+ (IC50 40.8 ± 12.3 µM), and d) P2Y12-mediated decrease in VASP phosphorylation (IC50 >250 µM). In the absence of added ADP, Ap4A had agonist effects on platelet P2X1 and P2Y12, but not P2Y1, receptors. Conclusion Ap4A, a constituent of platelet dense granules, is a) an antagonist of platelet P2Y1 and P2Y12 receptors, where it inhibits the effects of ADP, and b) an agonist of platelet P2X1 and P2Y12 receptors. PMID:19945153

Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ignarro, L.J.; Buga, G.M.; Wood, K.S.

1987-12-01

The objective of this study was to determine whether nitric oxide (NO) is responsible for the vascular smooth muscle relaxation elicited by endothelium-derived relaxing factor (EDRF). EDRF is an unstable humoral substance released from artery and vein that mediates the action of endothelium-dependent vasodilators. NO is and unstable endothelium-independent vasodilator that is released from vasodilator drugs such as nitroprusside and glyceryl trinitrate. The authors have repeatedly observed that the actions of NO on vascular smooth muscle closely resemble those of EDRF. In the present study the vascular effects of EDRF released from perfused bovine intrapulmonary artery and vein were comparedmore » with the effects of NO delivered by superfusion over endothelium-denuded arterial and venous strips arranged in a cascade. EDRF was indistinguishable from NO in that both were labile inactivated by pyrogallol or superoxide anion, stabilized by superoxide dismutase, and inhibited by oxyhemoglobin or potassium. Both EDRF and NO produced comparable increases in cyclic GMP accumulation in artery and vein, and this cyclic GMP accumulation was inhibited by pyrogallol, oxyhemoglobin, potassium, and methylene blue. EDRF was identified chemically as NO, or a labile nitroso species, by two procedures. Thus, EDRF released from artery and vein possesses identical and biological and chemical properties as NO.« less

Cardiovascular effects of Urtica dioica L. (Urticaceae) roots extracts: in vitro and in vivo pharmacological studies.

PubMed

Testai, Lara; Chericoni, Silvio; Calderone, Vincenzo; Nencioni, Giulia; Nieri, Paola; Morelli, Ivano; Martinotti, Enrica

2002-06-01

Urtica dioica (Urticaceae) is a plant principally used in the traditional medicine of oriental Marocco as antihypertensive remedy (J. Ethnopharmacol., 58 (1997), 45). The aim of this work was to evaluate a possible direct cardiovascular action of the plant and to investigate its mechanism of action. In aortic preparations with intact and functional endothelial layer, pre-contracted with KCl 20 mM or norepinephrine 3 microM, the crude aqueous and methanolic extracts of the plant roots, as well as purified fractions elicited a vasodilator action. Nevertheless, the vasodilator activity was not present in aortic rings without endothelial layer. In aortic rings with intact endothelial layer, the vasorelaxing effect was abolished by L-NAME, a NO-biosynthesis inhibitor, and ODQ, a guanylate cyclase inhibitor. Furthermore, potassium channel blockers (TEA, 4-aminopyridine, quinine, but not glybenclamide) antagonized the vasodilator action of the purified fraction F1W of U. dioica. The same fraction produced a marked decrease of inotropic activity, in spontaneously beating atria of guinea-pig, and a marked, but transient, hypotensive activity on the blood pressure of anaesthetized rats. It is concluded that U. dioica can produce hypotensive responses, through a vasorelaxing effect mediated by the release of endothelial nitric oxide and the opening of potassium channels, and through a negative inotropic action.

Role of L-arginine in the biological effects of blue light

NASA Astrophysics Data System (ADS)

Makela, Anu M.

2005-11-01

Arginine, a semi-essential amino acid, and metabolites of arginine exert multiple biological effects. It has been known that arginine causes the release of various hormones such as insulin, glucagon, growth hormone, prolactin, and adrenal catecholamines. Arginine infusion also produces vasodilation, and in the kidney increased plasma flow accompanied by increases in glomerular filtration rate (GFR). Recent studies have showed that blue and red light irradiation in vitro and in vivo can increase production of nitric oxide (NO), superoxide anion, and related reactive oxygen species (ROS). These then can modulate the production and secretion of several cytokines and other mediators and play an important role as regulatory mediators in signaling processes which can then modulate the production, mobilization and homing of stem cells. It is proposed that some of the therapeutic effects of light can be considered to be due to the changes in the metabolism of L-arginine. The regulation of L-arginine turnover by the use of light at blue wavelengths between 400nm and 510nm can be the explanation for some of the observed effects of blue light: lowering of blood pressure, pain killing effect, regulating insulin production, anti-inflammatory action, and possible effects on the release and homing of stem cells.

Endothelial function and sleep: associations of flow-mediated dilation with perceived sleep quality and rapid eye movement (REM) sleep.

PubMed

Cooper, Denise C; Ziegler, Michael G; Milic, Milos S; Ancoli-Israel, Sonia; Mills, Paul J; Loredo, José S; Von Känel, Roland; Dimsdale, Joel E

2014-02-01

Endothelial function typically precedes clinical manifestations of cardiovascular disease and provides a potential mechanism for the associations observed between cardiovascular disease and sleep quality. This study examined how subjective and objective indicators of sleep quality relate to endothelial function, as measured by brachial artery flow-mediated dilation (FMD). In a clinical research centre, 100 non-shift working adults (mean age: 36 years) completed FMD testing and the Pittsburgh Sleep Quality Index, along with a polysomnography assessment to obtain the following measures: slow wave sleep, percentage rapid eye movement (REM) sleep, REM sleep latency, total arousal index, total sleep time, wake after sleep onset, sleep efficiency and apnea-hypopnea index. Bivariate correlations and follow-up multiple regressions examined how FMD related to subjective (i.e., Pittsburgh Sleep Quality Index scores) and objective (i.e., polysomnography-derived) indicators of sleep quality. After FMD showed bivariate correlations with Pittsburgh Sleep Quality Index scores, percentage REM sleep and REM latency, further examination with separate regression models indicated that these associations remained significant after adjustments for sex, age, race, hypertension, body mass index, apnea-hypopnea index, smoking and income (Ps < 0.05). Specifically, as FMD decreased, scores on the Pittsburgh Sleep Quality Index increased (indicating decreased subjective sleep quality) and percentage REM sleep decreased, while REM sleep latency increased (Ps < 0.05). Poorer subjective sleep quality and adverse changes in REM sleep were associated with diminished vasodilation, which could link sleep disturbances to cardiovascular disease. © 2013 European Sleep Research Society.

Effects of dark chocolate and cocoa consumption on endothelial function and arterial stiffness in overweight adults.

PubMed

West, Sheila G; McIntyre, Molly D; Piotrowski, Matthew J; Poupin, Nathalie; Miller, Debra L; Preston, Amy G; Wagner, Paul; Groves, Lisa F; Skulas-Ray, Ann C

2014-02-01

The consumption of cocoa and dark chocolate is associated with a lower risk of CVD, and improvements in endothelial function may mediate this relationship. Less is known about the effects of cocoa/chocolate on the augmentation index (AI), a measure of vascular stiffness and vascular tone in the peripheral arterioles. We enrolled thirty middle-aged, overweight adults in a randomised, placebo-controlled, 4-week, cross-over study. During the active treatment (cocoa) period, the participants consumed 37 g/d of dark chocolate and a sugar-free cocoa beverage (total cocoa = 22 g/d, total flavanols (TF) = 814 mg/d). Colour-matched controls included a low-flavanol chocolate bar and a cocoa-free beverage with no added sugar (TF = 3 mg/d). Treatments were matched for total fat, saturated fat, carbohydrates and protein. The cocoa treatment significantly increased the basal diameter and peak diameter of the brachial artery by 6% (+2 mm) and basal blood flow volume by 22%. Substantial decreases in the AI, a measure of arterial stiffness, were observed in only women. Flow-mediated dilation and the reactive hyperaemia index remained unchanged. The consumption of cocoa had no effect on fasting blood measures, while the control treatment increased fasting insulin concentration and insulin resistance (P= 0·01). Fasting blood pressure (BP) remained unchanged, although the acute consumption of cocoa increased resting BP by 4 mmHg. In summary, the high-flavanol cocoa and dark chocolate treatment was associated with enhanced vasodilation in both conduit and resistance arteries and was accompanied by significant reductions in arterial stiffness in women.

Effect of genistein on endothelial function in postmenopausal women: a randomized, double-blind, controlled study.

PubMed

Squadrito, Francesco; Altavilla, Domenica; Crisafulli, Alessandra; Saitta, Antonino; Cucinotta, Domenico; Morabito, Nunziata; D'Anna, Rosario; Corrado, Francesco; Ruggeri, Pietro; Frisina, Nicola; Squadrito, Giovanni

2003-04-15

Genistein, a phytoestrogen found in soybeans, corrects endothelial dysfunction induced by oophorectomy in animals. Using a double-blind, controlled, randomized design, we evaluated its effects on endothelial function in women. We enrolled 79 healthy postmenopausal women (mean [+/- SD] age, 56 +/- 4 years) and randomly assigned them to receive continuous estrogen/progestin therapy (n = 26; 17beta-estradiol [1 mg/d] combined with norethisterone acetate [0.5 mg/d]), genistein (n = 27; 54 mg/d), or placebo (n = 26). Brachial artery flow-mediated, endothelium-dependent vasodilation and plasma levels of nitrites/nitrates (a marker of nitric oxide metabolism) and endothelin-1 were measured at baseline and after 1 year of therapy. Treatment with genistein increased levels of nitrites/nitrates (mean increase, 21 micromol/L; 95% confidence interval [CI]: 15 to 26 micromol/L; P <0.001 vs. placebo); estrogen/progestin therapy caused similar changes (P <0.001 vs. placebo). Plasma endothelin-1 levels decreased following 12 months of genistein (mean decrease, 7 pg/mL; 95% CI: 3 to 10 pg/mL; P <0.001 vs. placebo) and after 12 months of estrogen/progestin (P <0.001 vs. placebo). When compared with placebo, brachial artery flow-mediated dilation was improved by genistein (mean increase, 5.5%; 95% CI: 3.9% to 7.0%; P <0.001) and by estrogen/progestin (P <0.001). There were no significant differences between estrogen and genistein for any of these parameters (all P >0.4). One year of genistein therapy improves endothelium function in postmenopausal women to a similar extent as does an estrogen/progestin regimen.

Functional significance of differential eNOS translocation

PubMed Central

Sánchez, Fabiola A.; Savalia, Nirav B.; Durán, Ricardo G.; Lal, Brajesh K.; Boric, Mauricio P.; Durán, Walter N.

2006-01-01

Nitric oxide (NO) regulates flow and permeability. ACh and platelet-activating factor (PAF) lead to endothelial NO synthase (eNOS) phosphorylation and NO release. While ACh causes only vasodilation, PAF induces vasoconstriction and hyperpermeability. The key differential signaling mechanisms for discriminating between vasodilation and hyperpermeability are unknown. We tested the hypothesis that differential translocation may serve as a regulatory mechanism of eNOS to determine specific vascular responses. We used ECV-304 cells permanently transfected with eNOS-green fluorescent protein (ECVeNOS-GFP) and demonstrated that the agonists activate eNOS and reproduce their characteristic endothelial permeability effects in these cells. We evaluated eNOS localization by lipid raft analysis and immunofluorescence microscopy. After PAF and ACh, eNOS moves away from caveolae. eNOS distributes both in the plasma membrane and Golgi in control cells. ACh (10−5 M, 10−4 M) translocated eNOS preferentially to the trans-Golgi network (TGN) and PAF (10−7 M) preferentially to the cytosol. We suggest that PAF-induced eNOS translocation preferentially to cytosol reflects a differential signaling mechanism related to changes in permeability, whereas ACh-induced eNOS translocation to the TGN is related to vasodilation. PMID:16679407

DD angiotensin-converting enzyme gene polymorphism is associated with endothelial dysfunction in normal humans.

PubMed

Butler, R; Morris, A D; Burchell, B; Struthers, A D

1999-05-01

A polymorphism within the angiotensin-converting enzyme (ACE) gene may increase the risk of myocardial infarction in individuals previously thought to be at low cardiovascular risk. The mechanism through which it exerts this effect is unknown but may be due to increased angiotensin II-induced nitric oxide (NO) breakdown and/or reduced bradykinin-mediated NO release. We investigated whether endothelial function was different between different ACE genotypes. We performed a cross-sectional study comparing the endothelial function of the 3 genotypes (II: n=25; ID: n=31; DD: n=12). Mean+/-SD ages of the subjects were 24+/-4 (II), 25+/-6 (ID), and 25+/-6 (DD) years. We assessed the impact of the genotypes on endothelial function and found that the DD genotype was associated with a significant blunting in endothelial-dependent vasodilatation (forearm blood flow data are presented as mean+/-SD ratio of blood flow in response to 3 incrementally increasing doses of each vasoactive agent in the test arm to blood flow in the control arm; the comparison is between DD versus ID versus II; the P value is an expression of an overall difference by ANOVA, and the 95% CIs are of a pairwise comparison between genotypes): acetylcholine, 2.88+/-1.45 versus 3.81+/-1.93 versus 4.23+/-2.37 (P=0.002; 95% CI [II versus ID], -0.19 to 0.91; 95% CI [II versus DD], 0.36 to 1.80; 95% CI [ID versus DD], 0.02 to 1.42). There was also a significant difference with the endothelial-independent vasodilator sodium nitroprusside, with values of 2.11+/-1.00 versus 2.55+/-1.36 versus 2.75+/-1.18 (P<0.05; 95% CI [II versus ID], -0.15 to 0.51; 95% CI [II versus DD], 0.03 to 0.89; 95% CI [ID versus DD], -0.13 to 0.71), but not with verapamil. There was no effect of the ACE genotype on endothelial-dependent or -independent vasoconstrictors NG-monomethyl-L-arginine or norepinephrine. Investigating the effects of cigarette smoking on each genotype demonstrated that for II and DD genotypes, acetylcholine responses were further blunted if subjects smoked. These data demonstrate that the DD ACE genotype in a young population is associated with a blunting of stimulated endothelial NO and donated NO responses but not to non-NO vasodilators or vasoconstrictors.

Beta-blockers do not impair the cardiovascular benefits of endurance training in hypertensives.

PubMed

Westhoff, T H; Franke, N; Schmidt, S; Vallbracht-Israng, K; Zidek, W; Dimeo, F; van der Giet, M

2007-06-01

Aerobic physical exercise is broadly recommended as a helpful adjunct to obtain blood pressure control in hypertension. Beta-blockade interacts with heart rate, sympathetic tone, maximal workload and local lactate production. In the present randomized-controlled study, we compared the cardiovascular effects of an endurance training programme in elderly hypertensives with or without beta-blockers and developed a first approach to determine a lactate-based training heart rate in presence of beta-blockade. Fifty-two patients (23 with beta-blocker, 29 without beta-blocker) > or =60 years with systolic 24-h ambulatory blood pressure (ABP) > or =140 mm Hg and/or antihypertensive treatment were randomly assigned to sedentary activity or a heart-rate controlled 12-week treadmill exercise programme (lactate 2.0 mmol/l). In the exercise group, the training significantly decreased systolic and diastolic 24-h ABP, blood pressure on exertion (100 W) and increased endothelium-dependent vasodilation (flow-mediated vasodilation, FMD) and physical performance both in the presence and absence of beta-blockade (P<0.05 each). The extent of ABP reduction did not significantly differ in the presence or absence of beta-blockade (Delta systolic ABP 10.6+/-10.5 vs 10.6+/-8.8 mm Hg, Delta diastolic ABP 5.7+/-8.6 vs 5.8+/-4.0 mm Hg). Mean training heart rate was significantly lower in the patients on beta-blockers (97.2+/-7.7 vs 118.3+/-7.5/min, P<0.001). Lactate-based aerobic endurance training evokes comparable cardiovascular benefits in the presence and absence of beta-blockade including a marked improvement of endothelial function. In the present study, target training heart rate with beta-blockers is about 18% lower than without.

Exercise training improves in vivo endothelial repair capacity of early endothelial progenitor cells in subjects with metabolic syndrome.

PubMed

Sonnenschein, Kristina; Horváth, Tibor; Mueller, Maja; Markowski, Andrea; Siegmund, Tina; Jacob, Christian; Drexler, Helmut; Landmesser, Ulf

2011-06-01

Endothelial dysfunction and injury are considered to contribute considerably to the development and progression of atherosclerosis. It has been suggested that intense exercise training can increase the number and angiogenic properties of early endothelial progenitor cells (EPCs). However, whether exercise training stimulates the capacity of early EPCs to promote repair of endothelial damage and potential underlying mechanisms remain to be determined. The present study was designed to evaluate the effects of moderate exercise training on in vivo endothelial repair capacity of early EPCs, and their nitric oxide and superoxide production as characterized by electron spin resonance spectroscopy analysis in subjects with metabolic syndrome. Twenty-four subjects with metabolic syndrome were randomized to an 8 weeks exercise training or a control group. Superoxide production and nitric oxide (NO) availability of early EPCs were characterized by using electron spin resonance (ESR) spectroscopy analysis. In vivo endothelial repair capacity of EPCs was examined by transplantation into nude mice with defined carotid endothelial injury. Endothelium-dependent, flow-mediated vasodilation was analysed using high-resolution ultrasound. Importantly, exercise training resulted in a substantially improved in vivo endothelial repair capacity of early EPCs (24.0 vs 12.7%; p < 0.05) and improved endothelium-dependent vasodilation. Nitric oxide production of EPCs was substantially increased after exercise training, but not in the control group. Moreover, exercise training reduced superoxide production of EPCs, which was not observed in the control group. The present study suggests for the first time that moderate exercise training increases nitric oxide production of early endothelial progenitor cells and reduces their superoxide production. Importantly, this is associated with a marked beneficial effect on the in vivo endothelial repair capacity of early EPCs in subjects with metabolic syndrome.

Selective head cooling during neonatal seizures prevents postictal cerebral vascular dysfunction without reducing epileptiform activity

PubMed Central

Harsono, Mimily; Pourcyrous, Massroor; Jolly, Elliott J.; de Jongh Curry, Amy; Fedinec, Alexander L.; Liu, Jianxiong; Basuroy, Shyamali; Zhuang, Daming; Leffler, Charles W.

2016-01-01

Epileptic seizures in neonates cause cerebrovascular injury and impairment of cerebral blood flow (CBF) regulation. In the bicuculline model of seizures in newborn pigs, we tested the hypothesis that selective head cooling prevents deleterious effects of seizures on cerebral vascular functions. Preventive or therapeutic ictal head cooling was achieved by placing two head ice packs during the preictal and/or ictal states, respectively, for the ∼2-h period of seizures. Head cooling lowered the brain and core temperatures to 25.6 ± 0.3 and 33.5 ± 0.1°C, respectively. Head cooling had no anticonvulsant effects, as it did not affect the bicuculline-evoked electroencephalogram parameters, including amplitude, duration, spectral power, and spike frequency distribution. Acute and long-term cerebral vascular effects of seizures in the normothermic and head-cooled groups were tested during the immediate (2–4 h) and delayed (48 h) postictal periods. Seizure-induced cerebral vascular injury during the immediate postictal period was detected as terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive staining of cerebral arterioles and a surge of brain-derived circulating endothelial cells in peripheral blood in the normothermic group, but not in the head-cooled groups. During the delayed postictal period, endothelium-dependent cerebral vasodilator responses were greatly reduced in the normothermic group, indicating impaired CBF regulation. Preventive or therapeutic ictal head cooling mitigated the endothelial injury and greatly reduced loss of postictal cerebral vasodilator functions. Overall, head cooling during seizures is a clinically relevant approach to protecting the neonatal brain by preventing cerebrovascular injury and the loss of the endothelium-dependent control of CBF without reducing epileptiform activity. PMID:27591217

Effects and mechanisms of action of sildenafil citrate in human chorionic arteries

PubMed Central

Maharaj, Chrisen H; O'Toole, Daniel; Lynch, Tadhg; Carney, John; Jarman, James; Higgins, Brendan D; Morrison, John J; Laffey, John G

2009-01-01

Objectives Sildenafil citrate, a specific phosphodiesterase-5 inhibitor, is increasingly used for pulmonary hypertension in pregnancy. Sildenafil is also emerging as a potential candidate for the treatment of intra-uterine growth retardation and for premature labor. Its effects in the feto-placental circulation are not known. Our objectives were to determine whether phosphodiesterase-5 is present in the human feto-placental circulation, and to characterize the effects and mechanisms of action of sildenafil citrate in this circulation. Study Design Ex vivo human chorionic plate arterial rings were used in all experiments. The presence of phosphodiesterase-5 in the feto-placental circulation was determined by western blotting and immunohistochemical staining. In a subsequent series of pharmacologic studies, the effects of sildenafil citrate in pre-constricted chorionic plate arterial rings were determined. Additional studies examined the role of cGMP and nitric oxide in mediating the effects of sildenafil. Results Phosphodiesterase-5 mRNA and protein was demonstrated in human chorionic plate arteries. Immunohistochemistry demonstrated phosphodiesterase-5 within the arterial muscle layer. Sildenafil citrate produced dose dependent vasodilatation at concentrations at and greater than 10 nM. Both the direct cGMP inhibitor methylene blue and the cGMP-dependent protein kinase inhibitor Rp-8-Br-PET-cGMPS significantly attenuated the vasodilation produced by sildenafil citrate. Inhibition of NO production with L-NAME did not attenuate the vasodilator effects of sildenafil. In contrast, sildenafil citrate significantly enhanced the vasodilation produced by the NO donor sodium nitroprusside. Conclusion Phosphodiesterase-5 is present in the feto-placental circulation. Sildenafil citrate vasodilates the feto-placental circulation via a cGMP dependent mechanism involving increased responsiveness to NO. PMID:19389232

Fluid replacement modulates oxidative stress- but not nitric oxide-mediated cutaneous vasodilation and sweating during prolonged exercise in the heat.

PubMed

McNeely, Brendan D; Meade, Robert D; Fujii, Naoto; Seely, Andrew J E; Sigal, Ronald J; Kenny, Glen P

2017-12-01

The roles of nitric oxide synthase (NOS), reactive oxygen species (ROS), and angiotensin II type 1 receptor (AT 1 R) activation in regulating cutaneous vasodilation and sweating during prolonged (≥60 min) exercise are currently unclear. Moreover, it remains to be determined whether fluid replacement (FR) modulates the above thermoeffector responses. To investigate, 11 young men completed 90 min of continuous moderate intensity (46% V̇o 2peak ) cycling performed at a fixed rate of metabolic heat production of 600 W (No FR condition). On a separate day, participants completed a second session of the same protocol while receiving FR to offset sweat losses (FR condition). Cutaneous vascular conductance (CVC) and local sweat rate (LSR) were measured at four intradermal microdialysis forearm sites perfused with: 1 ) lactated Ringer (Control); 2 ) 10 mM N G -nitro-l-arginine methyl ester (l-NAME, NOS inhibition); 3 ) 10 mM ascorbate (nonselective antioxidant); or 4 ) 4.34 nM losartan (AT 1 R inhibition). Relative to Control (71% CVC max at both time points), CVC with ascorbate (80% and 83% CVC max ) was elevated at 60 and 90 min of exercise during FR (both P < 0.02) but not at any time during No FR (all P > 0.31). In both conditions, CVC was reduced at end exercise with l-NAME (60% CVC max ; both P < 0.02) but was not different relative to Control at the losartan site (76% CVC max ; both P > 0.19). LSR did not differ between sites in either condition (all P > 0.10). We conclude that NOS regulates cutaneous vasodilation, but not sweating, irrespective of FR, and that ROS influence cutaneous vasodilation during prolonged exercise with FR. Copyright © 2017 the American Physiological Society.

Simulated Microgravity Increases Cutaneous Blood Flow in the Head and Leg of Humans

NASA Technical Reports Server (NTRS)

Stout, M. Shannon; Watenpaugh, Donald E.; Breit, Gregory A.; Hargens, Alan R.

1995-01-01

The cutaneous micro-circulation vasodilates during acute 6 deg. head-down tilt (HDT, simulated microgravity) relative to upright conditions, more in the lower body than in the upper body. We expected that relative magnitudes of and differences between upper and lower body cutaneous blood flow elevation would be sustained during initial acclimation to simulated microgravity. We measured cutaneous micro-vascular blood flow with laser-Doppler flowmetry at the leg (over the distal tibia) and cheek (over the zygomatic arch) of eight healthy men before, during, and after 24 h of HDT. Results were calculated as a percentage of baseline value (100% measured during pre-tilt upright sitting). Cutaneous blood flow in the cheek increased significantly to 165 +/- 37% (mean + SE, p less than 0.05) at 9-12 h HDT, then returned to near baseline values by 24 h HDT (114 +/- 29%, NSD), despite increased local arterial pressure. Microvascular flow in the leg remained significantly elevated above baseline throughout 24 h HDT (427 +/- 85% at 3 h HDT and 215 +/- 142% at 24 h HDT, p less than 0.05). During the 6-h upright sitting recovery period, cheek and leg blood flow levels returned to near pre-tilt baseline values. Because hydrostatic effects of HDT increase local arterial pressure at the carotid sinus, baroreflex-mediated withdrawal of sympathetic tone probably contributed to increased microvascular flows at the head and leg during HDT. In the leg, baroreflex effects combined with minimal stimulation of local veno-arteriolar and myogenic autoregulatory vasoconstriction to elicit relatively larger and more sustained increases in cutaneous flow during HDT. In the cheek, delayed myogenic vasoconstriction and/or humoral effects apparently compensated for flow elevation by 24 h of HDT. Therefore, localized vascular adaptations to gravity probably explain differences in acclimation of lower and upper body blood flow to HDT and actual microgravity.

Substance P and neurokinin A metabolism by cultured human skeletal muscle myocytes and fibroblasts.

PubMed

Russell, J S; Chi, H; Lantry, L E; Stephens, R E; Ward, P E

1996-01-01

A recent study determined that cultured human skeletal muscle adult myoblasts, myotubes, and fibroblasts degraded angiotensins and kinins via neutral endopeptidase-24.11 (NEP-24.11: EC 3.4.24.11) and aminopeptidase N (APN: EC 3.4.11.2). Due to the possible importance of other peptides to skeletal muscle blood flow and function, the present study looked specifically at the metabolism of the neurokinins substance P (SP) and neurokinin A (NKA) by skeletal muscle peptidases. The results show that SP is degraded not only by NEP-24.11, but also sequentially by dipeptidyl(amino)peptidase IV (DAP IV: EC 3.4.14.5)/APN. NKA is unaffected by DAP IV but is metabolized by NEP-24.11 and APN. NEP-24.11 was inhibited by phosphoramidon (IC50 = 80 nM), thiorphan and ZINCOV, DAP IV by diprotin A (IC50 = 8 microM), and APN by amastatin (IC50 = 50 nM) and bestatin (IC50 = 100 microM). Skeletal muscle myocyte and fibroblast metabolism of SP and NKA may regulate local skeletal muscle vascular and extravascular functions including SP- and NKA-mediated nerve-induced vasodilation. Inhibition of both NEP-24.11 and DAP IV/APN may increase skeletal muscle blood flow and decrease peripheral vascular resistance via potentiation of local neurokinin levels.

Responses to hyperthermia. Optimizing heat dissipation by convection and evaporation: Neural control of skin blood flow and sweating in humans.

PubMed

Smith, Caroline J; Johnson, John M

2016-04-01

Under normothermic, resting conditions, humans dissipate heat from the body at a rate approximately equal to heat production. Small discrepancies between heat production and heat elimination would, over time, lead to significant changes in heat storage and body temperature. When heat production or environmental temperature is high the challenge of maintaining heat balance is much greater. This matching of heat elimination with heat production is a function of the skin circulation facilitating heat transport to the body surface and sweating, enabling evaporative heat loss. These processes are manifestations of the autonomic control of cutaneous vasomotor and sudomotor functions and form the basis of this review. We focus on these systems in the responses to hyperthermia. In particular, the cutaneous vascular responses to heat stress and the current understanding of the neurovascular mechanisms involved. The available research regarding cutaneous active vasodilation and vasoconstriction is highlighted, with emphasis on active vasodilation as a major responder to heat stress. Involvement of the vasoconstrictor and active vasodilator controls of the skin circulation in the context of heat stress and nonthermoregulatory reflexes (blood pressure, exercise) are also considered. Autonomic involvement in the cutaneous vascular responses to direct heating and cooling of the skin are also discussed. We examine the autonomic control of sweating, including cholinergic and noncholinergic mechanisms, the local control of sweating, thermoregulatory and nonthermoregulatory reflex control and the possible relationship between sudomotor and cutaneous vasodilator function. Finally, we comment on the clinical relevance of these control schemes in conditions of autonomic dysfunction. Copyright © 2016 Elsevier B.V. All rights reserved.

Immediate central and peripheral haemodynamic effects of a new vasodilating agent Pinacidil (P1134) in hypertensive man.

PubMed

Carlsen, J E; Kardel, T; Hilden, T; Tangø, M; Trap-Jensen, J

1981-08-01

The purpose of this study was to evaluate the immediate central and peripheral haemodynamic effects of a new vasodilating agent P 1134, in hypertensive man. After oral administration of 25 mg P 1134, the maximal haemodynamic changes were (mean +/- 1 SEM): mean blood pressure fell from 121.8 +/- 6.5 to 80.5 +/- 7.8 mmHg, heart rate increased 24.2 +/- 4.5 beats/min, cardiac output rose 2.9 +/- 0.3 1/min and forearm blood flow increased 1.0 +/- 0.1 ml/100 ml tissue/min. Stroke volume increased 17.0 +/- 2.1 ml and the inotropic state of the heart as judged from systolic time intervals increased. Total peripheral resistance and forearm vascular resistance were both reduced by approx. 50%. Linear correlations were found between the serum concentration of P 1134 and the change in mean blood pressure and total peripheral resistance. Changes in the other parameters mentioned above occurred progressively with changes in mean blood pressure and total peripheral resistance. It can be concluded that P 1134 is a very potent hypotensive agent with a haemodynamic profile identical to that seen with vasodilators with preferably act on precapillary resistance vessels. Potency and maximal efficacy exceeds that of hydralazine and seems like that of minoxidil. P 1134 is remarkably free from side-effects apart from causing water retention as all other vasodilators. It can be administered orally as well as intravenously. This makes P 1134 a very interesting compound in the treatment of moderate to severe hypertension, and further studies are well-founded.

Inhaled nitrite reverses hemolysis-induced pulmonary vasoconstriction in newborn lambs without blood participation

PubMed Central

Blood, Arlin B.; Schroeder, Hobe J.; Terry, Michael H.; Merrill-Henry, Jeanette; Bragg, Shannon L.; Vrancken, Kurt; Liu, Taiming; Herring, Jason L.; Sowers, Lawrence C.; Wilson, Sean M.; Power, Gordon G.

2011-01-01

Background Nitrite can be converted to nitric oxide (NO) by a number of different biochemical pathways. In newborn lambs an aerosol of inhaled nitrite has been found to reduce pulmonary blood pressure, possibly acting via conversion to NO by reaction with intraerythrocytic deoxyhemoglobin. If so, the vasodilating effects of nitrite would be attenuated by free hemoglobin in plasma that would rapidly scavenge NO. Methods and Results Pulmonary vascular pressures and resistances to flow were measured in anesthetized newborn lambs. Plasma hemoglobin concentrations were then elevated, resulting in marked pulmonary hypertension. This effect was attenuated if infused hemoglobin was first oxidized to methemoglobin which does not scavenge NO. These results further implicate NO as a tonic pulmonary vasodilator. Next, while free hemoglobin continued to be infused, the lambs were given inhaled NO gas (20 ppm), inhaled sodium nitrite aerosol (0.87 M), or an intravascular nitrite infusion (3 mg·hr−1 bolus, 5 mg·kg−1·hr−1 infusion). Inhaled NO and inhaled nitrite aerosol both resulted in pulmonary vasodilation. Intravascular infusion of nitrite, however, did not. Increases in exhaled NO gas were observed while breathing the nitrite aerosol (~20 ppb NO) but not during intravascular infusion of nitrite. Conclusions We conclude that the pulmonary vasodilating effect of inhaled nitrite results from its conversion to NO in airway and parenchymal lung tissue and is not dependent on reactions with deoxyhemoglobin in the pulmonary circulation. Inhaled nitrite aerosol remains a promising candidate to reduce pulmonary hypertension in clinical application. PMID:21282501

The effects of the ovarian cycle and pregnancy on uterine vascular impedance and uterine artery mechanics

PubMed Central

Sprague, Benjamin J.; Phernetton, Terrance M.; Magness, Ronald R.; Chesler, Naomi C.

2009-01-01

Objectives Uterine vascular resistance (UVR) is the ratio of systemic mean arterial pressure to mean uterine blood flow and is sensitive to changes in small arteries and arterioles. However, it provides little or no insight into changes in large, conduit arteries. Fluctuations in estrogen (E2) and progesterone (P4) levels during the ovarian cycle are thought to cause uterine resistance artery vasodilation; the effects on large arteries are unknown. Herein, our objective was to use the uterine vascular impedance, which is sensitive to changes in small and large arteries, to determine the effects of the ovarian cycle and pregnancy on the entire uterine vasculature. Study Design Uterine vascular perfusion pressure and flow rate were recorded simultaneously on anesthetized sheep in the nonpregnant (NP) luteal (NP-L, n=6) and follicular (NP-F, n=7) phases and in late gestation pregnant (CP, n=10) sheep. Impedance and metrics of impedance (input impedance Z0, index of wave reflection RW, characteristic impedance ZC) were calculated. E2 and P4 levels were measured from jugular vein blood samples. Finally, from pressure-diameter tests post-mortem, large uterine artery circumferential elastic modulus (ECirc) was measured. Significant differences were evaluated by two-way ANOVA or Student’s t-test. Results As expected, E2:P4 was higher in the NP-F group compared to the NP-L group (p<0.05). Also as expected, UVR and Z0 decreased in the follicular phase compared to the luteal (p<0.05), but RW, ZC, and ECirc were unaltered. Pregnancy not only substantially decreased UVR (and Z0) (p<0.00001) but also decreased ZC (p<0.001), RW (p<0.0001), ECirc (p<0.01), and pulse wave velocity (p<0.0001). Conclusions The E2:P4 ratio mediates resistance artery vasodilatation in nonpregnant states, but has no effect on conduit artery size or stiffness. In contrast, pregnancy causes dramatic vasodilation and remodeling, including substantial reductions in conduit artery stiffness and increases in conduit artery size, which affect pulsatile uterine hemodynamics. PMID:19297074

Cardiovascular effects in vitro of aqueous extract of wild strawberry (Fragaria vesca, L.) leaves.

PubMed

Mudnic, I; Modun, D; Brizic, I; Vukovic, J; Generalic, I; Katalinic, V; Bilusic, T; Ljubenkov, I; Boban, M

2009-05-01

In contrast to the strawberry fruits, strawberry leaves as a source of bioactive compounds with potentially beneficial biological effects have been largely overlooked. In this study we examined direct, dose-dependent effects of wild strawberry (Fragaria vesca, L.) leaves aqueous extract, in two experimental models and animal species, the isolated guinea pig hearts and rat aortic rings. Vasodilatory potential of the wild strawberry leaves extract was compared with vasodilatory activity of aqueous extract of hawthorn (Crataegus oxycantha, L) leaves with flowers, which can be regarded as a reference plant extract with a marked vasodilatory activity. The extracts were analysed by their "phenolic fingerprints", total phenolic content and antioxidative capacity. Their vasodilatory activity was determined and compared in the isolated aortic rings from 24 rats that were exposed to the extracts doses of 0.06, 0.6, 6, and 60 mg/100ml. Both extracts induced similar, dose-dependent vasodilation. Maximal relaxation was 72.2+/-4.4% and 81.3+/-4.5%, induced by the strawberry and hawthorn extract, respectively. To determine vasodilatory mechanisms of the wild strawberry leaves extract, endothelium-denuded and intact rings exposed to nitric oxide (NO) synthase inhibitor L-NAME or cyclooxygenase inhibitor indomethacin were used. Removal of the endothelium prevented and exposure to L-NAME or indomethacin strongly diminished the vasodilatatory response to the extract. In the isolated hearts (n=12), the wild strawberry extract was applied at concentrations of 0.06, 0.18, 0.6, and 1.8 mg/100ml. Each dose was perfused for 3.5 min with 15 min of washout periods. Heart contractility, electrophysiological activity, coronary flow and oxygen consumption were continuously monitored. The extract did not significantly affect heart rate and contractility, main parameters of the cardiac action that determine oxygen demands, while coronary flow increased up to 45% over control value with a simultaneous decrease of oxygen extraction by 34%. The results indicate that the aqueous extract of wild strawberry leaves is a direct, endothelium-dependent vasodilator, action of which is mediated by NO and cyclooxygenase products and which potency is similar to that of the hawthorn aqueous extract.

Defining the Relationship Between Biomarkers of Oxidative and Inflammatory Stress and the Risk for Atherosclerosis in Astronauts During and After Long-Duration Spaceflight

NASA Technical Reports Server (NTRS)

Lee, Stuart M. C.; Westby, Christian M.; Stenger, Michael B.; Ploutz-Snyder, Robert J.; Smith, Scott M.; Platts, Steven H.

2011-01-01

Future human space travel will primarily consist of long-duration missions aboard the International Space Station (ISS) or exploration class missions to Mars, its moons, or nearby asteroids. These missions will expose astronauts to increased risk of oxidative and inflammatory damage primarily from radiation, but also from psychological stress, reduced physical activity, diminished nutritional status, and, in the case of extravehicular activity, hyperoxic exposure. There is evidence that increased oxidative damage and inflammation can accelerate the development of atherosclerosis. PURPOSE The purpose of this proposal is to identify biomarkers of oxidative and inflammatory stress and to correlate them to indices of atherosclerosis risk before, during, and after long-duration spaceflight. METHODS To meet the objectives of the study, we will study astronauts before, during, and up to 5 years after long-duration missions aboard ISS. Biomarkers of oxidative and inflammatory stress, some of which we have previously shown to be elevated with spaceflight, will be measured before, during, and after spaceflight. Arterial structure will be monitored using ultrasound to measure carotid intima-medial thickness before, during, and after weightlessness. Carotid intima-medial thickness has been shown to be a better indicator than Framingham Risk scores for prediction of atherosclerosis. Arterial function will be monitored using brachial flow-mediated dilation before flight and after landing. Brachial flow-mediated dilation is a good index of endothelium-dependent vasodilation, which is a sensitive predictor of atherosclerotic risk. This is the first study to propose assessing atherosclerotic risk using biochemical, structural, and functional measures before, during, and immediately after spaceflight and structural functional measures for up to 5 years after landing. EXPECTED RESULTS We hypothesize that these biomarkers of oxidative and inflammatory stress will be increased with spaceflight and will correlate with increased carotid intima-medial thickness in- and postflight and with decreased flow-mediated dilation after the mission. Furthermore, we hypothesize that measures of oxidative stress will return to baseline after flight, but that biomarkers of inflammatory stress and vascular indices of atherosclerosis risk will remain elevated.

Thermoregulation During Spaceflight

NASA Technical Reports Server (NTRS)

Greenleaf, John E.; Fortney, Suzanne M.

1992-01-01

The purpose of this flight proposal is to investigate human thermoregulatory parameters during exercise in microgravity. The hypothesis to be tested is that microgravity-adopted astronauts will exhibit accentuated increases in their core temperature (excess hyperthermia) during exercise because of altered heat loss responses due to reduced sweating and/or accentuated vasodilation. The specific aims are (1) to compare core and skin temperature responses during moderate exercise before flight and inflight; (2) to determine whether the hypothesized inflight excessive hyperthermia is due to increased heat production, reduced, sweating, impaired peripheral vasodilation, or to some combination of these factors; and (3) to determine whether heat production at an exercise load of 60 percent of the maximal working capacity is similar preflight and inflight. It is expected that the astronauts will exhibit excessive hyperthermia during exposure to microgravity which will be caused by decreased sweating and decreased skin blood flow.

Effects of amlodipine and adenosine on coronary haemodynamics: in vivo study and numerical simulation.

PubMed

De Lazzari, Claudio; L'Abbate, Antonio; Micalizzi, Mauro; Trivella, Maria Giovanna; Neglia, Danilo

2014-11-01

Amlodipine (AMLO) is a calcium channel blocker with vasodilating properties, in which the specific effects on the coronary circulation are not fully known. Coronary flow velocity-pressure (F/P) curves were obtained at rest and during administration of AMLO (10 mg to 20 mg iv) or adenosine (ADO, 1 mg ic) in 10 normal subjects (six women, age 48 ± 14 years). F/P curves were reproduced in a numerical simulator of systemic and coronary circulations (CARDIOSIM(©)) by adjustment of coronary resistance ( > or < 100 μm diameter vessels) and extravascular resistance applied to smaller vessels at endocardial (ENDO), middle and epicardial (EPI) myocardial layers. Best matching of in silico to in vivo curves was achieved by trial and error approach. ADO induced 170% and 250% increase in coronary flow velocity CFV and F/P diastolic slope as compared to 80% and 25-30% increase induced by AMLO, respectively. In the cardiovascular model, AMLO effects were predicted by progressive reduction of>100 μm vessels resistance from EPI to ENDO. ADO effects were mimicked by reducing resistance of both>100 μm and < 100 μm vessels, progressively from EPI to ENDO in the latter. Additional reduction in extravascular resistance avoided to impose a transmural gradient of vasodilating effect for both drugs. Numerical simulation predicts vasodilating effects of AMLO mainly on larger arteries and of ADO on both>and < 100 μm vessels. In vivo F/P loops could be completely reproduced in silico by adding extravascular resistance reduction for both drugs. Numerical simulator is useful tool for exploring the coronary effects of cardioactive drugs.

Hepatic arterial vasodilation is independent of portal hypertension in early stages of cirrhosis.

PubMed

Moeller, Miriam; Thonig, Antje; Pohl, Sabine; Ripoll, Cristina; Zipprich, Alexander

2015-01-01

The compensatory increase in hepatic arterial flow with a decrease in portal venous flow is known as the hepatic arterial buffer response. In cirrhosis with elevated portal pressure, the vascular resistance of the hepatic artery is decreased. Whether this lower resistance of the hepatic artery is a consequence of portal hypertension or not remains unknown. The aim of the study was to investigate the hepatic arterial resistance and response to vasoconstriction in cirrhosis without portal hypertension (normal portal resistance). Cirrhosis was induced by CCl4-inhalation for 8 weeks (8W, normal portal resistance) and for 12-14 weeks (12W, elevated portal resistance). Bivascular liver perfusion was performed at 8W or 12W and dose response curves of methoxamine were obtained in the presence or absence of LNMMA (nitric oxide synthase blocker). Vascular resistances of the hepatic artery (HAR), portal vein (PVR) and sinusoids (SVR) were measured. Western Blot (WB) and Immunohistochemistry (IHC) were done to measure eNOS and HIF 1a expression. HAR in both groups of cirrhotic animals (8W and 12W) were lower compared to controls. Dose response curves to methoxamine revealed lower HAR in both cirrhotic models (8W and 12W) regardless the magnitude of portal resistance. LNMMA corrected the dose response curves in cirrhosis (8W and 12W) to control. WB and IHC show increased protein expression of eNOS and HIF1a in 8W and 12W. Hepatic arterial resistance is decreased in cirrhosis independent of portal resistance. Vasodilation of the hepatic artery in cirrhosis seems to be influenced by hypoxia rather than increase in portal resistance. Nitric oxide is the main vasodilator.

Hepatic Arterial Vasodilation Is Independent of Portal Hypertension in Early Stages of Cirrhosis

PubMed Central

Moeller, Miriam; Thonig, Antje; Pohl, Sabine; Ripoll, Cristina; Zipprich, Alexander

2015-01-01

Introduction The compensatory increase in hepatic arterial flow with a decrease in portal venous flow is known as the hepatic arterial buffer response. In cirrhosis with elevated portal pressure, the vascular resistance of the hepatic artery is decreased. Whether this lower resistance of the hepatic artery is a consequence of portal hypertension or not remains unknown. Study Aim The aim of the study was to investigate the hepatic arterial resistance and response to vasoconstriction in cirrhosis without portal hypertension (normal portal resistance). Methods Cirrhosis was induced by CCl4-inhalation for 8 weeks (8W, normal portal resistance) and for 12–14 weeks (12W, elevated portal resistance). Bivascular liver perfusion was performed at 8W or 12W and dose response curves of methoxamine were obtained in the presence or absence of LNMMA (nitric oxide synthase blocker). Vascular resistances of the hepatic artery (HAR), portal vein (PVR) and sinusoids (SVR) were measured. Western Blot (WB) and Immunohistochemistry (IHC) were done to measure eNOS and HIF 1a expression. Results HAR in both groups of cirrhotic animals (8W and 12W) were lower compared to controls. Dose response curves to methoxamine revealed lower HAR in both cirrhotic models (8W and 12W) regardless the magnitude of portal resistance. LNMMA corrected the dose response curves in cirrhosis (8W and 12W) to control. WB and IHC show increased protein expression of eNOS and HIF1a in 8W and 12W. Conclusion Hepatic arterial resistance is decreased in cirrhosis independent of portal resistance. Vasodilation of the hepatic artery in cirrhosis seems to be influenced by hypoxia rather than increase in portal resistance. Nitric oxide is the main vasodilator. PMID:25793622

Impaired Skeletal Muscle Vasodilation during Exercise in Heart Failure with Preserved Ejection Fraction

PubMed Central

Lee, Joshua F.; Barrett-O’Keefe, Zachary; Nelson, Ashley D.; Garten, Ryan S.; Ryan, John J.; Nativi-Nicolau, Jose N.; Richardson, Russell S.; Wray, D. Walter

2016-01-01

Background Exercise intolerance is a hallmark symptom of heart failure patients with preserved ejection fraction (HFpEF), which may be related to an impaired ability to appropriately increase blood flow to the exercising muscle. Methods We evaluated leg blood flow (LBF, ultrasound Doppler), heart rate (HR), stroke volume (SV), cardiac output (CO), and mean arterial blood pressure (MAP, photoplethysmography) during dynamic, single leg knee-extensor (KE) exercise in HFpEF patients (n = 21; 68 ± 2 yrs) and healthy controls (n = 20; 71 ± 2 yrs). Results HFpEF patients exhibited a marked attrition during KE exercise, with only 60% able to complete the exercise protocol. In participants who completed all exercise intensities (0-5-10-15W; HFpEF, n = 13; Controls, n = 16), LBF was not different at 0W and 5W, but was 15-25% lower in HFpEF compared to controls at 10W and 15W (P < 0.001). Likewise, leg vascular conductance (LVC), an index of vasodilation, was not different at 0W and 5W, but was 15-20% lower in HFpEF compared to controls at 10W and 15W (P < 0.05). In contrast to these peripheral deficits, exercise-induced changes in central variables (HR, SV, CO), as well as MAP, were similar between groups. Conclusions These data reveal a marked reduction in LBF and LVC in HFpEF patients during exercise that cannot be attributed to a disease-related alteration in central hemodynamics, suggesting that impaired vasodilation in the exercising skeletal muscle vasculature may play a key role in the exercise intolerance associated with this patient population. PMID:26970959

Wearing graduated compression stockings augments cutaneous vasodilation but not sweating during exercise in the heat.

PubMed

Fujii, Naoto; Nikawa, Toshiya; Tsuji, Bun; Kenny, Glen P; Kondo, Narihiko; Nishiyasu, Takeshi

2017-05-01

The activation of cutaneous vasodilation and sweating are essential to the regulation of core temperature during exercise in the heat. We assessed the effect of graduated compression induced by wearing stockings on cutaneous vasodilation and sweating during exercise in the heat (30°C). On two separate occasions, nine young males exercised for 45 min or until core temperature reached ~1.5°C above baseline resting while wearing either (1) stockings causing graduated compression (graduate compression stockings, GCS), or (2) loose-fitting stockings without compression (Control). Forearm vascular conductance was evaluated by forearm blood flow (venous occlusion plethysmography) divided by mean arterial pressure to estimate cutaneous vasodilation. Sweat rate was estimated using the ventilated capsule technique. Core and skin temperatures were measured continuously. Exercise duration was similar between conditions (Control: 42.2 ± 3.6 min vs. GCS: 42.2 ± 3.6 min, P  = 1.00). Relative to Control, GCS increased forearm vascular conductance during the late stages (≥30 min) of exercise (e.g., at 40 min, 15.6 ± 5.6 vs. 18.0 ± 6.0 units, P  = 0.01). This was paralleled by a greater sensitivity (23.1 ± 9.1 vs. 32.1 ± 15.0 units°C -1 , P  = 0.043) and peak level (14.1 ± 5.1 vs. 16.3 ± 5.7 units, P  = 0.048) of cutaneous vasodilation as evaluated from the relationship between forearm vascular conductance with core temperature. However, the core temperature threshold at which an increase in forearm vascular conductance occurred did not differ between conditions (Control: 36.9 ± 0.2 vs. GCS: 37.0 ± 0.3°C, P  = 0.13). In contrast, no effect of GCS on sweating was measured (all P  > 0.05). We show that the use of GCS during exercise in the heat enhances cutaneous vasodilation and not sweating. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Regulation of coronary blood flow

PubMed Central

Gorlin, Richard

1971-01-01

Coronary blood flow is dependent upon arterial pressure, diastolic time, and small vessel resistance. The system is regulated to achieve a low flow high oxygen extraction and low myocardial Po2. This setting is sensitive to change in oxygen needs. Regulation of blood flow occurs primarily through local intrinsic regulation, most likely through production of vasodilating metabolites in response to minimal degrees of ischaemia. Local regulation appears to dominate over remote regulation in most circumstances. Blood flow distribution to the myocardium is depth dependent as well as regional in variation. Both types of distribution of blood flow are profoundly disturbed in the presence of obstructive coronary atherosclerosis. This results in either concentric myocardial shells or patchy transmural zones of selective ischaemia with clear-cut but local abnormalities in metabolism and performance. Images PMID:4929442

Antispasmodic and vasodilator activities of Morinda citrifolia root extract are mediated through blockade of voltage dependent calcium channels.

PubMed

Gilani, Anwarul Hassan; Mandukhail, Saf-ur-Rehman; Iqbal, Javeid; Yasinzai, Masoom; Aziz, Nauman; Khan, Aslam; Najeeb-ur-Rehman

2010-01-13

Morinda citrifolia (Noni) is an edible plant with wide range of medicinal uses. It occurs exclusively in tropical climate zone from India through Southeast Asia and Australia to Eastern Polynesia and Hawaii. The objective of this study was to explore the possible mode(s) of action for its antispasmodic, vasodilator and cardio-suppressant effects to rationalize its medicinal use in gut and cardiovascular disorders. Isolated tissue preparations such as, rabbit jejunum, rat and rabbit aorta and guinea pig atria were used to test the antispasmodic and cardiovascular relaxant effects and the possible mode of action(s) of the 70% aqueous-ethanolic extract of Morinda citrifolia roots (Mc.Cr). The Mc.Cr produced a concentration-dependent relaxation of spontaneous and high K(+) induced contractions in isolated rabbit jejunum preparations. It also caused right ward shift in the concentration response curves of Ca(++), similar to that of verapamil. In guinea-pig right atria, Mc.Cr caused inhibition of both atrial force and rate of spontaneous contractions. In rabbit thoracic aortic preparations, Mc.Cr also suppressed contractions induced by phenylephrine (1.0 μM) in normal- Ca(++) and Ca(++)-free kreb solutions and by high K(+), similar to that of verapamil. In rat thoracic aortic preparations, Mc.Cr also relaxed the phenylephrine (1.0 μM)-induced contractions. The vasodilatory responses were not altered in the presence of L-NAME (0.1 mM) or atropine (1.0 μM) and removal of endothelium. These results suggest that the spasmolytic and vasodilator effects of Mc.Cr root extract are mediated possibly through blockade of voltage-dependent calcium channels and release of intracellular calcium, which may explain the medicinal use of Morinda citrifolia in diarrhea and hypertension. However, more detailed studies are required to assess the safety and efficacy of this plant.

Antispasmodic and vasodilator activities of Morinda citrifolia root extract are mediated through blockade of voltage dependent calcium channels

PubMed Central

2010-01-01

Background Morinda citrifolia (Noni) is an edible plant with wide range of medicinal uses. It occurs exclusively in tropical climate zone from India through Southeast Asia and Australia to Eastern Polynesia and Hawaii. The objective of this study was to explore the possible mode(s) of action for its antispasmodic, vasodilator and cardio-suppressant effects to rationalize its medicinal use in gut and cardiovascular disorders. Methods Isolated tissue preparations such as, rabbit jejunum, rat and rabbit aorta and guinea pig atria were used to test the antispasmodic and cardiovascular relaxant effects and the possible mode of action(s) of the 70% aqueous-ethanolic extract of Morinda citrifolia roots (Mc.Cr). Results The Mc.Cr produced a concentration-dependent relaxation of spontaneous and high K+ induced contractions in isolated rabbit jejunum preparations. It also caused right ward shift in the concentration response curves of Ca++, similar to that of verapamil. In guinea-pig right atria, Mc.Cr caused inhibition of both atrial force and rate of spontaneous contractions. In rabbit thoracic aortic preparations, Mc.Cr also suppressed contractions induced by phenylephrine (1.0 μM) in normal- Ca++ and Ca++-free Kerb's solutions and by high K+, similar to that of verapamil. In rat thoracic aortic preparations, Mc.Cr also relaxed the phenylephrine (1.0 μM)-induced contractions. The vasodilatory responses were not altered in the presence of L-NAME (0.1 mM) or atropine (1.0 μM) and removal of endothelium. Conclusions These results suggest that the spasmolytic and vasodilator effects of Mc.Cr root extract are mediated possibly through blockade of voltage-dependent calcium channels and release of intracellular calcium, which may explain the medicinal use of Morinda citrifolia in diarrhea and hypertension. However, more detailed studies are required to assess the safety and efficacy of this plant. PMID:20070879

Lack of angiopoietin-like-2 expression limits the metabolic stress induced by a high-fat diet and maintains endothelial function in mice.

PubMed

Yu, Carol; Luo, Xiaoyan; Farhat, Nada; Daneault, Caroline; Duquette, Natacha; Martel, Cécile; Lambert, Jean; Thorin-Trescases, Nathalie; Rosiers, Christine Des; Thorin, Eric

2014-08-15

Angiopoietin-like-2 (angptl2) is produced by several cell types including endothelial cells, adipocytes and macrophages, and contributes to the inflammatory process in cardiovascular diseases. We hypothesized that angptl2 impairs endothelial function, and that lowering angptl2 levels protects the endothelium against high-fat diet (HFD)-induced fat accumulation and hypercholesterolemia. Acute recombinant angptl2 reduced (P<0.05) acetylcholine-mediated vasodilation of isolated wild-type (WT) mouse femoral artery, an effect reversed (P<0.05) by the antioxidant N-acetylcysteine. Accordingly, in angptl2 knockdown (KD) mice, ACh-mediated endothelium-dependent vasodilation was greater (P<0.05) than in WT mice. In arteries from KD mice, prostacyclin contributed to the overall dilation unlike in WT mice. After a 3-month HFD, overall vasodilation was not altered, but dissecting out the endothelial intrinsic pathways revealed that NO production was reduced in arteries isolated from HFD-fed WT mice (P<0.05), while NO release was maintained in KD mice. Similarly, endothelium-derived hyperpolarizing factor (EDHF) was preserved in mesenteric arteries from HFD-fed KD mice but not in those from WT mice. Finally, the HFD increased (P<0.05) total cholesterol-to-high-density lipoprotein ratios, low-density lipoprotein-to-high-density lipoprotein ratios, and leptin levels in WT mice only, while glycemia remained similar in the 2 strains. KD mice displayed less triglyceride accumulation in the liver (P<0.05 versus WT), and adipocyte diameters in mesenteric and epididymal white adipose tissues were smaller (P<0.05) in KD than in WT fed an HFD, while inflammatory gene expression increased (P<0.05) in the fat of WT mice only. Lack of angptl2 expression limits the metabolic stress induced by an HFD and maintains endothelial function in mice. © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Lack of Angiopoietin‐Like‐2 Expression Limits the Metabolic Stress Induced by a High‐Fat Diet and Maintains Endothelial Function in Mice

PubMed Central

Yu, Carol; Luo, Xiaoyan; Farhat, Nada; Daneault, Caroline; Duquette, Natacha; Martel, Cécile; Lambert, Jean; Thorin‐Trescases, Nathalie; Rosiers, Christine Des; Thorin, Éric

2014-01-01

Background Angiopoietin‐like‐2 (angptl2) is produced by several cell types including endothelial cells, adipocytes and macrophages, and contributes to the inflammatory process in cardiovascular diseases. We hypothesized that angptl2 impairs endothelial function, and that lowering angptl2 levels protects the endothelium against high‐fat diet (HFD)‐induced fat accumulation and hypercholesterolemia. Methods and Results Acute recombinant angptl2 reduced (P<0.05) acetylcholine‐mediated vasodilation of isolated wild‐type (WT) mouse femoral artery, an effect reversed (P<0.05) by the antioxidant N‐acetylcysteine. Accordingly, in angptl2 knockdown (KD) mice, ACh‐mediated endothelium‐dependent vasodilation was greater (P<0.05) than in WT mice. In arteries from KD mice, prostacyclin contributed to the overall dilation unlike in WT mice. After a 3‐month HFD, overall vasodilation was not altered, but dissecting out the endothelial intrinsic pathways revealed that NO production was reduced in arteries isolated from HFD‐fed WT mice (P<0.05), while NO release was maintained in KD mice. Similarly, endothelium‐derived hyperpolarizing factor (EDHF) was preserved in mesenteric arteries from HFD‐fed KD mice but not in those from WT mice. Finally, the HFD increased (P<0.05) total cholesterol–to–high‐density lipoprotein ratios, low‐density lipoprotein–to–high‐density lipoprotein ratios, and leptin levels in WT mice only, while glycemia remained similar in the 2 strains. KD mice displayed less triglyceride accumulation in the liver (P<0.05 versus WT), and adipocyte diameters in mesenteric and epididymal white adipose tissues were smaller (P<0.05) in KD than in WT fed an HFD, while inflammatory gene expression increased (P<0.05) in the fat of WT mice only. Conclusions Lack of angptl2 expression limits the metabolic stress induced by an HFD and maintains endothelial function in mice. PMID:25128474

Relationship between instantaneous wave-free ratio and fractional flow reserve in patients receiving hemodialysis.

PubMed

Morioka, Yuta; Arashi, Hiroyuki; Otsuki, Hisao; Yamaguchi, Junichi; Hagiwara, Nobuhisa

2017-06-22

Instantaneous wave-free ratio (iFR) is a vasodilator-free index and is reported to have a good correlation with fractional flow reserve (FFR). Hemodialysis patients exhibit left ventricular hypertrophy, reduced arterial compliance, and impaired microcirculation. Such a coronary flow condition in these patients may influence the relationship between iFR and FFR. This study assessed the impact of hemodialysis on the relationship between iFR and FFR. The study enrolled 196 patients with 265 stenoses who underwent assessment via iFR, FFR assessment, and right heart catheterization. A good correlation between iFR and FFR was observed in hemodialysis patients. iFR in the hemodialysis group was significantly lower than in the non-hemodialysis group (0.81 ± 0.13 vs. 0.86 ± 0.13, p = 0.005), although no significant difference was found in FFR and percentage diameter stenosis. An iFR value of 0.84 was found to be equivalent to an FFR value of 0.8 in hemodialysis patients, which was lower than the standard predictive iFR range for ischemia. Vasodilator-free assessment by iFR could be beneficial in evaluating intermediate coronary stenosis in patients receiving hemodialysis. However, the threshold for iFR abnormality needs adjustment in hemodialysis patients, and larger clinical trials are required to confirm the results in this specific subset.

N-Acetylcysteine's Role in Sepsis and Potential Benefit in Patients With Microcirculatory Derangements.

PubMed

Chertoff, Jason

2018-02-01

To review the data surrounding the utility of N-acetylcysteine (NAC) in sepsis and identify areas needed for additional research. A review of articles describing the mechanisms of action and clinical use of NAC in sepsis. Despite many advances in critical care medicine, still as many as 50% of patients with septic shock die. Treatments thus far have focused on resuscitation and restoration of macrocirculatory targets in the early phases of sepsis, with less focus on microcirculatory dysfunction. N-acetylcysteine, due to its anti-inflammatory and antioxidative properties, has been readily investigated in sepsis and has yielded largely incongruous and disappointing results. In addition to its known anti-inflammatory and antioxidative roles, one underappreciated property of NAC is its ability to vasodilate the microcirculation and improve locoregional blood flow. Some investigators have sought to capitalize on this mechanism with promising results, as evidenced by microcirculatory vasodilation, improvements in regional blood flow and oxygen delivery, and reductions in lactic acidosis, organ failure, and mortality. In addition to its antioxidant and anti-inflammatory properties, N-acetylcysteine possesses vasodilatory properties that could benefit the microcirculation in sepsis. It is imperative that we investigate these properties to uncover NAC's full potential for benefit in sepsis.

Evaluation of the “Steal” Phenomenon on the Efficacy of Hypoxia Activated Prodrug TH-302 in Pancreatic Cancer

PubMed Central

Ibrahim-Hashim, Arig; Wojtkowiak, Jonathan W.; Hart, Charles P.; Zhang, Xiaomeng; Leos, Rafael; Martinez, Gary V.; Baker, Amanda F.; Gillies, Robert J.

2014-01-01

Pancreatic ductal adenocarcinomas are desmoplastic and hypoxic, both of which are associated with poor prognosis. Hypoxia-activated prodrugs (HAPs) are specifically activated in hypoxic environments to release cytotoxic or cytostatic effectors. TH-302 is a HAP that is currently being evaluated in a Phase III clinical trial in pancreatic cancer. Using animal models, we show that tumor hypoxia can be exacerbated using a vasodilator, hydralazine, improving TH-302 efficacy. Hydralazine reduces tumor blood flow through the “steal” phenomenon, in which atonal immature tumor vasculature fails to dilate in coordination with normal vasculature. We show that MIA PaCa-2 tumors exhibit a “steal” effect in response to hydralazine, resulting in decreased tumor blood flow and subsequent tumor pH reduction. The effect is not observed in SU.86.86 tumors with mature tumor vasculature, as measured by CD31 and smooth muscle actin (SMA) immunohistochemistry staining. Combination therapy of hydralazine and TH-302 resulted in a reduction in MIA PaCa-2 tumor volume growth after 18 days of treatment. These studies support a combination mechanism of action for TH-302 with a vasodilator that transiently increases tumor hypoxia. PMID:25532146

Pharmacology of RG W-2938: a cardiotonic agent with vasodilator activity.

PubMed

Barrett, J A; Woltmann, R F; Swillo, R S; Kasiewski, C; Faith, W C; Campbell, H F; Perrone, M H

1990-10-01

The cardiovascular effects of RG W-2938, 6-[6-(3,4-dihydro-3-methyl-2(1H)-2-oxoquinazolinyl)]-4,5-dihydro-3 (2H-pyridazinone, a new nonglycoside, noncatecholamine cardiotonic/vasodilator agent were examined in vivo in anesthetized and conscious dogs and in vitro in isolated guinea pig hearts; in the latter, RG W-2938 5 nmol-5 mumol increased contractility in a dose-related fashion. RG W-2938 30-300 micrograms/kg administered intravenously (i.v.) to anesthetized dogs increased contractile force while decreasing arterial pressure and total peripheral resistance (TPR) in a dose-related manner. Heart rate (HR) was only slightly increased, and aortic flow was not appreciably altered. A single oral dose of RG W-2938 0.3 mg/kg administered to conscious chronically instrumented dogs produced a marked and sustained increase in contractility 15-240 min after treatment while only slightly increasing HR. The effects of RG W-2938 30-300 micrograms/kg, i.v. were studied in a mecamylamine-propranolol-induced model of heart failure. RG W-2938 effectively reversed the drug-induced heart failure by increasing myocardial contractility and decreasing arterial pressure while only slightly affecting HR. These studies show that RG W-2938 is an orally effective positive inotropic/vasodilator agent.

No major impact of skin aging on the response of skin blood flow to a submaximal local thermal stimulus.

PubMed

Vionnet, Julien; Calero-Romero, Irene; Heim, Abigaël; Rotaru, Corina; Engelberger, Rolf Peter; Dischl, Benoît; Noël, Bernard; Liaudet, Lucas; Waeber, Bernard; Feihl, François

2014-11-01

This study was undertaken to investigate how aging affects dermal microvascular reactivity in skin areas differentially exposed to sunlight, and therefore to different degrees of photoaging. We assessed, in young (18-30 years, n = 13) and aged males (≥60 years, n = 13), the thigh, forearm, and forehead's skin vasodilatory response to local heating (LTH) with a LDI. In each subject and at each location, local Tskin was brought from 34°C (baseline) to 39 or 41°C for 30 minutes, to effect submaximal vasodilation, with maximal vasodilation then elicited by further heating to 44°C. The CVCs evaluated at baseline and after maximal vasodilation (CVCmax ) were higher in the forehead than in the two other anatomical locations. On all locations, CVCmax decreased with age but less markedly in the forehead compared to the two other locations. When expressed in % of CVCmax , the plateau increase of CVCs in response to submaximal temperatures (39 and 41°C) did not vary with age, and minimally so with location. Skin aging, whether intrinsic or combined with photoaging, reduces the maximal vasodilatory capacity of the dermal microcirculation, but not its reactivity to local heating. © 2014 John Wiley & Sons Ltd.

Inhibitory effect of chronic oral treatment with fluoxetine on capsaicin-induced external carotid vasodilatation in anaesthetised dogs.

PubMed

Muñoz-Islas, Enriqueta; González-Hernández, Abimael; Lozano-Cuenca, Jair; Ramírez-Rosas, Martha Beatríz; Medina-Santillán, Roberto; Centurión, David; MaassenVanDenBrink, Antoinette; Villalón, Carlos M

2015-10-01

During migraine, capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), resulting in cranial vasodilatation and central nociception. Moreover, 5-HT is involved in the pathophysiology of migraine and depression. Interestingly, some limited lines of evidence suggest that fluoxetine may be effective in migraine prophylaxis, but the underlying mechanisms are uncertain. Hence, this study investigated the canine external carotid vasodilator responses to capsaicin, α-CGRP and acetylcholine before and after acute and chronic oral treatment with fluoxetine. Forty-eight vagosympathectomised male mongrel dogs were prepared to measure blood pressure, heart rate and external carotid blood flow. The thyroid artery was cannulated for infusions of agonists. In 16 of these dogs, a spinal cannula was inserted (C1-C3) for infusions of 5-HT. The external carotid vasodilator responses to capsaicin, α-CGRP and acetylcholine remained unaffected after intracarotid or i.v. fluoxetine. In contrast, the vasodilator responses to capsaicin, but not those to α-CGRP or acetylcholine, were inhibited after chronic oral treatment with fluoxetine (300 µg/kg; for 90 days) or intrathecal 5-HT. Chronic oral fluoxetine inhibited capsaicin-induced external carotid vasodilatation, and this inhibition could partly explain its potential prophylactic antimigraine action. © International Headache Society 2015.

The 5-HT1-like receptor mediating the increase in canine external carotid blood flow: close resemblance to the 5-HT1D subtype.

PubMed Central

Villalón, C M; Terrón, J A

1994-01-01

1. It has recently been shown that the increase in external carotid blood flow induced by 5-hydroxy-tryptamine (5-HT) in the anaesthetized dog, being mimicked by 5-carboxamidotryptamine (5-CT), inhibited by methiothepin, vagosympathectomy and sympatho-inhibitory drugs, and resistant to blockade by ritanserin and MDL 72222, is mediated by stimulation of prejunctional 5-HT1-like receptors leading to an inhibitory action on carotid sympathetic nerves; these 5-HT1-like receptors are unrelated to either the 5-HT1A, 5-HT1B or 5-HT1C (now 5-HT2C) receptor subtypes. Inasmuch as 5-CT, 5-methoxytryptamine, sumatriptan and metergoline display high affinity, amongst other 5-HT binding sites, for the 5-HT1D subtype, in the present study we have used these drugs in an attempt to determine whether the above inhibitory prejunctional 5-HT1-like receptors correlate with the 5-HT1D subtype. 2. One-minute intracarotid (i.c.) infusions of 5-HT (0.3, 1, 3 and 10 micrograms), 5-CT (0.01, 0.03, 0.1 and 0.3 micrograms), 5-methoxytryptamine (1, 3, 10 and 30 micrograms) and sumatriptan (1, 3, 10, 30 and 100 micrograms) resulted in dose-dependent increases in external carotid blood flow (without changes in mean arterial blood pressure or heart rate) with the following rank order of agonist potency: 5-CT >> 5-HT > 5-methoxytryptamine > or = sumatriptan. Interestingly, sumatriptan-induced vasodilatation was followed by a more pronounced vasoconstriction. 3. The external carotid vasodilator effects of 5-HT, 5-CT, 5-methoxytryptamine and sumatriptan were dose-dependently and specifically antagonized by metergoline (10, 30 and/or 100 micrograms kg-1, i.v.).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7812603

Effects of six-month supplementation with beta-hydroxy-beta-methylbutyrate, glutamine, and arginine on vascular endothelial function of older adults

PubMed Central

Ellis, Amy; Patterson, Morgan; Dudenbostel, Tanja; Calhoun, David; Gower, Barbara

2015-01-01

Background Vascular endothelial function declines with advancing age, due in part to increased oxidative stress and inflammation, and this age-related vascular dysfunction has been identified as an independent risk factor for cardiovascular diseases (CVD). This double-blind, placebo-controlled trial investigated the effects of a dietary supplement containing β-hydroxy-β-methylbutyrate (HMB), glutamine, and arginine on endothelial-dependent vasodilation of older adults. Subjects/Methods Thirty-one community-dwelling men and women aged 65-87 years were randomly assigned to two groups. The treatment group received two doses of the supplement daily (totaling 3g HMB, 14g glutamine, 14g arginine) for six months while the control group received an isocaloric placebo. At baseline and week 24, vascular endothelial function was measured by flow-mediated dilation of the brachial artery, and fasting blood samples were obtained to measure high-sensitivity C-reactive protein (hsCRP) and tumor necrosis factor-α (TNF-α). Results Paired samples t-tests revealed a 27% increase in flow-mediated dilation among the treatment group (p=0.003) while no change was observed in the placebo group (p=0.651). Repeated-measures ANOVA verified a significant time by group interaction (p=0.038). Although no significant changes were observed for hsCRP or TNF-α, a trend was observed for increasing hsCRP among the placebo group only (p=0.059). Conclusions These results suggest that dietary supplementation of HMB, glutamine, and arginine may favorably impact vascular endothelial function in older adults. Additional studies are needed to elucidate whether reduced inflammation or other mechanisms may underlie the benefits of supplementation. PMID:26306566

Effects of 6-month supplementation with β-hydroxy-β-methylbutyrate, glutamine and arginine on vascular endothelial function of older adults.

PubMed

Ellis, A C; Patterson, M; Dudenbostel, T; Calhoun, D; Gower, B

2016-02-01

Vascular endothelial function declines with advancing age, due in part to increased oxidative stress and inflammation, and this age-related vascular dysfunction has been identified as an independent risk factor for cardiovascular diseases. This double-blind, placebo-controlled trial investigated the effects of a dietary supplement containing β-hydroxy-β-methylbutyrate (HMB), glutamine and arginine on endothelial-dependent vasodilation of older adults. A total of 31 community-dwelling men and women aged 65-87 years were randomly assigned to two groups. The treatment group received two doses of the supplement daily (totaling 3 g HMB, 14 g glutamine and 14 g arginine) for 6 months, whereas the control group received an isocaloric placebo. At baseline and week 24, vascular endothelial function was measured by flow-mediated dilation of the brachial artery, and fasting blood samples were obtained to measure high-sensitivity C-reactive protein (hsCRP) and tumor necrosis factor-α (TNF-α). Paired sample t-tests revealed a 27% increase in flow-mediated dilation among the treatment group (P=0.003), whereas no change was observed in the placebo group (P=0.651). Repeated-measures analysis of variance verified a significant time by group interaction (P=0.038). Although no significant changes were observed for hsCRP or TNF-α, a trend was observed for increasing hsCRP among the placebo group only (P=0.059). These results suggest that dietary supplementation of HMB, glutamine and arginine may favorably affect vascular endothelial function in older adults. Additional studies are needed to elucidate whether reduced inflammation or other mechanisms may underlie the benefits of supplementation.

Impact of volunteer-related and methodology-related factors on the reproducibility of brachial artery flow-mediated vasodilation: analysis of 672 individual repeated measurements.

PubMed

van Mil, Anke C C M; Greyling, Arno; Zock, Peter L; Geleijnse, Johanna M; Hopman, Maria T; Mensink, Ronald P; Reesink, Koen D; Green, Daniel J; Ghiadoni, Lorenzo; Thijssen, Dick H

2016-09-01

Brachial artery flow-mediated dilation (FMD) is a popular technique to examine endothelial function in humans. Identifying volunteer and methodological factors related to variation in FMD is important to improve measurement accuracy and applicability. Volunteer-related and methodology-related parameters were collected in 672 volunteers from eight affiliated centres worldwide who underwent repeated measures of FMD. All centres adopted contemporary expert-consensus guidelines for FMD assessment. After calculating the coefficient of variation (%) of the FMD for each individual, we constructed quartiles (n = 168 per quartile). Based on two regression models (volunteer-related factors and methodology-related factors), statistically significant components of these two models were added to a final regression model (calculated as β-coefficient and R). This allowed us to identify factors that independently contributed to the variation in FMD%. Median coefficient of variation was 17.5%, with healthy volunteers demonstrating a coefficient of variation 9.3%. Regression models revealed age (β = 0.248, P < 0.001), hypertension (β = 0.104, P < 0.001), dyslipidemia (β = 0.331, P < 0.001), time between measurements (β = 0.318, P < 0.001), lab experience (β = -0.133, P < 0.001) and baseline FMD% (β = 0.082, P < 0.05) as contributors to the coefficient of variation. After including all significant factors in the final model, we found that time between measurements, hypertension, baseline FMD% and lab experience with FMD independently predicted brachial artery variability (total R = 0.202). Although FMD% showed good reproducibility, larger variation was observed in conditions with longer time between measurements, hypertension, less experience and lower baseline FMD%. Accounting for these factors may improve FMD% variability.

Vasodilator-stimulated phosphoprotein promotes activation of hepatic stellate cells by regulating Rab11-dependent plasma membrane targeting of transforming growth factor beta receptors.

PubMed

Tu, Kangsheng; Li, Jiachu; Verma, Vikas K; Liu, Chunsheng; Billadeau, Daniel D; Lamprecht, Georg; Xiang, Xiaoyu; Guo, Luyang; Dhanasekaran, Renumathy; Roberts, Lewis R; Shah, Vijay H; Kang, Ningling

2015-01-01

Liver microenvironment is a critical determinant for development and progression of liver metastasis. Under transforming growth factor beta (TGF-β) stimulation, hepatic stellate cells (HSCs), which are liver-specific pericytes, transdifferentiate into tumor-associated myofibroblasts that promote tumor implantation (TI) and growth in the liver. However, the regulation of this HSC activation process remains poorly understood. In this study, we tested whether vasodilator-stimulated phosphoprotein (VASP) of HSCs regulated the TGF-β-mediated HSC activation process and tumor growth. In both an experimental liver metastasis mouse model and cancer patients, colorectal cancer cells reaching liver sinusoids induced up-regulation of VASP and alpha-smooth muscle actin (α-SMA) in adjacent HSCs. VASP knockdown in HSCs inhibited TGF-β-mediated myofibroblastic activation of HSCs, TI, and growth in mice. Mechanistically, VASP formed protein complexes with TGF-β receptor II (TβRII) and Rab11, a Ras-like small GTPase and key regulator of recycling endosomes. VASP knockdown impaired Rab11 activity and Rab11-dependent targeting of TβRII to the plasma membrane, thereby desensitizing HSCs to TGF-β1 stimulation. Our study demonstrates a requirement of VASP for TGF-β-mediated HSC activation in the tumor microenvironment by regulating Rab11-dependent recycling of TβRII to the plasma membrane. VASP and its effector, Rab11, in the tumor microenvironment thus present therapeutic targets for reducing TI and metastatic growth in the liver. © 2014 by the American Association for the Study of Liver Diseases.

Joint scientific statement of the European Association for the Study of Obesity and the European Society of Hypertension: Obesity and early vascular ageing.

PubMed

Jordan, Jens; Nilsson, Peter M; Kotsis, Vasilios; Olsen, Michael H; Grassi, Guido; Yumuk, Volkan; Hauner, Hans; Zahorska-Markiewicz, Barbara; Toplak, Hermann; Engeli, Stefan; Finer, Nick

2015-03-01

Current cardiovascular risk scores do not include obesity or fat distribution as independent factors, and may underestimate risk in obese individuals. Assessment of early vascular ageing (EVA) biomarkers including arterial stiffness, central blood pressure, carotid intima-media thickness and flow-mediated vasodilation may help to refine risk assessment in obese individuals in whom traditional cardiovascular risk scores and factors suggest no need for specific medical attention. A number of issues need to be addressed before this approach is ready for translation into routine clinical practice. Methodologies for measurements of vascular markers need to be further standardized and less operator-dependent. The utility of these nontraditional risk factors will also need to be proven in sufficiently large and properly designed interventional studies. Indeed, published studies on vascular markers in obesity and weight loss vary in quality and study design, are sometimes conducted in small populations, use a variety of differing methodologies and study differing vascular beds. Finally, current vascular measurements are still crude and may not be sufficient to cover the different aspects of EVA in obesity.

Tangeretin regulates platelet function through inhibition of phosphoinositide 3-kinase and cyclic nucleotide signaling.

PubMed

Vaiyapuri, Sakthivel; Ali, Marfoua S; Moraes, Leonardo A; Sage, Tanya; Lewis, Kirsty R; Jones, Chris I; Gibbins, Jonathan M

2013-12-01

Dietary flavonoids have long been appreciated in reducing cardiovascular disease risk factors, but their mechanisms of action are complex in nature. In this study, the effects of tangeretin, a dietary flavonoid, were explored on platelet function, signaling, and hemostasis. Tangeretin inhibited agonist-induced human platelet activation in a concentration-dependent manner. It inhibited agonist-induced integrin αIIbβ3 inside-out and outside-in signaling, intracellular calcium mobilization, and granule secretion. Tangeretin also inhibited human platelet adhesion and subsequent thrombus formation on collagen-coated surfaces under arterial flow conditions in vitro and reduced hemostasis in mice. Further characterization to explore the mechanism by which tangeretin inhibits platelet function revealed distinctive effects of platelet signaling. Tangeretin was found to inhibit phosphoinositide 3-kinase-mediated signaling and increase cGMP levels in platelets, although phosphodiesterase activity was unaffected. Consistent with increased cGMP levels, tangeretin increased the phosphorylation of vasodilator-stimulated phosphoprotein at S239. This study provides support for the ability and mechanisms of action of dietary flavonoids to modulate platelet signaling and function, which may affect the risk of thrombotic disease.

The Essential Role of Tick Salivary Glands and Saliva in Tick Feeding and Pathogen Transmission.

PubMed

Šimo, Ladislav; Kazimirova, Maria; Richardson, Jennifer; Bonnet, Sarah I

2017-01-01

As long-term pool feeders, ticks have developed myriad strategies to remain discreetly but solidly attached to their hosts for the duration of their blood meal. The critical biological material that dampens host defenses and facilitates the flow of blood-thus assuring adequate feeding-is tick saliva. Saliva exhibits cytolytic, vasodilator, anticoagulant, anti-inflammatory, and immunosuppressive activity. This essential fluid is secreted by the salivary glands, which also mediate several other biological functions, including secretion of cement and hygroscopic components, as well as the watery component of blood as regards hard ticks. When salivary glands are invaded by tick-borne pathogens, pathogens may be transmitted via saliva, which is injected alternately with blood uptake during the tick bite. Both salivary glands and saliva thus play a key role in transmission of pathogenic microorganisms to vertebrate hosts. During their long co-evolution with ticks and vertebrate hosts, microorganisms have indeed developed various strategies to exploit tick salivary molecules to ensure both acquisition by ticks and transmission, local infection and systemic dissemination within the vertebrate host.

The Essential Role of Tick Salivary Glands and Saliva in Tick Feeding and Pathogen Transmission

PubMed Central

Šimo, Ladislav; Kazimirova, Maria; Richardson, Jennifer; Bonnet, Sarah I.

2017-01-01

As long-term pool feeders, ticks have developed myriad strategies to remain discreetly but solidly attached to their hosts for the duration of their blood meal. The critical biological material that dampens host defenses and facilitates the flow of blood—thus assuring adequate feeding—is tick saliva. Saliva exhibits cytolytic, vasodilator, anticoagulant, anti-inflammatory, and immunosuppressive activity. This essential fluid is secreted by the salivary glands, which also mediate several other biological functions, including secretion of cement and hygroscopic components, as well as the watery component of blood as regards hard ticks. When salivary glands are invaded by tick-borne pathogens, pathogens may be transmitted via saliva, which is injected alternately with blood uptake during the tick bite. Both salivary glands and saliva thus play a key role in transmission of pathogenic microorganisms to vertebrate hosts. During their long co-evolution with ticks and vertebrate hosts, microorganisms have indeed developed various strategies to exploit tick salivary molecules to ensure both acquisition by ticks and transmission, local infection and systemic dissemination within the vertebrate host. PMID:28690983

[Effects of a smoking cessation education on smoking cessation, endothelial function, and serum carboxyhemoglobin in male patients with variant angina].

PubMed

Cho, Sook Hee

2012-04-01

The aim of this study was to evaluate the effects of a smoking cessation education on endothelial function and carboxyhemoglobin levels in smokers with variant angina. A nonequivalent control group pretest-posttest design was used. Participants were 60 male smokers with variant angina admitted to one hospital: the control group (30) between September and December, 2009, and the experimental group (30) between February and May, 2010. Endothelial function, as defined by flow-mediated vasodilation (FMD) of the brachial artery, and serum carboxyhemoglobin (COHb) were determined at baseline and at 3 months after the initiation of education in both groups. Three months after the program, smoking cessation was successful in 22 of the 30 smokers in the experimental group, but only in 4 of 30 smokers in the control group (p<.001). After the education, the experimental group showed a significant increase in FMD, and a significant decreased in serum COHb compared with the control group. The findings indicate that this smoking cessation education program is effective for hospitalized smokers with variant angina.

Altered skin flowmotion in hypertensive humans

PubMed Central

Bruning, R.S.; Kenney, W.L.; Alexander, L.M.

2017-01-01

Essential hypertensive humans exhibit attenuated cutaneous nitric oxide (NO)-dependent vasodilation. Using spectral analysis (fast Fourier transformation) we aimed to characterize the skin flowmotion contained in the laser-Doppler flowmetry recordings during local heating-induced vasodilation before and after concurrent pharmacological inhibition of nitric oxide synthase (NOS) in hypertensive and age-matched normotensive men and women. We hypothesized that hypertensive subjects would have lower total power spectral densities (PSD), specifically in the frequency intervals associated with intrinsic endothelial and neurogenic control of the microvasculature. Furthermore, we hypothesized that NOS inhibition would attenuate the endothelial frequency interval. Laser-Doppler flowmetry recordings during local heating experiments from 18 hypertensive (MAP: 108±2mmHg) and 18 normotensive (MAP: 88±2mmHg) men and women were analyzed. Within site NO-dependent vasodilation was assessed by perfusion of a non-specific NOS inhibitor (NG-nitro-L-arginine methyl ester; L-NAME) through intradermal microdialysis during the heating-induced plateau in skin blood flow. Local heating-induced vasodilation increased total PSD for all frequency intervals (all p<0.001). Hypertensives had a lower total PSD (p=0.03) and absolute neurogenic frequency intervals (p<0.01) compared to the normotensives. When normalized as a percentage of total PSD, hypertensives had reduced neurogenic (p<0.001) and augmented myogenic contributions (p=0.04) to the total spectrum. NOS inhibition decreased total PSD (p<0.001) for both groups, but hypertensives exhibited lower absolute endothelial (p<0.01), neurogenic (p<0.05), and total PSD (p<0.001) frequency intervals compared to normotensives. These data suggest that essential hypertension results in altered neurogenic and NOS-dependent control of skin flowmotion and support the use of spectral analysis as a non-invasive technique to study vasoreactivity. PMID:24418051

L-arginine as dietary supplement for improving microvascular function.

PubMed

Melik, Ziva; Zaletel, Polona; Virtic, Tina; Cankar, Ksenija

2017-01-01

Reduced availability of nitric oxide leads to dysfunction of endothelium which plays an important role in the development of cardiovascular diseases. The aim of the present study was to determine whether the dietary supplement L-arginine improves the endothelial function of microvessels by increasing nitric oxide production. We undertook experiments on 51 healthy male volunteers, divided into 4 groups based on their age and physical activity since regular physical activity itself increases endothelium-dependent vasodilation. The skin laser Doppler flux was measured in the microvessels before and after the ingestion of L-arginine (0.9 g). The endothelium-dependent vasodilation was assessed by acetylcholine iontophoresis and the endothelium-independent vasodilation by sodium nitroprusside iontophoresis. In addition, we measured endothelium-dependent and endothelium-independent vasodilation in 81 healthy subjects divided into four age groups. After the ingestion of L-arginine, the endothelium-dependent vasodilation in the young trained subjects increased (paired t-test, p < 0.05), while in the other groups it remained the same. There were no differences in the endothelium-independent vasodilation after ingestion of L-arginine. With aging endothelium-independent vasodilation decreased while endothelium-dependent vasodilation remained mainly unchanged. Obtained results demonstrated that a single dose of L-arginine influences endothelium-dependent vasodilation predominantly in young, trained individuals.

Too old to benefit from sports? The cardiovascular effects of exercise training in elderly subjects treated for isolated systolic hypertension.

PubMed

Westhoff, Timm H; Franke, Nadine; Schmidt, Sven; Vallbracht-Israng, Katja; Meissner, Romy; Yildirim, Havva; Schlattmann, Peter; Zidek, Walter; Dimeo, Fernando; van der Giet, Markus

2007-01-01

Hypertension in the elderly is commonly characterized by an elevation of pulse pressure. With regard to advanced arteriosclerosis and limited physical fitness, doubt was casted whether elderly patients still achieve relevant cardiovascular benefits by physical exercise. The present work examines the impact of pulse pressure as a footprint of vascular ageing on cardiovascular benefits of endurance training in elderly hypertensives. 54 patients > or =60 years with systolic 24-hour ambulatory blood pressure (ABP) >140 mm Hg and/or antihypertensive treatment and diastolic ABP < or =90 mm Hg were randomly assigned to sedentary activity or a 12-week treadmill exercise program (target lactate 2.5 +/- 0.5 mmol/l). Exercise significantly decreased systolic and diastolic ABP by 8.5 +/- 8.2 and 5.1 +/- 3.7 mm Hg (p < 0.001 each) and increased physical performance. Arterial compliance remained unchanged, whereas endothelium-dependent vasodilation--measured by flow-mediated dilation--significantly increased from 5.6 +/- 1.7 to 7.9 +/- 3.0% (p < 0.007). After adjustment for initial systolic ABP, pulse pressure did not affect the change of BP. The exercise-induced reduction of BP, which is mediated by improved endothelial function, is independent of pulse pressure. Thus, physical exercise is a helpful adjunct to control BP even in old hypertensives with markedly increased arterial stiffness. Copyright 2007 S. Karger AG, Basel.

Airway and Pulmonary β2-Adrenergic Vasodilatory Function in Current Smokers and Never Smokers.

PubMed

Hurwitz, Barry E; Mendes, Eliana S; Schmid, Andreas; Parker, Meela; Arana, Johana; Gonzalez, Alex; Wanner, Adam

2017-03-01

Cigarette smoking has been associated with diminished vasodilatory function in the airway circulation. It is possible that cigarette smoking similarly affects the pulmonary circulation before resting pulmonary circulatory abnormalities become manifested. The aim of this study was to compare the acute effect of inhaled albuterol on airway and pulmonary hemodynamic function as an index of β 2 -adrenoceptor-mediated vasodilation in smokers and never smokers. In 30 adults, airway and pulmonary vascular function was assessed before and 15 min after albuterol inhalation (270 μg). From mean systemic arterial pressure, cardiac output, airway blood flow, and mean pulmonary arterial pressure, airway vascular resistance (AVR) and pulmonary vascular resistance (PVR) were derived. Albuterol induced a substantial drop in mean (± SE) PVR (-67.2% ± 5%), with no difference between groups. In contrast, the albuterol-induced decrease in AVR was significantly greater in never smokers than in smokers (-28.6% ± 3% vs -3.1% ± 6%; P < .02). These results are consistent with a dysfunction in a β 2 -adrenergic signaling pathway mediating vasorelaxation in the airway circulation of current smokers. The vasodilatory deficit in the airway circulation but not in the pulmonary circulation could be related to local differences in the impact of cigarette smoke on the vascular endothelium. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Endothelium‐dependent vasodilatory signalling modulates α1‐adrenergic vasoconstriction in contracting skeletal muscle of humans

PubMed Central

Hearon, Christopher M.; Kirby, Brett S.; Luckasen, Gary J.; Larson, Dennis G.

2016-01-01

Key points ‘Functional sympatholysis’ describes the ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction, and is critical to ensure proper blood flow and oxygen delivery to metabolically active skeletal muscle. The signalling mechanism responsible for sympatholysis in healthy humans is unknown.Evidence from animal models has identified endothelium‐derived hyperpolarization (EDH) as a potential mechanism capable of attenuating sympathetic vasoconstriction.In this study, increasing endothelium‐dependent signalling during exercise significantly enhanced the ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction in humans.This is the first study in humans to identify endothelium‐dependent regulation of sympathetic vasoconstriction in contracting skeletal muscle, and specifically supports a role for EDH‐like vasodilatory signalling.Impaired functional sympatholysis is a common feature of cardiovascular ageing, hypertension and heart failure, and thus identifying fundamental mechanisms responsible for sympatholysis is clinically relevant. Abstract Stimulation of α‐adrenoceptors elicits vasoconstriction in resting skeletal muscle that is blunted during exercise in an intensity‐dependent manner. In humans, the underlying mechanisms remain unclear. We tested the hypothesis that stimulating endothelium‐dependent vasodilatory signalling will enhance the ability of contracting skeletal muscle to blunt α1‐adrenergic vasoconstriction. Changes in forearm vascular conductance (FVC; Doppler ultrasound, brachial intra‐arterial pressure via catheter) to local intra‐arterial infusion of phenylephrine (PE; α1‐adrenoceptor agonist) were calculated during (1) infusion of the endothelium‐dependent vasodilators acetylcholine (ACh) and adenosine triphosphate (ATP), the endothelium‐independent vasodilator (sodium nitroprusside, SNP), or potassium chloride (KCl) at rest; (2) mild or moderate intensity handgrip exercise; and (3) combined mild exercise + ACh, ATP, SNP, or KCl infusions in healthy adults. Robust vasoconstriction to PE was observed during vasodilator infusion alone and mild exercise, and this was blunted during moderate intensity exercise (ΔFVC: −34 ± 4 and −34 ± 3 vs. −13 ± 2%, respectively, P < 0.05). Infusion of ACh or ATP during mild exercise significantly attenuated PE vasoconstriction similar to levels observed during moderate exercise (ACh: −3 ± 4; ATP: −18 ± 4%). In contrast, infusion of SNP or KCl during mild exercise did not attenuate PE‐mediated vasoconstriction (−32 ± 5 and −46 ± 3%). To further study the role of endothelium‐dependent hyperpolarization (EDH), ACh trials were repeated with combined nitric oxide synthase and cyclooxygenase inhibition. Here, PE‐mediated vasoconstriction was blunted at rest (blockade: −20 ± 5 vs. control: −31 ± 3% vs.; P < 0.05) and remained blunted during exercise (blockade: −15 ± 5 vs. control: −14 ± 5%). We conclude that stimulation of EDH‐like vasodilatation can blunt α1‐adrenergic vasoconstriction in contracting skeletal muscle of humans. PMID:27561916

Endothelium-dependent vasodilatory signalling modulates α1 -adrenergic vasoconstriction in contracting skeletal muscle of humans.

PubMed

Hearon, Christopher M; Kirby, Brett S; Luckasen, Gary J; Larson, Dennis G; Dinenno, Frank A

2016-12-15

'Functional sympatholysis' describes the ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction, and is critical to ensure proper blood flow and oxygen delivery to metabolically active skeletal muscle. The signalling mechanism responsible for sympatholysis in healthy humans is unknown. Evidence from animal models has identified endothelium-derived hyperpolarization (EDH) as a potential mechanism capable of attenuating sympathetic vasoconstriction. In this study, increasing endothelium-dependent signalling during exercise significantly enhanced the ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction in humans. This is the first study in humans to identify endothelium-dependent regulation of sympathetic vasoconstriction in contracting skeletal muscle, and specifically supports a role for EDH-like vasodilatory signalling. Impaired functional sympatholysis is a common feature of cardiovascular ageing, hypertension and heart failure, and thus identifying fundamental mechanisms responsible for sympatholysis is clinically relevant. Stimulation of α-adrenoceptors elicits vasoconstriction in resting skeletal muscle that is blunted during exercise in an intensity-dependent manner. In humans, the underlying mechanisms remain unclear. We tested the hypothesis that stimulating endothelium-dependent vasodilatory signalling will enhance the ability of contracting skeletal muscle to blunt α 1 -adrenergic vasoconstriction. Changes in forearm vascular conductance (FVC; Doppler ultrasound, brachial intra-arterial pressure via catheter) to local intra-arterial infusion of phenylephrine (PE; α 1 -adrenoceptor agonist) were calculated during (1) infusion of the endothelium-dependent vasodilators acetylcholine (ACh) and adenosine triphosphate (ATP), the endothelium-independent vasodilator (sodium nitroprusside, SNP), or potassium chloride (KCl) at rest; (2) mild or moderate intensity handgrip exercise; and (3) combined mild exercise + ACh, ATP, SNP, or KCl infusions in healthy adults. Robust vasoconstriction to PE was observed during vasodilator infusion alone and mild exercise, and this was blunted during moderate intensity exercise (ΔFVC: -34 ± 4 and -34 ± 3 vs. -13 ± 2%, respectively, P < 0.05). Infusion of ACh or ATP during mild exercise significantly attenuated PE vasoconstriction similar to levels observed during moderate exercise (ACh: -3 ± 4; ATP: -18 ± 4%). In contrast, infusion of SNP or KCl during mild exercise did not attenuate PE-mediated vasoconstriction (-32 ± 5 and -46 ± 3%). To further study the role of endothelium-dependent hyperpolarization (EDH), ACh trials were repeated with combined nitric oxide synthase and cyclooxygenase inhibition. Here, PE-mediated vasoconstriction was blunted at rest (blockade: -20 ± 5 vs. -31 ± 3% vs.; P < 0.05) and remained blunted during exercise (blockade: -15 ± 5 vs. -14 ± 5%). We conclude that stimulation of EDH-like vasodilatation can blunt α 1 -adrenergic vasoconstriction in contracting skeletal muscle of humans. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Improved brachial artery shear patterns and increased flow-mediated dilation after low-volume high-intensity interval training in type 2 diabetes.

PubMed

Ghardashi Afousi, Alireza; Izadi, Mohammad Reza; Rakhshan, Kamran; Mafi, Farnoosh; Biglari, Soheil; Gandomkar Bagheri, Habibalah

2018-06-22

What is the central question of this study? Endothelial function is impaired because of increased oscillatory and retrograde shear in patients with type 2 diabetes. It is unclear whether low-volume high-intensity interval training and continuous moderate intensity exercise can modulate oscillatory and retrograde shear, blood flow and flow-mediated arterial dilation in these patients. What is the main finding and its importance? We found that low-volume high-intensity interval training, by increasing anterograde shear and decreasing retrograde shear and oscillatory index, can increase nitric oxide production and consequently result in increased flow-mediated dilation and outward arterial remodelling in patients with type 2 diabetes. Atherosclerosis in patients with type 2 diabetes is characterized by endothelial dysfunction associated with impaired flow-mediated dilation (FMD) and increases retrograde and oscillatory shear. The present study investigated endothelium-dependent vasodilation and shear rate in patients with type 2 diabetes at baseline and follow-up after 12 weeks of low-volume high-intensity interval training (LV-HIIT) or continuous moderate intensity training (CMIT). Seventy five sedentary patients with type 2 diabetes and untreated pre- or stage I hypertension were randomly divided into LV-HIIT, CMIT and control groups. The LV-HIIT group intervention was 12 intervals of 1.5 min at 85%-90% HR max and 2 min at 55%-60% HR max . The CMIT group intervention was 42 min of exercise at 70% HR max for 3 sessions per week during 12 weeks. High-resolution Doppler ultrasound was used to measure FMD, arterial diameter, anterograde and retrograde blood flow and shear rate patterns. Brachial artery FMD increased significantly in the LV-HIIT group (3.83 ± 1.13 baseline, 7.39 ± 3.6% follow-up), whereas there were no significant increase in the CMIT group (3.45 ± 0.97 baseline, 4.81 ± 2.36% follow-up) compared to the control group (3.16 ± 0.78 baseline, 4.04 ± 1.28% follow-up) (P < 0.05). Retrograde shear in the LV-HIIT group decreased significantly (P < 0.05), and no significant decrease in retrograde shear was seen in the CMIT group. Anterograde shear after LV-HIIT increased significantly (P < 0.05) but was unchanged in the CMIT group. However, oscillatory shear index in both exercise groups decreased significantly (P = 0.029). Nitrite/nitrate (NOx) level increased in both exercise groups, but the increase was greater in the LV-HIIT group (P < 0.001). Our results indicate that by increasing NOx, HIIT decreases the oscillatory shear-induced improvement in FMD and outward artery remodelling in patients with T2D. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Numerical analysis of wall shear stress in ascending aorta before tearing in type A aortic dissection.

PubMed

Chi, Qingzhuo; He, Ying; Luan, Yong; Qin, Kairong; Mu, Lizhong

2017-10-01

Although the incidence of many cardiovascular diseases has declined as medical treatments have improved, the prevalence of aortic dissection (AD) has increased. Compared to type B dissections, type A dissections are more severe, and most patients with type A dissections require surgical treatment. The objective of this study was to investigate the relationships between the wall shear stress (WSS) on the aortic endothelium and the frequent tearing positions using computational fluid dynamics. Five type A dissection cases and two normal aortas were included in the study. First, the structures of the aortas before the type A dissection were reconstructed on the basis of the original imaging data. Analyses of flow in the reconstructed premorbid structures reveals that the rupture positions in three of the five cases corresponded to the area of maximum elevated WSS. Moreover, the WSS at the junction of the aortic arch and descending aorta was found to be elevated, which is considered to be related to the locally disturbed helical flow. Meanwhile, the highest WSS in the patients with premorbid AD was found to be almost double that of the control group. Due to the noticeable morphological differences between the AD cases and the control group, the WSSs in the premorbid structures without vasodilation in the ascending part were estimated. The computational results revealed that the WSS was lower in the aorta without vasodilation, but the pressure drop in this situation was higher than that with vasodilation in the ascending aorta. Significant differences were seen between the AD cases and the control group in the angles of the side branches of the aortic arch and its bending degree. Dilation of the ascending aorta and alterations in the branching angles may be the key determinants of a high WSS that leads to type A dissection. Greater tortuosity of the aortic arch leads to stronger helical flow through the distal aortic arch, which may be related to tears in this region. Copyright © 2017 Elsevier Ltd. All rights reserved.

Enzyme Prodrug Therapy Achieves Site-Specific, Personalized Physiological Responses to the Locally Produced Nitric Oxide

PubMed Central

2018-01-01

Nitric oxide (NO) is a highly potent but short-lived endogenous radical with a wide spectrum of physiological activities. In this work, we developed an enzymatic approach to the site-specific synthesis of NO mediated by biocatalytic surface coatings. Multilayered polyelectrolyte films were optimized as host compartments for the immobilized β-galactosidase (β-Gal) enzyme through a screen of eight polycations and eight polyanions. The lead composition was used to achieve localized production of NO through the addition of β-Gal–NONOate, a prodrug that releases NO following enzymatic bioconversion. The resulting coatings afforded physiologically relevant flux of NO matching that of the healthy human endothelium. The antiproliferative effect due to the synthesized NO in cell culture was site-specific: within a multiwell dish with freely shared media and nutrients, a 10-fold inhibition of cell growth was achieved on top of the biocatalytic coatings compared to the immediately adjacent enzyme-free microwells. The physiological effect of NO produced via the enzyme prodrug therapy was validated ex vivo in isolated arteries through the measurement of vasodilation. Biocatalytic coatings were deposited on wires produced using alloys used in clinical practice and successfully mediated a NONOate concentration-dependent vasodilation in the small arteries of rats. The results of this study present an exciting opportunity to manufacture implantable biomaterials with physiological responses controlled to the desired level for personalized treatment. PMID:29570264

Cyclooxygenase inhibition improves endothelial vasomotor dysfunction of visceral adipose arterioles in human obesity

PubMed Central

Farb, Melissa G.; Tiwari, Stephanie; Karki, Shakun; Ngo, Doan TM; Carmine, Brian; Hess, Donald T.; Zuriaga, Maria A.; Walsh, Kenneth; Fetterman, Jessica L.; Hamburg, Naomi M.; Vita, Joseph A.; Apovian, Caroline M.; Gokce, Noyan

2013-01-01

Objective The purpose of this study was to determine whether cyclooxygenase inhibition improves vascular dysfunction of adipose microvessels from obese humans. Design and Methods In 20 obese subjects (age 37±12 yrs, BMI 47±8 kg/m2) we collected subcutaneous and visceral fat during bariatric surgery and characterized adipose depot-specific gene expression, endothelial cell phenotype, and microvascular function. Vasomotor function was assessed in response to endothelium-dependent agonists using videomicroscopy of small arterioles from fat. Results Arterioles from visceral fat exhibited impaired endothelium-dependent, acetylcholine-mediated vasodilation, compared to the subcutaneous depot (p<0.001). Expression of mRNA transcripts relevant to the cyclooxygenase pathway were upregulated in visceral compared to subcutaneous fat. Pharmacological inhibition of cyclooxygenase with indomethacin improved endothelium-dependent vasodilator function of arterioles from visceral fat by 2-fold (p=0.01), whereas indomethacin had no effect in the subcutaneous depot. Indomethacin increased activation via serine-1177 phosphorylation of endothelial nitric oxide synthase in response to acetylcholine in endothelial cells from visceral fat. Inhibition of endothelial nitric oxide synthase with Nω-nitro-L-arginine methyl ester abrogated the effects of cyclooxygenase-inhibition suggesting that vascular actions of indomethacin were related to increased nitric oxide bioavailability. Conclusions Our findings suggest that cyclooxygenase-mediated vasoconstrictor prostanoids partly contribute to endothelial dysfunction of visceral adipose arterioles in human obesity. PMID:23640904

Dynamic Inositol Trisphosphate-mediated Calcium Signals within Astrocytic Endfeet Underlie Vasodilation of Cerebral Arterioles

PubMed Central

Straub, Stephen V.; Bonev, Adrian D.; Wilkerson, M. Keith; Nelson, Mark T.

2006-01-01

Active neurons communicate to intracerebral arterioles in part through an elevation of cytosolic Ca2+ concentration ([Ca2+]i) in astrocytes, leading to the generation of vasoactive signals involved in neurovascular coupling. In particular, [Ca2+]i increases in astrocytic processes (“endfeet”), which encase cerebral arterioles, have been shown to result in vasodilation of arterioles in vivo. However, the spatial and temporal properties of endfoot [Ca2+]i signals have not been characterized, and information regarding the mechanism by which these signals arise is lacking. [Ca2+]i signaling in astrocytic endfeet was measured with high spatiotemporal resolution in cortical brain slices, using a fluorescent Ca2+ indicator and confocal microscopy. Increases in endfoot [Ca2+]i preceded vasodilation of arterioles within cortical slices, as detected by simultaneous measurement of endfoot [Ca2+]i and vascular diameter. Neuronal activity–evoked elevation of endfoot [Ca2+]i was reduced by inhibition of inositol 1,4,5-trisphosphate (InsP3) receptor Ca2+ release channels and almost completely abolished by inhibition of endoplasmic reticulum Ca2+ uptake. To probe the Ca2+ release mechanisms present within endfeet, spatially restricted flash photolysis of caged InsP3 was utilized to liberate InsP3 directly within endfeet. This maneuver generated large amplitude [Ca2+]i increases within endfeet that were spatially restricted to this region of the astrocyte. These InsP3-induced [Ca2+]i increases were sensitive to depletion of the intracellular Ca2+ store, but not to ryanodine, suggesting that Ca2+-induced Ca2+ release from ryanodine receptors does not contribute to the generation of endfoot [Ca2+]i signals. Neuronally evoked increases in astrocytic [Ca2+]i propagated through perivascular astrocytic processes and endfeet as multiple, distinct [Ca2+]i waves and exhibited a high degree of spatial heterogeneity. Regenerative Ca2+ release processes within the endfeet were evident, as were localized regions of Ca2+ release, and treatment of slices with the vasoactive neuropeptides somatostatin and vasoactive intestinal peptide was capable of inducing endfoot [Ca2+]i increases, suggesting the potential for signaling between local interneurons and astrocytic endfeet in the cortex. Furthermore, photorelease of InsP3 within individual endfeet resulted in a local vasodilation of adjacent arterioles, supporting the concept that astrocytic endfeet function as local “vasoregulatory units” by translating information from active neurons into complex InsP3-mediated Ca2+ release signals that modulate arteriolar diameter. PMID:17130519

Potentiation of the vascular response to kinins by inhibition of myocardial kininases.

PubMed

Dendorfer, A; Wolfrum, S; Schäfer, U; Stewart, J M; Inamura, N; Dominiak, P

2000-01-01

Inhibitors of angiotensin I-converting enzyme (ACE) are very efficacious in the potentiation of the actions of bradykinin (BK) and are able to provoke a B(2) receptor-mediated vasodilation even after desensitization of this receptor. Because this activity cannot be easily explained only by an inhibition of kinin degradation, direct interactions of ACE inhibitors with the B(2) receptor or its signal transduction have been hypothesized. To clarify the significance of degradation-independent potentiation, we studied the vasodilatory effects of BK and 2 degradation-resistant B(2) receptor agonists in the isolated rat heart, a model in which ACE and aminopeptidase P (APP) contribute equally to the degradation of BK. Coronary vasodilation to BK and to a peptidic (B6014) and a nonpeptidic (FR190997) degradation-resistant B(2) agonist was assessed in the presence or absence of the ACE inhibitor ramiprilat, the APP inhibitor mercaptoethanol, or both. Ramiprilat or mercaptoethanol induced leftward shifts in the BK dose-response curve (EC(50)=3.4 nmol/L) by a factor of 4.6 or 4.9, respectively. Combined inhibition of ACE and APP reduced the EC(50) of BK to 0.18 nmol/L (ie, by a factor of 19) but potentiated the activity of B6014 (EC(50)=1.9 nmol/L) only weakly without altering that of FR190997 (EC(50)=0.34 nmol/L). Desensitization of B(2) receptors was induced by the administration of BK (0.2 micromol/L) or FR190997 (0.1 micromol/L) for 30 minutes; the vascular reactivity to ramiprilat or increasing doses of BK was tested thereafter. After desensitization with BK, but not FR190997, an additional application of ramiprilat provoked a B(2) receptor-mediated vasodilation. High BK concentrations were still effective at the desensitized receptor. The process of desensitization was not altered by ramiprilat. These results show that in this model, all potentiating actions of ACE inhibitors on kinin-induced vasodilation are exclusively related to the reduction in BK breakdown and are equivalently provoked by APP inhibition. The desensitization of B(2) receptors is overcome by increasing BK concentrations, either directly or through the inhibition of ACE. These observations do not suggest any direct interactions of ACE inhibitors with the B(2) receptor or its signal transduction but point to a very high activity of BK degradation in the vicinity of the B(2) receptor in combination with a stimulation-dependent reduction in receptor affinity.

Flow dependence of forearm noradrenaline overflow, as assessed during mental stress and sodium nitroprusside infusion.

PubMed

Lindqvist, M; Melcher, A; Hjemdahl, P

1999-01-01

To evaluate the influence of blood flow on measurements of regional sympathetic nerve activity by radiotracer methodology ([3H]noradrenaline). Ten healthy men were studied under two conditions of elevated forearm blood flow: mental stress (Stroop colour word conflict test) and an intra-arterial infusion of sodium nitroprusside. Arterial blood pressure was measured invasively and forearm blood flow with strain-gauge plethysmography. Arterial and venous plasma adrenaline and noradrenaline were measured with high-performance liquid chromatography, and regional and total noradrenaline spillover were calculated. During mental stress, mean arterial pressure increased by 17%, heart rate by 16 beats/min, forearm blood flow by 117%, while forearm vascular resistance decreased by 44% (P < 0.001 for all). Sodium nitroprusside increased forearm blood flow dose-dependently, but elicited only minor effects on systemic haemodynamics. Mental stress increased arterial plasma noradrenaline by 52% (P < 0.001), and total body noradrenaline spillover by 75% (P < 0.001). During sodium nitroprusside infusion, arterial plasma noradrenaline increased only slightly and total body noradrenaline spillover was unaffected Forearm noradrenaline overflow increased from 5.4 +/- 0.9 to 16.9 +/- 2.6 pmol/min per I (P < 0.001) during mental stress and from 6.6 +/- 0.8 to 16.9 +/- 3.7 pmol/min per I (P < 0.001) during the second dose-step of sodium nitroprusside infusion. By intra-individual comparisons of forearm noradrenaline overflow increases during mental stress and during sodium nitroprusside infusion, with similar forearm blood flow increases, the flow dependence of forearm noradrenaline overflow was estimated. During mental stress, about 60% (median value, range 29-112%) of the increase in forearm noradrenaline overflow was attributed to the increase in forearm blood flow, whereas 40% was considered to reflect increased sympathetic nerve activity. There seems to be a considerable flow dependence of the regional overflow of noradrenaline, that is, a component of simple wash-out of noradrenaline from the forearm tissues during vasodilation. However, the present results still indicate that sympathetic nerve activity in the forearm is increased during mental stress, justifying the radiotracer technique for semiquantitative measurements, also during vasodilation.

Pathophysiology, diagnosis and treatment of intermittent claudication in patients with lumbar canal stenosis.

PubMed

Kobayashi, Shigeru

2014-04-18

Spinal nerve roots have a peculiar structure, different from the arrangements in the peripheral nerve. The nerve roots are devoid of lymphatic vessels but are immersed in the cerebrospinal fluid (CSF) within the subarachnoid space. The blood supply of nerve roots depends on the blood flow from both peripheral direction (ascending) and the spinal cord direction (descending). There is no hypovascular region in the nerve root, although there exists a so-called water-shed of the bloodstream in the radicular artery itself. Increased mechanical compression promotes the disturbance of CSF flow, circulatory disturbance starting from the venous congestion and intraradicular edema formation resulting from the breakdown of the blood-nerve barrier. Although this edema may diffuse into CSF when the subarachnoid space is preserved, the endoneurial fluid pressure may increase when the area is closed by increased compression. On the other hand, the nerve root tissue has already degenerated under the compression and the numerous macrophages releasing various chemical mediators, aggravating radicular symptoms that appear in the area of Wallerian degeneration. Prostaglandin E1 (PGE1) is a potent vasodilator as well as an inhibitor of platelet aggregation and has therefore attracted interest as a therapeutic drug for lumbar canal stenosis. However, investigations in the clinical setting have shown that PGE1 is effective in some patients but not in others, although the reason for this is unclear.

Pathophysiology, diagnosis and treatment of intermittent claudication in patients with lumbar canal stenosis

PubMed Central

Kobayashi, Shigeru

2014-01-01

Spinal nerve roots have a peculiar structure, different from the arrangements in the peripheral nerve. The nerve roots are devoid of lymphatic vessels but are immersed in the cerebrospinal fluid (CSF) within the subarachnoid space. The blood supply of nerve roots depends on the blood flow from both peripheral direction (ascending) and the spinal cord direction (descending). There is no hypovascular region in the nerve root, although there exists a so-called water-shed of the bloodstream in the radicular artery itself. Increased mechanical compression promotes the disturbance of CSF flow, circulatory disturbance starting from the venous congestion and intraradicular edema formation resulting from the breakdown of the blood-nerve barrier. Although this edema may diffuse into CSF when the subarachnoid space is preserved, the endoneurial fluid pressure may increase when the area is closed by increased compression. On the other hand, the nerve root tissue has already degenerated under the compression and the numerous macrophages releasing various chemical mediators, aggravating radicular symptoms that appear in the area of Wallerian degeneration. Prostaglandin E1 (PGE1) is a potent vasodilator as well as an inhibitor of platelet aggregation and has therefore attracted interest as a therapeutic drug for lumbar canal stenosis. However, investigations in the clinical setting have shown that PGE1 is effective in some patients but not in others, although the reason for this is unclear. PMID:24829876

Contribution of kv7.4/kv7.5 heteromers to intrinsic and calcitonin gene-related peptide-induced cerebral reactivity.

PubMed

Chadha, Preet S; Jepps, Thomas A; Carr, Georgina; Stott, Jennifer B; Zhu, Hei-Lei; Cole, William C; Greenwood, Iain A

2014-04-01

Middle cerebral artery (MCA) diameter is regulated by inherent myogenic activity and the effect of potent vasodilators such as calcitonin gene-related peptide (CGRP). Previous studies showed that MCAs express KCNQ1, 4, and 5 potassium channel genes, and the expression products (Kv7 channels) participate in the myogenic control of MCA diameter. The present study investigated the contribution of Kv7.4 and Kv7.5 isoforms to myogenic and CGRP regulation of MCA diameter and determined whether they were affected in hypertensive animals. Isometric tension recordings performed on MCA from normotensive rats produced CGRP vasodilations that were inhibited by the pan-Kv7 channel blocker linopirdine (P<0.01) and after transfection of arteries with siRNA against KCNQ4 (P<0.01) but not KCNQ5. However, isobaric myography revealed that myogenic constriction in response to increases in intravascular pressure (20-80 mm Hg) was affected by both KCNQ4 and KCNQ5 siRNA. Proximity ligation assay signals were equally abundant for Kv7.4/Kv7.4 or Kv7.4/Kv7.5 antibody combinations but minimal for Kv7.5/Kv7.5 antibodies or Kv7.4/7.1 combinations. In contrast to systemic arteries, Kv7 function and Kv7.4 abundance in MCA were not altered in hypertensive rats. This study reveals, for the first time to our knowledge, that in cerebral arteries, Kv7.4 and Kv7.5 proteins exist predominantly as a functional heterotetramer, which regulates intrinsic myogenicity and vasodilation attributed to CGRP. Surprisingly, unlike systemic arteries, Kv7 activity in MCAs is not affected by the development of hypertension, and CGRP-mediated vasodilation is well maintained. As such, cerebrovascular Kv7 channels could be amenable for therapeutic targeting in conditions such as cerebral vasospasm.

The effects of exercise on blood flow with reference to the human cardiovascular system: a finite element study

NASA Technical Reports Server (NTRS)

Sud, V. K.; Srinivasan, R. S.; Charles, J. B.; Bungo, M. W.

1992-01-01

This paper reports on a theoretical investigation into the effects of vasomotion on blood through the human cardiovascular system. The finite element method has been used to analyse the model. Vasoconstriction and vasodilation may be effected either through the action of the central nervous system or autoregulation. One of the conditions responsible for vasomotion is exercise. The proposed model has been solved and quantitative results of flows and pressures due to changing the conductances of specific networks of arterioles, capillaries and venules comprising the arms, legs, stomach and their combinations have been obtained.

Inhibition of soluble epoxide hydrolase limits niacin-induced vasodilation in mice

PubMed Central

Inceoglu, A. B.; Clifton, H.L.; Yang, J.; Hegedus, C.; Hammock, B. D.; Schaefer, S.

2012-01-01

Background The use of niacin in the treatment of dyslipidemias is limited by the common side effect of cutaneous vasodilation, commonly termed flushing. Flushing is thought to be due to release of the vasodilatory prostanoids PGD2 and PGE2 from arachidonic acid metabolism through the cyclooxygenase (COX) pathway. Arachidonic acid is also metabolized by the cytochrome P450 system which is regulated, in part, by the enzyme soluble epoxide hydrolase (sEH). Methods: These experiments used an established murine model in which ear tissue perfusion was measured by laser Doppler to test the hypothesis that inhibition of sEH would limit niacin-induced flushing. Results: Niacin-induced flushing was reduced from 506 ± 126 to 213 ± 39 % in sEH knockout animals. Pharmacologic treatment with 3 structurally distinct sEH inhibitors similarly reduced flushing in a dose dependent manner, with maximal reduction to 143±15% of baseline flow using a concentration of 1 mg/kg TPAU (1-trifluoromethoxyphenyl-3-(1-acetylpiperidin-4-yl) urea). Systemically administered PGD2 caused ear vasodilation which was not changed by either pharmacologic sEH inhibition or by sEH gene deletion. Conclusions: Inhibition of sEH markedly reduces niacin-induced flushing in this model without an apparent effect on the response to PGD2. sEH inhibition may be a new therapeutic approach to limit flushing in humans. PMID:22526297

Contribution of intravascular versus interstitial purines and nitric oxide in the regulation of exercise hyperaemia in humans

PubMed Central

Hellsten, Y; Nyberg, M; Mortensen, S P

2012-01-01

The regulation of blood flow to skeletal muscle involves a complex interaction between several locally formed vasodilators that are produced both in the skeletal muscle interstitium and intravascularly. The gas nitric oxide (NO) and the purines ATP and adenosine, are potent vasodilators that are formed by multiple cell types and released into the skeletal muscle interstitium and in plasma in response to muscle contraction. Cellular sources of ATP and NO in plasma are erythrocytes and endothelial cells, whereas interstitial sources are skeletal muscle cells and endothelial cells. Adenosine originates primarily from extracellular degradation of ATP. During exercise the concentrations of ATP and adenosine increase markedly in the interstitium with smaller increases occurring in plasma, and thus the interstitial concentration during exercise is severalfold higher than in plasma. The concentration of NO metabolites (NOx) in interstitium and plasma does not change during exercise and is similar in the two compartments. Adenosine and NO have been shown to contribute to exercise hyperaemia whereas the role of ATP remains unclear due to lack of specific purinergic receptor blockers. The relative role of intravascular versus interstitial vasodilators is not known but evidence suggests that both compartments are important. In cardiovascular disease, a reduced capacity to form adenosine in the muscle interstitium may be a contributing factor in increased peripheral vascular resistance. PMID:22733661

Reduction of renal mass is lethal in mice lacking vimentin. Role of endothelin-nitric oxide imbalance.

PubMed Central

Terzi, F; Henrion, D; Colucci-Guyon, E; Federici, P; Babinet, C; Levy, B I; Briand, P; Friedlander, G

1997-01-01

Modulation of vascular tone by chemical and mechanical stimuli is a crucial adaptive phenomenon which involves cytoskeleton elements. Disruption, by homologous recombination, of the gene encoding vimentin, a class III intermediate filament protein mainly expressed in vascular cells, was reported to result in apparently normal phenotype under physiological conditions. In this study, we evaluated whether the lack of vimentin affects vascular adaptation to pathological situations, such as reduction of renal mass, a pathological condition which usually results in immediate and sustained vasodilation of the renal vascular bed. Ablation of 3/4 of renal mass was constantly lethal within 72 h in mice lacking vimentin (Vim-/-), whereas no lethality was observed in wild-type littermates. Death in Vim-/- mice resulted from end-stage renal failure. Kidneys from Vim-/- mice synthesized more endothelin, but less nitric oxide (NO), than kidneys from normal animals. In vitro, renal resistance arteries from Vim-/- mice were selectively more sensitive to endothelin, less responsive to NO-dependent vasodilators, and exhibited an impaired flow (shear stress)- induced vasodilation, which is NO dependent, as compared with those from normal littermates. Finally, in vivo administration of bosentan, an endothelin receptor antagonist, totally prevented lethality in Vim-/- mice. These results suggest that vimentin plays a key role in the modulation of vascular tone, possibly via the tuning of endothelin-nitric oxide balance. PMID:9294120

Impaired cerebral microcirculation induced by ammonium chloride in rats is due to cortical adenosine release.

PubMed

Bjerring, Peter Nissen; Bjerrum, Esben Jannik; Larsen, Fin Stolze

2018-06-01

Liver failure results in hyperammonaemia, impaired regulation of cerebral microcirculation, encephalopathy, and death. However, the key mediator that alters cerebral microcirculation remains unidentified. In this study we show that topically applied ammonium significantly increases periarteriolar adenosine tone on the brain surface of healthy rats and is associated with a disturbed microcirculation. Cranial windows were prepared in anaesthetized Wistar rats. The flow velocities were measured by speckle contrast imaging and compared before and after 30 min of exposure to 10 mM ammonium chloride applied on the brain surface. These flow velocities were compared with those for control groups exposed to artificial cerebrospinal fluid or ammonium plus an adenosine receptor antagonist. A flow preservation curve was obtained by analysis of flow responses to a haemorrhagic hypotensive challenge and during stepwise exsanguination. The periarteriolar adenosine concentration was measured with enzymatic biosensors inserted in the cortex. After ammonium exposure the arteriolar flow velocity increased by a median (interquartile range) of 21.7% (23.4%) vs. 7.2% (10.2%) in controls (n = 10 and n = 6, respectively, p <0.05), and the arteriolar surface area increased. There was a profound rise in the periarteriolar adenosine concentration. During the hypotensive challenge the flow decreased by 27.8% (14.9%) vs. 9.2% (14.9%) in controls (p <0.05). The lower limit of flow preservation remained unaffected, 27.7 (3.9) mmHg vs. 27.6 (6.4) mmHg, whereas the autoregulatory index increased, 0.29 (0.33) flow units per millimetre of mercury vs. 0.03 (0.21) flow units per millimetre of mercury (p <0.05). When ammonium exposure was combined with topical application of an adenosine receptor antagonist, the autoregulatory index was normalized. Vasodilation of the cerebral microcirculation during exposure to ammonium chloride is associated with an increase in the adenosine tone. Application of a specific adenosine receptor antagonist restores the regulation of the microcirculation. This indicates that adenosine could be a key mediator of the brain dysfunction seen during hyperammonaemia and is a potential therapeutic target. In patients with liver failure, disturbances in brain function are caused in part by ammonium toxicity. In our project we studied how ammonia, through adenosine release, affects the blood flow in the brain of rats. In our experimental model we demonstrated that the detrimental effect of ammonia on blood flow regulation was counteracted by blocking the adenosine receptors in the brain. With this observation we identified a novel potential treatment target. If we can confirm our findings in a future clinical study, this might help patients with liver failure and the severe condition called hepatic encephalopathy. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Microvascular dysfunction following multi-walled carbon nanotube exposure is mediated by thrombospondin-1 receptor CD47.

PubMed

Mandler, W Kyle; Nurkiewicz, Timothy R; Porter, Dale W; Kelley, Eric E; Olfert, I Mark

2018-05-21

Pulmonary exposure to multi-walled carbon nanotubes (MWCNT) disrupts peripheral microvascular function. Thrombospondin-1 (TSP-1) is highly expressed during lung injury and has been shown to alter microvascular reactivity. It is unclear exactly how TSP-1 exerts effects on vascular function, but we hypothesized that the TSP-1 receptor CD47 may mediate changes in vasodilation.Wildtype (WT) or CD47 knockout (CD47 KO) C57B6/J-background animals were exposed to 50 µg of MWCNT or saline control via pharyngeal aspiration. Twenty-four hours post-exposure, intravital microscopy was performed to assess arteriolar dilation and venular leukocyte adhesion and rolling. To assess tissue redox status, electron paramagnetic resonance and NOx measurements were performed, while inflammatory biomarkers were measured via multiplex assay.Vasodilation was impaired in the WT+MWCNT group compared to control (57±9% vs 90±2% relaxation), while CD47 KO animals showed no impairment (108±8% relaxation). Venular leukocyte adhesion and rolling increased by > 2-fold, while the CD47 KO group showed no change. Application of the antioxidant apocynin rescued normal leukocyte activity in the WT+MWCNT group. Lung and plasma NOx were reduced in the WT+MWCNT group by 47% and 32%, respectively, while the CD47 KO groups were unchanged from control. Some inflammatory cytokines were increased in the CD47+MWCNT group only.In conclusion, TSP-1 is an important ligand mediating MWCNT-induced microvascular dysfunction, and CD47 is a component of this dysregulation. CD47 activation likely disrupts nitric oxide (•NO) signaling and promotes leukocyte-endothelial interactions. Impaired •NO production, signaling, and bioavailability is linked to a variety of cardiovascular diseases in which TSP-1/CD47 may play an important role.

Increased superoxide production and altered nitric oxide-mediated relaxation in the aorta of young but not old male relaxin-deficient mice.

PubMed

Ng, Hooi H; Jelinic, Maria; Parry, Laura J; Leo, Chen-Huei

2015-07-15

The vascular effects of exogenous relaxin (Rln) treatment are well established and include decreased myogenic reactivity and enhanced relaxation responses to vasodilators in small resistance arteries. These vascular responses are reduced in older animals, suggesting that Rln is less effective in mediating arterial function with aging. The present study investigated the role of endogenous Rln in the aorta and the possibility that vascular dysfunction occurs more rapidly with aging in Rln-deficient (Rln(-/-)) mice. We compared vascular function and underlying vasodilatory pathways in the aorta of male wild-type (Rln(+/+)) and Rln(-/-) mice at 4 and 16 mo of age using wire myography. Superoxide production, but not nitrotyrosine or NADPH oxidase expression, was significantly increased in the aorta of young Rln(-/-) mice, whereas endothelial nitric oxide (NO) synthase and basal NO availability were both significantly decreased compared with Rln(+/+) mice. In the presence of the cyclooxygenase inhibitor indomethacin, sensitivity to ACh was significantly decreased in young Rln(-/-) mice, demonstrating altered NO-mediated relaxation that was normalized in the presence of a membrane-permeable SOD or ROS scavenger. These vascular phenotypes were not exacerbated in old Rln(-/-) mice and, in most cases, did not differ significantly from old Rln(+/+) mice. Despite the vascular phenotypes in Rln(-/-) mice, endothelium-dependent and -independent vasodilation were not adversely affected. Our data show a role for endogenous Rln in reducing superoxide production and maintaining NO availability in the aorta but also demonstrate that Rln deficiency does not compromise vascular function in this artery or exacerbate endothelial dysfunction associated with aging. Copyright © 2015 the American Physiological Society.

Aging-associated sensory neuropathy alters pressure-induced vasodilation in humans.

PubMed

Fromy, Bérengère; Sigaudo-Roussel, Dominique; Gaubert-Dahan, Marie-Line; Rousseau, Pascal; Abraham, Pierre; Benzoni, Daniel; Berrut, Gilles; Saumet, Jean Louis

2010-03-01

Healthy skin is protected from pressure-induced ischemic damage because of the presence of pressure-induced vasodilation (PIV). PIV relies on small sensory nerve fibers and endothelial function. Since aging alters both nervous and vascular functions, we hypothesized that PIV is altered with aging. We compared PIV in non-neuropathic and neuropathic older subjects (60-75 years) with that of young subjects (20-35 years). Laser Doppler flowmetry was used to evaluate the cutaneous responses to local pressure application, acetylcholine, and local heating. Quantitative sensory tests were used to evaluate sensory-nerve-fiber function. The non-neuropathic older subjects had an impaired PIV (12+/-7% increase in blood flow with pressure) compared with young subjects (62+/-4%, P<0.001). In the presence of peripheral neuropathy, the older subjects were totally deprived of PIV, leading to early pressure-induced cutaneous ischemia (-31+/-10%, P<0.001). This inability of the skin to adapt to localized pressure in older subjects is related to the severity of the sensory-fiber dysfunction rather than to endothelial dysfunction, which was comparable between the non-neuropathic (141+/-19% increased blood flow with acetylcholine, P<0.05) and neuropathic older subjects (145+/-28% increase, P<0.05) compared with young subjects (234+/-25% increase).

Model of the transient neurovascular response based on prompt arterial dilation

PubMed Central

Kim, Jung Hwan; Khan, Reswanul; Thompson, Jeffrey K; Ress, David

2013-01-01

Brief neural stimulation results in a stereotypical pattern of vascular and metabolic response that is the basis for popular brain-imaging methods such as functional magnetic resonance imagine. However, the mechanisms of transient oxygen transport and its coupling to cerebral blood flow (CBF) and oxygen metabolism (CMRO2) are poorly understood. Recent experiments show that brief stimulation produces prompt arterial vasodilation rather than venous vasodilation. This work provides a neurovascular response model for brief stimulation based on transient arterial effects using one-dimensional convection–diffusion transport. Hemoglobin oxygen dissociation is included to enable predictions of absolute oxygen concentrations. Arterial CBF response is modeled using a lumped linear flow model, and CMRO2 response is modeled using a gamma function. Using six parameters, the model successfully fit 161/166 measured extravascular oxygen time courses obtained for brief visual stimulation in cat cerebral cortex. Results show how CBF and CMRO2 responses compete to produce the observed features of the hemodynamic response: initial dip, hyperoxic peak, undershoot, and ringing. Predicted CBF and CMRO2 response amplitudes are consistent with experimental measurements. This model provides a powerful framework to quantitatively interpret oxygen transport in the brain; in particular, its intravascular oxygen concentration predictions provide a new model for fMRI responses. PMID:23756690

Dynamic characteristics of laser Doppler flowmetry signals obtained in response to a local and progressive pressure applied on diabetic and healthy subjects

NASA Astrophysics Data System (ADS)

Humeau, Anne; Koitka, Audrey; Abraham, Pierre; Saumet, Jean-Louis; L'Huillier, Jean-Pierre

2004-09-01

In the biomedical field, the laser Doppler flowmetry (LDF) technique is a non-invasive method to monitor skin perfusion. On the skin of healthy humans, LDF signals present a significant transient increase in response to a local and progressive pressure application. This vasodilatory reflex response may have important implications for cutaneous pathologies involved in various neurological diseases and in the pathophysiology of decubitus ulcers. The present work analyses the dynamic characteristics of these signals on young type 1 diabetic patients, and on healthy age-matched subjects. To obtain accurate dynamic characteristic values, a de-noising wavelet-based algorithm is first applied to LDF signals. All the de-noised signals are then normalised to the same value. The blood flow peak and the time to reach this peak are then calculated on each computed signal. The results show that a large vasodilation is present on signals of healthy subjects. The mean peak occurs at a pressure of 3.2 kPa approximately. However, a vasodilation of limited amplitude appears on type 1 diabetic patients. The maximum value is visualised, on the average, when the pressure is 1.1 kPa. The inability for diabetic patients to increase largely their cutaneous blood flow may bring explanations to foot ulcers.

[Effect of caffeine on myocardial blood flow during pharmacological vasodilation].

PubMed

Wielepp, J P; Fricke, E; Horstkotte, D; Burchert, W

2005-02-01

Pharmacologic stress with adenosine is frequently used for noninvasive detection of coronary artery disease. Dietary intake of caffeinated food, beverages or medications might alter adenosine-induced hyperemic blood flow, thereby compromising the diagnostic sensitivity of adenosine stress testing. In this case we report on a male patient with CAD. Myocardial blood flow at rest and during adenosine-induced hyperemia 2 hours after consumption of decaffeinated coffee and again without caffeine intake were quantified by ammonia PET. After caffeine intake there was a clearly diminished increase of myocardial blood flow during adenosine. The average coronary flow reserve in the myocardium was 1.3 after caffeine. In the baseline study without caffeine the coronary flow reserve has been improved to 2.3. Caffeine intake alters the coronary vasodilatory capacity. These findings emphasize the importance of carefully screening patients for intake of caffeinated food prior to adenosine stress testing.

The effects of hypertension on the cerebral circulation

PubMed Central

Pires, Paulo W.; Dams Ramos, Carla M.; Matin, Nusrat

2013-01-01

Maintenance of brain function depends on a constant blood supply. Deficits in cerebral blood flow are linked to cognitive decline, and they have detrimental effects on the outcome of ischemia. Hypertension causes alterations in cerebral artery structure and function that can impair blood flow, particularly during an ischemic insult or during periods of low arterial pressure. This review will focus on the historical discoveries, novel developments, and knowledge gaps in 1) hypertensive cerebral artery remodeling, 2) vascular function with emphasis on myogenic reactivity and endothelium-dependent dilation, and 3) blood-brain barrier function. Hypertensive artery remodeling results in reduction in the lumen diameter and an increase in the wall-to-lumen ratio in most cerebral arteries; this is linked to reduced blood flow postischemia and increased ischemic damage. Many factors that are increased in hypertension stimulate remodeling; these include the renin-angiotensin-aldosterone system and reactive oxygen species levels. Endothelial function, vital for endothelium-mediated dilation and regulation of myogenic reactivity, is impaired in hypertension. This is a consequence of alterations in vasodilator mechanisms involving nitric oxide, epoxyeicosatrienoic acids, and ion channels, including calcium-activated potassium channels and transient receptor potential vanilloid channel 4. Hypertension causes blood-brain barrier breakdown by mechanisms involving inflammation, oxidative stress, and vasoactive circulating molecules. This exposes neurons to cytotoxic molecules, leading to neuronal loss, cognitive decline, and impaired recovery from ischemia. As the population ages and the incidence of hypertension, stroke, and dementia increases, it is imperative that we gain a better understanding of the control of cerebral artery function in health and disease. PMID:23585139

A comparison of dobutamine and levosimendan on hepatic blood flow in patients with a low cardiac output state after cardiac surgery: a randomised controlled study.

PubMed

Alvarez, J; Baluja, A; Selas, S; Otero, P; Rial, M; Veiras, S; Caruezo, V; Taboada, M; Rodriguez, I; Castroagudin, J; Tome, S; Rodriguez, A; Rodriguez, J

2013-11-01

Liver dysfunction due to a low cardiac output state after cardiac surgery is associated with a poor prognosis, but whether one inotrope is superior to another in improving hepatic perfusion remains uncertain. This study compared the systemic and hepatic haemodynamic effects of levosimendan to dobutamine in patients with a low cardiac output state (cardiac index < 2.2 l/min/m2) after on-pump cardiac surgery. A total of 25 patients were randomised to receive either an intravenous bolus of levosimendan (12 µg/kg) over 15 minutes, followed by an infusion of 0.2 µg/kg/min for 24 hours, or an infusion of dobutamine 7.5 µg/kg/min for 24 hours and completed the study. The systemic and hepatic haemodynamics at 24 and 48 hours were all better after levosimendan than dobutamine (dobutamine group: cardiac index (l/min/m2)=2.51 [standard deviation ±0.29], 2.40±0.23; portal vein flow (ml/min): 614.0±124.7, 585.9±144.8; pulsatility index: 2.02±0,28, 2.98±0.27 versus the levosimendan group: cardiac index: 3.02± 0.27, 2.98± 0.30; portal vein flow: 723.0± 143.5, 702.9±117.8; pulsatility index: 1.71±0.26, 1.73±0.27). The improvement in portal vein blood flow at 48 hours was significantly better after levosimendan than dobutamine (41% vs. 11% increment from baseline, P<0.05). In addition, there was a significant reduction in hepatic artery resistance after levosimendan but not dobutamine (resistance index reduction 6.5% vs. 0%, P<0.05). In summary, levosimendan can be considered as a selective liver vasodilator and can improve hepatic blood flow through both the hepatic artery and portal venous system, whereas dobutamine can only improve the portal venous blood flow without vasodilating the hepatic artery.

Mitochondrial redox plays a critical role in the paradoxical effects of NAPDH oxidase-derived ROS on coronary endothelium

PubMed Central

Shafique, Ehtesham; Torina, Anali; Reichert, Karla; Colantuono, Bonnie; Nur, Nasifa; Zeeshan, Khawaja; Ravichandran, Vani; Liu, Yuhong; Feng, Jun; Zeeshan, Khawaja; Benjamin, Laura E.; Irani, Kaikobad; Harrington, Elizabeth O.; Sellke, Frank W.; Abid, Md. Ruhul

2017-01-01

Aims There are conflicting reports on the role of reactive oxygen species (ROS) i.e. beneficial vs. harmful, in vascular endothelium. Here, we aim to examine whether duration of exposure to ROS and/or subcellular ROS levels are responsible for the apparently paradoxical effects of oxidants on endothelium. Methods and results We have recently generated binary (Tet-ON/OFF) conditional transgenic mice (Tet-Nox2:VE-Cad-tTA) that can induce 1.8 ± 0.42-fold increase in NADPH oxidase (NOX)-derived ROS specifically in vascular endothelium upon withdrawal of tetracycline from the drinking water. Animals were divided in two groups: one exposed to high endogenous ROS levels for 8 weeks (short-term) and the other for 20 weeks (long-term). Using endothelial cells (EC) isolated from mouse hearts (MHEC), we demonstrate that both short-term and long-term increase in NOX-ROS induced AMPK-mediated activation of eNOS. Interestingly, although endothelium-dependent nitric oxide (NO)-mediated coronary vasodilation was significantly increased after short-term increase in NOX-ROS, coronary vasodilation was drastically reduced after long-term increase in ROS. We also show that short-term ROS increase induced proliferation in EC and angiogenic sprouting in the aorta. In contrast, long-term increase in cytosolic ROS resulted in nitrotyrosine-mediated inactivation of mitochondrial (mito) antioxidant MnSOD, increase in mito-ROS, loss of mitochondrial membrane potential (Δψm), decreased EC proliferation and angiogenesis. Conclusion The findings suggest that NOX-derived ROS results in increased mito-ROS. Whereas short-term increase in mito-ROS was counteracted by MnSOD, long-term increase in ROS resulted in nitrotyrosine-mediated inactivation of MnSOD, leading to unchecked increase in mito-ROS and loss of Δψm followed by inhibition of endothelial function and proliferation. PMID:28088753

Bone Morphogenic Protein 4-Smad-Induced Upregulation of Platelet-Derived Growth Factor AA Impairs Endothelial Function.

PubMed

Hu, Weining; Zhang, Yang; Wang, Li; Lau, Chi Wai; Xu, Jian; Luo, Jiang-Yun; Gou, Lingshan; Yao, Xiaoqiang; Chen, Zhen-Yu; Ma, Ronald Ching Wan; Tian, Xiao Yu; Huang, Yu

2016-03-01

Bone morphogenic protein 4 (BMP4) is an important mediator of endothelial dysfunction in cardio-metabolic diseases, whereas platelet-derived growth factors (PDGFs) are major angiogenic and proinflammatory mediator, although the functional link between these 2 factors is unknown. The present study investigated whether PDGF mediates BMP4-induced endothelial dysfunction in diabetes mellitus. We generated Ad-Bmp4 to overexpress Bmp4 and Ad-Pdgfa-shRNA to knockdown Pdgfa in mice through tail intravenous injection. SMAD4-shRNA lentivirus, SMAD1-shRNA, and SMAD5 shRNA adenovirus were used for knockdown in human and mouse endothelial cells. We found that PDGF-AA impaired endothelium-dependent vasodilation in aortas and mesenteric resistance arteries. BMP4 upregulated PDGF-AA in human and mouse endothelial cells, which was abolished by BMP4 antagonist noggin or knockdown of SMAD1/5 or SMAD4. BMP4-impared relaxation in mouse aorta was also ameliorated by PDGF-AA neutralizing antibody. Tail injection of Ad-Pdgfa-shRNA ameliorates endothelial dysfunction induced by Bmp4 overexpression (Ad-Bmp4) in vivo. Serum PDGF-AA was elevated in both diabetic patients and diabetic db/db mice compared with nondiabetic controls. Pdgfa-shRNA or Bmp4-shRNA adenovirus reduced serum PDGF-AA concentration in db/db mice. PDGF-AA neutralizing antibody or tail injection with Pdgfa-shRNA adenovirus improved endothelial function in aortas and mesenteric resistance arteries from db/db mice. The effect of PDGF-AA on endothelial function in mouse aorta was also inhibited by Ad-Pdgfra-shRNA to inhibit PDGFRα. The present study provides novel evidences to show that PDGF-AA impairs endothelium-dependent vasodilation and PDGF-AA mediates BMP4-induced adverse effect on endothelial cell function through SMAD1/5- and SMAD4-dependent mechanisms. Inhibition of PGDF-AA ameliorates vascular dysfunction in diabetic mice. © 2016 American Heart Association, Inc.

C-peptide has no effect on forearm blood flow during local hyperinsulinaemia in healthy humans

PubMed Central

Langenberger, Herbert; Schaller, Georg; Pleiner, Johannes; Mittermayer, Friedrich; Bayerle-Eder, Michaela; Wolzt, Michael

2003-01-01

Background C-peptide increases forearm blood flow (FBF) in patients with Type 1 diabetes, probably by interaction with insulin, but not in healthy subjects. It is unclear if the vasodilating effect is sealed at normal fasting insulin concentrations. Methods The effects of C-peptide alone and during local hyperinsulinaemia were studied in healthy young men. Subjects received intra-arterial insulin at 6 pmol min−1 (low dose) or placebo for 60 min with subsequent coinfusion of C-peptide at increasing doses of 2–60 pmol min−1 in a double-blind crossover study (n = 8). In control experiments insulin at 30 pmol min−1 (high dose) was coinfused with C-peptide (n = 3). FBF was measured by strain-gauge plethysmography. Results Placebo had no effect on FBF (mean percentage change from baseline at 50 min −3.1%, 95% confidence interval [CI]−14.9, + 8.7). Insulin infusion slightly enhanced FBF by + 10.2% (95% CI −6.8, + 27.2; low dose) and + 17.6% (95% CI −38.8, + 74.0; high dose), respectively. The mean individual difference of the change in FBF between low-dose insulin and placebo was + 13.3% (95% CI −6.0, + 32.7; P = NS). Infusion of C-peptide increased local C-peptide concentrations from 1.8 ± 0.1 ng ml−1 to 6.1 ± 2.8 ng ml−1, but had no effect on FBF during placebo or hyperinsulinaemia (mean difference vs low dose insulin −16.0%, 95% CI −38.9, + 6.9). Conclusion The vasodilating effect of C-peptide seen in Type 1 diabetes is not detectable during fasting or hyperinsulinaemia in the forearm vasculature of healthy subjects. This suggests saturation of its vasodilating potency at insulin concentrations within the normal or in the supraphysiological range. PMID:12814445

Thrombospondin-1 and Angiotensin II Inhibit Soluble Guanylyl Cyclase through an Increase in Intracellular Calcium Concentration

PubMed Central

Ramanathan, Saumya; Mazzalupo, Stacy; Boitano, Scott; Montfort, William R.

2011-01-01

Nitric Oxide (NO) regulates cardiovascular hemostasis by binding to soluble guanylyl cyclase (sGC), leading to cGMP production, reduced cytosolic calcium concentration ([Ca2+]i) and vasorelaxation. Thrombospondin-1 (TSP-1), a secreted matricellular protein, was recently discovered to inhibit NO signaling and sGC activity. Inhibition of sGC requires binding to cell-surface receptor CD47. Here, we show that a TSP-1 C-terminal fragment (E3CaG1) readily inhibits sGC in Jurkat T cells, and that inhibition requires an increase in [Ca2+]i. Using flow cytometry, we show that E3CaG1 binds directly to CD47 on the surface of Jurkat T cells. Using digital imaging microscopy on live cells, we further show that E3CaG1 binding results in a substantial increase in [Ca2+]i, up to 300 nM. Addition of angiotensin II, a potent vasoconstrictor known to increase [Ca2+]i, also strongly inhibits sGC activity. sGC isolated from calcium-treated cells or from cell-free lysates supplemented with Ca2+ remains inhibited, while addition of kinase inhibitor staurosporine prevents inhibition, indicating inhibition is likely due to phosphorylation. Inhibition is through an increase in Km for GTP, which rises to 834 µM for the NO-stimulated protein, a 13-fold increase over the uninhibited protein. Compounds YC-1 and BAY 41-2272, allosteric stimulators of sGC that are of interest for treating hypertension, overcome E3CaG1-mediated inhibition of NO-ligated sGC. Taken together, these data suggest that sGC not only lowers [Ca2+]i in response to NO, inducing vasodilation, but is also inhibited by high [Ca2+]i, providing a fine balance between signals for vasodilation and vasoconstriction. PMID:21823650

Endothelial dysfunction, abnormal vascular structure and lower urinary tract symptoms in men and women.

PubMed

Matsui, Shogo; Kajikawa, Masato; Maruhashi, Tatsuya; Iwamoto, Yumiko; Oda, Nozomu; Kishimoto, Shinji; Hashimoto, Haruki; Hidaka, Takayuki; Kihara, Yasuki; Chayama, Kazuaki; Hida, Eisuke; Goto, Chikara; Aibara, Yoshiki; Nakashima, Ayumu; Yusoff, Farina Mohamad; Noma, Kensuke; Kuwahara, Yoshitaka; Matsubara, Akio; Higashi, Yukihito

2018-06-15

Lower urinary tract symptoms (LUTS) is not only common symptoms in elderly men and women but also risk of future cardiovascular events. The purpose of this study was to evaluate the relationships of vascular function and structure with LUTS in men and women. We investigated flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) as vascular function, brachial-ankle pulse wave velocity (baPWV) as vascular structure, and LUTS assessed by International Prostate Symptom Score (IPSS) in 287 men and 147 women. IPSS was significantly correlated with traditional cardiovascular risk factors, Framingham risk score, FMD, NID and baPWV. Moderate to severe LUTS was associated with the prevalence of coronary heart disease in men but not in women. In men, FMD and NID were significantly lower in the moderate to severe LUTS group than in the none to mild LUTS group (2.1 ± 2.0% vs. 4.0 ± 3.0% and 9.3 ± 6.1% vs. 12.8 ± 6.6%, P < 0.001, respectively). baPWV was significantly higher in the moderate to severe LUTS group than in the none to mild LUTS group (1722 ± 386 cm/s vs. 1509 ± 309 cm/s, P < 0.001). In multivariate analysis, FMD was independently associated with a decrease in the odds ratio of moderate to severe LUTS in men (OR: 0.83, 95% CI, 0.72-0.95; P = 0.008) but not in women. NID and baPWV were not independently associated with moderate to severe LUTS either in men or women. These findings suggest that endothelial dysfunction is associated with LUTS in men. LUTS in men may be useful for a predictor of cardiovascular events. URL for Clinical Trial: http://UMIN; Registration Number for Clinical Trial: UMIN000003409. Copyright © 2018 Elsevier B.V. All rights reserved.

Dose-related effects of red wine and alcohol on hemodynamics, sympathetic nerve activity, and arterial diameter.

PubMed

Spaak, Jonas; Merlocco, Anthony C; Soleas, George J; Tomlinson, George; Morris, Beverley L; Picton, Peter; Notarius, Catherine F; Chan, Christopher T; Floras, John S

2008-02-01

The cardiovascular benefits of light to moderate red wine consumption often have been attributed to its polyphenol constituents. However, the acute dose-related hemodynamic, vasodilator, and sympathetic neural effects of ethanol and red wine have not been characterized and compared in the same individual. We sought to test the hypotheses that responses to one and two alcoholic drinks differ and that red wine with high polyphenol content elicits a greater effect than ethanol alone. Thirteen volunteers (24-47 yr; 7 men, 6 women) drank wine, ethanol, and water in a randomized, single-blind trial on three occasions 2 wk apart. One drink of wine and ethanol increased blood alcohol to 38 +/- 2 and 39 +/- 2 mg/dl, respectively, and two drinks to 72 +/- 4 and 83 +/- 3 mg/dl, respectively. Wine quadrupled plasma resveratrol (P < 0.001) and increased catechin (P < 0.03). No intervention affected blood pressure. One drink had no heart rate effect, but two drinks of wine increased heart rate by 5.7 +/- 1.6 beats/min; P < 0.001). Cardiac output fell 0.8 +/- 0.3 l/min after one drink of ethanol and wine (both P < 0.02) but increased after two drinks of ethanol (+0.8 +/- 0.3 l/min) and wine (+1.2 +/- 0.3 l/min) (P < 0.01). One alcoholic drink did not alter muscle sympathetic nerve activity (MSNA), while two drinks increased MSNA by 9-10 bursts/min (P < 0.001). Brachial artery diameter increased after both one and two alcoholic drinks (P < 0.001). No beverage augmented, and the second wine dose attenuated (P = 0.02), flow-mediated vasodilation. One drink of ethanol dilates the brachial artery without activating sympathetic outflow, whereas two drinks increase MSNA, heart rate, and cardiac output. These acute effects, which exhibit a narrow dose response, are not modified by red wine polyphenols.

Tea Consumption Enhances Endothelial-Dependent Vasodilation; a Meta-Analysis

PubMed Central

Ras, Rouyanne T.; Zock, Peter L.; Draijer, Richard

2011-01-01

Background Tea consumption is associated with a lower risk of cardiovascular disease including stroke. Direct effects of tea components on the vasculature, particularly the endothelium, may partly explain this association. Objective We performed a meta-analysis of controlled human intervention studies on the effect of tea on flow-mediated dilation (FMD) of the brachial artery, a measurement of endothelial function, which is suggested to be associated with cardiovascular risk. Methods Human intervention studies were identified by systematic search of the databases Medline, Embase, Chemical Abstracts and Biosis through March 2009 and by hand-searching related articles. Studies were selected based on predefined criteria: intervention with tea as the sole experimental variable, placebo-controlled design, and no missing data on FMD outcome or its variability. A random effects model was used to calculate the pooled overall effect on FMD due to the intake of tea. The impact of various subject and treatment characteristics was investigated in the presence of heterogeneity. Results In total, 9 studies from different research groups were included with 15 relevant study arms. The overall absolute increase in FMD of tea vs. placebo was 2.6% of the arterial diameter (95% CI: 1.8-3.3%; P-value <0.001) for a median daily dose of 500 mL of tea (2–3 cups). This is a relative increase of approximately 40% compared to the average FMD of 6.3% measured under placebo or baseline conditions. There was significant heterogeneity between studies (P-value <0.001) that might partly be explained by the cuff position either distal or proximal to the area of FMD measurement. No indication for publication bias was found. Conclusion Moderate consumption of tea substantially enhances endothelial-dependent vasodilation. This may provide a mechanistic explanation for the reduced risk of cardiovascular events and stroke observed among tea drinkers. PMID:21394199

Hemodynamic and neurohumoral effects of various grades of selective adenosine transport inhibition in humans. Implications for its future role in cardioprotection.

PubMed

Rongen, G A; Smits, P; Ver Donck, K; Willemsen, J J; De Abreu, R A; Van Belle, H; Thien, T

1995-02-01

In 12 healthy male volunteers (27-53 yr), a placebo-controlled randomized double blind cross-over trial was performed to study the effect of the intravenous injection of 0.25, 0.5, 1, 2, 4, and 6 mg draflazine (a selective nucleoside transport inhibitor) on hemodynamic and neurohumoral parameters and ex vivo nucleoside transport inhibition. We hypothesized that an intravenous draflazine dosage without effect on hemodynamic and neurohumoral parameters would still be able to augment the forearm vasodilator response to intraarterially infused adenosine. Heart rate (electrocardiography), systolic blood pressure (Dinamap 1846 SX; Critikon, Portanje Electronica BV, Utrecht, The Netherlands) plasma norepinephrine and epinephrine increased dose-dependently and could almost totally be abolished by caffeine pretreatment indicating the involvement of adenosine receptors. Draflazine did not affect forearm blood flow (venous occlusion plethysmography). Intravenous injection of 0.5 mg draflazine did not affect any of the measured hemodynamic parameters but still induced a significant ex vivo nucleoside-transport inhibition of 31.5 +/- 4.1% (P < 0.05 vs placebo). In a subgroup of 10 subjects the brachial artery was cannulated to infuse adenosine (0.15, 0.5, 1.5, 5, 15, and 50 micrograms/100 ml forearm per min) before and after intravenous injection of 0.5 mg draflazine. Forearm blood flow amounted 1.9 +/- 0.3 ml/100 ml forearm per min for placebo and 1.8 +/- 0.2, 2.0 +/- 0.3, 3.8 +/- 0.9, 6.3 +/- 1.2, 11.3 +/- 2.2, and 19.3 +/- 3.9 ml/100 ml forearm per min for the six incremental adenosine dosages, respectively. After the intravenous draflazine infusion, these values were 1.6 +/- 0.2 ml/100 ml forearm per min for placebo and 2.1 +/- 0.3, 3.3 +/- 0.6, 5.8 +/- 1.1, 6.9 +/- 1.4, 14.4 +/- 2.9, and 23.5 +/- 4.0 ml/100 ml forearm per min, respectively (Friedman ANOVA: P < 0.05 before vs after draflazine infusion). In conclusion, a 30-50% inhibition of adenosine transport significantly augments the forearm vasodilator response to adenosine without significant systemic effects. These results suggest that draflazine is a feasible tool to potentiate adenosine-mediated cardioprotection in man.

Mechanism of reduction of mitral regurgitation with vasodilator therapy.

PubMed

Yoran, C; Yellin, E L; Becker, R M; Gabbay, S; Frater, R W; Sonnenblick, E H

1979-04-01

Acute mitral regurgitation was produced in six open chest dogs by excising a portion of the anterior valve leaflet. Electromagnetic flow probes were placed in the left atrium around the mitral anulus and in the ascending aorta to determine phasic left ventricular filling volume, regurgitant volume and stroke volume. The systolic pressure gradient was calculated from simultaneously measured high fidelity left atrial and left ventricular pressures. The effective mitral regurgitant orifice area was calculated from Gorlin's hydraulic equation. Infusion of nitroprusside resulted in a significant reduction in mitral regurgitation. No significant change occurred in the systolic pressure gradient between the left ventricle and the left atrium because both peak left ventricular pressure and left atrial pressure were reduced. The reduction of mitral regurgitation was largely due to reduction in the size of the mitral regurgitant orifice. Reduction of ventricular volume rather than the traditional concept of reduction of impedance of left ventricular ejection may explain the effects of vasodilators in reducing mitral regurgitation.

Calcium antagonism: aldosterone and vascular responses to catecholamines and angiotensin II in man.

PubMed

Elliott, H L

1993-12-01

Effects of calcium antagonists on pressor mechanisms: A number of differences have been reported in the variable extent to which calcium antagonists interfere with various pressor mechanisms. In theory, high lipid solubility, membrane-binding characteristics and a prolonged duration of action appear to be requirements for a calcium antagonist to affect mechanisms such as vasodilation, endogenous vasoconstrictor responses, hormone release and natriuretic activity. Reduction in peripheral vascular resistance: A reduction in peripheral vascular resistance is fundamental to the antihypertensive effect not only of calcium antagonists but also of angiotensin converting enzyme inhibitors and alpha 1-adrenoceptor antagonists. However, only the calcium antagonists interfere directly with the pressor responses mediated by both the adrenergic nervous system and the renin-angiotensin system. Mechanism of lacidipine effects: Preliminary results with the new dihydropyridine calcium antagonist lacidipine indicate that it not only has vasodilator activity but that it also interferes with both adrenergic and non-adrenergic endogenous vasoconstrictor mechanisms. This may provide additional potentially beneficial cardiovascular effects, particularly in relation to left ventricular hypertrophy and dysfunction.

Inhaled Nitric Oxide in Acute Lung Disease.

DTIC Science & Technology

1995-01-01

play a pivotal and central cellular, NO. combines with the heme molecules role in many of the clinical manifestations of ARDS, it present in...blood flow to trate anion (NO3), and b) reaction with 02 to form poorly ventilated lung segments and further compro- nitrite anion (NO2) (23, 24). It...is the most consistent feature of creases in methemoglobin levels (Table 1). Plasma NO- therapy. Theoretically, inhaled NO. vasodilates nitrite levels

Vasodilator Stress Single-Photon Emission Computed Tomography or Contrast Stress Echocardiography Association with Hard Cardiac Events in Suspected Coronary Artery Disease.

PubMed

Gaibazzi, Nicola; Siniscalchi, Carmine; Porter, Thomas R; Crocamo, Antonio; Basaglia, Manuela; Boffetti, Francesca; Lorenzoni, Valentina

2018-06-01

We compared the long-term outcome of subjects without prior cardiac disease who underwent either vasodilator single-photon emission computed tomography (SPECT) or contrast stress-echocardiography (cSE) for suspected coronary artery disease (CAD). Subjects who underwent vasodilator SPECT or cSE between 2008 and 2012 for suspected CAD but no history of cardiac disease were included. We retrospectively compared the association of each method with combined all-cause death and nonfatal myocardial infarction and their positive predictive value (PPV) for angiographically obstructive CAD. A total of 1,387 subjects were selected: 497 who underwent SPECT and 890 who underwent cSE. During 4 years of mean follow-up there were 78 hard events in the cSE group and 51 in the SPECT group. Event-free survival in subjects testing positive for ischemia, either with SPECT or cSE, was significantly worse both in the overall population and after propensity matching patients. In multivariable analyses, vasodilator SPECT or cSE demonstrated significant stratification capability with an ischemic test doubling (SPECT) or more than doubling (cSE) the risk of future hard events independently from other variables. PPV of vasodilator SPECT for the diagnosis of obstructive CAD was inferior to vasodilator cSE (PPV = 63% vs 89%, respectively; P < .001). Our study suggests that the associations of vasodilator SPECT or cSE with outcome are comparable, with cSE demonstrating better diagnostic PPV for CAD. The absence of ionizing radiation and anticipated lower costs from higher PPV suggest that vasodilator cSE is a valid alternative to vasodilator SPECT as a gatekeeper in subjects without a prior history of CAD. Copyright © 2018 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

‘Fine-tuning’ blood flow to the exercising muscle with advancing age: an update

PubMed Central

Wray, D. Walter; Richardson, Russell S.

2016-01-01

During dynamic exercise, oxygen demand from the exercising muscle is dramatically elevated, requiring a marked increase in skeletal muscle blood flow that is accomplished through a combination of systemic sympathoexcitation and local metabolic vasodilatation. With advancing age, the balance between these factors appears to be disrupted in favour of vasoconstriction, leading to an impairment in exercising skeletal muscle blood flow in the elderly. This ‘hot topic’ review aims to provide an update to our current knowledge of age-related changes in the neural and local mechanisms that contribute to this ‘fine-tuning’ of blood flow during exercise. The focus is on results from recent human studies that have adopted a reductionist approach to explore how age-related changes in both vasodilators (nitric oxide) and vasoconstrictors (endothelin-1, α-adrenergic agonists and angiotensin II) interact and how these changes impact blood flow to the exercising skeletal muscle with advancing age. PMID:25858164

Effect of diabetes on the cutaneous microcirculation of the feet in patients with intermittent claudication.

PubMed

Klonizakis, M; Manning, G; Lingam, K; Donnelly, R; Yeung, J M C

2015-01-01

To evaluate endothelial-dependent and - independent cutaneous vasodilator responses in the feet of patients with peripheral arterial disease (PAD) with or without Type 2 diabetes. Cutaneous microvascular responses in the dorsum of both lower limbs were measured in the supine position using Laser Doppler Fluximetry combined with iontophoretic administration of endothelial-dependent (acetylcholine, Ach) and -independent (sodium nitroprusside, SNP) vasodilators in diabetic (n = 19) and non diabetic (n = 17) patients with PAD (presenting as unilateral calf intermittent claudication (IC). In patients with diabetes and IC, endothelial-dependent vasodilation was significantly impaired in the symptomatic limb [74 (57,105) vs 68 (24,81) PU, Z =-2.79, p = 0.005] compared to the asymptomatic limb. Patients without diabetes showed no impairment of vasodilation. Resting ankle-brachial pressure index did not identify the presence of abnormalities in microvascular function. The combination of diabetes and PAD is associated with a reduction in endothelial-dependent cutaneous vasodilation in the feet without an associated reduction in endothelial independent vasodilation.

Nitric oxide synthase inhibition attenuates cutaneous vasodilation during the post-menopausal hot flash

PubMed Central

Hubing, Kimberly A.; Wingo, Jonathan E.; Brothers, R. Matthew; Coso, Juan Del; Low, David A.; Crandall, Craig G.

2010-01-01

Objective The purpose of this study was to test the hypothesis that local inhibition of nitric oxide and prostaglandin synthesis attenuates cutaneous vasodilator responses during post-menopausal hot flashes. Methods Four microdialysis membranes were inserted into forearm skin (dorsal surface) of 8 post-menopausal women (mean ± SD, 51±7 y). Ringers solution (control), 10mM Ketorolac (Keto) to inhibit prostaglandin synthesis, 10mM NG-L-arginine methyl ester (L-NAME) to inhibit nitric oxide synthase, and a combination of 10mM Keto + 10mM L-NAME were each infused at the separate sites. Skin blood flow at each site was indexed using laser-Doppler flowmetry. Cutaneous vascular conductance (CVC) was calculated as laser-Doppler flux/mean arterial blood pressure and was expressed as a percentage of the maximal calculated CVC (CVCmax) obtained following infusion of 50mM sodium nitropruside at all sites at the end of the study. Data from 13 hot flashes were analyzed. Results At the control site, the mean ± SD peak increase in CVC was 15.5±6% CVCmax units. This value was not different relative to the peak increase in CVC at the Keto site (13.0±5 % CVCmax units, P = 0.09). However, the peak increase in CVC during the flash was attenuated at the L-NAME and L-NAME + Keto sites (7.4±4 % CVCmax units and 8.7±7 % CVCmax units, respectively) relative to both the control and the Keto sites (P<0.05 for both comparisons). There were no significant differences in the peak increases in sweat rate between any of the sites (P = 0.24). Conclusions These data demonstrate that cutaneous vasodilation during a hot flash has a nitric oxide component. Increases in CVC despite the inhibition of prostaglandin synthesis suggest prostaglandins do not contribute to cutaneous vasodilation during a hot flash. PMID:20505548

Effects of ionotropic glutamate receptor antagonists on rat dural artery diameter in an intravital microscopy model.

PubMed

Chan, K Y; Gupta, S; de Vries, R; Danser, A H J; Villalón, C M; Muñoz-Islas, E; Maassenvandenbrink, A

2010-07-01

During migraine, trigeminal nerves may release calcitonin gene-related peptide (CGRP), inducing cranial vasodilatation and central nociception; hence, trigeminal inhibition or blockade of craniovascular CGRP receptors may prevent this vasodilatation and abort migraine headache. Several preclinical studies have shown that glutamate receptor antagonists affect the pathophysiology of migraine. This study investigated whether antagonists of NMDA (ketamine and MK801), AMPA (GYKI52466) and kainate (LY466195) glutamate receptors affected dural vasodilatation induced by alpha-CGRP, capsaicin and periarterial electrical stimulation in rats, using intravital microscopy. Male Sprague-Dawley rats were anaesthetized and the overlying bone was thinned to visualize the dural artery. Then, vasodilator responses to exogenous (i.v. alpha-CGRP) and endogenous (released by i.v. capsaicin and periarterial electrical stimulation) CGRP were elicited in the absence or presence of the above antagonists. alpha-CGRP, capsaicin and periarterial electrical stimulation increased dural artery diameter. Ketamine and MK801 inhibited the vasodilator responses to capsaicin and electrical stimulation, while only ketamine attenuated those to alpha-CGRP. In contrast, GYKI52466 only attenuated the vasodilatation to exogenous alpha-CGRP, while LY466195 did not affect the vasodilator responses to endogenous or exogenous CGRP. Although GYKI52466 has not been tested clinically, our data suggest that it would not inhibit migraine via vascular mechanisms. Similarly, the antimigraine efficacy of LY466195 seems unrelated to vascular CGRP-mediated pathways and/or receptors. In contrast, the cranial vascular effects of ketamine and MK801 may represent a therapeutic mechanism, although the same mechanism might contribute, peripherally, to cardiovascular side effects.

Topical Vasodilators in Microsurgery: What Is the Evidence?

PubMed

Rinkinen, Jacob; Halvorson, Eric G

2017-01-01

Background  Topical vasodilators are frequently used during free tissue transfer to prevent and treat vasospasm and microvascular thrombosis. A variety of agents have been studied and are available, yet most microsurgeons select an agent based on anecdotal evidence or personal training. Our aim was to review the literature on topical vasodilators so microsurgeons can make more informed decisions about which agent to use. Methods  A systemic review of the literature was performed on PubMed, EMBASE, and Google Scholar using keywords "topical vasodilator," "antispasmodic," "vasospasm," "free flaps," and "microsurgery." Studies were included if they provided a comparative quantitative assessment of topical vasodilators and were written in English. In vitro, in vivo , and clinical studies were included. Results  A total of 15 studies were identified and included in our analysis. The three most common classes of topical vasodilator include local anesthetics, phosphodiesterase inhibitors, and calcium channel blockers (CCBs). Of the most commonly used topical vasodilators, CCBs (nifedipine and verapamil) were most effective followed by papaverine and lidocaine. Conclusion  The most effective topical vasodilators appear to be CCBs including nifedipine, nicardipine, and verapamil. Evidence suggests that these agents are more effective than papaverine and lidocaine solutions that are commonly used. Future research should directly compare individual CCBs to assess the most effective agent. Studies to date have focused on vessels other than those used by microsurgeons, and therefore further studies specific to these vessels are warranted. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Scaffold-free, Human Mesenchymal Stem Cell-Based Tissue Engineered Blood Vessels.

PubMed

Jung, Youngmee; Ji, HaYeun; Chen, Zaozao; Fai Chan, Hon; Atchison, Leigh; Klitzman, Bruce; Truskey, George; Leong, Kam W

2015-10-12

Tissue-engineered blood vessels (TEBV) can serve as vascular grafts and may also play an important role in the development of organs-on-a-chip. Most TEBV construction involves scaffolding with biomaterials such as collagen gel or electrospun fibrous mesh. Hypothesizing that a scaffold-free TEBV may be advantageous, we constructed a tubular structure (1 mm i.d.) from aligned human mesenchymal cell sheets (hMSC) as the wall and human endothelial progenitor cell (hEPC) coating as the lumen. The burst pressure of the scaffold-free TEBV was above 200 mmHg after three weeks of sequential culture in a rotating wall bioreactor and perfusion at 6.8 dynes/cm(2). The interwoven organization of the cell layers and extensive extracellular matrix (ECM) formation of the hMSC-based TEBV resembled that of native blood vessels. The TEBV exhibited flow-mediated vasodilation, vasoconstriction after exposure to 1 μM phenylephrine and released nitric oxide in a manner similar to that of porcine femoral vein. HL-60 cells attached to the TEBV lumen after TNF-α activation to suggest a functional endothelium. This study demonstrates the potential of a hEPC endothelialized hMSC-based TEBV for drug screening.

Ultrasound measurement of peripheral endothelial dysfunction in type 2 diabetic patients: correlation with risk factors

PubMed Central

Bosevski, Marijan; Georgievska-Ismail, Ljubica

2010-01-01

The purpose of the study was to assess the endothelial dysfunction (ED) in type 2 diabetic patients ultrasonographicaly and estimate the correlation of ED with glycemia and other cardio-metabolic risk factors. 171 patient (age 60,0 + 8,5 years) with diagnosed type 2 diabetes and coronary artery disease (CAD) were randomly included in a cross sectional study. B-mode ultrasound system with a linear transducer of 7.5 MHz was used for evaluation of flow-mediated vasodilation in brachial artery (FMV). FMV was presented as a change of brachial artery diameter at rest and after limb ischemia, previously provoked by cuff inflation. Peripheral ED was found in 77,2% (132 patients). Multivariate logistic regression model defined: age (OR 1,071, 95% CI 1,003 1,143) and plasma cholesterol (OR 4,083 95%CI 1,080 17,017) as determinants for ED. Linear multivariate analysis presented duration of diabetes (Beta 0,173, Sig 0,024), and glycemia (Beta 0,132, Sig 0,044) to be associated independently with FMV value. Estimated factors influencing FMV might be potential therapeutic targets for presented endothelial dysfunction in type 2 diabetic patients with coronary artery disease. PMID:20507285

Endothelial function in patients with migraine during the interictal period.

PubMed

Silva, Federico A; Rueda-Clausen, Christian F; Silva, Sandra Y; Zarruk, Juan G; Guzmán, Juan C; Morillo, Carlos A; Vesga, Boris; Pradilla, Gustavo; Flórez, Mildred; López-Jaramillo, Patricio

2007-01-01

The aim of this study is to evaluate endothelial function in migraineurs subjects during the asymptomatic period. Migraine has been proposed as a risk factor for cerebrovascular events. The underlying mechanisms that relate these 2 pathologies are unknown. Nitric oxide (NO) has been proposed as the final causative molecule of migraine. Increased NO metabolites concentrations have been reported in migraineurs subjects during acute migraine attacks, but there is no evidence indicating alterations in endothelial NO release during the symptom free period in theses subjects. Fifty migraineurs subjects and 25 healthy subjects matched by gender and age were included. Every subject underwent a complete examination that included medical history, physical examination, resting electrocardiogram, forearm flow-mediated vasodilation (FMD), blood determinations of fasting nitrates and nitrites (NO(2) (-)+ NO(3) (-)), glucose, lipid profile, creatinine, C-reactive protein, and blood cell count. No differences in FMD or NO(2) (-)+ NO(3) (-) were detected among groups. The only difference between migraineurs and control subjects was a higher mean blood pressure 92.1 (8.8) mmHg versus 86.7 (8.2) mmHg P= .01. The endothelial function is not altered during the interictal period in migraineurs subjects.

Placental oxidative stress and maternal endothelial function in pregnant women with normotensive fetal growth restriction.

PubMed

Yoshida, Atsumi; Watanabe, Kazushi; Iwasaki, Ai; Kimura, Chiharu; Matsushita, Hiroshi; Wakatsuki, Akihiko

2018-04-01

The purpose of this study was to investigate the relationship between placental oxidative stress and maternal endothelial function in pregnant women with normotensive fetal growth restriction (FGR). We examined serum concentrations of oxygen free radicals (d-ROMs), maternal angiogenic factor (PlGF), and sFlt-1, placental oxidative DNA damage, and maternal endothelial function in 17 women with early-onset preeclampsia (PE), 18 with late-onset PE, 14 with normotensive FGR, and 21 controls. Flow-mediated vasodilation (FMD) was assessed as a marker of maternal endothelial function. Immunohistochemical analysis was performed to measure the proportion of placental trophoblast cell nuclei staining positive for 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. Maternal serum d-ROM, sFlt-1 concentrations, and FMD did not significantly differ between the control and normotensive FGR groups. The proportion of nuclei staining positive for 8-OHdG was significantly higher in the normotensive FGR group relative to the control group. Our findings demonstrate that, despite the presence of placental oxidative DNA damage as observed in PE patients, pregnant women with normotensive FGR show no increase in the concentrations of sFlt-1 and d-ROMs, or a decrease in FMD.

The regular consumption of a polyphenol-rich apple does not influence endothelial function: a randomised double-blind trial in hypercholesterolemic adults.

PubMed

Auclair, S; Chironi, G; Milenkovic, D; Hollman, P C H; Renard, C M G C; Mégnien, J-L; Gariepy, J; Paul, J-L; Simon, A; Scalbert, A

2010-10-01

Epidemiological studies suggest that apple consumption is associated with a reduction in cardiovascular disease risk. Apple polyphenols may contribute to explain these effects. Endothelial dysfunction has been associated with early stage of atherosclerosis and polyphenols from various dietary sources have been shown to reverse it. The aim of the present study was to investigate the effect of the consumption of a polyphenol-rich apple on endothelial function. In all, 30 hypercholesterolemic volunteers were included in a double-blind, randomized crossover trial. They successively consumed 40 g of two lyophilized apples, polyphenol-rich and polyphenol-poor, providing respectively 1.43 and 0.21 g polyphenols per day during two 4-week periods separated by a 4-week washout period. Brachial artery flow-mediated vasodilation (FMD) was assessed at the beginning and at the end of each intervention period. FMD did not differ between the polyphenol-rich and the polyphenol-poor apples, neither did the other cardiovascular disease risk factors (plasma lipids, homocysteine, antioxidant capacity). These data suggest that over a 4-week period, the consumption of a polyphenol-rich apple does not improve vascular function in hypercholesterolemic patients.

Pharmacological vasodilation improves insulin-stimulated muscle protein anabolism but not glucose utilization in older adults.

PubMed

Timmerman, Kyle L; Lee, Jessica L; Fujita, Satoshi; Dhanani, Shaheen; Dreyer, Hans C; Fry, Christopher S; Drummond, Micah J; Sheffield-Moore, Melinda; Rasmussen, Blake B; Volpi, Elena

2010-11-01

Skeletal muscle protein metabolism is resistant to the anabolic action of insulin in healthy, nondiabetic older adults. This defect is associated with impaired insulin-induced vasodilation and mTORC1 signaling. We hypothesized that, in older subjects, pharmacological restoration of insulin-induced capillary recruitment would improve the response of muscle protein synthesis and anabolism to insulin. Twelve healthy, nondiabetic older subjects (71 ± 2 years) were randomized to two groups. Subjects were studied at baseline and during local infusion in one leg of insulin alone (Control) or insulin plus sodium nitroprusside (SNP) at variable rate to double leg blood flow. We measured leg blood flow by dye dilution; muscle microvascular perfusion with contrast enhanced ultrasound; Akt/mTORC1 signaling by Western blotting; and muscle protein synthesis, amino acid, and glucose kinetics using stable isotope methodologies. There were no baseline differences between groups. Blood flow, muscle perfusion, phenylalanine delivery to the leg, and intracellular availability of phenylalanine increased significantly (P < 0.05) in SNP only. Akt phosphorylation increased in both groups but increased more in SNP (P < 0.05). Muscle protein synthesis and net balance (nmol · min(-1) · 100 ml · leg(-1)) increased significantly (P < 0.05) in SNP (synthesis, 43 ± 6 to 129 ± 25; net balance, -16 ± 3 to 26 ± 12) but not in Control (synthesis, 41 ± 10 to 53 ± 8; net balance, -17 ± 3 to -2 ± 3). Pharmacological enhancement of muscle perfusion and amino acid availability during hyperinsulinemia improves the muscle protein anabolic effect of insulin in older adults.

Hindlimb unweighting decreases endothelium-dependent dilation and eNOS expression in soleus not gastrocnemius

NASA Technical Reports Server (NTRS)

Woodman, C. R.; Schrage, W. G.; Rush, J. W.; Ray, C. A.; Price, E. M.; Hasser, E. M.; Laughlin, M. H.

2001-01-01

We tested the hypothesis that hindlimb unweighting (HLU) decreases endothelium-dependent vasodilation and expression of endothelial nitric oxide synthase (eNOS) and superoxide dismutase-1 (SOD-1) in arteries of skeletal muscle with reduced blood flow during HLU. Sprague-Dawley rats (300-350 g) were exposed to HLU (n = 15) or control (n = 15) conditions for 14 days. ACh-induced dilation was assessed in muscle with reduced [soleus (Sol)] or unchanged [gastrocnemius (Gast)] blood flow during HLU. eNOS and SOD-1 expression were measured in feed arteries (FA) and in first-order (1A), second-order (2A), and third-order (3A) arterioles. Dilation to infusion of ACh in vivo was blunted in Sol but not Gast. In arteries of Sol muscle, HLU decreased eNOS mRNA and protein content. eNOS mRNA content was significantly less in Sol FA (35%), 1A arterioles (25%) and 2A arterioles (18%). eNOS protein content was less in Sol FA (64%) and 1A arterioles (65%) from HLU rats. In arteries of Gast, HLU did not decrease eNOS mRNA or protein. SOD-1 mRNA expression was less in Sol 2A arterioles (31%) and 3A arterioles (29%) of HLU rats. SOD-1 protein content was less in Sol FA (67%) but not arterioles. SOD-1 mRNA and protein content were not decreased in arteries from Gast. These data indicate that HLU decreases endothelium-dependent vasodilation, eNOS expression, and SOD-1 expression primarily in arteries of Sol muscle where blood flow is reduced during HLU.

Role of nitrite in regulation of fetal cephalic circulation in sheep

PubMed Central

Truong, Giang T; Schröder, Hobe J; Liu, Taiming; Zhang, Meijuan; Kanda, Eriko; Bragg, Shannon; Power, Gordon G; Blood, Arlin B

2014-01-01

Nitrite has been postulated to provide a reservoir for conversion to nitric oxide (NO), especially in tissues with reduced oxygen levels as in the fetus. Nitrite would thus provide local vasodilatation and restore a balance between oxygen supply and need, a putative mechanism of importance especially in the brain. The current experiments test the hypothesis that exogenous nitrite acts as a vasodilator in the cephalic vasculature of the intact, near term fetal sheep. Fetuses were first instrumented to measure arterial blood pressure and carotid artery blood flow and then studied 4–5 days later while in utero without anaesthesia. Initially l-nitro-arginine (LNNA) was given to block endogenous NO production. Carotid resistance to flow increased 2-fold from 0.54 ± 0.01 (SEM) to 1.20 ± 0.08 mmHg min ml−1 (in 13 fetuses, P < 0.001), indicating NO tonically reduces cerebral vascular tone. Sodium nitrite (or saline as control) was then infused in increasing step-doses from 0.01 to 33 μm in half-log increments over a period of 2 h. Carotid artery pressure, blood flow and vascular resistance did not change compared to fetuses receiving saline, even at plasma nitrite concentrations two orders of magnitude above the physiological range. The results indicate that while cephalic vascular tone is controlled by endogenous nitric oxide synthase activity, exogenously administered nitrite is not a vasodilator at physiological concentrations in the vasculature served by the carotid artery of fetal sheep. PMID:24535441

Correlation of transient adenosine release and oxygen changes in the caudate-putamen

PubMed Central

Wang, Ying; Venton, B. Jill

2016-01-01

Adenosine is an endogenous nucleoside that modulates important physiological processes, such as vasodilation, in the central nervous system. A rapid, 2–4 seconds, mode of adenosine signaling has been recently discovered, but the relationship between this type of adenosine and blood flow change has not been characterized. In this study, adenosine and oxygen changes were simultaneously measured using fast-scan cyclic voltammetry. Oxygen changes occur when there is an increase in local cerebral blood flow and thus are a measure of vasodilation. About 34% of adenosine transients in the rat caudate-putamen are correlated with a subsequent transient change in oxygen. The amount of oxygen was correlated with the concentration of adenosine release and larger adenosine transients (over 0.4 μM) always had subsequent oxygen changes. The average duration of adenosine and oxygen transients were 3.2 seconds and 3.5 seconds, respectively. On average, the adenosine release starts and peaks 0.2 seconds prior to the oxygen. The A2a antagonist, SCH442416, decreased the number of both adenosine and oxygen transient events by about 32%. However, the A1 antagonist, DPCPX, did not significantly affect simultaneous adenosine and oxygen release. The nitric oxide (NO) synthase inhibitor L-NAME also did not affect the concentration or number of adenosine and oxygen release events. These results demonstrate that both adenosine and oxygen release are modulated via A2a receptors. The correlation of transient concentrations, time delay between adenosine and oxygen peaks, and effect of A2a receptors suggests adenosine modulates blood flow on a rapid, sub-second time scale. PMID:27314215

Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy.

PubMed

Mata, Karina M; Li, Wei; Reslan, Ossama M; Siddiqui, Waleed T; Opsasnick, Lauren A; Khalil, Raouf A

2015-11-15

Normal pregnancy is associated with adaptive hemodynamic, hormonal, and vascular changes, and estrogen (E2) may promote vasodilation during pregnancy; however, the specific E2 receptor (ER) subtype, post-ER signaling mechanism, and vascular bed involved are unclear. We tested whether pregnancy-associated vascular adaptations involve changes in the expression/distribution/activity of distinct ER subtypes in a blood vessel-specific manner. Blood pressure (BP) and plasma E2 were measured in virgin and pregnant (day 19) rats, and the thoracic aorta, carotid artery, mesenteric artery, and renal artery were isolated for measurements of ERα, ERβ, and G protein-coupled receptor 30 [G protein-coupled ER (GPER)] expression and tissue distribution in parallel with relaxation responses to E2 (all ERs) and the specific ER agonist 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)-tris-phenol (PPT; ERα), diarylpropionitrile (DPN; ERβ), and G1 (GPER). BP was slightly lower and plasma E2 was higher in pregnant versus virgin rats. Western blots revealed increased ERα and ERβ in the aorta and mesenteric artery and GPER in the aorta of pregnant versus virgin rats. Immunohistochemistry revealed that the increases in ERs were mainly in the intima and media. In phenylephrine-precontracted vessels, E2 and PPT caused relaxation that was greater in the aorta and mesenteric artery but similar in the carotid and renal artery of pregnant versus virgin rats. DPN- and G1-induced relaxation was greater in the mesenteric and renal artery than in the aorta and carotid artery, and aortic relaxation to G1 was greater in pregnant versus virgin rats. The nitric oxide synthase inhibitor N(ω)-nitro-l-arginine methyl ester with or without the cyclooxygenase inhibitor indomethacin with or without the EDHF blocker tetraethylammonium or endothelium removal reduced E2, PPT, and G1-induced relaxation in the aorta of pregnant rats, suggesting an endothelium-dependent mechanism, but did not affect E2-, PPT-, DPN-, or G1-induced relaxation in other vessels, suggesting endothelium-independent mechanisms. E2, PPT, DPN, and G1 caused relaxation of Ca(2+) entry-dependent KCl contraction, and the effect of PPT was greater in the mesenteric artery of pregnant versus virgin rats. Thus, during pregnancy, an increase in ERα expression in endothelial and vascular smooth muscle layers of the aorta and mesenteric artery is associated with increased ERα-mediated relaxation via endothelium-derived vasodilators and inhibition of Ca(2+) entry into vascular smooth muscle, supporting a role of aortic and mesenteric arterial ERα in pregnancy-associated vasodilation. GPER may contribute to aortic relaxation while enhanced ERβ expression could mediate other genomic vascular effects during pregnancy. Copyright © 2015 the American Physiological Society.

Vildagliptin Improves Endothelium-Dependent Vasodilatation in Type 2 Diabetes

PubMed Central

van Poppel, Pleun C.M.; Netea, Mihai G.; Smits, Paul; Tack, Cees J.

2011-01-01

OBJECTIVE To investigate whether the dipeptidyl peptidase-4 inhibitor vildagliptin improves endothelium-dependent vasodilatation in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Sixteen subjects with type 2 diabetes (age 59.8 ± 6.8 years, BMI 29.1 ± 4.8 kg/m2, HbA1c 6.97 ± 0.61) on oral blood glucose–lowering treatment were included. Participants received vildagliptin 50 mg b.i.d. or acarbose 100 mg t.i.d. for four consecutive weeks in a randomized, double-blind, cross-over design. At the end of each treatment period, we measured forearm vasodilator responses to intra-arterially administered acetylcholine (endothelium-dependent vasodilator) and sodium nitroprusside (endothelium-independent vasodilator). RESULTS Infusion of acetylcholine induced a dose-dependent increase in forearm blood flow in the experimental arm, which was higher during vildagliptin (3.1 ± 0.7, 7.9 ± 1.1, and 12.6 ± 1.4 mL ⋅ dL−1 ⋅ min−1 in response to three increasing dosages of acetylcholine) than during acarbose (2.0 ± 0.7, 5.0 ± 1.2, and 11.7 ± 1.6 mL ⋅ dL−1 ⋅ min−1, respectively; P = 0.01 by two-way ANOVA). Treatment with vildagliptin did not significantly change the vascular responses to sodium nitroprusside. CONCLUSIONS Four weeks’ treatment with vildagliptin improves endothelium-dependent vasodilatation in subjects with type 2 diabetes. This observation might have favorable cardiovascular implications. PMID:21788633

Sex-specific effects of cardiovascular risk factors on endothelium-dependent dilation and endothelin activity in middle-aged women and men.

PubMed

Brar, Vijaywant; Gill, Sartaj; Cardillo, Carmine; Tesauro, Manfredi; Panza, Julio A; Campia, Umberto

2015-01-01

Healthy middle-aged postmenopausal women have higher endothelium-dependent dilation and lower vasoconstrictor activity of endothelin-1 than men. Whether these sex-specific differences extend to patients with cardiovascular risk factors has not been investigated. The current study aimed to determine whether, in patients with cardiovascular risk factors, sex-specific differences exist in endothelium-dependent dilation and endothelin-1 activity. Forearm blood flow responses were measured by strain-gauge plethysmography during the intra-arterial infusion of acetylcholine, sodium nitroprusside, and the selective endothelin type A receptor blocker BQ-123 in 50 women and 64 men with cardiovascular risk factors. Acetylcholine and sodium nitroprusside induced a significant vasodilation in women and men alike (p < 0.01 for both). Also BQ-123 caused a significant vasodilation (p < 0.001) in both groups. The vasodilator response to acetylcholine was greater in women compared to men; however there were no differences in the response to sodium nitroprusside and BQ-123 (p = NS for both) between the two sex groups. Middle-aged women with cardiovascular risk factors have significantly higher endothelium-dependent dilation than middle-aged men; however, vascular endothelin 1 activity is similar in the two groups. These findings suggest that the presence of cardiovascular risk factors is associated with sex-specific effects on endothelium-dependent dilation but not on endothelin 1 activity. Further study is needed to confirm our findings and to characterize the mechanisms underlying this sex-specific regulation of endothelial function.

Characterizing rapid-onset vasodilation to single muscle contractions in the human leg

PubMed Central

Credeur, Daniel P.; Holwerda, Seth W.; Restaino, Robert M.; King, Phillip M.; Crutcher, Kiera L.; Laughlin, M. Harold; Padilla, Jaume

2014-01-01

Rapid-onset vasodilation (ROV) following single muscle contractions has been examined in the forearm of humans, but has not yet been characterized in the leg. Given known vascular differences between the arm and leg, we sought to characterize ROV following single muscle contractions in the leg. Sixteen healthy men performed random ordered single contractions at 5, 10, 20, 40, and 60% of their maximum voluntary contraction (MVC) using isometric knee extension made with the leg above and below heart level, and these were compared with single isometric contractions of the forearm (handgrip). Single thigh cuff compressions (300 mmHg) were utilized to estimate the mechanical contribution to leg ROV. Continuous blood flow was determined by duplex-Doppler ultrasound and blood pressure via finger photoplethysmography (Finometer). Single isometric knee extensor contractions produced intensity-dependent increases in peak leg vascular conductance that were significantly greater than the forearm in both the above- and below-heart level positions (e.g., above heart level: leg 20% MVC, +138 ± 28% vs. arm 20% MVC, +89 ± 17%; P < 0.05). Thigh cuff compressions also produced a significant hyperemic response, but these were brief and smaller in magnitude compared with single isometric contractions in the leg. Collectively, these data demonstrate the presence of a rapid and robust vasodilation to single muscle contractions in the leg that is largely independent of mechanical factors, thus establishing the leg as a viable model to study ROV in humans. PMID:25539935

Substance P increases sympathetic activity during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition.

PubMed

Devin, Jessica K; Pretorius, Mias; Nian, Hui; Yu, Chang; Billings, Frederic T; Brown, Nancy J

2014-05-01

Dipeptidyl peptidase-4 inhibitors prevent the degradation of incretin hormones and reduce postprandial hyperglycemia in patients with type 2 diabetes mellitus. Dipeptidyl peptidase-4 degrades other peptides with a penultimate proline or alanine, including bradykinin and substance P, which are also substrates of angiotensin-converting enzyme (ACE). During ACE inhibition, substance P is inactivated primarily by dipeptidyl peptidase-4, whereas bradykinin is first inactivated by aminopeptidase P. This study tested the hypothesis that dipeptidyl peptidase-4 inhibition potentiates vasodilator and fibrinolytic responses to substance P when ACE is inhibited. Twelve healthy subjects participated in this randomized, double-blinded, placebo-controlled crossover study. On each study day, subjects received sitagliptin 200 mg by mouth or placebo. Substance P and bradykinin were infused via brachial artery before and during intra-arterial enalaprilat. Sitagliptin and enalaprilat each reduced forearm vascular resistance and increased forearm blood flow without affecting mean arterial pressure, but there was no interactive effect of the inhibitors. Enalaprilat increased bradykinin-stimulated vasodilation and tissue plasminogen activator release; sitagliptin did not affect these responses to bradykinin. The vasodilator response to substance P was unaffected by sitagliptin and enalaprilat; however, substance P increased heart rate and vascular release of norepinephrine during combined ACE and dipeptidyl peptidase-4 inhibition. In women, sitagliptin diminished tissue plasminogen activator release in response to substance P both alone and during enalaprilat. Substance P increases sympathetic activity during combined ACE and dipeptidyl peptidase-4 inhibition. - URL: http://www.clinicaltrials.gov. Unique identifier: NCT01413542.

Substance P increases Sympathetic Activity during Combined Angiotensin Converting Enzyme and Dipeptidyl Peptidase-4 Inhibition

PubMed Central

Devin, Jessica K.; Pretorius, Mias; Nian, Hui; Yu, Chang; Billings, Frederic T.; Brown, Nancy J.

2014-01-01

Dipeptidyl peptidase-4 inhibitors prevent the degradation of incretin hormones and reduce post-prandial hyperglycemia in patients with type 2 diabetes mellitus. Dipeptidyl peptidase-4 degrades other peptides with a penultimate proline or alanine, including bradykinin and substance P, which are also substrates of angiotensin-converting enzyme. During angiotensin-converting enzyme inhibition, substance P is inactivated primarily by dipeptidyl peptidase-4, while bradykinin is first inactivated by aminopeptidase P. This study tested the hypothesis that dipeptidyl peptidase-4 inhibition potentiates vasodilator and fibrinolytic responses to substance P when angiotensin-converting enzyme is inhibited. Twelve healthy subjects participated in this randomized, double-blinded, placebo-controlled crossover study. On each study day, subjects received sitagliptin 200 mg p.o. or placebo. Substance P and bradykinin were infused via brachial artery before and during intra-arterial enalaprilat. Sitagliptin and enalaprilat each reduced forearm vascular resistance and increased forearm blood flow without affecting mean arterial pressure, but there was no interactive effect of the inhibitors. Enalaprilat increased bradykinin-stimulated vasodilation and tissue plasminogen activator release; sitagliptin did not affect these responses to bradykinin. The vasodilator response to substance P was unaffected by sitagliptin and enalaprilat, however, substance P increased heart rate and vascular release of norepinephrine during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition. In women, sitagliptin diminished tissue plasminogen activator release in response to substance P both alone and during enalaprilat. Substance P increases sympathetic activity during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition. PMID:24516103

In vivo measurement of astrocytic endfoot Ca2+ and parenchymal vessel responses during 4-AP induced epilepsy using two-photon fluorescence lifetime microscopy

NASA Astrophysics Data System (ADS)

Zhang, Cong; Tabatabaei, Maryam; Bélanger, Samuel; Girouard, Hélène; Moeini, Mohammad; Lu, Xuecong; Lesage, Frédéric

2018-02-01

Neurovascular coupling (NVC) is defined as a local increase in cerebral blood flow in response to neuronal activity, it forms the basis of functional brain imaging and is altered during epilepsy. Because astrocytic calcium signaling (Ca2+) has been involved in the response of parenchymal vessels, this study investigates the role of this pathway during epilepsy. We exploit 4-Aminopyridine (4-AP) induced epileptic seizures to show that absolute Ca2+ concentration in astrocytic endfeet correlates with the changes in diameter of parenchymal vessels during neural activity in vivo. A two-photon laser scanning fluorescence lifetime microscopy was developed to simultaneously monitor free Ca2+ concentration in astrocytic endfeet with the calcium-sensitive indicator Oregon Green 488 BAPTA-1 (OGB-1) and the diameter of parenchymal vessels in the somatosensory cortex of mice following 4-AP injection. Our results reveal that the resting Ca2+ concentration in glial cells was spatially heterogeneous and that resting Ca2+ concentration in somatic regions was significantly higher than in endfoot regions. Moreover, following 4-AP injection in the somatosensory cortex of mice, we observed increases of Ca2+ in astrocytic endfeet associated with vasodilation of parenchymal vessels for each individual ictal event in the epileptic focus. However, vasodilation was seen to be inhibited by increase in absolute resting Ca2+ concentration. Our results suggest a role for baseline astrocytic Ca2+ concentration in vasodilation.

Leg blood flow is impaired during small muscle mass exercise in patients with COPD.

PubMed

Iepsen, U W; Munch, G W; Rugbjerg, M; Ryrsø, C K; Secher, N H; Hellsten, Y; Lange, P; Pedersen, B K; Thaning, P; Mortensen, S P

2017-09-01

Skeletal muscle blood flow is regulated to match the oxygen demand and dysregulation could contribute to exercise intolerance in patients with chronic obstructive pulmonary disease (COPD). We measured leg hemodynamics and metabolites from vasoactive compounds in muscle interstitial fluid and plasma at rest, during one-legged knee-extensor exercise, and during arterial infusions of sodium nitroprusside (SNP) and acetylcholine (ACh), respectively. Ten patients with moderate to severe COPD and eight age- and sex-matched healthy controls were studied. During knee-extensor exercise (10 W), leg blood flow was lower in the patients compared with the controls (1.82 ± 0.11 vs. 2.36 ± 0.14 l/min, respectively; P < 0.05), which compromised leg oxygen delivery (372 ± 26 vs. 453 ± 32 ml O 2 /min, respectively; P < 0.05). At rest, plasma endothelin-1 (vasoconstrictor) was higher in the patients with COPD ( P < 0.05) and also tended to be higher during exercise ( P = 0.07), whereas the formation of interstitial prostacyclin (vasodilator) was only increased in the controls. There was no difference between groups in the nitrite/nitrate levels (vasodilator) in plasma or interstitial fluid during exercise. Moreover, patients and controls showed similar vasodilatory capacity in response to both endothelium-independent (SNP) and endothelium-dependent (ACh) stimulation. The results suggest that leg muscle blood flow is impaired during small muscle mass exercise in patients with COPD possibly due to impaired formation of prostacyclin and increased levels of endothelin-1. NEW & NOTEWORTHY This study demonstrates that chronic obstructive pulmonary disease (COPD) is associated with a reduced blood flow to skeletal muscle during small muscle mass exercise. In contrast to healthy individuals, interstitial prostacyclin levels did not increase during exercise and plasma endothelin-1 levels were higher in the patients with COPD. Copyright © 2017 the American Physiological Society.

Pathophysiology of Acute Kidney Injury

PubMed Central

Basile, David P.; Anderson, Melissa D.; Sutton, Timothy A.

2014-01-01

Acute kidney injury (AKI) is the leading cause of nephrology consultation and is associated with high mortality rates. The primary causes of AKI include ischemia, hypoxia or nephrotoxicity. An underlying feature is a rapid decline in GFR usually associated with decreases in renal blood flow. Inflammation represents an important additional component of AKI leading to the extension phase of injury, which may be associated with insensitivity to vasodilator therapy. It is suggested that targeting the extension phase represents an area potential of treatment with the greatest possible impact. The underlying basis of renal injury appears to be impaired energetics of the highly metabolically active nephron segments (i.e., proximal tubules and thick ascending limb) in the renal outer medulla, which can trigger conversion from transient hypoxia to intrinsic renal failure. Injury to kidney cells can be lethal or sublethal. Sublethal injury represents an important component in AKI, as it may profoundly influence GFR and renal blood flow. The nature of the recovery response is mediated by the degree to which sublethal cells can restore normal function and promote regeneration. The successful recovery from AKI depends on the degree to which these repair processes ensue and these may be compromised in elderly or CKD patients. Recent data suggest that AKI represents a potential link to CKD in surviving patients. Finally, earlier diagnosis of AKI represents an important area in treating patients with AKI that has spawned increased awareness of the potential that biomarkers of AKI may play in the future. PMID:23798302

Drag reducing polymers improve tissue perfusion via modification of the RBC traffic in microvessels.

PubMed

Marhefka, J N; Zhao, R; Wu, Z J; Velankar, S S; Antaki, J F; Kameneva, M V

2009-01-01

This paper reports a novel, physiologically significant, microfluidic phenomenon generated by nanomolar concentrations of drag-reducing polymers (DRP) dissolved in flowing blood, which may explain previously demonstrated beneficial effects of DRP on tissue perfusion. In microfluidic systems used in this study, DRP additives were found to significantly modify traffic of red blood cells (RBC) into microchannel branches as well as reduce the near-wall cell-free layer, which normally is found in microvessels with a diameter smaller than 0.3 mm. The reduction in plasma layer size led to attenuation of the so-called "plasma skimming" effect at microchannel bifurcations, increasing the number of RBC entering branches. In vivo, these changes in RBC traffic may facilitate gas transport by increasing the near vessel wall concentration of RBC and capillary hematocrit. In addition, an increase in near-wall viscosity due to the redirection of RBC in this region may potentially decrease vascular resistance as a result of increased wall shear stress, which promotes endothelium mediated vasodilation. These microcirculatory phenomena can explain the previously reported beneficial effects of DRP on hemodynamics in vivo observed in many animal studies. We also report here our finding that DRP additives reduce flow separations at microchannel expansions, deflecting RBC closer to the wall and eliminating the plasma recirculation zone. Although the exact mechanism of the DRP effects on RBC traffic in microchannels is yet to be elucidated, these findings may further DRP progress toward clinical use.

Drag reducing polymers improve tissue perfusion via modification of the RBC traffic in microvessels

PubMed Central

Marhefka, J.N.; Zhao, R.; Wu, Z.; Velankar, S.S.; Antaki, J.F.; Kameneva, M.V.

2011-01-01

This paper reports a novel, physiologically significant, microfluidic phenomenon generated by nanomolar concentrations of drag-reducing polymers (DRP) dissolved in flowing blood, which may explain previously demonstrated beneficial effects of DRP on tissue perfusion. In microfluidic systems used in this study, DRP additives were found to significantly modify traffic of red blood cells (RBC) into microchannel branches as well as reduce the near-wall cell-free layer, which normally is found in microvessels with a diameter smaller than 0.3 mm. The reduction in plasma layer size led to attenuation of the so-called “plasma skimming” effect at microchannel bifurcations, increasing the number of RBC entering branches. In vivo, these changes in RBC traffic may facilitate gas transport by increasing the near vessel wall concentration of RBC and capillary hematocrit. In addition, an increase in near-wall viscosity due to the redirection of RBC in this region may potentially decrease vascular resistance as a result of increased wall shear stress, which promotes endothelium mediated vasodilation. These microcirculatory phenomena may explain the previously reported beneficial effects of DRP on hemodynamics in vivo observed in many animal studies. We also report here our finding that DRP additives reduce flow separations at microchannel expansions, deflecting RBC closer to the wall and eliminating the plasma recirculation zone. Although the exact mechanism of the DRP effects on RBC traffic in microchannels is yet to be elucidated, these findings may further DRP progress toward clinical use. PMID:19721190

Tumor necrosis factor-alpha inhibits insulin's stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans.

PubMed

Rask-Madsen, Christian; Domínguez, Helena; Ihlemann, Nikolaj; Hermann, Thomas; Køber, Lars; Torp-Pedersen, Christian

2003-10-14

Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)-alpha inhibits insulin-stimulated glucose uptake and insulin-stimulated endothelial function in humans. Healthy, lean male volunteers were studied. On each study day, 3 acetylcholine (ACh) or sodium nitroprusside (SNP) dose-response studies were performed by infusion into the brachial artery. Before and during the last 2 dose-response studies, insulin and/or TNF-alpha were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220+/-44%. This increase was completely inhibited during coinfusion of TNF-alpha (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow. Furthermore, TNF-alpha inhibited the ACh forearm blood flow response (P<0.001), and this inhibition was larger during insulin infusion (P=0.01) but not further increased by NG-monomethyl-L-arginine acetate (P=0.2). Insulin potentiated the SNP response less than the ACh response and the effect of TNF-alpha was smaller (P<0.001); TNF-alpha had no effect on the SNP response without insulin infusion. Thus, TNF-alpha inhibition of the combined response to insulin and ACh was likely mediated through inhibition of NO production. These results support the concept that TNF-alpha could play a role in the development of insulin resistance in humans, both in muscle and in vascular tissue.

Regional peripheral and CNS hemodynamic effects of intrathecal administration of a substance P receptor agonist.

PubMed

Helke, C J; Phillips, E T; O'Neill, J T

1987-11-01

Regional CNS and peripheral hemodynamic effects of the intrathecal (i.t.) administration of a substance P receptor agonist, [pGlu5,MePhe8,MeGly9]-substance P5-11 ([DiMe]-SP), were studied in anesthetized rats with the radioactive microsphere technique. It was previously shown that [DiMe]-SP caused a sympathetically mediated increase in mean arterial pressure (MAP) by an action within the spinal cord. In this study, [DiMe]-SP (5 and 33 nmol, i.t.) increased MAP. The 5 nmol dose increased resistance in cutaneous, renal, splanchnic, and adrenal vascular beds but decreased resistance, and increased blood flow in some skeletal muscle beds. Total peripheral resistance was unchanged. The 33 nmol dose increased resistance in each peripheral vascular bed analyzed and increased total peripheral resistance. Whereas each dose increased heart rate, stroke volume and cardiac output were unchanged with the 5 nmol dose and were reduced with the 33 nmol dose. Neither dose of [DiMe]-SP significantly altered regional brain or spinal cord blood flows. These data show that the i.t. administration of the SP agonist, [DiMe]-SP, increased vascular tone to most peripheral vascular beds whereas the low dose caused a vasodilation of skeletal muscle. These effects are consistent with the notion of a dose-related activation of SP receptors in the spinal cord affecting sympathetic outflow to the adrenals and to the vasculature.

Metabolism, Seizures, and Blood Flow in Brain Following Organophosphate Exposure: Mechanisms of Action and Possible Therapeutic Agents

DTIC Science & Technology

1991-01-31

oxotremorine and arecoline have established the involvement of a cholinergic muscarinic mechanism in OP-induced seizure, but not in OP-induced vasodilation. To...brain transport ofI glc, Ch, leu, and gly, additional influx measurements were made following expssure to carbachol, arecoline, oxotremorine , and AF64a...such as oxotremorine (53, 54). Although the primary effect of OPs on brain ACh levels is well established, their additional primary and secondary

Corticotropin-releasing factor: effect on cerebral blood flow in physiologic and ischaemic conditions.

PubMed

De Michele, Manuela; Touzani, Omar; Foster, Alan C; Fieschi, Cesare; Sette, Giuliano; McCulloch, James

2005-09-01

The expression of corticotrophin-releasing factor (CRF) receptors in cerebral arteries and arterioles suggests that CRF may modulate cerebral blood flow (CBF). In the present study, the effects of CRF, CRF-like peptides and the CRF broad spectrum antagonist DPhe-CRF on CBF have been investigated under normal physiologic conditions and in the margins of focal ischaemic insult. The experiments were carried out in anaesthetised and ventilated rats. Changes in CBF after subarachnoid microapplication of CRF and related peptides were assessed with a laser-Doppler flowmetry (LDF) probe. In the ischaemic animals, agents were injected approximately 60 minutes after permanent middle cerebral artery occlusion (MCAo). Microapplication of CRF and related peptides in normal rats into the subarachnoid space produced sustained concentration-dependent increases in CBF. This effect was attenuated by co-application with DPhe-CRF, which did not alter CBF itself. A second microapplication of CRF 30 min after the first failed to produce increases in CBF in normal animals. Microapplication of CRF in the subarachnoid space overlying the ischaemic cortex effected minor increases in CBF whereas D-Phe-CRF had no significant effect on CBF. Activation of the CRF peptidergic system increases CBF in the rat. Repeated activation of CRF receptors results in tachyphylaxis of the vasodilator response. CRF vasodilator response is still present after MCAo in the ischaemic penumbra, suggesting that the CRF peptidergic system may modulate CBF in ischaemic stroke.

Interactions between beta-2 adrenoceptor gene variation, cardiovascular control and dietary sodium in healthy young adults

PubMed Central

Eisenach, John H; Schroeder, Darrell R; Pavey, Emily S; Penheiter, Alan R; Knutson, Jean N; Turner, Stephen T; Joyner, Michael J

2014-01-01

Dietary sodium affects function of the beta-2 adrenoceptor (ADRB2). We tested the hypothesis that haplotype variation in the ADRB2 gene would influence the cardiovascular and regional vasodilator responses to sympathoexcitatory manoeuvres following low, normal and high sodium diets, and ADRB2-mediated forearm vasodilation in the high sodium condition. Seventy-one healthy young adults were grouped by double homozygous haplotypes: Arg16+Gln27 (n = 31), the rare Gly16+Gln27 (n = 10) and Gly16+Glu27 (n = 30). Using a randomized cross-over design, subjects were studied following 5 days of controlled low, normal and high sodium with 1 month or longer between diets (and low hormone phase of the menstrual cycle). All three visits utilized ECG and finger plethysmography for haemodynamic measures, and the high sodium visit included a brachial arterial catheter for forearm vasodilator responses to isoprenaline with plethysmography. Lymphocytes were sampled for ex vivo analysis of ADRB2 density and binding conformation. We found a main effect of haplotype on ADRB2 density (P = 0.03) with the Gly16+Glu27 haplotype having the greatest density (low, normal, high sodium: 12.9 ± 0.9, 13.5 ± 0.9 and 13.6 ± 0.8 fmol mg−1 protein, respectively) and Arg16+Gln27 having the least (9.3 ± 0.6, 10.1 ± 0.5 and 10.3 ± 0.6  fmol mg−1 protein, respectively), but there were no sodium or haplotype effects on receptor binding conformation. In the mental stress trial, there was a main effect of haplotype on cardiac output (P = 0.04), as Arg16+Gln27 had the lowest responses. Handgrip and forearm vasodilation yielded no haplotype differences, and no correlations were present for ADRB2 density and haemodynamics. Our findings support cell-based evidence that ADRB2 haplotype influences ADRB2 protein expression independent of dietary sodium, yet the haemodynamic consequences appear modest in healthy humans. PMID:25260632

Speckle-correlation monitoring of the internal micro-vascular flow

NASA Astrophysics Data System (ADS)

Zimnyakov, D. A.; Khmara, M. B.; Vilensky, M. A.; Kozlov, V. V.; Gorfinkel, I. V.; Zdrajevsky, R. A.

2009-10-01

The results of experimental study of possibility to monitor the micro-vascular blood flow in superficial tissues of various organs with the use of endoscope-based full-field speckle correlometer are presented. The blood microcirculation monitoring was carried out in the course of the laparotomy of abdominal cavity of laboratory animals (rats). Transfer of laser light to the area of interest and scattered radiation from the probed zone to the detector (CMOS camera) was carried out via fiber-optic bundles of endoscopic system. Microscopic hemodynamics was analyzed for small intestine, liver, spleen, kidney, and pancreas under different conditions (normal state, provocated peritonitis and ischemia, administration of vasodilative agents such as papaverine, lidocaine). The prospects and problems of internal monitoring of microvascular flow in laboratory and clinical conditions are discussed.

Effects of isradipine and other calcium antagonists on arteriovenous-shunt flow in anesthetized rabbits and cats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hof, R.P.

The effects of vasodilators on arteriovenous (AV)-shunt flow was investigated in anesthetized cats and rabbits, using the tracer microsphere method. In cats, the calcium antagonist isradipine reduced AV-shunt flow; verapamil showed a similar tendency and nicardipine was without effect. Dihydralazine strongly increased, but nitroglycerin and dipyridamole decreased AV-shunt flow. In rabbits, the effects of isradipine and verapamil were similar to those seen in cats. Sodium nitroprusside had no effect, whereas prazosin, minoxidil, and the potassium-channel activator cromakalim increased AV-shunt flow. The contrasting effects of drugs sharing the same mechanism of action suggest that target-tissue selectivity is more important than themore » mechanism of action. An increase of AV-shunt flow is unlikely to be beneficial but could be associated with a number of undesirable side effects. It might negatively affect migraine sufferers and, if AV-shunt dilatation shows no tolerance development, it represents an unnecessary hemodynamic burden for the heart.« less

Dose-dependent increases in flow-mediated dilation following acute cocoa ingestion in healthy older adults

PubMed Central

Feehan, Robert P.; Kunselman, Allen R.; Preston, Amy G.; Miller, Debra L.; Lott, Mary E. J.

2011-01-01

An inverse relation exists between intake of flavonoid-rich foods, such as cocoa, and cardiovascular-related mortality. Favorable effects of flavonoids on the endothelium may underlie these associations. We performed a randomized, double-blind, placebo-controlled study to test the hypothesis that acute cocoa ingestion dose dependently increases endothelium-dependent vasodilation, as measured by an increase in brachial artery flow-mediated dilation (FMD), in healthy older adults. Measurements were obtained before (preingestion) and after (1- and 2-h postingestion) ingestion of 0 (placebo), 2, 5, 13, and 26 g of cocoa in 23 adults (63 ± 2 yr old, mean ± SE). Changes in brachial artery FMD 1- and 2-h postingestion compared with preingestion were used to determine the effects of cocoa. FMD was unchanged 1 (Δ−0.3 ± 0.2%)- and 2-h (Δ0.1 ± 0.1%) after placebo (0 g cocoa). In contrast, FMD increased both 1-h postingestion (2 g cocoa Δ0.0 ± 0.2%, 5 g cocoa Δ0.8 ± 0.3%, 13 g cocoa Δ1.0 ± 0.3%, and 26 g cocoa Δ1.6 ± 0.3%: P < 0.05 compared with placebo for 5, 13, and 26 g cocoa) and 2-h postingestion (2 g cocoa Δ0.5 ± 0.3%, 5 g cocoa Δ1.0 ± 0.3%, 13 g cocoa Δ1.4 ± 0.2%, and 26 g cocoa Δ2.5 ± 0.4%: P < 0.05 compared with placebo for 5, 13, and 26 g cocoa) on the other study days. A serum marker of cocoa ingestion (total epicatechin) correlated with increased FMD 1- and 2-h postingestion (r = 0.44–0.48; both P < 0.05). Collectively, these results indicate that acute cocoa ingestion dose dependently increases brachial artery FMD in healthy older humans. These responses may help to explain associations between flavonoid intake and cardiovascular-related mortality in humans. PMID:21903881

Impaired postprandial tissue regulation of blood flow in insulin resistance: a determinant of cardiovascular risk?

PubMed

Summers, L K; Samra, J S; Frayn, K N

1999-11-01

The insulin resistant state is a major risk factor for coronary artery disease. This increased risk is likely to be due to associated lipid and coagulation abnormalities rather than just abnormalities in glucose metabolism or hyperinsulinaemia alone. Exaggerated postprandial lipaemia is a well-recognised associate of insulin resistance and postprandial hypertriglyceridaemia is particularly important in the development of coronary atheroma. It seems likely that insulin is one of the hormonal regulators of adipose tissue and skeletal muscle blood flow. The reduced blood flow and blunting of the postprandial rise of peripheral blood flow in insulin resistance may decrease chylomicron-triglyceride delivery to muscle in subjects with insulin resistance. This, in turn, will lead to increased production of atherogenic particles. We propose that impaired postprandial vasodilation, already recognised as a key feature of glucose intolerance, is also the cause of impaired lipid metabolism in insulin resistant subjects and predisposes them to cardiovascular disease.

Hyperbaric oxygenation affects the mechanisms of acetylcholine-induced relaxation in diabetic rats.

PubMed

Unfirer, Sanela; Mihalj, Martina; Novak, Sanja; Kibel, Aleksandar; Cavka, Ava; Mijalevic, Zrinka; Gros, Mario; Brizic, Ivica; Budimir, Danijela; Cosic, Anita; Boban, Mladen; Drenjancevic, Ines

2016-01-01

The effects of hyperbaric oxygenation (HBO₂) on acetylcholine-induced vasorelaxation (AChIR) were evaluated in male Sprague-Dawley (SD) rats randomized into four groups: healthy controls (Ctrl), diabetic rats (DM), and control and diabetic rats that underwent hyperbaric oxygenation (Ctrl+HBO₂ and DM+HBO₂). AChIR was measured in aortic rings, with L-NAME, indomethacin, or MS-PPOH and a combination of inhibitors. mRNA expression of eNOS, iNOS, COX-1 and COX-2 was assessed by qPCR, and protein expression of CYP4A(1-3) by Western blot. Plasma antioxidative capacity and systemic oxidative stress were determined with the ferric reducing ability of plasma (FRAP) and thiobarbituric acid-reactive substances (TBARS) assays, respectively. AChIR was preserved in all groups of rats, but mediated with different mechanisms. In all experimental groups of rats, AChIR was mediated mainly by NO, with the contribution of CYP450 vasodilator metabolites. This effect was the most prominent in the DM+HBO₂ group of rats. The TBARS was significantly higher in both DM and DM+HBO₂ groups compared to respective controls. eNOS expression was upregulated in the DM+HBO₂ group compared to other groups, COX-1 expression was upregulated in the DM+HBO₂ group compared to the control. CYP450-4A1 / A2/A3protein expression was significantly higher expressed in both hyperbaric groups compared to their respective controls. In conclusion, HBO₂ affected all three vasodilator pathways and shifted AChIR to CYP450 enzymes pathway. Copyright© Undersea and Hyperbaric Medical Society.

Vasodilator-stimulated Phosphoprotein (VASP) Regulates Actin Polymerization and Contraction in Airway Smooth Muscle by a Vinculin-dependent Mechanism*

PubMed Central

Wu, Yidi; Gunst, Susan J.

2015-01-01

Vasodilator-stimulated phosphoprotein (VASP) can catalyze actin polymerization by elongating actin filaments. The elongation mechanism involves VASP oligomerization and its binding to profilin, a G-actin chaperone. Actin polymerization is required for tension generation during the contraction of airway smooth muscle (ASM); however, the role of VASP in regulating actin dynamics in ASM is not known. We stimulated ASM cells and tissues with the contractile agonist acetylcholine (ACh) or the adenylyl cyclase activator, forskolin (FSK), a dilatory agent. ACh and FSK stimulated VASP Ser157 phosphorylation by different kinases. Inhibition of VASP Ser157 phosphorylation by expression of the mutant VASP S157A in ASM tissues suppressed VASP phosphorylation and membrane localization in response to ACh, and also inhibited contraction and actin polymerization. ACh but not FSK triggered the formation of VASP-VASP complexes as well as VASP-vinculin and VASP-profilin complexes at membrane sites. VASP-VASP complex formation and the interaction of VASP with vinculin and profilin were inhibited by expression of the inactive vinculin mutant, vinculin Y1065F, but VASP phosphorylation and membrane localization were unaffected. We conclude that VASP phosphorylation at Ser157 mediates its localization at the membrane, but that VASP Ser157 phosphorylation and membrane localization are not sufficient to activate its actin catalytic activity. The interaction of VASP with activated vinculin at membrane adhesion sites is a necessary prerequisite for VASP-mediated molecular processes necessary for actin polymerization. Our results show that VASP is a critical regulator of actin dynamics and tension generation during the contractile activation of ASM. PMID:25759389

Carbon Monoxide and Nitric Oxide Mediate Cytoskeletal Reorganization in Microvascular Cells via Vasodilator-Stimulated Phosphoprotein Phosphorylation

PubMed Central

Li Calzi, Sergio; Purich, Daniel L.; Chang, Kyung Hee; Afzal, Aqeela; Nakagawa, Takahiko; Busik, Julia V.; Agarwal, Anupam; Segal, Mark S.; Grant, Maria B.

2008-01-01

OBJECTIVE— We examined the effect of the vasoactive agents carbon monoxide (CO) and nitric oxide (NO) on the phosphorylation and intracellular redistribution of vasodilator-stimulated phosphoprotein (VASP), a critical actin motor protein required for cell migration that also controls vasodilation and platelet aggregation. RESEARCH DESIGN AND METHODS— We examined the effect of donor-released CO and NO in endothelial progenitor cells (EPCs) and platelets from nondiabetic and diabetic subjects and in human microvascular endothelial cells (HMECs) cultured under low (5.5 mmol/l) or high (25 mmol/l) glucose conditions. VASP phosphorylation was evaluated using phosphorylation site-specific antibodies. RESULTS— In control platelets, CO selectively promotes phosphorylation at VASP Ser-157, whereas NO promotes phosphorylation primarily at Ser-157 and also at Ser-239, with maximal responses at 1 min with both agents on Ser-157 and at 15 min on Ser-239 with NO treatment. In diabetic platelets, neither agent resulted in VASP phosphorylation. In nondiabetic EPCs, NO and CO increased phosphorylation at Ser-239 and Ser-157, respectively, but this response was markedly reduced in diabetic EPCs. In endothelial cells cultured under low glucose conditions, both CO and NO induced phosphorylation at Ser-157 and Ser-239; however, this response was completely lost when cells were cultured under high glucose conditions. In control EPCs and in HMECs exposed to low glucose, VASP was redistributed to filopodia-like structures following CO or NO exposure; however, redistribution was dramatically attenuated under high glucose conditions. CONCLUSIONS— Vasoactive gases CO and NO promote cytoskeletal changes through site- and cell type–specific VASP phosphorylation, and in diabetes, blunted responses to these agents may lead to reduced vascular repair and tissue perfusion. PMID:18559661

Melatonin mediates vasodilation through both direct and indirect activation of BKCa channels.

PubMed

Zhao, T; Zhang, H; Jin, C; Qiu, F; Wu, Y; Shi, L

2017-10-01

Melatonin, synthesized primarily by the pineal gland, is a neuroendocrine hormone with high membrane permeability. The vascular effects of melatonin, including vasoconstriction and vasodilation, have been demonstrated in numerous studies. However, the mechanisms underlying these effects are not fully understood. Large-conductance Ca 2+ -activated K + (BK Ca ) channels are expressed broadly on smooth muscle cells and play an important role in vascular tone regulation. This study explored the mechanisms of myocyte BK Ca channels and endothelial factors underlying the action of melatonin on the mesenteric arteries (MAs). Vascular contractility and patch-clamp studies were performed on myocytes of MAs from Wistar rats. Melatonin induced significant vasodilation on MAs. In the presence of N ω -nitro-l-arginine methyl ester (l-NAME), a potent endothelial oxide synthase (eNOS) inhibitor, melatonin elicited concentration-dependent relaxation, with lowered pIC 50 The effect of melatonin was significantly attenuated in the presence of BK Ca channel blocker iberiotoxin or MT1/MT2 receptor antagonist luzindole in both (+) l-NAME and (-) l-NAME groups. In the (+) l-NAME group, iberiotoxin caused a parallel rightward shift of the melatonin concentration-relaxation curve, with pIC 50 lower than that of luzindole. Both inside-out and cell-attached patch-clamp recordings showed that melatonin significantly increased the open probability, mean open time and voltage sensitivity of BK Ca channels. In a cell-attached patch-clamp configuration, the melatonin-induced enhancement of BK Ca channel activity was significantly suppressed by luzindole. These findings indicate that in addition to the activation of eNOS, melatonin-induced vasorelaxation of MAs is partially attributable to its direct (passing through the cell membrane) and indirect (via MT1/MT2 receptors) activation of the BK Ca channels on mesenteric arterial myocytes. © 2017 Society for Endocrinology.

KV7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine

PubMed Central

Goodwill, Adam G.; Fu, Lijuan; Noblet, Jillian N.; Casalini, Eli D.; Berwick, Zachary C.; Kassab, Ghassan S.; Tune, Johnathan D.

2016-01-01

Hydrogen peroxide (H2O2) and voltage-dependent K+ (KV) channels play key roles in regulating coronary blood flow in response to metabolic, ischemic, and paracrine stimuli. The KV channels responsible have not been identified, but KV7 channels are possible candidates. Existing data regarding KV7 channel function in the coronary circulation (limited to ex vivo assessments) are mixed. Thus we examined the hypothesis that KV7 channels are present in cells of the coronary vascular wall and regulate vasodilation in swine. We performed a variety of molecular, biochemical, and functional (in vivo and ex vivo) studies. Coronary arteries expressed KCNQ genes (quantitative PCR) and KV7.4 protein (Western blot). Immunostaining demonstrated KV7.4 expression in conduit and resistance vessels, perhaps most prominently in the endothelial and adventitial layers. Flupirtine, a KV7 opener, relaxed coronary artery rings, and this was attenuated by linopirdine, a KV7 blocker. Endothelial denudation inhibited the flupirtine-induced and linopirdine-sensitive relaxation of coronary artery rings. Moreover, linopirdine diminished bradykinin-induced endothelial-dependent relaxation of coronary artery rings. There was no effect of intracoronary flupirtine or linopirdine on coronary blood flow at the resting heart rate in vivo. Linopirdine had no effect on coronary vasodilation in vivo elicited by ischemia, H2O2, or tachycardia. However, bradykinin increased coronary blood flow in vivo, and this was attenuated by linopirdine. These data indicate that KV7 channels are expressed in some coronary cell type(s) and influence endothelial function. Other physiological functions of coronary vascular KV7 channels remain unclear, but they do appear to contribute to endothelium-dependent responses to paracrine stimuli. PMID:26825518

KV7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine.

PubMed

Goodwill, Adam G; Fu, Lijuan; Noblet, Jillian N; Casalini, Eli D; Sassoon, Daniel; Berwick, Zachary C; Kassab, Ghassan S; Tune, Johnathan D; Dick, Gregory M

2016-03-15

Hydrogen peroxide (H2O2) and voltage-dependent K(+) (KV) channels play key roles in regulating coronary blood flow in response to metabolic, ischemic, and paracrine stimuli. The KV channels responsible have not been identified, but KV7 channels are possible candidates. Existing data regarding KV7 channel function in the coronary circulation (limited to ex vivo assessments) are mixed. Thus we examined the hypothesis that KV7 channels are present in cells of the coronary vascular wall and regulate vasodilation in swine. We performed a variety of molecular, biochemical, and functional (in vivo and ex vivo) studies. Coronary arteries expressed KCNQ genes (quantitative PCR) and KV7.4 protein (Western blot). Immunostaining demonstrated KV7.4 expression in conduit and resistance vessels, perhaps most prominently in the endothelial and adventitial layers. Flupirtine, a KV7 opener, relaxed coronary artery rings, and this was attenuated by linopirdine, a KV7 blocker. Endothelial denudation inhibited the flupirtine-induced and linopirdine-sensitive relaxation of coronary artery rings. Moreover, linopirdine diminished bradykinin-induced endothelial-dependent relaxation of coronary artery rings. There was no effect of intracoronary flupirtine or linopirdine on coronary blood flow at the resting heart rate in vivo. Linopirdine had no effect on coronary vasodilation in vivo elicited by ischemia, H2O2, or tachycardia. However, bradykinin increased coronary blood flow in vivo, and this was attenuated by linopirdine. These data indicate that KV7 channels are expressed in some coronary cell type(s) and influence endothelial function. Other physiological functions of coronary vascular KV7 channels remain unclear, but they do appear to contribute to endothelium-dependent responses to paracrine stimuli. Copyright © 2016 the American Physiological Society.

Nitroglycerin Use in Myocardial Infarction Patients: Risks and Benefits

PubMed Central

Ferreira, Julio C.B.; Mochly-Rosen, Daria

2012-01-01

Acute myocardial infarction and its sequelae are leading causes of morbidity and mortality worldwide. Nitroglycerin remains a first-line treatment for angina pectoris and acute myocardial infarction. Nitroglycerin achieves its benefit by giving rise to nitric oxide, which causes vasodilation and increases blood flow to the myocardium. However, continuous delivery of nitroglycerin results in tolerance, limiting the use of this drug. Nitroglycerin tolerance is due, at least in part, to inactivation of aldehyde dehydrogenase 2 (ALDH2), an enzyme that converts nitroglycerin to the vasodilator, nitric oxide. We have recently found that, in addition to nitroglycerin’s effect on the vasculature, sustained treatment with nitroglycerin negatively affects cardiomyocyte viability following ischemia, thus resulting in increased infarct size in a myocardial infarction model in animals. Co-administration of Alda-1, an activator of ALDH2, with nitroglycerin improves metabolism of reactive aldehyde adducts and prevents the nitroglycerin-induced increase in cardiac dysfunction following myocardial infarction. In this review, we describe the molecular mechanisms associated with the benefits and risks of nitroglycerin administration in myocardial infarction. (167 of 200). PMID:22040938

Role of nitric oxide synthases in early blood-brain barrier disruption following transient focal cerebral ischemia.

PubMed

Jiang, Zheng; Li, Chun; Arrick, Denise M; Yang, Shu; Baluna, Alexandra E; Sun, Hong

2014-01-01

The role of nitric oxide synthases (NOSs) in early blood-brain barrier (BBB) disruption was determined using a new mouse model of transient focal cerebral ischemia. Ischemia was induced by ligating the middle cerebral artery (MCA) at its M2 segment and reperfusion was induced by releasing the ligation. The diameter alteration of the MCA, arterial anastomoses and collateral arteries were imaged and measured in real time. BBB disruption was assessed by Evans Blue (EB) and sodium fluorescein (Na-F) extravasation at 3 hours of reperfusion. The reperfusion produced an extensive vasodilation and a sustained hyperemia. Although expression of NOSs was not altered at 3 hours of reperfusion, L-NAME (a non-specific NOS inhibitor) abolished reperfusion-induced vasodilation/hyperemia and significantly reduced EB and Na-F extravasation. L-NIO (an endothelial NOS (eNOS) inhibitor) significantly attenuated cerebral vasodilation but not BBB disruption, whereas L-NPA and 7-NI (neuronal NOS (nNOS) inhibitors) significantly reduced BBB disruption but not cerebral vasodilation. In contrast, aminoguanidine (AG) (an inducible NOS (iNOS) inhibitor) had less effect on either cerebral vasodilation or BBB disruption. On the other hand, papaverine (PV) not only increased the vasodilation/hyperemia but also significantly reduced BBB disruption. Combined treatment with L-NAME and PV preserved the vasodilation/hyperemia and significantly reduced BBB disruption. Our findings suggest that nNOS may play a major role in early BBB disruption following transient focal cerebral ischemia via a hyperemia-independent mechanism.

Elevated extracellular potassium prior to muscle contraction reduces onset and steady-state exercise hyperemia in humans.

PubMed

Terwoord, Janée D; Hearon, Christopher M; Luckasen, Gary J; Richards, Jennifer C; Joyner, Michael J; Dinenno, Frank A

2018-05-03

The increase in interstitial potassium (K + ) during muscle contractions is thought to be a vasodilatory signal that contributes to exercise hyperemia. To determine the role of extracellular K + in exercise hyperemia, we perfused skeletal muscle with K + prior to contractions such that the effect of any endogenously-released K + would be minimized. We tested the hypothesis that local, intra-arterial infusion of potassium chloride (KCl) at rest would impair vasodilation in response to subsequent rhythmic handgrip exercise in humans. In 11 young adults, we determined forearm blood flow (FBF; Doppler ultrasound) and vascular conductance (FVC; FBF/mean arterial pressure) during 4 minutes of rhythmic handgrip exercise at 10% of maximal voluntary contraction during 1) control conditions (CTRL), 2) infusion of KCl prior to the initiation of exercise, and 3) infusion of sodium nitroprusside (SNP) as a control vasodilator. Infusion of KCl or SNP elevated resting FVC similarly prior to the onset of exercise (CTRL: 39 {plus minus} 6 vs. KCl: 81 {plus minus} 12 and SNP: 82 {plus minus} 13 ml/min/100 mmHg; both P < 0.05 vs. CTRL). Infusion of KCl at rest diminished the hyperemic (Δ FBF) and vasodilatory (Δ FVC) response to subsequent exercise by 22 {plus minus} 5% and 30 {plus minus} 5%, respectively (both P < 0.05 vs. CTRL), whereas SNP did not affect the change in FBF (P = 0.74 vs. CTRL) or FVC (P = 0.61 vs. CTRL) from rest to steady-state exercise. These findings implicate the K + ion as an essential vasodilator substance contributing to exercise hyperemia in humans.

Modification of cutaneous vasodilator response to heat stress by daytime exogenous melatonin administration.

PubMed

Aoki, Ken; Stephens, Dan P; Zhao, Kun; Kosiba, Wojciech A; Johnson, John M

2006-09-01

In humans, the nocturnal fall in internal temperature is associated with increased endogenous melatonin and with a shift in the thermoregulatory control of skin blood flow (SkBF), suggesting a role for melatonin in the control of SkBF. The purpose of this study was to test whether daytime exogenous melatonin would shift control of SkBF to lower internal temperatures during heat stress, as is seen at night. Healthy male subjects (n = 8) underwent body heating with melatonin administration (Mel) or without (control), in random order at least 1 wk apart. SkBF was monitored at sites pretreated with bretylium to block vasoconstrictor nerve function and at untreated sites. Cutaneous vascular conductance, calculated from SkBF and arterial pressure, sweating rate (SR), and heart rate (HR) were monitored. Skin temperature was elevated to 38 degrees C for 35-50 min. Baseline esophageal temperature (Tes) was lower in Mel than in control (P < 0.01). The Tes threshold for cutaneous vasodilation and the slope of cutaneous vascular conductance with respect to Tes were also lower in Mel at both untreated and bretylium-treated sites (P < 0.05). The Tes threshold for the onset of sweating and the Tes for a standard HR were reduced in Mel. The slope of the relationship of HR, but not SR, to Tes was lower in Mel (P < 0.05). These findings suggest that melatonin affects the thermoregulatory control of SkBF during hyperthermia via the cutaneous active vasodilator system. Because control of SR and HR are also modified, a central action of melatonin is suggested.

Effect of acute aerobic exercise and histamine receptor blockade on arterial stiffness in African Americans and Caucasians

PubMed Central

Ranadive, Sushant M.; Lane-Cordova, Abbi D.; Kappus, Rebecca M.; Behun, Michael A.; Cook, Marc D.; Woods, Jeffrey A.; Wilund, Kenneth R.; Baynard, Tracy; Fernhall, Bo

2017-01-01

African Americans (AA) exhibit exaggerated central blood pressure (BP) and arterial stiffness measured by pulse wave velocity (PWV) in response to an acute bout of maximal exercise compared with Caucasians (CA). However, whether potential racial differences exist in central BP, elastic, or muscular arterial distensibility after submaximal aerobic exercise remains unknown. Histamine receptor activation mediates sustained postexercise hyperemia in CA but the effect on arterial stiffness is unknown. This study sought to determine the effects of an acute bout of aerobic exercise on central BP and arterial stiffness and the role of histamine receptors, in AA and CA. Forty-nine (22 AA, 27 CA) young and healthy subjects completed the study. Subjects were randomly assigned to take either histamine receptor antagonist or control placebo. Central blood BP and arterial stiffness measurements were obtained at baseline, and at 30, 60, and 90 min after 45 min of moderate treadmill exercise. AA exhibited greater central diastolic BP, elevated brachial PWV, and local carotid arterial stiffness after an acute bout of submaximal exercise compared with CA, which may contribute to their higher risk of cardiovascular disease. Unexpectedly, histamine receptor blockade did not affect central BP or PWV in AA or CA after exercise, but it may play a role in mediating local carotid arterial stiffness. Furthermore, histamine may mediate postexercise carotid arterial dilation in CA but not in AA. These observations provide evidence that young and healthy AA exhibit an exaggerated hemodynamic response to exercise and attenuated vasodilator response compared with CA. NEW & NOTEWORTHY African Americans are at greater risk for developing cardiovascular disease than Caucasians. We are the first to show that young and healthy African Americans exhibit greater central blood pressure, elevated brachial stiffness, and local carotid arterial stiffness following an acute bout of submaximal exercise compared with Caucasians, which may contribute to their higher risk of cardiovascular disease. Furthermore, African Americans exhibit attenuated vasodilator response compared with Caucasians. PMID:27979988

Effect of acute aerobic exercise and histamine receptor blockade on arterial stiffness in African Americans and Caucasians.

PubMed

Yan, Huimin; Ranadive, Sushant M; Lane-Cordova, Abbi D; Kappus, Rebecca M; Behun, Michael A; Cook, Marc D; Woods, Jeffrey A; Wilund, Kenneth R; Baynard, Tracy; Halliwill, John R; Fernhall, Bo

2017-02-01

African Americans (AA) exhibit exaggerated central blood pressure (BP) and arterial stiffness measured by pulse wave velocity (PWV) in response to an acute bout of maximal exercise compared with Caucasians (CA). However, whether potential racial differences exist in central BP, elastic, or muscular arterial distensibility after submaximal aerobic exercise remains unknown. Histamine receptor activation mediates sustained postexercise hyperemia in CA but the effect on arterial stiffness is unknown. This study sought to determine the effects of an acute bout of aerobic exercise on central BP and arterial stiffness and the role of histamine receptors, in AA and CA. Forty-nine (22 AA, 27 CA) young and healthy subjects completed the study. Subjects were randomly assigned to take either histamine receptor antagonist or control placebo. Central blood BP and arterial stiffness measurements were obtained at baseline, and at 30, 60, and 90 min after 45 min of moderate treadmill exercise. AA exhibited greater central diastolic BP, elevated brachial PWV, and local carotid arterial stiffness after an acute bout of submaximal exercise compared with CA, which may contribute to their higher risk of cardiovascular disease. Unexpectedly, histamine receptor blockade did not affect central BP or PWV in AA or CA after exercise, but it may play a role in mediating local carotid arterial stiffness. Furthermore, histamine may mediate postexercise carotid arterial dilation in CA but not in AA. These observations provide evidence that young and healthy AA exhibit an exaggerated hemodynamic response to exercise and attenuated vasodilator response compared with CA. NEW & NOTEWORTHY African Americans are at greater risk for developing cardiovascular disease than Caucasians. We are the first to show that young and healthy African Americans exhibit greater central blood pressure, elevated brachial stiffness, and local carotid arterial stiffness following an acute bout of submaximal exercise compared with Caucasians, which may contribute to their higher risk of cardiovascular disease. Furthermore, African Americans exhibit attenuated vasodilator response compared with Caucasians. Copyright © 2017 the American Physiological Society.

Nitric oxide mediates local activity-dependent excitatory synapse development.

PubMed

Nikonenko, Irina; Nikonenko, Alexander; Mendez, Pablo; Michurina, Tatyana V; Enikolopov, Grigori; Muller, Dominique

2013-10-29

Learning related paradigms play an important role in shaping the development and specificity of synaptic networks, notably by regulating mechanisms of spine growth and pruning. The molecular events underlying these synaptic rearrangements remain poorly understood. Here we identify NO signaling as a key mediator of activity-dependent excitatory synapse development. We find that chronic blockade of NO production in vitro and in vivo interferes with the development of hippocampal and cortical excitatory spine synapses. The effect results from a selective loss of activity-mediated spine growth mechanisms and is associated with morphological and functional alterations of remaining synapses. These effects of NO are mediated by a cGMP cascade and can be reproduced or prevented by postsynaptic expression of vasodilator-stimulated phosphoprotein phospho-mimetic or phospho-resistant mutants. In vivo analyses show that absence of NO prevents the increase in excitatory synapse density induced by environmental enrichment and interferes with the formation of local clusters of excitatory synapses. We conclude that NO plays an important role in regulating the development of excitatory synapses by promoting local activity-dependent spine-growth mechanisms.

Changes in Retinal and Choroidal Vascular Blood Flow after Oral Sildenafil: An Optical Coherence Tomography Angiography Study.

PubMed

Berrones, David; Salcedo-Villanueva, Guillermo; Morales-Cantón, Virgilio; Velez-Montoya, Raul

2017-01-01

To describe changes in the retina and choroidal flow by optical coherence tomography angiography (OCT-A) after a single dose of oral sildenafil. A case-control study. Patients in the study group received 50 mg of oral sildenafil. Patients in the control group received a sham pill. Retinal and choroidal images were obtained at baseline (before pill ingestion) and 1 hour after ingestion. Central macular and choroidal thickness, choroidal and outer retina flow, and the retinal and choroidal vascular density were compared using a Mann-Whitney U test. Twenty eyes were enrolled into the study group and 10 eyes in the control group. There was a significant difference in central choroidal thickness and outer retina blood flow between groups after 1 hour of sildenafil ingestion ( p < 0.01). There were no differences in central macular thickness, choroidal flow, and retinal vascular density among groups. A single dose of oral sildenafil increases choroidal thickness, probably due to sildenafil-induced vasodilation.

Changes in Retinal and Choroidal Vascular Blood Flow after Oral Sildenafil: An Optical Coherence Tomography Angiography Study

PubMed Central

Berrones, David; Morales-Cantón, Virgilio

2017-01-01

Purpose To describe changes in the retina and choroidal flow by optical coherence tomography angiography (OCT-A) after a single dose of oral sildenafil. Method A case-control study. Patients in the study group received 50 mg of oral sildenafil. Patients in the control group received a sham pill. Retinal and choroidal images were obtained at baseline (before pill ingestion) and 1 hour after ingestion. Central macular and choroidal thickness, choroidal and outer retina flow, and the retinal and choroidal vascular density were compared using a Mann-Whitney U test. Results Twenty eyes were enrolled into the study group and 10 eyes in the control group. There was a significant difference in central choroidal thickness and outer retina blood flow between groups after 1 hour of sildenafil ingestion (p < 0.01). There were no differences in central macular thickness, choroidal flow, and retinal vascular density among groups. Conclusions A single dose of oral sildenafil increases choroidal thickness, probably due to sildenafil-induced vasodilation. PMID:29129998

BK Channels in the Vascular System.

PubMed

Krishnamoorthy-Natarajan, G; Koide, M

2016-01-01

Autoregulation of blood flow is essential for the preservation of organ function to ensure continuous supply of oxygen and essential nutrients and removal of metabolic waste. This is achieved by controlling the diameter of muscular arteries and arterioles that exhibit a myogenic response to changes in arterial blood pressure, nerve activity and tissue metabolism. Large-conductance voltage and Ca(2+)-dependent K(+) channels (BK channels), expressed exclusively in smooth muscle cells (SMCs) in the vascular wall of healthy arteries, play a critical role in regulating the myogenic response. Activation of BK channels by intracellular, local, and transient ryanodine receptor-mediated "Ca(2+) sparks," provides a hyperpolarizing influence on the SMC membrane potential thereby decreasing the activity of voltage-dependent Ca(2+) channels and limiting Ca(2+) influx to promote SMC relaxation and vasodilation. The BK channel α subunit, a large tetrameric protein with each monomer consisting of seven-transmembrane domains, a long intracellular C-terminal tail and an extracellular N-terminus, associates with the β1 and γ subunits in vascular SMCs. The BK channel is regulated by factors originating within the SMC or from the endothelium, perivascular nerves and circulating blood, that significantly alter channel gating properties, Ca(2+) sensitivity and expression of the α and/or β1 subunit. The BK channel thus serves as a central receiving dock that relays the effects of the changes in several such concomitant autocrine and paracrine factors and influences cardiovascular health. This chapter describes the primary mechanism of regulation of myogenic response by BK channels and the alterations to this mechanism wrought by different vasoactive mediators. © 2016 Elsevier Inc. All rights reserved.

Effect of wood smoke exposure on vascular function and thrombus formation in healthy fire fighters.

PubMed

Hunter, Amanda L; Unosson, Jon; Bosson, Jenny A; Langrish, Jeremy P; Pourazar, Jamshid; Raftis, Jennifer B; Miller, Mark R; Lucking, Andrew J; Boman, Christoffer; Nyström, Robin; Donaldson, Kenneth; Flapan, Andrew D; Shah, Anoop S V; Pung, Louis; Sadiktsis, Ioannis; Masala, Silvia; Westerholm, Roger; Sandström, Thomas; Blomberg, Anders; Newby, David E; Mills, Nicholas L

2014-12-09

Myocardial infarction is the leading cause of death in fire fighters and has been linked with exposure to air pollution and fire suppression duties. We therefore investigated the effects of wood smoke exposure on vascular vasomotor and fibrinolytic function, and thrombus formation in healthy fire fighters. In a double-blind randomized cross-over study, 16 healthy male fire fighters were exposed to wood smoke (~1 mg/m³ particulate matter concentration) or filtered air for one hour during intermittent exercise. Arterial pressure and stiffness were measured before and immediately after exposure, and forearm blood flow was measured during intra-brachial infusion of endothelium-dependent and -independent vasodilators 4-6 hours after exposure. Thrombus formation was assessed using the ex vivo Badimon chamber at 2 hours, and platelet activation was measured using flow cytometry for up to 24 hours after the exposure. Compared to filtered air, exposure to wood smoke increased blood carboxyhaemoglobin concentrations (1.3% versus 0.8%; P < 0.001), but had no effect on arterial pressure, augmentation index or pulse wave velocity (P > 0.05 for all). Whilst there was a dose-dependent increase in forearm blood flow with each vasodilator (P < 0.01 for all), there were no differences in blood flow responses to acetylcholine, sodium nitroprusside or verapamil between exposures (P > 0.05 for all). Following exposure to wood smoke, vasodilatation to bradykinin increased (P = 0.003), but there was no effect on bradykinin-induced tissue-plasminogen activator release, thrombus area or markers of platelet activation (P > 0.05 for all). Wood smoke exposure does not impair vascular vasomotor or fibrinolytic function, or increase thrombus formation in fire fighters. Acute cardiovascular events following fire suppression may be precipitated by exposure to other air pollutants or through other mechanisms, such as strenuous physical exertion and dehydration.

[Role of endothelium-derived nitric oxide in sustained flow-dependent dilatation of human peripheral conduit arteries].

PubMed

Bellien, J; Joannidès, R; Iacob, M; Eltchaninoff, H; Thuillez, Ch

2003-01-01

Endothelial dysfunction is involved in the pathogenesis of cardiovascular diseases and is generally associated to the decrease in arterial nitric oxide (NO) availability. In humans, endothelial function can be evaluated by the post-ischaemic flow-dependent dilatation (FDD) of peripheral conduit arteries which is mainly mediated by the NO release when short duration of reactive hyperaemia are used (3 to 5 min ischaemia). However, recent studies suggest that the role of NO in this response decreases as the duration of the hyperaemic stimulation increases. The aim of the present study was thus, to evaluate, in healthy subjects, the role of NO in the FDD of conduct arteries in response to a sustained stimulation. Radial artery diameter (echotracking) and flow (Doppler) were measured, 7 cm under the elbow line, at baseline and during post-ischaemic hyperaemia (10 min wrist cuff inflation) in 10 healthy subjects (age: 24 +/- 1 years) in control period and after acute blockade of the endothelial NO-synthase by local infusion of NG-monomethyl L-arginine (L-NMMA, brachial artery, 8 mumol/min, 7 min). Endothelium-independent dilatation was studied by mean of sodium nitroprusside infusion (SNP: 5, 10 and 20 nmol/min, 3 min each dose before and after L-NMMA). L-NMMA administration decreased radial artery blood flow at base (Control: 14 +/- 2 vs L-NMMA: 10 +/- 1 ml/min, P < 0.05) and increased radial artery vasodilatation in response to SNP (P < 0.05) thus, demonstrating NO-synthase inhibition. Therefore, after L-NMMA there was a small decrease in radial FDD (Control: base: 2.52 +/- 0.05 mm, FDD: 11.3 +/- 0.6% vs L-NMMA: base: 2.51 +/- 0.04 mm: FDD: 9.0 +/- 0.9%; p < 0.05) without change in hyperaemia. In conclusion, our results demonstrate, in contrast to those obtained after short duration of hyperaemia, that the relative implication of NO in the flow-dependent vasodilatation of peripheral conduit arteries in humans decreases in response to sustained stimulation and suggest, in these experimental conditions, an associated flow-dependent vasodilating mechanism that is unaffected by the NO-synthase inhibition.

Mediation of the vasoactive properties of diadenosine tetraphosphate via various purinoceptors.

PubMed

van der Giet, M; Jankowski, J; Schlüter, H; Zidek, W; Tepel, M

1998-12-01

The vasoactive properties of P1,P4-diadenosine tetraphosphate (Ap4A) were studied by measuring the effects of perfusion pressure of a rat isolated perfused kidney. The vasoconstrictive response to Ap4A was mediated to a large extent to a P2X receptor which could be shown by inhibition with pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid tetrasodium. The remaining vasoconstriction of Ap4A could be blocked by a 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective A1 receptor antagonist In raised tone preparation Ap4A evoked vasodilation when P2 receptors were blocked by suramin. The dilation was not mediated by a P2Y receptor as the effect could not be blocked by suramin. Ap4A induces vasoconstriction via A1 and P2X receptors and vasodilatation via an unidentified receptor which is not a P2Y receptor. Ap4A may play an important role in kidney perfusion and, thus, in blood-pressure control.

Mechanism of action vasodilation Annona muricata L. leaves extract mediated vascular smooth muscles

NASA Astrophysics Data System (ADS)

Ismail, S.; Hayati, N.; Rahmawati, N.

2018-04-01

Annona muricata L. leaves (AML) is used as ethnomedicine by the Dayak Abai ethnicity in North Kalimantan for its already known use to reduce blood pressure. However, the mechanism of action in the vessel is still poorly understood. Aim study to prove the mechanism of action of AML in blood vessels. AML was extracted with a maceration technique using ethanol solvent. Mechanism of action test was performed with isolated rat aortic with endothelium (endo-intact) and without endothelium (endo-denuded). AML extract intervention on rats aorta with endo-intact and endo-denuded can induction vasodilatation activity. Increasing AML extract concentration can improve decrease vasodilatation activity on isolated rats aortic with endo-intact compared to endo-denuded, it means that endothelium can weaken vasodilatation activity of aorta mediated by vascular smooth muscle after the extract was given.

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

PubMed Central

Tykocki, Nathan R.; Boerman, Erika M.; Jackson, William F.

2017-01-01

Vascular tone of resistance arteries and arterioles determines peripheral vascular resistance, contributing to the regulation of blood pressure and blood flow to, and within the body’s tissues and organs. Ion channels in the plasma membrane and endoplasmic reticulum of vascular smooth muscle cells (SMCs) in these blood vessels importantly contribute to the regulation of intracellular Ca2+ concentration, the primary determinant of SMC contractile activity and vascular tone. Ion channels provide the main source of activator Ca2+ that determines vascular tone, and strongly contribute to setting and regulating membrane potential, which, in turn, regulates the open-state-probability of voltage gated Ca2+ channels (VGCCs), the primary source of Ca2+ in resistance artery and arteriolar SMCs. Ion channel function is also modulated by vasoconstrictors and vasodilators, contributing to all aspects of the regulation of vascular tone. This review will focus on the physiology of VGCCs, voltage-gated K+ (KV) channels, large-conductance Ca2+-activated K+ (BKCa) channels, strong-inward-rectifier K+ (KIR) channels, ATP-sensitive K+ (KATP) channels, ryanodine receptors (RyRs), inositol 1,4,5-trisphosphate receptors (IP3Rs), and a variety of transient receptor potential (TRP) channels that contribute to pressure-induced myogenic tone in resistance arteries and arterioles, the modulation of the function of these ion channels by vasoconstrictors and vasodilators, their role in the functional regulation of tissue blood flow and their dysfunction in diseases such as hypertension, obesity, and diabetes. PMID:28333380

Inhibition of nitric oxide synthesis in forearm vasculature of insulin-dependent diabetic patients: blunted vasoconstriction in patients with microalbuminuria.

PubMed

Elliott, T G; Cockcroft, J R; Groop, P H; Viberti, G C; Ritter, J M

1993-12-01

1. Microalbuminuria is a risk factor for cardiovascular disease in patients with insulin-dependent diabetes mellitus, and may be a marker of microvascular dysfunction including endothelial damage. The purpose of this study was to determine whether vasoconstrictor responses to NG-monomethyl-L-arginine, an inhibitor of endothelium-derived relaxing factor/nitric oxide biosynthesis, differ between healthy subjects and insulin-dependent patients with or without microalbuminuria. 2. Twenty-eight insulin-dependent diabetic patients (14 with normal albumin excretion, 14 with microalbuminuria) were studied under euglycaemic conditions, together with 14 healthy control subjects. Forearm vascular responses to brachial artery infusions of NG-monomethyl-L-arginine, sodium nitroprusside (an endothelium-independent nitrovasodilator) and carbachol (an endothelium-dependent vasodilator) were determined by strain gauge plethysmography. 3. Basal blood flow and vasodilator responses were similar in each group. NG-Monomethyl-L-arginine reduced blood flow by 41.3 +/- 2.3% (mean +/- SEM) in healthy control subjects, 34.0 +/- 3.4% in diabetic patients without microalbuminuria and 29.2 +/- 2.0% in diabetic patients with microalbuminuria. Diabetic patients differed from healthy subjects (P = 0.005), due to a difference between control subjects and microalbuminuric diabetic patients (P < 0.001). NG-Monomethyl-L-arginine did not influence nitroprusside responses but reduced carbachol responses in control subjects and normoalbuminuric diabetic patients but not in microalbuminuric diabetic patients. 4. These results provide evidence of abnormal endothelium-derived relaxing factor/nitric oxide biosynthesis in insulin-dependent diabetic patients with microalbuminuria.

Increased muscle blood supply and transendothelial nutrient and insulin transport induced by food intake and exercise: effect of obesity and ageing

PubMed Central

Strauss, Juliette A.; Shepherd, Sam O.; Keske, Michelle A.; Cocks, Matthew

2015-01-01

Abstract This review concludes that a sedentary lifestyle, obesity and ageing impair the vasodilator response of the muscle microvasculature to insulin, exercise and VEGF‐A and reduce microvascular density. Both impairments contribute to the development of insulin resistance, obesity and chronic age‐related diseases. A physically active lifestyle keeps both the vasodilator response and microvascular density high. Intravital microscopy has shown that microvascular units (MVUs) are the smallest functional elements to adjust blood flow in response to physiological signals and metabolic demands on muscle fibres. The luminal diameter of a common terminal arteriole (TA) controls blood flow through up to 20 capillaries belonging to a single MVU. Increases in plasma insulin and exercise/muscle contraction lead to recruitment of additional MVUs. Insulin also increases arteriolar vasomotion. Both mechanisms increase the endothelial surface area and therefore transendothelial transport of glucose, fatty acids (FAs) and insulin by specific transporters, present in high concentrations in the capillary endothelium. Future studies should quantify transporter concentration differences between healthy and at risk populations as they may limit nutrient supply and oxidation in muscle and impair glucose and lipid homeostasis. An important recent discovery is that VEGF‐B produced by skeletal muscle controls the expression of FA transporter proteins in the capillary endothelium and thus links endothelial FA uptake to the oxidative capacity of skeletal muscle, potentially preventing lipotoxic FA accumulation, the dominant cause of insulin resistance in muscle fibres. PMID:25627798

Evidence that inhibitory factor extracted from bovine retractor penis is nitrite, whose acid-activated derivative is stabilized nitric oxide.

PubMed Central

Martin, W.; Smith, J. A.; Lewis, M. J.; Henderson, A. H.

1988-01-01

1. Unactivated extracts of bovine retractor penis (BRP) contains 3-7 microM nitrite. Acid-activation of these extracts at pH 2 for 10 min followed by neutralization generates the active form of inhibitory factor (IF; assayed by its vasodilator action on rabbit aorta), and is associated with partial loss of nitrite. 2. Increasing the time of acid-activation at pH 2 from 10 to 60 min with intermittent vortex mixing generates greater vasodilator activity and increases nitrite loss. 3. When acid-activated and neutralized extracts are incubated at 37 degrees C or 30 min or boiled for 5 min, vasodilator activity is lost and nitrite content increased. Reactivation of these samples at pH 2 for 10 min followed by neutralization leads to partial recoveries of vasodilator activity with loss in nitrite content. 4. Addition of sodium nitrite to BRP extracts increases acid-activatable vasodilator activity pro rata. 5. Acid-activation of aqueous sodium nitrite solutions results in less loss of nitrite and generation of less vasodilator activity than BRP extracts. Vasodilatation is only transient and is rapidly abolished on neutralization, whereas responses to acid-activated BRP extracts are more prolonged and activity is stable on ice. 6. Bovine aortic endothelial cells yield vasodilator activity that is indistinguishable from that isolated from BRP. It is activated by acid, stable on ice, abolished by boiling or by haemoglobin, and appears to be due to the generation of nitric oxide (NO) from nitrite.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2897219

Impaired vasodilator response to organic nitrates in isolated basilar arteries

PubMed Central

Martens, Dorothee; Kojda, Georg

2001-01-01

The differential responsiveness of various sections and regions in the vascular system to the vasodilator activity of organic nitrates is important for the beneficial antiischaemic effects of these drugs. In this study we examined the vasodilator activity of organic nitrates in cerebral arteries, where vasodilation causes substantial nitrate induced headache. Isolated porcine basilar and coronary arteries were subjected to increasing concentrations of glyceryl trinitrate (GTN), isosorbide-5-nitrate (ISMN) and pentaerythritol tetranitrate (PETN). S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and endothelium-dependent vasodilation was investigated for comparison purpose. The vasodilator potency (halfmaximal effective concentration in −logM) of GTN (4.33±0.1, n=8), ISMN (1.61±0.07, n=7) and PETN (>10 μM, n=7) in basilar arteries was more than 100 fold lower than that of GTN (6.52±0.06, n=12), ISMN (3.66±0.08, n=10) and PETN (6.3±0.13, n=8) observed in coronary arteries. In striking contrast, the vasodilator potency of SNAP (halfmaximal effective concentration in −logM) was almost similar in basilar (7.76±0.05, n=7) and coronary arteries (7.59±0.05, n=9). Likewise, no difference in endothelium dependent relaxation was observed. Denudation of the endothelium resulted in a small increase of the vasodilator potency (halfmaximal effective concentration in −logM) of GTN (4.84±0.09, n=7, P<0.03) in basilar arteries and similar results were obtained in the presence of the NO-synthase inhibitor Nω-nitro-L-arginine (4.59±0.05, n=9, P<0.03). These results suggest that cerebral conductance blood vessels such as porcine basilar arteries seems to have a reduced expression and/or activity of certain cellular enzymatic electron transport systems such as cytochrome P450 enzymes, which are necessary to bioconvert organic nitrates to NO. PMID:11156558

UVA irradiation of human skin vasodilates arterial vasculature and lowers blood pressure independently of nitric oxide synthase.

PubMed

Liu, Donald; Fernandez, Bernadette O; Hamilton, Alistair; Lang, Ninian N; Gallagher, Julie M C; Newby, David E; Feelisch, Martin; Weller, Richard B

2014-07-01

The incidence of hypertension and cardiovascular disease (CVD) correlates with latitude and rises in winter. The molecular basis for this remains obscure. As nitric oxide (NO) metabolites are abundant in human skin, we hypothesized that exposure to UVA may mobilize NO bioactivity into the circulation to exert beneficial cardiovascular effects independently of vitamin D. In 24 healthy volunteers, irradiation of the skin with two standard erythemal doses of UVA lowered blood pressure (BP), with concomitant decreases in circulating nitrate and rises in nitrite concentrations. Unexpectedly, acute dietary intervention aimed at modulating systemic nitrate availability had no effect on UV-induced hemodynamic changes, indicating that cardiovascular effects were not mediated via direct utilization of circulating nitrate. UVA irradiation of the forearm caused increased blood flow independently of NO synthase (NOS) activity, suggesting involvement of pre-formed cutaneous NO stores. Confocal fluorescence microscopy studies of human skin pre-labeled with the NO-imaging probe diaminofluorescein 2 diacetate revealed that UVA-induced NO release occurs in a NOS-independent, dose-dependent manner, with the majority of the light-sensitive NO pool in the upper epidermis. Collectively, our data provide mechanistic insights into an important function of the skin in modulating systemic NO bioavailability, which may account for the latitudinal and seasonal variations of BP and CVD.

Short-term tibolone does not interfere with endothelial function: a double-blinded, randomized, controlled trial.

PubMed

Celani, M F S; Hurtado, R; Brandão, A H F; Maciel da Fonseca, A M R; Geber, S

2016-06-01

Objective To evaluate the effect of short-term hormone replacement therapy with tibolone 2.5 mg daily on endothelial function of healthy postmenopausal women, using flow-mediated dilation (FMD) of the brachial artery. Methods We performed a randomized, double-blinded, placebo-controlled study. A total of 100 healthy postmenopausal women were randomly allocated to receive tibolone (n = 50) or placebo (n = 50) for 28 days. Measurement of the FMD of the brachial artery was performed before and after the use of tibolone and placebo. Results A total of 31 women completed the study in the tibolone group, and 32 women completed the study in the control group. The results of the FMD measurements obtained from the women in the two groups before treatment were similar (0.018 and 0.091, for tibolone and placebo, p = 0.57). The values of the FMD in women who used tibolone and placebo, before and after the treatment, were similar in both groups. The numbers of women who presented an increase in the values of the FMD in both groups were also similar. Conclusion Our results demonstrate that the administration of 2.5 mg tibolone to healthy postmenopausal women for 28 days does not promote endothelial-dependent vasodilation, measured by FMD of the brachial artery.

Concord Grape Juice Polyphenols and Cardiovascular Risk Factors: Dose-Response Relationships

PubMed Central

Blumberg, Jeffrey B.; Vita, Joseph A.; Chen, C. -Y. Oliver

2015-01-01

Pure fruit juices provide nutritional value with evidence suggesting some of their benefits on biomarkers of cardiovascular disease risk may be derived from their constituent polyphenols, particularly flavonoids. However, few data from clinical trials are available on the dose-response relationship of fruit juice flavonoids to these outcomes. Utilizing the results of clinical trials testing single doses, we have analyzed data from studies of 100% Concord grape juice by placing its flavonoid content in the context of results from randomized clinical trials of other polyphenol-rich foods and beverages describing the same outcomes but covering a broader range of intake. We selected established biomarkers determined by similar methods for measuring flow-mediated vasodilation (FMD), blood pressure, platelet aggregation, and the resistance of low density lipoprotein cholesterol (LDL) to oxidation. Despite differences among the clinical trials in the treatment, subjects, and duration, correlations were observed between the dose and FMD. Inverse dose-response relationships, albeit with lower correlation coefficients, were also noted for the other outcomes. These results suggest a clear relationship between consumption of even modest serving sizes of Concord grape juice, flavonoid intake, and effects on risk factors for cardiovascular disease. This approach to dose-response relationships may prove useful for testing other individual foods and beverages. PMID:26633488

Evaluating endothelial function of the common carotid artery: an in vivo human model.

PubMed

Mazzucco, S; Bifari, F; Trombetta, M; Guidi, G C; Mazzi, M; Anzola, G P; Rizzuto, N; Bonadonna, R

2009-03-01

Flow mediated dilation (FMD) of peripheral conduit arteries is a well-established tool to evaluate endothelial function. The aims of this study are to apply the FMD model to cerebral circulation by using acetazolamide (ACZ)-induced intracranial vasodilation as a stimulus to increase common carotid artery (CCA) diameter in response to a local increase of blood flow velocity (BFV). In 15 healthy subjects, CCA end-diastolic diameter and BFV, middle cerebral artery (MCA) BFV and mean arterial blood pressure (MBP) were measured at basal conditions, after an intravenous bolus of 1g ACZ, and after placebo (saline) sublingual administration at the 15th and 20th minute. In a separate session, the same parameters were evaluated after placebo (saline) infusion instead of ACZ and after 10 microg/m(2) bs and 300 microg of glyceryl trinitrate (GTN), administered sublingually, at the 15th and 20th minute, respectively. After ACZ bolus, there was a 35% maximal MCA mean BFV increment (14th minute), together with a 22% increase of mean CCA end-diastolic BFV and a CCA diameter increment of 3.9% at the 3rd minute (p=0.024). There were no MBP significant variations up to the 15th minute (p=0.35). After GTN administration, there was a significant increment in CCA diameter (p<0.00001). ACZ causes a detectable CCA dilation in healthy individuals concomitantly with an increase in BFV. Upon demonstration that this phenomenon is endothelium dependent, this experimental model might become a valuable tool to assess endothelial function in the carotid artery.

Cerebroprotective functions of HO-2.

PubMed

Parfenova, Helena; Leffler, Charles W

2008-01-01

The constitutive isoform of heme oxygenase, HO-2, is highly expressed in the brain and in cerebral vessels. HO-2 functions in the brain have been evaluated using pharmacological inhibitors of the enzyme and HO-2 gene deletion in in vivo animal models and in cultured cells (neurons, astrocytes, cerebral vascular endothelial cells). Rapid activation of HO-2 via post-translational modifications without upregulation of HO-2 expression or HO-1 induction coincides with the increase in cerebral blood flow aimed at maintaining brain homeostasis and neuronal survival during seizures, hypoxia, and hypotension. Pharmacological inhibition or gene deletion of brain HO-2 exacerbates oxidative stress induced by seizures, glutamate, and inflammatory cytokines, and causes cerebral vascular injury. Carbon monoxide (CO) and bilirubin, the end products of HO-catalyzed heme degradation, have distinct cytoprotective functions. CO, by binding to a heme prosthetic group, regulates the key components of cell signaling, including BK(Ca) channels, guanylyl cyclase, NADPH oxidase, and the mitochondria respiratory chain. Cerebral vasodilator effects of CO are mediated via activation of BK(Ca) channels and guanylyl cyclase. CO, by inhibiting the major components of endogenous oxidant-generating machinery, NADPH oxidase and the cytochrome C oxidase of the mitochondrial respiratory chain, blocks formation of reactive oxygen species. Bilirubin, via redox cycling with biliverdin, is a potent oxidant scavenger that removes preformed oxidants. Overall, HO-2 has dual housekeeping cerebroprotective functions by maintaining autoregulation of cerebral blood flow aimed at improving neuronal survival in a changing environment, and by providing an effective defense mechanism that blocks oxidant formation and prevents cell death caused by oxidative stress.

A high precision dual feedback pump for unsteady perfusion of small organs.

PubMed

Sutton, D W; Mead, E H; Schmid-Schönbein, G W

1989-01-01

A dynamic pump system is described for perfusion of small organs with whole blood. The pump system was designed with the following aims: Very low flowrates to perfuse single organs in small rodents; high dynamic response for pressure or flow to permit experimenting with a harmonic signal at frequencies up to 20 Hz or by way of sharp step transients in less than 10 msec; high precision to allow detection of fine physiological details, and minimum blood cell trauma or cell activation by use of a piston principle. Representative pressure-flow curves are shown for the rat gracilis muscle after vasodilation. The curves are highly reproducible and serve as a complimentary dataset for microvascular observations in the same organ.

Ex vivo and in vivo studies of CME-1, a novel polysaccharide purified from the mycelia of Cordyceps sinensis that inhibits human platelet activation by activating adenylate cyclase/cyclic AMP.

PubMed

Lu, Wan-Jung; Chang, Nen-Chung; Jayakumar, Thanasekaran; Liao, Jiun-Cheng; Lin, Mei-Jiun; Wang, Shwu-Huey; Chou, Duen-Suey; Thomas, Philip Aloysius; Sheu, Joen-Rong

2014-12-01

CME-1, a novel water-soluble polysaccharide, was purified from the mycelia of Cordyceps sinensis, and its chemical structure was characterized to contain mannose and galactose in a ratio of 4:6 (27.6 kDa). CME-1 was originally observed to exert a potent inhibitory effect on tumor migration and a cytoprotective effect against oxidative stress. Activation of platelets caused by arterial thrombosis is relevant to various cardiovascular diseases (CVDs). However, no data are available concerning the effects of CME-1 on platelet activation. Hence, the purpose of this study was to examine the ex vivo and in vivo antithrombotic effects of CME-1 and its possible mechanisms in platelet activation. The aggregometry, immunoblotting, flow cytometric analysis and platelet functional analysis were used in this study. CME-1 (2.3-7.6 μM) exhibited highly potent activity in inhibiting human platelet aggregation when stimulated by collagen, thrombin, and arachidonic acid but not by U46619. CME-1 inhibited platelet activation accompanied by inhibiting Akt, mitogen-activated protein kinases (MAPKs), thromboxane B2 (TxB2) and hydroxyl radical (OH(●)) formation. However, CME-1 interrupted neither FITC-triflavin nor FITC-collagen binding to platelets. CME-1 markedly increased cyclic AMP levels, but not cyclic GMP levels, and stimulated vasodilator-stimulated phosphoprotein (VASP) phosphorylation. SQ22536, an inhibitor of adenylate cyclase, but not ODQ, an inhibitor of guanylate cyclase, obviously reversed the CME-1-mediated effects on platelet aggregation and vasodilator-stimulated phosphoprotein (VASP), Akt, p38 MAPK phosphorylation, and TxB2 formation. CME-1 substantially prolonged the closure time of whole blood and the occlusion time of platelet plug formation. This study demonstrates for the first time that CME-1 exhibits highly potent antiplatelet activity that may initially activate adenylate cyclase/cyclic AMP and, subsequently, inhibit intracellular signals (such as Akt and MAPKs), ultimately inhibiting platelet activation. This novel role of CME-1 indicates that CME-1 exhibits high potential for application in treating and preventing CVDs. Copyright © 2014 Elsevier Ltd. All rights reserved.

Acute antioxidant supplementation and skeletal muscle vascular conductance in aged rats: role of exercise and fiber type.

PubMed

Hirai, Daniel M; Copp, Steven W; Schwagerl, Peter J; Haub, Mark D; Poole, David C; Musch, Timothy I

2011-04-01

Age-related increases in oxidative stress contribute to impaired skeletal muscle vascular control. However, recent evidence indicates that antioxidant treatment with tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) attenuates flow-mediated vasodilation in isolated arterioles from the highly oxidative soleus muscle of aged rats. Whether antioxidant treatment with tempol evokes similar responses in vivo at rest and during exercise in senescent individuals and whether this effect varies based on muscle fiber type composition are unknown. We tested the hypothesis that redox modulation via acute systemic tempol administration decreases vascular conductance (VC) primarily in oxidative hindlimb locomotor muscles at rest and during submaximal whole body exercise (treadmill running at 20 m/min, 5% grade) in aged rats. Eighteen old (25-26 mo) male Fischer 344 x Brown Norway rats were assigned to either rest (n = 8) or exercise (n = 10) groups. Regional VC was determined via radiolabeled microspheres before and after intra-arterial administration of tempol (302 μmol/kg). Tempol decreased mean arterial pressure significantly by 9% at rest and 16% during exercise. At rest, similar VC in 26 out of 28 individual hindlimb muscles or muscle parts following tempol administration compared with control resulted in unchanged total hindlimb muscle VC (control: 0.18 ± 0.02; tempol: 0.17 ± 0.05 ml·min(-1)·100 g(-1)·mmHg(-1); P > 0.05). During exercise, all individual hindlimb muscles or muscle parts irrespective of fiber type composition exhibited either an increase or no change in VC with tempol (i.e., ↑11 and ↔17 muscles or muscle parts), such that total hindlimb VC increased by 25% (control: 0.93 ± 0.04; tempol: 1.15 ± 0.09 ml·min(-1)·100 g(-1)·mmHg(-1); P ≤ 0.05). These results demonstrate that acute systemic administration of the antioxidant tempol significantly impacts the control of regional vascular tone in vivo presumably via redox modulation and improves skeletal muscle vasodilation independently of fiber type composition during submaximal whole body exercise in aged rats.

Direct sGC Activation Bypasses NO Scavenging Reactions of Intravascular Free Oxy-Hemoglobin and Limits Vasoconstriction

PubMed Central

Tabima, D. Marcela; Specht, Patricia A.C.; Tejero, Jesús; Champion, Hunter C.; Kim-Shapiro, Daniel B.; Baust, Jeff; Mik, Egbert G.; Hildesheim, Mariana; Stasch, Johannes-Peter; Becker, Eva-Maria; Truebel, Hubert

2013-01-01

Abstract Aims: Hemoglobin-based oxygen carriers (HBOC) provide a potential alternative to red blood cell (RBC) transfusion. Their clinical application has been limited by adverse effects, in large part thought to be mediated by the intravascular scavenging of the vasodilator nitric oxide (NO) by cell-free plasma oxy-hemoglobin. Free hemoglobin may also cause endothelial dysfunction and platelet activation in hemolytic diseases and after transfusion of aged stored RBCs. The new soluble guanylate cyclase (sGC) stimulator Bay 41-8543 and sGC activator Bay 60-2770 directly modulate sGC, independent of NO bioavailability, providing a potential therapeutic mechanism to bypass hemoglobin-mediated NO inactivation. Results: Infusions of human hemoglobin solutions and the HBOC Oxyglobin into rats produced a severe hypertensive response, even at low plasma heme concentrations approaching 10 μM. These reactions were only observed for ferrous oxy-hemoglobin and not analogs that do not rapidly scavenge NO. Infusions of L-NG-Nitroarginine methyl ester (L-NAME), a competitive NO synthase inhibitor, after hemoglobin infusion did not produce additive vasoconstriction, suggesting that vasoconstriction is related to scavenging of vascular NO. Open-chest hemodynamic studies confirmed that hypertension occurred secondary to direct effects on increasing vascular resistance, with limited negative cardiac inotropic effects. Intravascular hemoglobin reduced the vasodilatory potency of sodium nitroprusside (SNP) and sildenafil, but had no effect on vasodilatation by direct NO-independent activation of sGC by BAY 41-8543 and BAY 60-2770. Innovation and Conclusion: These data suggest that both sGC stimulators and sGC activators could be used to restore cyclic guanosine monophosphate-dependent vasodilation in conditions where cell-free plasma hemoglobin is sufficient to inhibit endogenous NO signaling. Antioxid. Redox Signal. 19, 2232–2243. PMID:23697678

Regulation of the Na(+)-K(+)-2Cl(-) cotransporter by cGMP/cGMP-dependent protein kinase I after furosemide administration.

PubMed

Limmer, Franziska; Schinner, Elisabeth; Castrop, Hayo; Vitzthum, Helga; Hofmann, Franz; Schlossmann, Jens

2015-10-01

Sodium chloride reabsorption in the thick ascending limb of the loop of Henle is mediated by the Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). The loop diuretic furosemide is a potent inhibitor of NKCC2. However, less is known about the mechanism regulating the electrolyte transporter. Considering the well-established effects of nitric oxide on NKCC2 activity, cGMP is likely involved in this regulation. cGMP-dependent protein kinase I (cGKI; PKGI) is a cGMP target protein that phosphorylates different substrates after activation through cGMP. We investigated the potential correlation between the cGMP/cGKI pathway and NKCC2 regulation. We treated wild-type (wt) and cGKIα-rescue mice with furosemide. cGKIα-rescue mice expressed cGKIα only under the control of the smooth muscle-specific transgelin (SM22) promoter in a cGKI deficient background. Furosemide treatment increased the urine excretion of sodium and chloride in cGKIα-rescue mice compared to that in wt mice. We analyzed the phosphorylation of NKCC2 by western blotting and immunostaining using the phosphospecific antibody R5. The administration of furosemide significantly increased the phosphorylated NKCC2 signal in wt but not in cGKIα-rescue mice. NKCC2 activation led to its phosphorylation and membrane translocation. To examine whether cGKI was involved in this process, we analyzed vasodilator-stimulated phosphoprotein, which is phosphorylated by cGKI. Furosemide injection resulted in increased vasodilator-stimulated phosphoprotein phosphorylation in wt mice. We hypothesize that furosemide administration activated cGKI, leading to NKCC2 phosphorylation and membrane translocation. This cGKI-mediated pathway could be a mechanism to compensate for the inhibitory effect of furosemide on NKCC2. © 2015 FEBS.

The Role of Nitroglycerin and Other Nitrogen Oxides in Cardiovascular Therapeutics.

PubMed

Divakaran, Sanjay; Loscalzo, Joseph

2017-11-07

The use of nitroglycerin in the treatment of angina pectoris began not long after its original synthesis in 1847. Since then, the discovery of nitric oxide as a biological effector and better understanding of its roles in vasodilation, cell permeability, platelet function, inflammation, and other vascular processes have advanced our knowledge of the hemodynamic (mostly mediated through vasodilation of capacitance and conductance arteries) and nonhemodynamic effects of organic nitrate therapy, via both nitric oxide-dependent and -independent mechanisms. Nitrates are rapidly absorbed from mucous membranes, the gastrointestinal tract, and the skin; thus, nitroglycerin is available in a number of preparations for delivery via several routes: oral tablets, sublingual tablets, buccal tablets, sublingual spray, transdermal ointment, and transdermal patch, as well as intravenous formulations. Organic nitrates are commonly used in the treatment of cardiovascular disease, but clinical data limit their use mostly to the treatment of angina. They are also used in the treatment of subsets of patients with heart failure and pulmonary hypertension. One major limitation of the use of nitrates is the development of tolerance. Although several agents have been studied for use in the prevention of nitrate tolerance, none are currently recommended owing to a paucity of supportive clinical data. Only 1 method of preventing nitrate tolerance remains widely accepted: the use of a dosing strategy that provides an interval of no or low nitrate exposure during each 24-h period. Nitric oxide's important role in several cardiovascular disease mechanisms continues to drive research toward finding novel ways to affect both endogenous and exogenous sources of this key molecular mediator. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Leptin resistance extends to the coronary vasculature in prediabetic dogs and provides a protective adaptation against endothelial dysfunction.

PubMed

Knudson, Jarrod D; Dincer, U Deniz; Dick, Gregory M; Shibata, Haruki; Akahane, Rie; Saito, Masayuki; Tune, Johnathan D

2005-09-01

Hyperleptinemia, associated with prediabetes, is an independent risk factor for coronary artery disease and a mediator of coronary endothelial dysfunction. We previously demonstrated that acutely raising the leptin concentration to levels comparable with those observed in human obesity significantly attenuates coronary dilation/relaxation to acetylcholine (ACh) both in vivo in anesthetized dogs and in vitro in isolated canine coronary rings. Accordingly, the purpose of this investigation was to extend these studies to a model of prediabetes with chronic hyperleptinemia. In the present investigation, experiments were conducted on control and high-fat-fed dogs. High-fat feeding caused a significant increase (131%) in plasma leptin concentration. Furthermore, in high-fat-fed dogs, exogenous leptin did not significantly alter vascular responses to ACh in vivo or in vitro. Coronary vasodilator responses to ACh (0.3-30.0 microg/min) and sodium nitroprusside (1.0-100.0 microg/min) were not significantly different from those observed in control dogs. Also, high-fat feeding did not induce a switch to an endothelium-derived hyperpolarizing factor as a major mediator of muscarinic coronary vasodilation, because dilation to ACh was abolished by combined pretreatment with N(omega)-nitro-l-arginine methyl ester (150 microg/min ic) and indomethacin (10 mg/kg iv). Quantitative, real-time PCR revealed no significant difference in coronary artery leptin receptor gene expression between control and high-fat-fed dogs. In conclusion, high-fat feeding induces resistance to the coronary vascular effects of leptin, and this represents an early protective adaptation against endothelial dysfunction. The resistance is not due to altered endothelium-dependent or -independent coronary dilation, increased endothelium-derived hyperpolarizing factor, or changes in coronary leptin receptor mRNA levels.

Endothelin A receptor antagonists in congestive heart failure: blocking the beast while leaving the beauty untouched?

PubMed

Spieker, L E; Noll, G; Ruschitzka, F T; Lüscher, T F

2001-12-01

Congestive heart failure (CHF) is a disease process characterized by impaired left ventricular function, increased peripheral and pulmonary vascular resistance and reduced exercise tolerance and dyspnea. Thus, mediators involved in the control of myocardial function and vascular tone may be involved in its pathophysiology. The family of endothelins (ET) consists of four closely related peptides, ET-1, ET-2, ET-3, and ET-4, which cause vasoconstriction, cell proliferation, and myocardial effects through activation of ET(A) receptors. In contrast, endothelial ET(B) receptors mediate vasodilation via release of nitric oxide and prostacyclin. In addition, ET(B) receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Thus, infusion of an ET(A) receptor antagonist into the brachial artery in healthy humans leads to vasodilation whereas infusion of an ET(B) receptor antagonist causes vasoconstriction. ET-1 plasma levels are elevated in CHF and correlate both with the hemodynamic severity and with symptoms. Plasma levels of ET-1 and its precursor, big ET-1, are strong independent predictors of death in patients after myocardial infarction and with CHF. ET-1 contributes to increased systemic and pulmonary vascular resistance, vascular dysfunction, myocardial ischemia, and renal impairment in CHF. Selective ET(A) as well as combined ET(A/B) receptor antagonists have been studied in patients with CHF showing impressive hemodynamic improvements (i.e. reduced peripheral vascular and pulmonary resistance as well as increased cardiac output). These results indicate that ET receptor antagonists indeed have a potential to improve hemodynamics, symptoms, and potentially prognosis of CHF which still carries a high mortality.

COPD as an endothelial disorder: endothelial injury linking lesions in the lungs and other organs? (2017 Grover Conference Series)

PubMed Central

Polverino, Francesca; Celli, Bartolome R.

2018-01-01

Chronic obstructive pulmonary disease (COPD) is characterized by chronic expiratory airflow obstruction that is not fully reversible. COPD patients develop varying degrees of emphysema, small and large airway disease, and various co-morbidities. It has not been clear whether these co-morbidities share common underlying pathogenic processes with the pulmonary lesions. Early research into the pathogenesis of COPD focused on the contributions of injury to the extracellular matrix and pulmonary epithelial cells. More recently, cigarette smoke-induced endothelial dysfunction/injury have been linked to the pulmonary lesions in COPD (especially emphysema) and systemic co-morbidities including atherosclerosis, pulmonary hypertension, and chronic renal injury. Herein, we review the evidence linking endothelial injury to COPD, and the pathways underlying endothelial injury and the “vascular COPD phenotype” including: (1) direct toxic effects of cigarette smoke on endothelial cells; (2) generation of auto-antibodies directed against endothelial cells; (3) vascular inflammation; (4) increased oxidative stress levels in vessels inducing increases in lipid peroxidation and increased activation of the receptor for advanced glycation end-products (RAGE); (5) reduced activation of the anti-oxidant pathways in endothelial cells; (6) increased endothelial cell release of mediators with vasoconstrictor, pro-inflammatory, and remodeling activities (endothelin-1) and reduced endothelial cell expression of mediators that promote vasodilation and homeostasis of endothelial cells (nitric oxide synthase and prostacyclin); and (7) increased endoplasmic reticular stress and the unfolded protein response in endothelial cells. We also review the literature on studies of drugs that inhibit RAGE signaling in other diseases (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), or vasodilators developed for idiopathic pulmonary arterial hypertension that have been tested on cell culture systems, animal models of COPD, and/or smokers and COPD patients. PMID:29468936

Dietary antioxidants preserve endothelium-dependent vessel relaxation in cholesterol-fed rabbits.

PubMed Central

Keaney, J F; Gaziano, J M; Xu, A; Frei, B; Curran-Celentano, J; Shwaery, G T; Loscalzo, J; Vita, J A

1993-01-01

Recent evidence suggests that dietary therapy with lipid-soluble antioxidants may be beneficial for patients with atherosclerotic vascular disease but the potential mechanism(s) for these observations remain obscure. Abnormalities in endothelium-dependent control of vascular tone develop early in the course of atherosclerosis and may result from oxidative modification of low density lipoproteins. We examined the role of dietary antioxidants in preserving normal endothelial cell vasodilator function in cholesterol-fed rabbits with particular attention to possible effects on serum lipoproteins, low density lipoprotein oxidation, and atherogenesis. Male New Zealand White rabbits were fed diets containing no additive (controls), 1% cholesterol (cholesterol group), or 1% cholesterol chow supplemented with either beta-carotene (0.6 g/kg of chow) or alpha-tocopherol (1000 international units/kg of chow) for a 28-day period. After dietary therapy, thoracic aortae were harvested for assay of vascular function and for pathologic examination and tissue antioxidant levels. Compared to controls, acetylcholine- and A23187-mediated endothelium-dependent relaxations were significantly impaired in vessels from the cholesterol group (P < 0.001), whereas vessels from animals treated with beta-carotene or alpha-tocopherol demonstrated normal endothelium-dependent arterial relaxation. Preservation of endothelial function was associated with vascular incorporation of alpha-tocopherol and beta-carotene but was unrelated to plasma lipoprotein levels, smooth muscle cell function, or the extent of atherosclerosis. Increased low density lipoprotein resistance to ex vivo copper-mediated oxidation was observed only in the alpha-tocopherol group. Our results suggest that dietary antioxidants may benefit patients with atherosclerosis by preserving endothelial vasodilator function through a mechanism related to vascular tissue antioxidant content and not reflected by assay of low density lipoprotein resistance to ex vivo oxidation. PMID:8265642

The Mediation of Platelet Quiescence by NO-Releasing Polymers via cGMP-Induced Serine 239 Phosphorylation of Vasodilator-Stimulated Phosphoprotein

PubMed Central

Major, Terry C; Handa, Hitesh; Brisbois, Elizabeth J; Reynolds, Melissa M; Annich, Gail M; Meyerhoff, Mark E; Bartlett, Robert H

2013-01-01

Nitric oxide (NO) releasing (NORel) materials have been shown to create localized increases in NO concentration by the release of NO from a diazeniumdiaolate-containing or S-nitrosothiol-containing polymer coating and the improvement of extracorporeal circulation (ECC) hemocompatibility. However, the mechanism and, in particular, the platelet upregulation of the NO/cGMP signaling protein, vasodilator-stimulated phosphoprotein phosphorylated at serine 239 (P-VASP (ser 239), for the improved ECC hemocompatibility via NO release still needs elucidation. In this work, two NORel polymeric coatings were evaluated in a 4 h rabbit thrombogenicity (RT) model and the anti-thrombotic mechanism investigated for rabbit platelet P-VASP upregulation. Polymer films containing 25 wt% diazeniumdiolated dibutylhexansdiamine (DBHD) or 5 wt% S-nitroso-N-acetylpenicillamine (SNAP) coated on the inner walls of ECC circuits yielded significantly reduced ECC thrombus formation and maintained normal platelet aggregation compared to polymer controls after 4 h of blood exposure. Platelet P-VASP (ser 239), a useful tool to monitor NO/cGMP signaling, was upregulated after 4 h on ECC and markedly increased after ex vivo sodium nitroprusside (SNP) stimulation. Interestingly, in the rabbit platelet, NO did not upregulate the cAMP P-VASP phosphoprotein P-VASP (ser 157) as previously shown in human platelets. These results suggest that NORel polymers preserve rabbit platelet quiescence by sustainng a level of cGMP signaling as monitored by P-VASP (ser 239) upregulation. The upregulation of this NO-mediated platelet signaling mechanism in this RT model indicates the potential for improved thromboresistance of any NORel-coated medical device. PMID:23906514

Use-dependent loss of active sympathetic neurogenic vasodilation after nitric oxide synthase inhibition in conscious rats. Evidence for the presence of preformed stores of nitric oxide-containing factors

NASA Technical Reports Server (NTRS)

Davisson, R. L.; Shaffer, R. A.; Johnson, A. K.; Lewis, S. J.

1996-01-01

In this study, we examined whether air-jet stress-induced active sympathetic hindlimb vasodilation in conscious rats involves the release of preformed stores of nitric oxide-containing factors. We determined the effects of repeated episodes of air-jet stress (six episodes given 5 minutes apart) on mean arterial pressure and vascular resistances in the mesenteric bed and intact and sympathetically denervated hindlimb beds of conscious rats treated with saline or the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 25 mumol/kg IV). In saline-treated rats, air-jet stress produced alerting behavior, minor changes in blood pressure, pronounced mesenteric vaso-constriction, and immediate and marked vasodilation in the sympathetically intact hindlimb but a minor vasodilation in the sympathetically denervated hindlimb. Each air-jet stress produced virtually identical responses. In L-NAME-treated rats, the first air-jet stress produced vasodilator responses in the sympathetically intact and sympathetically denervated hindlimbs that were similar to those in the saline-treated rats. However, each subsequent air-jet stress produced progressively smaller vasodilator responses in the sympathetically intact but not the sympathetically denervated hindlimb. There was no loss of air-jet stress-induced alerting behavior or mesenteric vasoconstriction, suggesting that L-NAME did not interfere with the central processing of the air-jet or the resultant changes in autonomic nerve activity. The progressive diminution of air-jet stress-induced vasodilation in the intact hindlimb of L-NAME-treated rats may be due to the use-dependent depletion of preformed stores of nitric oxide-containing factors that cannot be replenished in the absence of nitric oxide synthesis.

A potential nitrergic mechanism of action for indomethacin, but not of other COX inhibitors: relevance to indomethacin-sensitive headaches.

PubMed

Summ, Oliver; Andreou, Anna P; Akerman, Simon; Goadsby, Peter J

2010-12-01

Non-steroidal anti-inflammatory drugs (NSAIDs) that act as cyclo-oxygenase (COX) inhibitors are commonly used in the treatment of a range of headache disorders, although their mechanism of action is unclear. Indomethacin is of particular interest given its very special effect in some primary headaches. Here the in vivo technique of intravital microscopy in rats has been utilised as a model of trigeminovascular nociception to study the potential mechanism of action of indomethacin. Dural vascular changes were produced using electrical (neurogenic) dural vasodilation (NDV), calcitonin gene-related peptide (CGRP) induced dural vasodilation and nitric oxide (NO) induced dural vasodilation using NO donors. In each of these settings the effect of intravenously administered indomethacin (5 mg kg(-1)), naproxen (30 mg kg(-1)) and ibuprofen (30 mg kg(-1)) was tested. All of the tested drugs significantly inhibited NDV (between 30 and 52%). Whilst none of them was able to inhibit CGRP-induced dural vasodilation, only indomethacin reduced NO induced dural vasodilation (35 ± 7%, 10 min post administration). We conclude NSAIDs inhibit release of CGRP after NDV without an effect on CGRP directly. Further we describe a differentiating effect of indomethacin inhibiting nitric oxide induced dural vasodilation that is potentially relevant to understanding its unique action in disorders such as paroxysmal hemicrania and hemicrania continua.

A theoretical description of arterial pressure-flow relationships with verification in the isolated hindlimb of the dog.

PubMed

Jackman, A P; Green, J F

1990-01-01

We developed and tested a new two-compartment serial model of the arterial vasculature which unifies the capacitance (downstream arterial compliance) and waterfall (constant downstream pressure load) theories of blood flow through the arteries. In this model, blood drains from an upstream compliance through a resistance into a downstream compliance which empties into the veins through a downstream resistance which terminates in a constant pressure load. Using transient arterial pressure data obtained from an isolated canine hindlimb preparation, we tested this model, using a stop-flow technique. Numerical parameter estimation techniques were used to estimate the physiologic parameters of the model. The downstream compliance was found to be more than ten times larger than the upstream compliance and the constant pressure load was significantly above venous pressures but decreased in response to vasodilation. Our results support the applicability of both the capacitance and waterfall theories.

Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study.

PubMed

Solini, Anna; Giannini, Livia; Seghieri, Marta; Vitolo, Edoardo; Taddei, Stefano; Ghiadoni, Lorenzo; Bruno, Rosa Maria

2017-10-23

Sodium-glucose cotransporter-2 inhibitors reduce blood pressure (BP) and renal and cardiovascular events in patients with type 2 diabetes through not fully elucidated mechanisms. Aim of this study was to investigate whether dapagliflozin is able to acutely modify systemic and renal vascular function, as well as putative mechanisms. Neuro-hormonal and vascular variables, together with 24 h diuresis, urinary sodium, glucose, isoprostanes and free-water clearance were assessed before and after a 2-day treatment with dapagliflozin 10 mg QD in sixteen type 2 diabetic patients; data were compared with those obtained in ten patients treated with hydrochlorothiazide 12.5 mg QD. Brachial artery endothelium-dependent and independent vasodilation (by flow-mediated dilation) and pulse wave velocity were assessed. Renal resistive index was obtained at rest and after glyceryl trinitrate administration. Differences were analysed by repeated measures ANOVA, considering treatment as between factor and time as within factor; Bonferroni post hoc comparison test was also used. Dapagliflozin decreased systolic BP and induced an increase in 24 h diuresis to a similar extent of hydrochlorothiazide; 24 h urinary glucose and serum magnesium were also increased. 24 h urinary sodium and fasting blood glucose were unchanged. Oxidative stress was reduced, as by a decline in urinary isoprostanes. Flow-mediated dilation was significantly increased (2.8 ± 2.2 to 4.0 ± 2.1%, p < 0.05), and pulse-wave-velocity was reduced (10.1 ± 1.6 to 8.9 ± 1.6 m/s, p < 0.05), even after correction for mean BP. Renal resistive index was reduced (0.62 ± 0.04 to 0.59 ± 0.05, p < 0.05). These vascular modifications were not observed in hydrochlorothiazide-treated individuals. An acute treatment with dapagliflozin significantly improves systemic endothelial function, arterial stiffness and renal resistive index; this effect is independent of changes in BP and occurs in the presence of stable natriuresis, suggesting a fast, direct beneficial effect on the vasculature, possibly mediated by oxidative stress reduction.

Vasodilators

MedlinePlus

... directly on the vessel walls are hydralazine and minoxidil. Doctors prescribe vasodilators to prevent, treat or improve ... http://www.micromedexsolutions.com. Accessed May 23, 2016. Minoxidil. Micromedex 2.0 Healthcare Series. http://www.micromedexsolutions. ...

Vasoconstrictor and vasodilator responses to tryptamine of rat-isolated perfused mesentery: comparison with tyramine and β-phenylethylamine

PubMed Central

Anwar, MA; Ford, WR; Broadley, KJ; Herbert, AA

2012-01-01

BACKGROUND AND PURPOSE Tryptamine increases blood pressure by vasoconstriction, but little is known about its actions on the mesentery, in particular the resistance arteries. Tryptamine interacts with trace amine-associated receptors (TAARs) and because of its structural similarity to 5-HT, it may also interact with 5-HT receptors. Our hypothesis is therefore that the rat mesenteric arterial bed will exhibit vasopressor and vasodepressor responses to tryptamine via both 5-HT and TAARs. EXPERIMENTAL APPROACH Tryptamine-evoked responses were assayed from pressure changes of the rat-isolated mesenteric vasculature perfused at constant flow rate in the absence and presence of adrenoceptor and 5-HT receptor antagonists. KEY RESULTS Tryptamine caused dose-dependent vasoconstriction of the mesenteric arterial bed as increases in perfusion pressure. These were unaffected by the α1-adrenoceptor antagonist, prazosin, but were attenuated by the non-selective α-adrenoceptor antagonist, phentolamine. The 5-HT2A receptor antagonists, ketanserin and ritanserin, abolished the tryptamine-induced pressure increases to reveal vasodilator responses in mesenteric beds preconstricted with phenylephrine. These tryptamine-induced vasodilator responses were unaffected by the 5-HT7 receptor antagonist, SB269970, but were eliminated by the NOS inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME). Tyramine and β-phenylethylamine also caused vasodilatation in pre-constricted vasculature, which was also abolished by L-NAME. CONCLUSIONS AND IMPLICATIONS Tryptamine causes vasoconstriction of the mesenteric vasculature via 5-HT2A receptors, which when inhibited exposed vasorelaxant effects in pre-constricted tissues. The vasodilatation was independent of 5-HT2A and 5-HT7 receptors but like that for tyramine and β-phenylethylamine was due to NO release. Potency orders suggest TAAR involvement in the vasodilatation by these trace amines. PMID:21958009

Vasoconstrictor and vasodilator responses to tryptamine of rat-isolated perfused mesentery: comparison with tyramine and β-phenylethylamine.

PubMed

Anwar, M A; Ford, W R; Broadley, K J; Herbert, A A

2012-04-01

Tryptamine increases blood pressure by vasoconstriction, but little is known about its actions on the mesentery, in particular the resistance arteries. Tryptamine interacts with trace amine-associated receptors (TAARs) and because of its structural similarity to 5-HT, it may also interact with 5-HT receptors. Our hypothesis is therefore that the rat mesenteric arterial bed will exhibit vasopressor and vasodepressor responses to tryptamine via both 5-HT and TAARs. Tryptamine-evoked responses were assayed from pressure changes of the rat-isolated mesenteric vasculature perfused at constant flow rate in the absence and presence of adrenoceptor and 5-HT receptor antagonists. Tryptamine caused dose-dependent vasoconstriction of the mesenteric arterial bed as increases in perfusion pressure. These were unaffected by the α(1) -adrenoceptor antagonist, prazosin, but were attenuated by the non-selective α-adrenoceptor antagonist, phentolamine. The 5-HT(2A) receptor antagonists, ketanserin and ritanserin, abolished the tryptamine-induced pressure increases to reveal vasodilator responses in mesenteric beds preconstricted with phenylephrine. These tryptamine-induced vasodilator responses were unaffected by the 5-HT(7) receptor antagonist, SB269970, but were eliminated by the NOS inhibitor, N(ω) -nitro-L-arginine methyl ester (L-NAME). Tyramine and β-phenylethylamine also caused vasodilatation in pre-constricted vasculature, which was also abolished by L-NAME. Tryptamine causes vasoconstriction of the mesenteric vasculature via 5-HT(2A) receptors, which when inhibited exposed vasorelaxant effects in pre-constricted tissues. The vasodilatation was independent of 5-HT(2A) and 5-HT(7) receptors but like that for tyramine and β-phenylethylamine was due to NO release. Potency orders suggest TAAR involvement in the vasodilatation by these trace amines. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chronic endurance exercise training offsets the age-related attenuation in contraction-induced rapid vasodilation

PubMed Central

Hughes, William E.; Ueda, Kenichi

2016-01-01

Aging is associated with attenuated contraction-induced rapid onset vasodilation (ROV). We sought to examine whether chronic exercise training would improve ROV in older adults. Additionally, we examined whether a relationship between cardiorespiratory fitness and ROV exists in young and older adults. Chronically exercise-trained older adults (n = 16; 66 ± 2 yr, mean ± SE) performed single muscle contractions in the forearm and leg at various intensities. Brachial and femoral artery diameter and blood velocity were measured using Doppler ultrasound. Vascular conductance (VC) was calculated as the quotient of blood flow (ml/min) and mean arterial pressure (mmHg). These data were compared with our previously published work from an identical protocol in 16 older untrained (66 ± 1 yr, mean ± SE) and 14 young (23 ± 1 yr) adults. Peak (ΔVCpeak) and total vasodilator (VCtotal) responses were greater in trained compared with untrained older adults across leg exercise intensities (P < 0.05). There were no differences in responses between trained older and young adults in the arm or leg at any exercise intensity (P > 0.05). Comparison of ΔVCpeak in a subset of subjects at an absolute workload in the leg revealed that trained older adults exhibited augmented responses relative to untrained older adults. Exercise capacity (V̇o2 peak) was associated with ΔVCpeak and VCtotal across arm (r = 0.59–0.64) and leg exercise intensities (r = 0.55–0.68, P < 0.05) in older adults. Our data demonstrate that 1) chronic exercise training improves ROV in the arm and leg of trained older adults, such that age-related differences in ROV are abolished, and 2) VO2peak is associated with ΔVCpeak responses in both limbs of older adults. PMID:27032899

Superoxide scavenging effects of N-acetylcysteine and vitamin C in subjects with essential hypertension.

PubMed

Schneider, Markus P; Delles, Christian; Schmidt, Bernhard M W; Oehmer, Sebastian; Schwarz, Thomas K; Schmieder, Roland E; John, Stefan

2005-08-01

It is not known whether the beneficial effects of N-acetylcysteine (NAC) in conditions associated with increased oxidative stress are caused by direct superoxide scavenging. We therefore compared the acute superoxide scavenging efficacy of NAC against vitamin C (VITC) on impaired endothelium-dependent vasodilation in subjects with essential hypertension. In a cross-over randomized study, the effects of intra-arterial administration of either NAC (48 mg/min) or VITC (18 mg/min) were examined in 15 subjects with essential hypertension and in 15 normotensive control subjects. Both endothelium-dependent and endothelium-independent vasodilation were determined as forearm blood flow (FBF) response to the intra-arterial administration of acetylcholine (Ach) and sodium nitroprusside (NP) in doses of 12 and 48 mug/min and 3.2 and 12.8 mug/min, respectively. Subjects with essential hypertension had impaired responses to both doses of Ach (Delta% FBF to higher dose of Ach: 325 +/- 146 in subjects with essential hypertension v 540 +/- 199 in control subjects; P = .02) and an impaired response to the higher dose of NP (330 +/- 108 v 500 +/- 199; P = .03). The intra-arterial administration of NAC had no effect on these responses (higher dose of Ach: 325 +/- 146 without v 338 +/- 112 with NAC, NS). In contrast, intra-arterial VITC improved both the response to Ach (320 +/- 132 without v 400 +/- 185 with VITC, P = .05) and to NP (383 +/- 162 v 447 +/- 170, P = .05). We found that NAC showed no statistically significant effect on either endothelium-dependent or endothelium-independent vasodilation in hypertensive subjects, whereas VITC did. We conclude that NAC is therefore not an effective superoxide scavenger in vivo. Other, nonimmediate effects such as the generation of glutathione may explain the beneficial effects of NAC in conditions associated with oxidative stress.

Acute eprosartan-induced intrarenal vasodilation in hypertensive humans is not influenced by dietary sodium intake or angiotensin II co-infusion.

PubMed

van Twist, Daan J L; Houben, Alfons J H M; de Leeuw, Peter W; Kroon, Abraham A

2016-08-01

Angiotensin II (Ang II) is thought to play an important role in the development of hypertension. Nevertheless, knowledge on the angiotensin II type-1-receptors (AT1Rs) in the hypertensive kidney and the influence of sodium intake and renin-angiotensin system activity on intrarenal AT1R blockade is scarce. To improve our understanding of renal AT1Rs in hypertensive patients, we studied the effects of acute, local administration of AT1R-blocker eprosartan in kidneys of patients with essential hypertension (off medication). In 73 hypertensive patients who were scheduled for diagnostic renal angiography, we measured renal blood flow (Xenon washout method) before and during intrarenal infusion of two incremental doses of eprosartan (3 and 10 μg/kg/min for 15 min per dose). We hypothesized that the vasodilatory effects of eprosartan would be enhanced by low sodium intake and would be reduced during Ang II co-infusion. Therefore, we allocated the patients to either a high or a low sodium diet and coinfused Ang II (1 ng/kg/min) in a subgroup. Eprosartan infusion resulted in intrarenal vasodilation in all groups. No differences in the magnitude of this effect were found between the groups. No correlation was found between 24-h urinary sodium excretion (a proxy for dietary sodium intake) and the effect of eprosartan. Eprosartan-induced vasodilation is not influenced by sodium intake and/or co-infusion of Ang II. These rather unexpected findings could be explained by differences between circulating and tissue Ang II levels, variations in AT1R expression, and/or stimulation of other vasodilatory pathways.

Chronic endurance exercise training offsets the age-related attenuation in contraction-induced rapid vasodilation.

PubMed

Hughes, William E; Ueda, Kenichi; Casey, Darren P

2016-06-01

Aging is associated with attenuated contraction-induced rapid onset vasodilation (ROV). We sought to examine whether chronic exercise training would improve ROV in older adults. Additionally, we examined whether a relationship between cardiorespiratory fitness and ROV exists in young and older adults. Chronically exercise-trained older adults (n = 16; 66 ± 2 yr, mean ± SE) performed single muscle contractions in the forearm and leg at various intensities. Brachial and femoral artery diameter and blood velocity were measured using Doppler ultrasound. Vascular conductance (VC) was calculated as the quotient of blood flow (ml/min) and mean arterial pressure (mmHg). These data were compared with our previously published work from an identical protocol in 16 older untrained (66 ± 1 yr, mean ± SE) and 14 young (23 ± 1 yr) adults. Peak (ΔVCpeak) and total vasodilator (VCtotal) responses were greater in trained compared with untrained older adults across leg exercise intensities (P < 0.05). There were no differences in responses between trained older and young adults in the arm or leg at any exercise intensity (P > 0.05). Comparison of ΔVCpeak in a subset of subjects at an absolute workload in the leg revealed that trained older adults exhibited augmented responses relative to untrained older adults. Exercise capacity (V̇o2 peak) was associated with ΔVCpeak and VCtotal across arm (r = 0.59-0.64) and leg exercise intensities (r = 0.55-0.68, P < 0.05) in older adults. Our data demonstrate that 1) chronic exercise training improves ROV in the arm and leg of trained older adults, such that age-related differences in ROV are abolished, and 2) VO2peak is associated with ΔVCpeak responses in both limbs of older adults. Copyright © 2016 the American Physiological Society.

Rhynchophylla total alkaloid rescues autophagy, decreases oxidative stress and improves endothelial vasodilation in spontaneous hypertensive rats.

PubMed

Li, Chao; Jiang, Feng; Li, Yun-Lun; Jiang, Yue-Hua; Yang, Wen-Qing; Sheng, Jie; Xu, Wen-Juan; Zhu, Qing-Jun

2018-03-01

Autophagy plays an important role in alleviating oxidative stress and stabilizing atherosclerotic plaques. However, the potential role of autophagy in endothelial vasodilation function has rarely been studied. This study aimed to investigate whether rhynchophylla total alkaloid (RTA) has a positive role in enhancing autophagy through decreasing oxidative stress, and improving endothelial vasodilation. In oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs), RTA (200 mg/L) significantly suppressed ox-LDL-induced oxidative stress through rescuing autophagy, and decreased cell apoptosis. In spontaneous hypertensive rats (SHR), administration of RTA (50 mg·kg -1 ·d -1 , ip, for 6 weeks) improved endothelin-dependent vasodilation of thoracic aorta rings. Furthermore, RTA administration significantly increased the antioxidant capacity and alleviated oxidative stress through enhancing autophagy in SHR. In ox-LDL-treated HUVECs, we found that the promotion of autophagy by RTA resulted in activation of the AMP-activated protein kinase (AMPK) signaling pathway. Our results show that RTA treatment rescues the ox-LDL-induced autophagy impairment in HUVECs and improves endothelium-dependent vasodilation function in SHR.

Low-pressure sequential compression of lower limbs enhances forearm skin blood flow.

PubMed

Amah, Guy; Voicu, Sebastian; Bonnin, Philippe; Kubis, Nathalie

2016-12-01

We investigated whether forearm skin blood flow could be improved when a multilayer pulsatile inflatable suit was applied at a low pressure to the lower limbs and abdomen. We hypothesized that a non-invasive purely mechanical stimulation of the lower limbs could induce remote forearm blood flow modifications. The pulsatile suit induced a sequential compartmentalized low compression (65 mmHg), which was synchronized with each diastole of the cardiac cycle with each phase evolving centripetally (lower limbs to abdomen). Modifications of the forearm skin blood flow were continuously recorded by laser Doppler flowmetry (LDF) at baseline and during the pulsatile suit application. Endothelium-dependent and endothelium-independent vasodilations of the forearm skin microcirculation were measured by LDF in response to a local transdermal iontophoretic application of acetylcholine (ACh-test) and to hyperthermia (hyperT- test). Twenty-four healthy volunteers, 12 men and 12 women (43±14 years) were included in the study. LDF responses increased 1) under pulsatile suit (97±106%, p.

Orthostatic Hypotension

MedlinePlus

... the body), resulting from the excessive use of diuretics, vasodilators, or other types of drugs, dehydration, or ... the body), resulting from the excessive use of diuretics, vasodilators, or other types of drugs, dehydration, or ...

Comparative effect of ace inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutase.

PubMed

Hornig, B; Landmesser, U; Kohler, C; Ahlersmann, D; Spiekermann, S; Christoph, A; Tatge, H; Drexler, H

2001-02-13

Flow-dependent, endothelium-mediated vasodilation (FDD) and activity of extracellular superoxide dismutase (EC-SOD), the major antioxidative enzyme of the arterial wall, are severely impaired in patients with coronary artery disease (CAD). We hypothesized that both ACE inhibitor (ACEI) and angiotensin II type 1 receptor antagonist (AT(1)-A) increase bioavailability of nitric oxide (NO) by reducing oxidative stress in the vessel wall, possibly by increasing EC-SOD activity. Thirty-five patients with CAD were randomized to 4 weeks of ACEI (ramipril 10 mg/d) or AT(1)-A (losartan 100 mg/d). FDD of the radial artery was determined by high-resolution ultrasound before and after intra-arterial N-monomethyl-L-arginine (L-NMMA) to inhibit NO synthase and before and after intra-arterial vitamin C to determine the portion of FDD inhibited by oxygen free radicals. EC-SOD activity was determined after release from endothelium by heparin bolus injection. FDD was improved after ramipril and losartan (each group P<0.01), and in particular, the portion of FDD mediated by NO, ie, inhibited by L-NMMA, was increased by >75% (each group P<0.01). Vitamin C improved FDD initially, an effect that was lost after ramipril or losartan. After therapy, EC-SOD activity was increased by >200% in both groups (ACEI, 14.4+/-1.1 versus 3.8+/-0.9 and AT(1)-A, 13.5+/-1.0 versus 3.9+/-0.9 U. mL(-1). min(-1); each P<0.01). CONCLUSIONS-Four weeks of therapy with ramipril or losartan improves endothelial function to similar extents in patients with CAD by increasing the bioavailability of NO. Our results suggest that beneficial long-term effects of interference with the renin-angiotensin system may be related to reduction of oxidative stress within the arterial wall, mediated in part by increased EC-SOD activity.

Memantine Inhibits α3β2-nAChRs-Mediated Nitrergic Neurogenic Vasodilation in Porcine Basilar Arteries

PubMed Central

Wu, Celeste Yin-Chieh; Chen, Po-Yi; Chen, Mei-Fang; Kuo, Jon-Son; Lee, Tony Jer-Fu

2012-01-01

Memantine, an NMDA receptor antagonist used for treatment of Alzheimer’s disease (AD), is known to block the nicotinic acetylcholine receptors (nAChRs) in the central nervous system (CNS). In the present study, we examined by wire myography if memantine inhibited α3β2-nAChRs located on cerebral perivascular sympathetic nerve terminals originating in the superior cervical ganglion (SCG), thus, leading to inhibition of nicotine-induced nitrergic neurogenic dilation of isolated porcine basilar arteries. Memantine concentration-dependently blocked nicotine-induced neurogenic dilation of endothelium-denuded basilar arteries without affecting that induced by transmural nerve stimulation, sodium nitroprusside, or isoproterenol. Furthermore, memantine significantly inhibited nicotine-elicited inward currents in Xenopous oocytes expressing α3β2-, α7- or α4β2-nAChR, and nicotine-induced calcium influx in cultured rat SCG neurons. These results suggest that memantine is a non-specific antagonist for nAChR. By directly inhibiting α3β2-nAChRs located on the sympathetic nerve terminals, memantine blocks nicotine-induced neurogenic vasodilation of the porcine basilar arteries. This effect of memantine is expected to reduce the blood supply to the brain stem and possibly other brain regions, thus, decreasing its clinical efficacy in the treatment of Alzheimer’s disease. PMID:22792283

Endothelial dysfunction in the regulation of portal hypertension

PubMed Central

Iwakiri, Yasuko

2013-01-01

Portal hypertension is caused by an increased intrahepatic resistance, a major consequence of cirrhosis. Endothelial dysfunction in liver sinusoidal endothelial cells (LSECs) decreases the production of vasodilators, such as nitric oxide (NO) and favors vasoconstriction. This contributes to an increased vascular resistance in the intrahepatic/sinusoidal microcirculation. Portal hypertension, once developed, causes endothelial cell (EC) dysfunction in the extrahepatic, i.e. splanchnic and systemic, circulation. Unlike LSEC dysfunction, EC dysfunction in the splanchnic and systemic circulation overproduces vasodilator molecules, leading to arterial vasodilatation. In addition, portal hypertension leads to the formation of portosystemic collateral vessels. Both arterial vasodilatation and portosystemic collateral vessel formation exacerbate portal hypertension by increasing the blood flow through the portal vein. Pathologic consequences, such as esophageal varices and ascites, result. While the sequence of pathological vascular events in cirrhosis and portal hypertension have been elucidated, the underlying cellular and molecular mechanisms causing EC dysfunctions are not yet fully understood. This review article summarizes the current cellular and molecular studies on EC dysfunctions found during the development of cirrhosis and portal hypertension with a focus on intra- and extrahepatic circulation. The article ends by discussing future directions of study for EC dysfunctions. PMID:21745318

Atrial Natriuretic Peptide Accelerates Human Endothelial Progenitor Cell-Stimulated Cutaneous Wound Healing and Angiogenesis.

PubMed

Lee, Tae Wook; Kwon, Yang Woo; Park, Gyu Tae; Do, Eun Kyoung; Yoon, Jung Won; Kim, Seung-Chul; Ko, Hyun-Chang; Kim, Moon-Bum; Kim, Jae Ho

2018-05-26

Atrial natriuretic peptide (ANP) is a powerful vasodilating peptide secreted by cardiac muscle cells, and endothelial progenitor cells (EPCs) have been reported to stimulate cutaneous wound healing by mediating angiogenesis. To determine whether ANP can promote the EPC-mediated repair of injured tissues, we examined the effects of ANP on the angiogenic properties of EPCs and on cutaneous wound healing. In vitro, ANP treatment enhanced the migration, proliferation, and endothelial tube-forming abilities of EPCs. Furthermore, small interfering RNA-mediated silencing of natriuretic peptide receptor-1, which is a receptor for ANP, abrogated ANP-induced migration, tube formation, and proliferation of EPCs. In a murine cutaneous wound model, administration of either ANP or EPCs had no significant effect on cutaneous wound healing or angiogenesis in vivo, whereas the co-administration of ANP and EPCs synergistically potentiated wound healing and angiogenesis. In addition, ANP promoted the survival and incorporation of transplanted EPCs into newly formed blood vessels in wounds. These results suggest ANP accelerates EPC-mediated cutaneous wound healing by promoting the angiogenic properties and survival of transplanted EPCs. This article is protected by copyright. All rights reserved. © 2018 by the Wound Healing Society.

Arterial alterations in severely obese children with obstructive sleep apnoea.

PubMed

Dubern, Beatrice; Aggoun, Yacine; Boulé, Michèle; Fauroux, Brigitte; Bonnet, Damien; Tounian, Patrick

2010-05-03

Obstructive sleep apnoea (OSA) in obese adults is associated with cardiovascular disease independently of obesity. Vascular alterations exist in children with obesity and may constitute the first stage in the development of adulthood cardiovascular disease. To investigate the relationship between OSA and early arterial alterations in obese children. Cross-sectional study of a prospective cohort. A total of 51 children with severe obesity managed at a teaching hospital outpatient clinic. Polysomnography was performed. We measured the intima-media thickness and incremental elastic modulus (Einc) to assess the mechanical characteristics of the common carotid artery. Arterial endothelial function was evaluated by measuring flow-mediated dilation and glyceryl trinitrate-mediated dilation (GTNMD) of the brachial artery. A total of 24 (47%) children had a desaturation index (DI) >10/h and 7 (14%) had a respiratory event index >10/h. DI >10/h was associated with significantly higher values of Einc (4.0 + or - 0.5 vs. 2.4 + or - 0.4 mm Hg(-1) x 10(3), p=0.003) and GTNMD (18.0 + or - 1.1 vs. 14.1 + or - 1.0 %, p=0.02) after adjustment for age, sex, body mass index, fasting insulin, and leptin. In the univariate analysis, GTNMD correlated positively with DI (r=0.14, p=0.02) after adjustment for age, sex, fasting insulin and leptin. By multivariate analysis with BMI as an additional independent variable, both GTNMD and Einc correlated significantly with DI (beta=0.4, p=0.02 and beta=0.27, p=0.04, respectively). OSA in children is associated with arterial alterations independently from obesity. The increased vasodilation in response to glyceryl trinitrate reflects pre-existing vasoconstriction probably induced by intermittent hypoxia. OSA should be detected early in children with severe obesity.

Depletion in LpA-I:A-II particles enhances HDL-mediated endothelial protection in familial LCAT deficiency[S

PubMed Central

Gomaraschi, Monica; Ossoli, Alice; Castelnuovo, Samuela; Simonelli, Sara; Pavanello, Chiara; Balzarotti, Gloria; Arca, Marcello; Di Costanzo, Alessia; Sampietro, Tiziana; Vaudo, Gaetano; Baldassarre, Damiano; Veglia, Fabrizio; Franceschini, Guido; Calabresi, Laura

2017-01-01

The aim of this study was to evaluate the vasoprotective effects of HDL isolated from carriers of LCAT deficiency, which are characterized by a selective depletion of LpA-I:A-II particles and predominance of preβ migrating HDL. HDLs were isolated from LCAT-deficient carriers and tested in vitro for their capacity to promote NO production and to inhibit vascular cell adhesion molecule-1 (VCAM-1) expression in cultured endothelial cells. HDLs from carriers were more effective than control HDLs in promoting eNOS activation with a gene-dose-dependent effect (PTrend = 0.048). As a consequence, NO production induced by HDL from carriers was significantly higher than that promoted by control HDL (1.63 ± 0.24-fold vs. 1.34 ± 0.07-fold, P = 0.031). HDLs from carriers were also more effective than control HDLs in inhibiting the expression of VCAM-1 (homozygotes, 65.0 ± 8.6%; heterozygotes, 53.1 ± 7.2%; controls, 44.4 ± 4.1%; PTrend = 0.0003). The increased efficiency of carrier HDL was likely due to the depletion in LpA-I:A-II particles. The in vitro findings might explain why carriers of LCAT deficiency showed flow-mediated vasodilation and plasma-soluble cell adhesion molecule concentrations comparable to controls, despite low HDL-cholesterol levels. These results indicate that selective depletion of apoA-II-containing HDL, as observed in carriers of LCAT deficiency, leads to an increased capacity of HDL to stimulate endothelial NO production, suggesting that changes in HDL apolipoprotein composition may be the target of therapeutic interventions designed to improve HDL functionality. PMID:28351888

Control of the neurovascular coupling by nitric oxide-dependent regulation of astrocytic Ca2+ signaling

PubMed Central

Muñoz, Manuel F.; Puebla, Mariela; Figueroa, Xavier F.

2015-01-01

Neuronal activity must be tightly coordinated with blood flow to keep proper brain function, which is achieved by a mechanism known as neurovascular coupling. Then, an increase in synaptic activity leads to a dilation of local parenchymal arterioles that matches the enhanced metabolic demand. Neurovascular coupling is orchestrated by astrocytes. These glial cells are located between neurons and the microvasculature, with the astrocytic endfeet ensheathing the vessels, which allows fine intercellular communication. The neurotransmitters released during neuronal activity reach astrocytic receptors and trigger a Ca2+ signaling that propagates to the endfeet, activating the release of vasoactive factors and arteriolar dilation. The astrocyte Ca2+ signaling is coordinated by gap junction channels and hemichannels formed by connexins (Cx43 and Cx30) and channels formed by pannexins (Panx-1). The neuronal activity-initiated Ca2+ waves are propagated among neighboring astrocytes directly via gap junctions or through ATP release via connexin hemichannels or pannexin channels. In addition, Ca2+ entry via connexin hemichannels or pannexin channels may participate in the regulation of the astrocyte signaling-mediated neurovascular coupling. Interestingly, nitric oxide (NO) can activate connexin hemichannel by S-nitrosylation and the Ca2+-dependent NO-synthesizing enzymes endothelial NO synthase (eNOS) and neuronal NOS (nNOS) are expressed in astrocytes. Therefore, the astrocytic Ca2+ signaling triggered in neurovascular coupling may activate NO production, which, in turn, may lead to Ca2+ influx through hemichannel activation. Furthermore, NO release from the hemichannels located at astrocytic endfeet may contribute to the vasodilation of parenchymal arterioles. In this review, we discuss the mechanisms involved in the regulation of the astrocytic Ca2+ signaling that mediates neurovascular coupling, with a special emphasis in the possible participation of NO in this process. PMID:25805969

Arteriolar oxygen reactivity: where is the sensor and what is the mechanism of action?

PubMed Central

2016-01-01

Abstract Arterioles in the peripheral microcirculation are exquisitely sensitive to changes in PO2 in their environment: increases in PO2 cause vasoconstriction while decreases in PO2 result in vasodilatation. However, the cell type that senses O2 (the O2 sensor) and the signalling pathway that couples changes in PO2 to changes in arteriolar tone (the mechanism of action) remain unclear. Many (but not all) ex vivo studies of isolated cannulated resistance arteries and large, first‐order arterioles support the hypothesis that these vessels are intrinsically sensitive to PO2 with the smooth muscle, endothelial cells, or red blood cells serving as the O2 sensor. However, in situ studies testing these hypotheses in downstream arterioles have failed to find evidence of intrinsic O2 sensitivity, and instead have supported the idea that extravascular cells sense O2. Similarly, ex vivo studies of isolated, cannulated resistance arteries and large first‐order arterioles support the hypotheses that O2‐dependent inhibition of production of vasodilator cyclooxygenase products or O2‐dependent destruction of nitric oxide mediates O2 reactivity of these upstream vessels. In contrast, most in vivo studies of downstream arterioles have disproved these hypotheses and instead have provided evidence supporting the idea that O2‐dependent production of vasoconstrictors mediates arteriolar O2 reactivity, with significant regional heterogeneity in the specific vasoconstrictor involved. Oxygen‐induced vasoconstriction may serve as a protective mechanism to reduce the oxidative burden to which a tissue is exposed, a process that is superimposed on top of the local mechanisms which regulate tissue blood flow to meet a tissue's metabolic demand. PMID:27324312

Mitochondrial DNA damage and vascular function in patients with diabetes mellitus and atherosclerotic cardiovascular disease.

PubMed

Fetterman, Jessica L; Holbrook, Monica; Westbrook, David G; Brown, Jamelle A; Feeley, Kyle P; Bretón-Romero, Rosa; Linder, Erika A; Berk, Brittany D; Weisbrod, Robert M; Widlansky, Michael E; Gokce, Noyan; Ballinger, Scott W; Hamburg, Naomi M

2016-03-31

Prior studies demonstrate mitochondrial dysfunction with increased reactive oxygen species generation in peripheral blood mononuclear cells in diabetes mellitus. Oxidative stress-mediated damage to mitochondrial DNA promotes atherosclerosis in animal models. Thus, we evaluated the relation of mitochondrial DNA damage in peripheral blood mononuclear cells s with vascular function in patients with diabetes mellitus and with atherosclerotic cardiovascular disease. We assessed non-invasive vascular function and mitochondrial DNA damage in 275 patients (age 57 ± 9 years, 60 % women) with atherosclerotic cardiovascular disease alone (N = 55), diabetes mellitus alone (N = 74), combined atherosclerotic cardiovascular disease and diabetes mellitus (N = 48), and controls age >45 without diabetes mellitus or atherosclerotic cardiovascular disease (N = 98). Mitochondrial DNA damage measured by quantitative PCR in peripheral blood mononuclear cells was higher with clinical atherosclerosis alone (0.55 ± 0.65), diabetes mellitus alone (0.65 ± 1.0), and combined clinical atherosclerosis and diabetes mellitus (0.89 ± 1.32) as compared to control subjects (0.23 ± 0.64, P < 0.0001). In multivariable models adjusting for age, sex, and relevant cardiovascular risk factors, clinical atherosclerosis and diabetes mellitus remained associated with higher mitochondrial DNA damage levels (β = 0.14 ± 0.13, P = 0.04 and β = 0.21 ± 0.13, P = 0.002, respectively). Higher mitochondrial DNA damage was associated with higher baseline pulse amplitude, a measure of arterial pulsatility, but not with flow-mediated dilation or hyperemic response, measures of vasodilator function. We found greater mitochondrial DNA damage in patients with diabetes mellitus and clinical atherosclerosis. The association of mitochondrial DNA damage and baseline pulse amplitude may suggest a link between mitochondrial dysfunction and excessive small artery pulsatility with potentially adverse microvascular impact.

Increased muscle blood supply and transendothelial nutrient and insulin transport induced by food intake and exercise: effect of obesity and ageing.

PubMed

Wagenmakers, Anton J M; Strauss, Juliette A; Shepherd, Sam O; Keske, Michelle A; Cocks, Matthew

2016-04-15

This review concludes that a sedentary lifestyle, obesity and ageing impair the vasodilator response of the muscle microvasculature to insulin, exercise and VEGF-A and reduce microvascular density. Both impairments contribute to the development of insulin resistance, obesity and chronic age-related diseases. A physically active lifestyle keeps both the vasodilator response and microvascular density high. Intravital microscopy has shown that microvascular units (MVUs) are the smallest functional elements to adjust blood flow in response to physiological signals and metabolic demands on muscle fibres. The luminal diameter of a common terminal arteriole (TA) controls blood flow through up to 20 capillaries belonging to a single MVU. Increases in plasma insulin and exercise/muscle contraction lead to recruitment of additional MVUs. Insulin also increases arteriolar vasomotion. Both mechanisms increase the endothelial surface area and therefore transendothelial transport of glucose, fatty acids (FAs) and insulin by specific transporters, present in high concentrations in the capillary endothelium. Future studies should quantify transporter concentration differences between healthy and at risk populations as they may limit nutrient supply and oxidation in muscle and impair glucose and lipid homeostasis. An important recent discovery is that VEGF-B produced by skeletal muscle controls the expression of FA transporter proteins in the capillary endothelium and thus links endothelial FA uptake to the oxidative capacity of skeletal muscle, potentially preventing lipotoxic FA accumulation, the dominant cause of insulin resistance in muscle fibres. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

The effects of nitroglycerin during cardiopulmonary resuscitation.

PubMed

Stefaniotou, Antonia; Varvarousi, Giolanda; Varvarousis, Dimitrios P; Xanthos, Theodoros

2014-07-05

The outcome for both in-hospital and out-of hospital cardiac arrest remains dismal. Vasopressors are used to increase coronary perfusion pressure and thus facilitate return of spontaneous circulation during cardiopulmonary resuscitation. However, they are associated with a number of potential adverse effects and may decrease endocardial and cerebral organ blood flow. Nitroglycerin has a favourable haemodynamic profile which promotes forward blood flow. Several studies suggest that combined use of nitroglycerin with vasopressors during resuscitation, is associated with increased rates of resuscitation and improved post-resuscitation outcome. This article reviews the effects of nitroglycerin during cardiopulmonary resuscitation and postresuscitation period, as well as the beneficial outcomes of a combination regimen consisting of a vasopressor and a vasodilator, such as nitroglycerin. Copyright © 2014 Elsevier B.V. All rights reserved.

[Vasodilative effects of indole alkaloids obtained from domestic plants, Uncaria rhynchophylla Miq. and Amsonia elliptica Roem. et Schult].

PubMed

Ozaki, Y

1990-02-01

Vasodilative effects of hirsutine (HS) and hirsuteine (HST) which were isolated from the domestic plant Uncaria rhynchophylla Miq. and beta-yohimbine (beta-Y) which was isolated from the domestic plant Amsonia elliptica Roem. et Schult. were carried out. In the hind-limb artery of anesthetized dogs, intra-arterial administration of HS, HST and beta-Y caused a vasodilatation. The vasodilative potency of HS was somewhat stronger than that of HST, and the potency of both alkaloids was approximately equal to that of papaverine. The vasodilative effect of beta-Y was similar to that of yohimbine, which is considered to be derived from its alpha-adrenoceptor blocking effect, and the potency of both alkaloids was approximately the same, while the effect of beta-Y was stronger than that of papaverine. In the coronary artery, HS showed a vasodilatation and its potency was weaker than that of papaverine. Also, HS showed the same effect in the cerebral artery, and the potency of HS was approximately the same as that of papaverine. These results suggest that the mode of the vasodilative effect induced by HS may partly differ from that of papaverine.

Practical Management of Patients with a History of Immediate Hypersensitivity to Common non-Beta-Lactam Drugs.

PubMed

Macy, Eric

2016-01-01

Immediate hypersensitivity reactions to medications are among the most feared adverse drug reactions, because of their close association with anaphylaxis. This review discusses a practical management approach for patients with a history of an immediate hypersensitivity to a non-beta-lactam medication, where reexposure to the implicated, or similar, medication is clinically necessary. Mechanisms associated with severe immediate hypersensitivity reactions include IgE-mediated mast cell activation, complement-mediated mast cell activation, and direct mast cell activation. Immediate hypersensitivity reactions may also be mediated by vasodilators, other pharmacologic mechanisms, or be secondary to underlying patient-specific biochemical abnormalities such as endocrine tumors or chronic spontaneous urticaria. The key features in the reaction history and the biochemistry of the implicated medication are discussed. Most individuals with a history of immediate hypersensitivity to a medication, who require reuse of that drug, can be safely retreated with a therapeutic course of the implicated drug after a full-dose challenge, graded challenge, or desensitization, with or without premedication and/or any preliminary diagnostic testing, depending on the specific situation.

Synchronisation of Cold Induced Vasodilation in the Fingers of Two Immersed Hands

DTIC Science & Technology

1992-10-14

TNO Institute for Perception TNO Defence Research "D SYL--. j. 1O)rowort IZF 1992 B-l SYNCHRONISATION OF COLD INDUCED H.A.M. Daanen VASODILATION IN...Defence Research KPmN, 3,9Z( TD (.L - ?29 ’- . The Net Fax +313463 5 39 77 Telephone +31 3463 5 62 11 TNO.-rport IZF 1992 B-11 SYNCHRONISATION OF COLD...DISCUSSION 12 5 CONCLUSIONS 15 REFERENCES 16 Report No.: IZF 1992 - I1 Title: Synchronisation of cold induced vasodilation in the fingers (f two immersed

Sustained resveratrol infusion increases natriuresis independent of renal vasodilation.

PubMed

Gordish, Kevin L; Beierwaltes, William H

2014-09-01

Resveratrol is reported to exert cardio-renal protective effects in animal models of pathology, yet the mechanisms underlying these effects are poorly understood. Previously, we reported an i.v. bolus of resveratrol induces renal vasodilation by increasing nitric oxide bioavailability and inhibiting reactive oxygen species. Thus, we hypothesized a sustained infusion of resveratrol would also increase renal blood flow (RBF), and additionally glomerular filtration rate (GFR). We infused vehicle for 30 min followed by 30 min resveratrol at either: 0, 0.5, 1.0, 1.5 mg/min, and measured RBF, renal vascular resistance (RVR), GFR, and urinary sodium excretion. At all three doses, blood pressure and GFR remained unchanged. Control RBF was 7.69 ± 0.84 mL/min/gkw and remained unchanged by 0.5 mg/min resveratrol (7.88 ± 0.94 mL/min/gkw, n = 9), but urinary sodium excretion increased from 2.19 ± 1.1 to 5.07 ± 0.92 μmol/min/gkw (n = 7, P < 0.01). In separate experiments, 1.0 mg/min resveratrol increased RBF by 17%, from 7.16 ± 0.29 to 8.35 ± 0.42 mL/min/gkw (P < 0.01, n = 10), decreased RVR 16% from 13.63 ± 0.65 to 11.36 ± 0.75 ARU (P < 0.003) and increased sodium excretion from 1.57 ± 0.46 to 3.10 ± 0.80 μmol/min/gkw (n = 7, P < 0.04). At the 1.5 mg/min dose, resveratrol increased RBF 12% from 6.76 ± 0.57 to 7.58 ± 0.60 mL/min/gkw (n = 8, P < 0.003), decreased RVR 15% (15.58 ± 1.35 to 13.27 ± 1.14 ARU, P < 0.003) and increased sodium excretion (3.99 ± 1.71 to 7.80 ± 1.51 μmol/min/gkw, n = 8, P < 0.04). We conclude that a constant infusion of resveratrol can induce significant renal vasodilation while not altering GFR or blood pressure. Also, resveratrol infusion produced significant natriuresis at all doses, suggesting it may have a direct effect on renal tubular sodium handling independent of renal perfusion pressure or flow. © 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Beta-adrenoceptor dysfunction after inhibition of NO synthesis

NASA Technical Reports Server (NTRS)

Whalen, E. J.; Johnson, A. K.; Lewis, S. J.

2000-01-01

G(s) protein-coupled beta-adrenoceptors rapidly desensitize on exposure to agonists in reconstituted membrane preparations, whereas rapid tachyphylaxis to beta-adrenoceptor-mediated vasodilation does not readily occur in vivo. This study examined the possibility that endothelium-derived nitrosyl factors prevent the rapid desensitization of beta-adrenoceptors in the vascular smooth muscle of resistance arteries in pentobarbital-anesthetized rats. The fall in mean arterial blood pressure and in hindquarter vascular resistance produced by the beta-adrenoceptor agonist isoproterenol (ISO, 0.1 to 10 microg/kg IV) was slightly but significantly smaller in rats treated with the NO synthase inhibitor N:(G)-nitro-L-arginine methyl ester (L-NAME, 100 micromol/kg IV) than in saline-treated rats. The ISO-induced fall in mesenteric resistance was similar in L-NAME-treated and in saline-treated rats. The fall in hindquarter vascular resistance and in mesenteric resistance produced by ISO (8 x 10 microg/kg IV) was subject to tachyphylaxis on repeated injection in rats treated with L-NAME (100 micromol/kg IV) but not in rats treated with saline. Injections of L-S:-nitrosocysteine (1200 nmol/kg IV), a lipophobic S:-nitrosothiol, before each injection of ISO (10 microg/kg IV) prevented tachyphylaxis to ISO in L-NAME-treated rats. The vasodilator effects of ISO (0.1 to 10 microg/kg IV) in L-NAME-treated rats that received 8 injections of ISO (10 microg/kg IV) were markedly smaller than in L-NAME-treated rats that received 8 injections of saline. These results indicate that (1) the vasodilator actions of ISO in pentobarbital-anesthetized rats only minimally involve the release of endothelium-derived nitrosyl factors, (2) the effects of ISO are subject to development of tachyphylaxis in L-NAME-treated rats, and (3) tachyphylaxis to ISO is prevented by L-S:-nitrosocysteine. These findings suggest that endothelium-derived nitrosyl factors may prevent desensitization of beta-adrenoceptors in vivo.

Vasodilator effects and putative guanylyl cyclase stimulation by 2-nitro-1-phenylethanone and 2-nitro-2-phenyl-propane-1,3-diol on rat aorta.

PubMed

Vasconcelos, Thiago Brasileiro de; Ribeiro-Filho, Helder Veras; Lahlou, Saad; Pereira, José Geraldo de Carvalho; Oliveira, Paulo Sérgio Lopes de; Magalhães, Pedro Jorge Caldas

2018-07-05

Compounds containing a nitro group may reveal vasodilator properties. Several nitro compounds have a NO 2 group in a short aliphatic chain connected to an aromatic group. In this study, we evaluated in rat aorta the effects of two nitro compounds, with emphasis on a putative recruitment of the soluble guanylate cyclase (sGC) pathway to induce vasodilation. Isolated aortic rings were obtained from male Wistar rats to compare the effects induced by 2-nitro-1-phenylethanone (NPeth) or 2-nitro-2-phenyl-propane-1,3-diol (NPprop). In aortic preparations contracted with phenylephrine or KCl, NPeth and NPprop induced vasorelaxant effects that did not depend on the integrity of vascular endothelium. NPeth had a lesser vasorelaxant efficacy than NPprop and only the NPprop effects were inhibited by pretreatment with the sGC inhibitors, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or methylene blue. In an ODQ-preventable manner, NPprop inhibited the contractile component of the phenylephrine-induced response mediated by intracellular Ca 2+ release or by extracellular Ca 2+ recruitment through receptor- or voltage-operated Ca 2+ channels. In contrast, NPprop was inert against the transient contraction induced by caffeine in Ca 2+ -free medium. In an ODQ-dependent manner, NPprop inhibited the contraction induced by the protein kinase C activator phorbol 12,13-dibutyrate or by the tyrosine phosphatase inhibitor sodium orthovanadate. In silico docking analysis of a sGC homologous protein revealed preferential site for NPprop. In conclusion, the nitro compounds NPeth and NPprop induced vasorelaxation in rat aortic rings. Aliphatic chain substituents selectively interfered in the ability of these compounds to induce vasorelaxant effects, and only NPprop relaxed aortic rings via a sGC pathway. Copyright © 2018 Elsevier B.V. All rights reserved.

Nebivolol: impact on cardiac and endothelial function and clinical utility.

PubMed

Toblli, Jorge Eduardo; DiGennaro, Federico; Giani, Jorge Fernando; Dominici, Fernando Pablo

2012-01-01

Endothelial dysfunction is a systemic pathological state of the endothelium characterized by a reduction in the bioavailability of vasodilators, essentially nitric oxide, leading to impaired endothelium-dependent vasodilation, as well as disarrangement in vascular wall metabolism and function. One of the key factors in endothelial dysfunction is overproduction of reactive oxygen species which participate in the development of hypertension, atherosclerosis, diabetes, cardiac hypertrophy, heart failure, ischemia-reperfusion injury, and stroke. Because impaired endothelial activity is believed to have a major causal role in the pathophysiology of vascular disease, hypertension, and heart failure, therapeutic agents which modify this condition are of clinical interest. Nebivolol is a third-generation β-blocker with high selectivity for β1-adrenergic receptors and causes vasodilation by interaction with the endothelial L-arginine/ nitric oxide pathway. This dual mechanism of action underscores several hemodynamic qualities of nebivolol, which include reductions in heart rate and blood pressure and improvements in systolic and diastolic function. Although nebivolol reduces blood pressure to a degree similar to that of conventional β-blockers and other types of antihypertensive drugs, it may have advantages in populations with difficult-to-treat hypertension, such as patients with heart failure along with other comorbidities, like diabetes and obesity, and elderly patients in whom nitric oxide-mediated endothelial dysfunction may be more pronounced. Furthermore, recent data indicate that nebivolol appears to be a cost-effective treatment for elderly patients with heart failure compared with standard care. Thus, nebivolol is an effective and well tolerated agent with benefits above those of traditional β-blockers due to its influence on nitric oxide release, which give it singular hemodynamic effects, cardioprotective activity, and a good tolerability profile. This paper reviews the pharmacology structure and properties of nebivolol, focusing on endothelial dysfunction, clinical utility, comparative efficacy, side effects, and quality of life in general with respect to the other antihypertensive agents.

Contribution of KV1.5 Channel to H2O2-Induced Human Arteriolar Dilation and its Modulation by Coronary Artery Disease

PubMed Central

Nishijima, Yoshinori; Cao, Sheng; Chabowski, Dawid S.; Korishettar, Ankush; Ge, Alyce; Zheng, Xiaodong; Sparapani, Rodney; Gutterman, David D.; Zhang, David X.

2016-01-01

Rationale Hydrogen peroxide (H2O2) regulates vascular tone in the human microcirculation under physiological and pathophysiological conditions. It dilates arterioles by activating BKCa channels in subjects with coronary artery disease (CAD), but its mechanisms of action in subjects without CAD (non-CAD) as compared to those with CAD remain unknown. Objective We hypothesize that H2O2-elicited dilation involves different K+ channels in non-CAD versus CAD, resulting in an altered capacity for vasodilation during disease. Methods and Results H2O2 induced endothelium-independent vasodilation in non-CAD adipose arterioles, which was reduced by paxilline, a BKCa channel blocker, and by 4-AP, a KV channel blocker. Assays of mRNA transcripts, protein expression and subcellular localization revealed that KV1.5 is the major KV1 channel expressed in vascular smooth muscle cells (VSMCs) and is abundantly localized on the plasma membrane. The selective KV1.5 blocker DPO-1 and the KV1.3/1.5 blocker Psora-4 reduced H2O2-elicited dilation to a similar extent as 4-AP, but the selective KV1.3 blocker PAP-1 was without effect. In arterioles from CAD subjects, H2O2-induced dilation was significantly reduced and this dilation was inhibited by paxilline but not by 4-AP, DPO-1 or Psora-4. KV1.5 cell membrane localization and DPO-1-sensitive K+ currents were markedly reduced in isolated VSMCs from CAD arterioles, although mRNA or total cellular protein expression were largely unchanged. Conclusions In human arterioles, H2O2-induced dilation is impaired in CAD, which is associated with a transition from a combined BKCa- and KV (KV1.5)-mediated vasodilation toward a BKCa-predominant mechanism of dilation. Loss of KV1.5 vasomotor function may play an important role in microvascular dysfunction in CAD or other vascular diseases. PMID:27872049

Blood pressure measurement with the tail-cuff method in Wistar and spontaneously hypertensive rats: influence of adrenergic- and nitric oxide-mediated vasomotion.

PubMed

Fritz, M; Rinaldi, G

2008-01-01

Systolic blood pressure (SBP) is still measured in rats by the tail-cuff method, allowing readings when pulse/flow disappears during cuff inflation and reappears during deflation, separated by a compression interval. Although cuff deflation is habitually used to estimate SBP, we found cuff deflation-cuff inflation pressure to be usually negative, indicating that cuff deflation pressure < cuff inflation pressure. SBP was measured in 226 male Wistar and SHR utilizing compression intervals of different durations, and also pharmacological interventions intended to modulate the cuff deflation-cuff inflation cycle. Direct, simultaneous intravascular measurements were also performed in some animals. With compression interval congruent with 15 s, cuff deflation-cuff inflation was--6 +/- 0.6 mmHg in 73 Wistar and--6 +/- 1.4 mmHg in 51 SHR. Lengthening compression interval up to 4 min increased cuff deflation-cuff inflation pressure significantly to--27 +/- 3 mmHg in Wistar and to - 31 +/- 5 mmHg in SHR, suggesting accumulation of a vasodilating mediator. This increase of cuff deflation-cuff inflation pressure was prevented by papaverine (totally in Wistar, partially in SHR), indicating its dependence on vasodilatory capacity. Adrenergic blockade decreased cuff deflation-cuff inflation pressure to--13 +/- 5 mmHg (P < 0.05) in SHR, but had no effect in Wistar rats. Injection of L-NAME decreased cuff deflation-cuff inflation pressure to--5 +/- 2 mmHg (P < 0.05) in Wistar rats but was ineffective in SHR. Simultaneous measurements by tail-cuff method and carotid cannulation revealed that the cuff inflation most accurately estimated the intravascular SBP. 1) Cuff inflation measurements should be considered representative of SBP, as cuff deflation can underestimate SBP depending on compression interval duration, 2) nitric oxide accumulation due to flow deprivation is the main cause of SBP underestimation by cuff deflation in Wistar, and 3) in SHR, nitric oxide effects were minimal, and sympathetic activation plus physical factors seemed to predominate in the determining the outcome of measurements.

Cross-talk between hydrogen sulfide and carbon monoxide in the mechanism of experimental gastric ulcers healing, regulation of gastric blood flow and accompanying inflammation.

PubMed

Magierowski, Marcin; Magierowska, Katarzyna; Hubalewska-Mazgaj, Magdalena; Surmiak, Marcin; Sliwowski, Zbigniew; Wierdak, Mateusz; Kwiecien, Slawomir; Chmura, Anna; Brzozowski, Tomasz

2018-03-01

Hydrogen sulfide (H 2 S) and carbon monoxide (CO) exert gastroprotection against acute gastric lesions. We determined the cross-talk between H 2 S and CO in gastric ulcer healing process and regulation of gastric blood flow (GBF) at ulcer margin. Male Wistar rats with acetic acid-induced gastric ulcers were treated i.g. throughout 9 days with vehicle (control), NaHS (0.1-10 mg/kg) +/- zinc protoporphyrin (ZnPP, 10 mg/kg), d,l-propargylglycine (PAG, 30 mg/kg), CO-releasing CORM-2 (2.5 mg/kg) +/- PAG. GBF was assessed by laser flowmetry, ulcer area was determined by planimetry/histology. Gastric mucosal H 2 S production was analysed spectrophotometrically. Protein and/or mRNA expression at ulcer margin for vascular endothelial growth factor (VEGF)A, epidermal growth factor receptor (EGFr), cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST), heme oxygenases (HOs), nuclear factor (erythroid-derived 2)-like 2 (Nrf-2), cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), IL-1β, TNF-α and hypoxia inducible factor (HIF)-1α were determined by real-time PCR or western blot. IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IFN-γ, TNF-α, GM-CSF plasma concentration was assessed using Luminex platform. NaHS dose-dependently decreased ulcer area and increased GBF but ZnPP attenuated these effects. PAG decreased H 2 S production but failed to affect CORM-2-mediated ulcer healing and vasodilation. NaHS increased Nrf-2, EGFr, VEGFA and decreased pro-inflammatory markers expression and IL-1β, IL-2, IL-13, TNF-α, GM-CSF plasma concentration. CORM-2 decreased IL-1β and GM-CSF plasma levels. We conclude that NaHS accelerates gastric ulcer healing increasing microcirculation and Nrf-2, EGFr, VEGFA expression. H 2 S-mediated ulcer healing involves endogenous CO activity while CO does not require H 2 S. NaHS decreases systemic inflammation more effectively than CORM-2. Copyright © 2017 Elsevier Inc. All rights reserved.

Intake of red wine increases the number and functional capacity of circulating endothelial progenitor cells by enhancing nitric oxide bioavailability.

PubMed

Huang, Po-Hsun; Chen, Yung-Hsiang; Tsai, Hsiao-Ya; Chen, Jia-Shiong; Wu, Tao-Cheng; Lin, Feng-Yen; Sata, Masataka; Chen, Jaw-Wen; Lin, Shing-Jong

2010-04-01

Red wine (RW) consumption has been associated with a reduction of cardiovascular events, but limited data are available on potential mediating mechanisms. This study tested the hypothesis that intake of RW may promote the circulating endothelial progenitor cell (EPC) level and function through enhancement of nitric oxide bioavailability. Eighty healthy, young subjects were randomized and assigned to consume water (100 mL), RW (100 mL), beer (250 mL), or vodka (30 mL) daily for 3 weeks. Flow cytometry was used to quantify circulating EPC numbers, and in vitro assays were used to evaluate EPC functions. After RW ingestion, endothelial function determined by flow-mediated vasodilation was significantly enhanced; however, it remained unchanged after water, beer, or vodka intake. There were significantly increased numbers of circulating EPC (defined as KDR(+)CD133(+), CD34(+)CD133(+), CD34(+)KDR(+)) and EPC colony-forming units only in the RW group (all P<0.05). Only RW ingestion significantly enhanced plasma levels of nitric oxide and decreased asymmetrical dimethylarginine (both P<0.01). Incubation of EPC with RW (but not beer or ethanol) and resveratrol in vitro attenuated tumor necrosis factor-alpha-induced EPC senescence and improved tumor necrosis factor-alpha-suppressed EPC functions and tube formation. Incubation with nitric oxide donor sodium nitroprusside significantly ameliorated the inhibition of tumor necrosis factor-alpha on EPC proliferation, but incubation with endothelial nitric oxide synthase inhibitor l-NAME and PI3K inhibitor markedly attenuated the effect of RW on EPC proliferation. The intake of RW significantly enhanced circulating EPC levels and improved EPC functions by modifying nitric oxide bioavailability. These findings may help explain the beneficial effects of RW on the cardiovascular system. This study demonstrated that a moderate intake of RW can enhance circulating levels of EPC in healthy subjects by increasing nitric oxide availability. Direct incubation of EPC with RW and resveratrol can modify the functions of EPC, including attenuation of senescence and promotion of EPC adhesion, migration, and tube formation. These data suggest that RW ingestion may alter the biology of EPC, and these alterations may contribute to its unique cardiovascular-protective effect.

Effects of cranberry juice consumption on vascular function in patients with coronary artery disease.

PubMed

Dohadwala, Mustali M; Holbrook, Monika; Hamburg, Naomi M; Shenouda, Sherene M; Chung, William B; Titas, Megan; Kluge, Matthew A; Wang, Na; Palmisano, Joseph; Milbury, Paul E; Blumberg, Jeffrey B; Vita, Joseph A

2011-05-01

Cranberry juice contains polyphenolic compounds that could improve endothelial function and reduce cardiovascular disease risk. The objective was to examine the effects of cranberry juice on vascular function in subjects with coronary artery disease. We completed an acute pilot study with no placebo (n = 15) and a chronic placebo-controlled crossover study (n = 44) that examined the effects of cranberry juice on vascular function in subjects with coronary artery disease. In the chronic crossover study, subjects with coronary heart disease consumed a research preparation of double-strength cranberry juice (54% juice, 835 mg total polyphenols, and 94 mg anthocyanins) or a matched placebo beverage (480 mL/d) for 4 wk each with a 2-wk rest period between beverages. Beverage order was randomly assigned, and participants refrained from consuming other flavonoid-containing beverages during the study. Vascular function was measured before and after each beverage, with follow-up testing ≥12 h after consumption of the last beverage. Mean (±SD) carotid-femoral pulse wave velocity, a measure of central aortic stiffness, decreased after cranberry juice (8.3 ± 2.3 to 7.8 ± 2.2 m/s) in contrast with an increase after placebo (8.0 ± 2.0 to 8.4 ± 2.8 m/s) (P = 0.003). Brachial artery flow-mediated dilation, digital pulse amplitude tonometry, blood pressure, and carotid-radial pulse wave velocity did not change. In the uncontrolled pilot study, we observed improved brachial artery flow-mediated dilation (7.7 ± 2.9% to 8.7 ± 3.1%, P = 0.01) and digital pulse amplitude tonometry ratio (0.10 ± 0.12 to 0.23 ± 0.16, P = 0.001) 4 h after consumption of a single 480-mL portion of cranberry juice. Chronic cranberry juice consumption reduced carotid femoral pulse wave velocity-a clinically relevant measure of arterial stiffness. The uncontrolled pilot study suggested an acute benefit; however, no chronic effect on measures of endothelial vasodilator function was found. This trial was registered at clinicaltrials.gov as NCT00553904.

Effects of cranberry juice consumption on vascular function in patients with coronary artery disease123

PubMed Central

Dohadwala, Mustali M; Holbrook, Monika; Hamburg, Naomi M; Shenouda, Sherene M; Chung, William B; Titas, Megan; Kluge, Matthew A; Wang, Na; Palmisano, Joseph; Milbury, Paul E; Blumberg, Jeffrey B; Vita, Joseph A

2011-01-01

Background: Cranberry juice contains polyphenolic compounds that could improve endothelial function and reduce cardiovascular disease risk. Objective: The objective was to examine the effects of cranberry juice on vascular function in subjects with coronary artery disease. Design: We completed an acute pilot study with no placebo (n = 15) and a chronic placebo-controlled crossover study (n = 44) that examined the effects of cranberry juice on vascular function in subjects with coronary artery disease. Results: In the chronic crossover study, subjects with coronary heart disease consumed a research preparation of double-strength cranberry juice (54% juice, 835 mg total polyphenols, and 94 mg anthocyanins) or a matched placebo beverage (480 mL/d) for 4 wk each with a 2-wk rest period between beverages. Beverage order was randomly assigned, and participants refrained from consuming other flavonoid-containing beverages during the study. Vascular function was measured before and after each beverage, with follow-up testing ≥12 h after consumption of the last beverage. Mean (±SD) carotid-femoral pulse wave velocity, a measure of central aortic stiffness, decreased after cranberry juice (8.3 ± 2.3 to 7.8 ± 2.2 m/s) in contrast with an increase after placebo (8.0 ± 2.0 to 8.4 ± 2.8 m/s) (P = 0.003). Brachial artery flow-mediated dilation, digital pulse amplitude tonometry, blood pressure, and carotid-radial pulse wave velocity did not change. In the uncontrolled pilot study, we observed improved brachial artery flow-mediated dilation (7.7 ± 2.9% to 8.7 ± 3.1%, P = 0.01) and digital pulse amplitude tonometry ratio (0.10 ± 0.12 to 0.23 ± 0.16, P = 0.001) 4 h after consumption of a single 480-mL portion of cranberry juice. Conclusions: Chronic cranberry juice consumption reduced carotid femoral pulse wave velocity—a clinically relevant measure of arterial stiffness. The uncontrolled pilot study suggested an acute benefit; however, no chronic effect on measures of endothelial vasodilator function was found. This trial was registered at clinicaltrials.gov as NCT00553904. PMID:21411615

Effect of Muscadine Grape Seed Supplementation on Vascular Function in Subjects with or at Risk for Cardiovascular Disease: A Randomized Crossover Trial

PubMed Central

Mellen, Philip B.; Daniel, Kurt R.; Brosnihan, K. Bridget; Hansen, Kim J.; Herrington, David M.

2012-01-01

Background Muscadine grape seeds have high concentrations of polyphenolic compounds with antioxidant and other properties that would be expected to have favorable effects on endothelial function. Objectives To evaluate the effect of muscadine grape seed supplementation on endothelial function and cardiovascular risk factors in subjects with increased cardiovascular risk. Design In a randomized, double-blind, placebo-controlled crossover trial, 50 adults with coronary disease or ≥1 cardiac risk factor received muscadine grape seed supplementation (1300 mg daily) and placebo for 4 weeks each, with a 4-week washout. Resting brachial diameter and brachial flow-mediated dilation (FMD) and biomarkers of inflammation, lipid peroxidation, and antioxidant capacity were determined at the beginning and end of each period and compared in mixed linear models. Results There was no evidence of improved FMD (% change) with muscadine grape seed (muscadine grape seed: pre 5.2% ± 0.3%, post 4.6% ± 0.3%, p = 0.06; placebo: pre 5.3% ± 0.4%, post 5.2% ± 0.4%, p = 0.82; p for muscadine grape seed vs. placebo = 0.25). However, there was a significant increase in baseline diameter (mm) with muscadine grape seed supplementation (muscadine grape seed: pre 4.05 ± 0.09, post 4.23 ± 0.10, p = 0.002; placebo: pre 4.12 ± 0.11, post 4.12 ± 0.10, p = 0.93; p for muscadine grape seed vs. placebo = 0.026). All other biomarkers were not significantly altered by muscadine grape seed supplementation. Conclusions Four weeks of muscadine grape seed supplementation in subjects with increased cardiovascular risk did not produce a statistically significant increase in brachial flow-mediated vasodilation or a significant change in other biomarkers of inflammation, lipid peroxidation, or antioxidant capacity. However, the muscadine grape seed supplement did result in a significant increase in resting brachial diameter. The clinical significance of the effect on resting diameter is not yet established. More research is warranted to fully characterize the vascular effects of this and other grape-derived nutritional supplements and to determine whether these vascular effects translate into important clinical benefits. PMID:21504973

Effect of muscadine grape seed supplementation on vascular function in subjects with or at risk for cardiovascular disease: a randomized crossover trial.

PubMed

Mellen, Philip B; Daniel, Kurt R; Brosnihan, K Bridget; Hansen, Kim J; Herrington, David M

2010-10-01

Muscadine grape seeds have high concentrations of polyphenolic compounds with antioxidant and other properties that would be expected to have favorable effects on endothelial function. To evaluate the effect of muscadine grape seed supplementation on endothelial function and cardiovascular risk factors in subjects with increased cardiovascular risk. In a randomized, double-blind, placebo-controlled crossover trial, 50 adults with coronary disease or ≥1 cardiac risk factor received muscadine grape seed supplementation (1300 mg daily) and placebo for 4 weeks each, with a 4-week washout. Resting brachial diameter and brachial flow-mediated dilation (FMD) and biomarkers of inflammation, lipid peroxidation, and antioxidant capacity were determined at the beginning and end of each period and compared in mixed linear models. There was no evidence of improved FMD (% change) with muscadine grape seed (muscadine grape seed: pre 5.2% ± 0.3%, post 4.6% ± 0.3%, p = 0.06; placebo: pre 5.3% ± 0.4%, post 5.2% ± 0.4%, p = 0.82; p for muscadine grape seed vs. placebo = 0.25). However, there was a significant increase in baseline diameter (mm) with muscadine grape seed supplementation (muscadine grape seed: pre 4.05 ± 0.09, post 4.23 ± 0.10, p = 0.002; placebo: pre 4.12 ± 0.11, post 4.12 ± 0.10, p = 0.93; p for muscadine grape seed vs. placebo = 0.026). All other biomarkers were not significantly altered by muscadine grape seed supplementation. Four weeks of muscadine grape seed supplementation in subjects with increased cardiovascular risk did not produce a statistically significant increase in brachial flow-mediated vasodilation or a significant change in other biomarkers of inflammation, lipid peroxidation, or antioxidant capacity. However, the muscadine grape seed supplement did result in a significant increase in resting brachial diameter. The clinical significance of the effect on resting diameter is not yet established. More research is warranted to fully characterize the vascular effects of this and other grape-derived nutritional supplements and to determine whether these vascular effects translate into important clinical benefits.