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Sample records for induced hypertension pih

  1. A molecular variant of angiotensinogen (M235T) in Korean pregnancy-induced hypertension (PIH) patients

    SciTech Connect

    Kim, Y.T.; Lee, C.; Lim, H.K.

    1994-09-01

    Objective: to illustrate an association between Korean PIH patients and a molecular variant (M235T) in the angiotensinogen gene on chromosome 1q42-43. Material: DNA from peripheral blood of 21 Korean normo-tensive pregnant women and 16 Korean PIH patients. Methods: PCR was performed and the PCR product was digested with Tth111I. The amplification yielded a product of 165 bp. Presence of C at position 704 was identified by cleavage with Tth111I, that generated a fragment of 141 bp. Results: In the PIH group, 2 cases showed 141 bp, 5 cases showed 165 bp, and 9 cases showed both 165 and 141 bp. In the normo-tensive group, 4 cases showed 141 bp, 4 cases showed 165 bp, and 13 cases showed both bands. Conclusion: We could not provide any definite conclusion that the molecular variant (M235T) of angiotensinogen had an association with Korean PIH in this preliminary study. More cases are required to confirm the association between Korean PIH and the molecular variant (M235T) of angiotensinogen.

  2. Pathophysiology of placentation abnormalities in pregnancy-induced hypertension

    PubMed Central

    Furuya, Mitsuko; Ishida, Junji; Aoki, Ichiro; Fukamizu, Akiyoshi

    2008-01-01

    During embryogenesis and development, the fetus obtains oxygen and nutrients from the mother through placental microcirculation. The placenta is a distinctive organ that develops and differentiates per se, and that organizes fetal growth and maternal condition in the entire course of gestation. Several life-threatening diseases during pregnancy, such as pregnancy-induced hypertension (PIH) and eclampsia, are closely associated with placental dysfunction. Genetic susceptibilities and poor placentation have been investigated intensively to understand the pathophysiology of PIH. It is currently thought that poor placentation hypothesis, in which extravillous trophoblasts fail to invade sufficiently the placental bed, explains in part maternal predisposition to this disease. Cumulative studies have suggested that hypoxic micromilieu of fetoplacental site, shear stress of uteroplacental blood flow, and aberrantly secreted proinflammatory substances into maternal circulation synergistically contribute to the progression of PIH. For example, soluble form of vascular endothelial growth factor receptor-1 (sVEGFR-1) and soluble form of CD105 are elevated in circulation of PIH mothers. However, it remains to be poorly understood the pathological events in the placenta during the last half of gestation as maternal systemic disorders get worse. For better understanding and effective therapeutic approaches to PIH, it is important to clarify pathological course of PIH-associated changes in the placenta. In this review, current understanding of placental development and the pathophysiology of PIH placenta are summarized. In addition, recent findings of vasoactive signalings in PIH and rodent PIH models are discussed. PMID:19337544

  3. Pregnancy-induced hypertension and congenital hearing loss.

    PubMed

    Wells, M D

    1991-07-01

    It has been suggested that pregnancy-induced hypertension (PIH--pre-eclampsia or toxaemia of pregnancy) may cause sensorineural hearing loss (SNHL) in the offspring. To establish the validity of this concept a clinical survey of the prevalence of congenital hearing loss in relation to PIH in the South East Kent Health District in the United Kingdom over a period of 4 years was undertaken. Description of the temporal bones in a case of PIH is presented. The total number of live births in this period was 12,927, out of which 512 mothers (3.9%) were diagnosed as having PIH. To date 17 cases of bilateral SNHL have been diagnosed in this period (excluding known syndromes, conductive hearing loss and unilateral SNHL). One of the mothers of these children had PIH. It is possible that otologists, in the absence of any obvious cause, have attributed the cause of bilateral SNHL to PIH. Histopathological findings in temporal bones from a 29-week fetus, whose cause of death was severe maternal hypertension, showed massive haemorrhages in the inner ear and middle ear and internal auditory meatus, a frequent finding in temporal bones obtained at autopsy from fetuses and neonates who were born prematurely. This study suggests that PIH per se is unlikely to cause SNHL in the newborn. PMID:1917337

  4. Pregnancy-Induced Hypertension

    MedlinePLUS

    ... PIH is more common during a woman's first pregnancy and in women whose mothers or sisters had PIH. The risk of PIH is higher in women carrying multiple babies, in teenage mothers and in women older than 40 years ...

  5. Drug-induced hypertension

    MedlinePLUS

    Drug-induced hypertension is high blood pressure caused by using a chemical substance, drug, or medication. ... found. Secondary hypertension occurs because of another disorder. Drug-induced hypertension is a form of secondary hypertension ...

  6. Parent-offspring conflict and the persistence of pregnancy-induced hypertension in modern humans.

    PubMed

    Hollegaard, Birgitte; Byars, Sean G; Lykke, Jacob; Boomsma, Jacobus J

    2013-01-01

    Preeclampsia is a major cause of perinatal mortality and disease affecting 5-10% of all pregnancies worldwide, but its etiology remains poorly understood despite considerable research effort. Parent-offspring conflict theory suggests that such hypertensive disorders of pregnancy may have evolved through the ability of fetal genes to increase maternal blood pressure as this enhances general nutrient supply. However, such mechanisms for inducing hypertension in pregnancy would need to incur sufficient offspring health benefits to compensate for the obvious risks for maternal and fetal health towards the end of pregnancy in order to explain why these disorders have not been removed by natural selection in our hunter-gatherer ancestors. We analyzed >750,000 live births in the Danish National Patient Registry and all registered medical diagnoses for up to 30 years after birth. We show that offspring exposed to pregnancy-induced hypertension (PIH) in trimester 1 had significantly reduced overall later-life disease risks, but increased risks when PIH exposure started or developed as preeclampsia in later trimesters. Similar patterns were found for first-year mortality. These results suggest that early PIH leading to improved postpartum survival and health represents a balanced compromise between the reproductive interests of parents and offspring, whereas later onset of PIH may reflect an unbalanced parent-offspring conflict at the detriment of maternal and offspring health. PMID:23451092

  7. Choroidal thickening and macular serous retinal detachment in pregnancy-induced hypertension

    PubMed Central

    Aoyagi, Ranko; Hayashi, Takaaki; Tsuneoka, Hiroshi

    2015-01-01

    Objective The purpose of this study was to report optical coherence tomography (OCT) and angiographic findings in a patient with pregnancy-induced hypertension (PIH). Case report A 39-year-old woman, who was diagnosed with PIH, reported blurred and distorted vision at 5 days after an emergency cesarean delivery. OCT revealed a large serous retinal detachment (SRD) that included areas in the macula, along with an increased choroidal thickness noted in both eyes. Indocyanine green angiograms indicated delayed filling of the choroidal circulation in the early phase but choroidal hyperpermeability in the mid-phase. The SRD was gradually resolving without any treatment except for antihypertensive drugs. At 40 days after the initial examination, OCT revealed both the disappearance of the SRD and marked improvement of the choroidal thickening. Conclusion Ophthalmologists need to be aware that PIH can cause choroidal ischemia, a breakdown of the outer bloodretinal barrier, and lead to the development of SRD. PMID:26635487

  8. Pregnancy-induced hypertension is associated with elevation of aggregability of red blood cells.

    PubMed

    Gamzu, Ronni; Barshtein, Gregory; Tsipis, Felix; Lessing, Joseph B; Berliner, Abraham S; Kupferminc, Michael J; Eldor, Amiram; Yedgar, Shaul

    2002-01-01

    In order to differentiate between the contributions of cellular and plasmatic factors to the elevated aggregation in pregnancy-induced hypertension (PIH), we determined RBC aggregation in autologous plasma and in plasma-free medium. The aggregation was determined as a function of shear stress, to evaluate the strength of the intercellular interaction. These procedures were applied to RBC from PIH women (n=20), normotensive pregnant (NTP) women (n=15), and non-pregnant (control) women (n=15). The average aggregate size (AAS) in plasma for PIH, NTP and control RBC was 38.7+/-3.2, 28.4+/-3.0, and 11.5+/-2.2 (P<0.05, between the three groups), respectively. For the same groups, the aggregation in plasma-free standard medium was 17.3+/-2.0, 12.0+/-1.2 and 10.0+/-1.6 (P<0.05 between PIH and the other two groups), respectively. The contribution of plasma to the elevated aggregation was 75% and 88% for PIH and NTP respectively. Tau(S50), the shear stress required to singly disperse 50% of the RBC population, in plasma and in standard medium, was about the same for PIH and NTP, and both were markedly higher than that for control RBC. These findings suggest that the increased aggregation of RBC from women with PIH, over those at of NTP women, may be due largely to changes in cellular factors and the increased aggregability has the potential to affect blood flow mainly in low-flow states such as in the placental intervillous space. PMID:12454372

  9. Posterior Reversible Encephelopathy Syndrome Presenting as Quadriparesis in Pregnancy Induced Hypertension

    PubMed Central

    Pranita; Kumar, Ajit; Shahi, Seema

    2015-01-01

    Pregnancy Induced Hypertension (PIH) is a condition characterised by raised blood pressure in pregnancy. It affects approximately one out of every 14 pregnant women. Although PIH more commonly occurs during first pregnancy, it can also occur in subsequent pregnancies. It can present with variable complications related to vasospasm. But focal neurologic deficits are extremely rare in patients with PIH. We report a case of quadriparesis due to posterior reversible encephalopathy syndrome (PRES). A 36 year old full term pregnant female was admitted for emergency lower segment caesarean section (LSCS) as a result of uncontrolled PIH with early clinical signs of left ventricular failure. She was recovering well from pulmonary oedema after being provided with mechanical ventilation. However on 4th day she developed sudden onset quadriparesis without any alteration in sensorium, bladder & bowel disturbance or any sensory deficit. Diffusion weighted neuroimaging (DWI) was carried out which revealed finding suggestive of PRES. The patient was treated with antihypertensive which followed improvement in neurological deficit. Although rare, PRES should be considered as a potential cause of acute onset focal neurological deficit in pregnant females with PIH. With this case report we have tried to create awareness and vigilance about rare but potentially serious yet salvageable condition like PRES. PMID:26023585

  10. Maternal renal artery Doppler sonographic changes in pregnancy-induced hypertension in South West Nigeria

    PubMed Central

    Ogunmoroti, Olusanmi Abel; Ayoola, Oluwagbemiga Oluwole; Makinde, Olufemiwa Niyi; Idowu, Bukunmi Michael

    2015-01-01

    Background: To evaluate the renal arterial hemodynamic changes caused by pregnancy-induced hypertension using Doppler ultrasonography. Materials and Methods: Eighty (80) subjects with pregnancy-induced hypertension (PIH) and 160 controls (80 pregnant normotensive women and 80 healthy, non-pregnant women) underwent triplex renal sonography prospectively to determine their renal volumes and right renal artery Doppler indices. Results: The peak systolic velocity, end diastolic velocity, pulsatility index, systolic/diastolic ratio and acceleration time were respectively significantly higher in the PIH group (68.67 cm/s, 21.55 cm/s, 1.23, 3.38, 123.2 ms) than the pregnant, normotensive group (65.19 cm/s, 20.27 cm/s, 0.88, 3.35, 61.14 ms) and healthy, non-pregnant group (52.06 cm/s, 18.27 cm/s, 0.84, 2.90, 68.48 ms). Resistivity index was also increased in the PIH group, but this was not statistically significant. Conversely, the systolic acceleration was significantly lower in the PIH group (6.06 m/s2) compared to the pregnant, normotensive group (11.82 m/s2) and healthy, non-pregnant group (8.26 m/s2). The right renal volume of the PIH group (132.76 cm3) was significantly higher that of the pregnant, normotensive group (125.29 cm3) and healthy, non-pregnant group (91.66 cm3). The same pattern was observed in the left renal volume which was 168.78 cm3, 164.95 cm3 and 113.80 cm3 in the study groups, respectively. Conclusion: Renal Doppler ultrasound is clinically relevant in the diagnosis and follow-up of renal complications in patients with pregnancy-induced hypertension. PMID:26229227

  11. A Combined Supplementation of Omega-3 Fatty Acids and Micronutrients (Folic Acid, Vitamin B12) Reduces Oxidative Stress Markers in a Rat Model of Pregnancy Induced Hypertension

    PubMed Central

    Kemse, Nisha G.; Kale, Anvita A.; Joshi, Sadhana R.

    2014-01-01

    Objectives Our earlier studies have highlighted that an altered one carbon metabolism (vitamin B12, folic acid, and docosahexaenoic acid) is associated with preeclampsia. Preeclampsia is also known to be associated with oxidative stress and inflammation. The current study examines whether maternal folic acid, vitamin B12 and omega-3 fatty acid supplementation given either individually or in combination can ameliorate the oxidative stress markers in a rat model of pregnancy induced hypertension (PIH). Materials and Methods Pregnant Wistar rats were assigned to control and five treatment groups: PIH; PIH + vitamin B12; PIH + folic acid; PIH + Omega-3 fatty acids and PIH + combined micronutrient supplementation (vitamin B12 + folic acid + omega-3 fatty acids). L-Nitroarginine methylester (L-NAME; 50 mg/kg body weight/day) was used to induce hypertension during pregnancy. Blood Pressure (BP) was recorded during pregnancy and dams were dissected at d20 of gestation. Results Animals from the PIH group demonstrated higher (p<0.01 for both) systolic and diastolic BP; lower (p<0.01) pup weight; higher dam plasma homocysteine (p<0.05) and dam and offspring malondialdehyde (MDA) (p<0.01), lower (p<0.05) placental and offspring liver DHA and higher (p<0.01) tumor necrosis factoralpha (TNF?) levels as compared to control. Individual micronutrient supplementation did not offer much benefit. In contrast, combined supplementation lowered systolic BP, homocysteine, MDA and placental TNF-? levels in dams and liver MDA and protein carbonyl in the offspring as compared to PIH group. Conclusion Key constituents of one carbon cycle (folic acid, vitamin B12 and DHA) may play a role in reducing oxidative stress and inflammation in preeclampsia. PMID:25405347

  12. Nicotine Inhibits Cytokine Production by Placenta Cells via NF?B: Potential Role in Pregnancy-Induced Hypertension

    PubMed Central

    Dowling, Oonagh; Rochelson, Burton; Way, Kathleen; Al-Abed, Yousef; Metz, Christine N

    2007-01-01

    Pregnancy-induced hypertension (PIH), also known as preeclampsia, is one of the major causes of maternal and fetal death. While the precise cause of PIH is not known, aberrant cytokine production and placenta participation are considered to be important factors. Gestational cigarette smoking, which is widely accepted to be harmful to both the mother and fetus, is protective against PIH. Based on the antiinflammatory activity of nicotine, the major component of cigarettes, we examined the effect of nicotine and other cholinergic agonists on placental inflammatory responses ex vivo. We observed that nicotine and other cholinergic agonists significantly suppress placenta cytokine production following stimulation. Placenta cells express the ?7 nicotinic acetylcholine receptor (?7nAChR), and using cholinergic antagonists, we demonstrated that the antiinflammatory effect of nicotine and other cholinergic agonists is, in part, mediated through the nAChR pathway. By contrast, cholinergic stimulation had no effect on the expression of soluble fms-like tyrosine kinase (sFlt), an antiangiogenic substance implicated in maternal vascular dysfunction during PIH. Mechanistic studies reveal that cholinergic agonists exert their antiinflammatory effects through the NF?B pathway. Taken together, our results suggest that cholinergic agonists, including nicotine, may reduce cytokine production by placenta cells via NF?B to protect against PIH. PMID:17878927

  13. [Use of calcium for the prevention of pregnancy-induced hypertension].

    PubMed

    Lpez-Jaramillo, P; de Flix, M

    1991-02-01

    The Andean population of Ecuador is exposed to major risk factors associated with pregnancy-induced hypertension (PIH). The disease is very frequent, and perinatal and maternal death rates are high. Recently a causal relationship has been suggested between dietary calcium deficiency and PIH, with the proposal that calcium supplements be given throughout pregnancy in order to prevent the disease. This article reviews a series of clinical tests carried out over a six-year period which have demonstrated that calcium supplementation is an effective low-cost measure for reducing the frequency of PIH in women whose intake of the mineral is low. It is not yet known how calcium reduces the risk of PIH. It is suggested that adequate intake of the mineral keeps serum levels of calcium within its narrow physiological limits; these are crucial for the synthesis of nitric oxide in the vascular endothelium, a substance that appears to be responsible for maintaining the vasodilatation that characterizes normal pregnancy. However, before the general use of calcium supplements can be recommended, it will be necessary to conduct epidemiological studies on larger numbers of women. PMID:1828158

  14. Is the serum l-arginine level during early pregnancy a predictor of pregnancy-induced hypertension?

    PubMed Central

    Wang, Jingwen; Kotani, Tomomi; Tsuda, Hiroyuki; Mano, Yukio; Sumigama, Seiji; Li, Hua; Komatsu, Koji; Miki, Rika; Maruta, Ei; Niwa, Yoshimitsu; Mitsui, Takashi; Yoshida, Shigeru; Yamashita, Mamoru; Tamakoshi, Koji; Kikkawa, Fumitaka

    2015-01-01

    The objective of this study was to determine the concentration of serum l-arginine in healthy pregnant women and infant cord blood and to compare them with those in patients with pregnancy-induced hypertension (PIH). The serum concentration of l-arginine in normal pregnant women at early gestation (n = 186) was determined and analyzed based on maternal factors such as the age, pre-pregnancy body mass index (BMI), smoking and alcohol habits before pregnancy. Similarly, the concentration of cord blood of the newborns (n = 142) was also analyzed. These values were compared with those in the PIH group (n = 21). The potential risk factors for PIH were also estimated. The serum concentration of l-arginine at early gestation in normal pregnant women (88.65 ± 19.96 µM) was not affected by the maternal age and BMI before pregnancy. A lower l-arginine concentration at early gestation (<70 µM) significantly elevated PIH risk [adjusted odds ratio (OR) = 4.26, 95% CI 1.29–14.50]. In addition, either women with large body mass before pregnancy (BMI>25 kg/m2) or primipara women also showed a significant association with PIH risk [adjusted OR = 10.55 (2.95–40.68); 5.25 (1.72–19.15), respectively]. In conclusion, a lower l-arginine concentration at early gestation, overweight before pregnancy (BMI>25 kg/m2) and primipara could predict to the development of PIH. PMID:26236104

  15. Maternal chronic HBV infection would not increase the risk of pregnancy-induced hypertension--results from pregnancy cohort in Liuyang rural China.

    PubMed

    Huang, Xin; Tan, Hongzhuan; Li, Xun; Zhou, Shujin; Wen, Shi Wu; Luo, Meiling

    2014-01-01

    The relationship between maternal HBV (hepatitis B virus) infection and pregnancy-induced hypertension (PIH) is inconclusive. Few studies have been conducted in rural areas of China. In order to examine the association between maternal chronic HBV infection and risk of PIH in Liuyang rural area China, we enrolled 6,195 eligible pregnant women in 2010-2011 in selected 14 towns of Liuyang on their first prenatal visit to local maternity care unit. A total of 461 subjects (7.44% (95%CI: 6.79%, 8.10%)) were identified with positive HBsAg status (exposed group) and 5734 were non-HBV carriers (unexposed group). Multivariate log-binomial regression models were used to estimate the risk of PIH, gestational hypertension (GH), and preeclampsia (PE) in relation to maternal chronic HBV infection. There are total of 455 subjects diagnosed with PIH (7.34% (95%CI: 6.70%, 7.99%)), including 371 GH (5.99% (95%CI: 5.40%, 6.58%)) and 81 PE (1.31% (95%CI: 1.07%, 1.64%)). The crude risk ratio between PIH, GH, PE and maternal HBV infection were 1.20 (95%CI: 0.88, 1.64), 1.30(95%CI: 0.93, 1.81) and 0.79 (95%CI: 0.32, 1.93), respectively. After adjustment for gravidity history, abortion history, family history of Diabetes Mellitus (DM) and family history of hypertension, positive HBsAg status was still not significantly associated with PIH (RR = 1.18, 95%CI: 0.87, 1.62), GH (RR = 1.27, 95%CI: 0.91, 1.78) or PE (RR = 0.79, 95%CI: 0.32, 1.95). Additional adjustment for maternal age, marital status, parity history, family history of DM, Body Mass Index at first antenatal visit, folic acid supplementation, smoking status during pregnancy and economic status of living area, multivariate analysis provided similar results. In conclusion, our study found that maternal chronic HBV infection prevalence rate is 7.4% among Liuyang rural area and there is no significant association between maternal HBV infection and the risk of PIH, GH or PE. PMID:25479003

  16. Application of Optical Coherence Tomography and Contrast Sensitivity Test for Observing Fundus Changes of Patients With Pregnancy-Induced Hypertension Syndrome.

    PubMed

    Wang, Zhixue; Zou, Yuanyuan; Li, Wenying; Wang, Xueyan; Zhang, Min; Wang, Wenying

    2015-11-01

    This study was aimed to investigate the fundus changes of patients with pregnancy-induced hypertension syndrome (PIHS) using optical coherence tomography (OCT) technology and contrast sensitivity (CS) tests.Ninety-eight patients with PIHS underwent routine eye examinations including vision correction, fundus examination, OCT, and CS tests. The CS test was performed at low, medium, and high frequency, respectively. Moreover, the difference in CS tests between 2 groups was analyzed by independent-samples T test. The Kruskal-Wallis rank sum test and linear regression model were used to detect the correlation of OCT with CS, respectively. Meanwhile Satterthwaite approximate T test was adopted for pairwise comparisons after nonparametric analysis of variance.The OCT test revealed that 56.76% of the examined eyes showed shallow retinal detachment in the macula lutea and around the optic disk. The differences in CS at each spatial frequency between the case and control group were statistically significant (P?PIHS. OCT and CS tests might be valuable methods in observing fundus changes for PIHS patients. PMID:26554764

  17. An exploratory analysis of the utility of adding cardiorespiratory biofeedback in the standard care of pregnancy-induced hypertension.

    PubMed

    Cullins, Sandy W; Gevirtz, Richard N; Poeltler, Debra M; Cousins, Larry M; Edward Harpin, R; Muench, Frederick

    2013-09-01

    This study examined the efficacy of a cardiorespiratory biofeedback intervention compared to bed rest in the treatment of 47 women diagnosed with pregnancy-induced hypertension (PIH). The investigation consisted of a historical control group with 31 PIH subjects receiving treatment as usual (TAU), bed rest and antihypertensive medications, and an experimental group with 16 PIH subjects receiving TAU and instruction on using a portable respiratory sinus arrhythmia (RSA) biofeedback device once daily until delivery. Results indicated that systolic and diastolic blood pressure levels were unchanged for either group. Failing to find the intended main effects, a series of exploratory analyses were performed. Findings of associated hypotheses revealed that the RSA BF group had a 35 % higher birth weight than the TAU group. The gestational age at delivery was 10 % greater in the RSA BF group than in the TAU group. A significant relationship was found between the StressEraser Total and the 1-min Apgar score. Eighty-one percent of the subjects stated that the device was relaxing. Fifty percent of the subjects believed that the device helped them fall asleep. Overall, these results suggest that portable RSA biofeedback may be effective in reducing stress during pregnancy and improving perinatal outcomes. PMID:23613006

  18. [Observation of qi-gong treatment in 60 cases of pregnancy-induced hypertension].

    PubMed

    Zhou, M R; Lian, M R

    1989-01-01

    Qi-gong relaxation exercise was used for treatment of pregnancy induced hypertension(PIH). Patients exercised 3 times a day until labor. In this study, there were two groups with 60 cases of PIH who had delivered in each group, they were treated by Qi-gong for one group and by medicine for another used as control. The clinical efficacy was evaluated according to PIH combined scores showed effective for 54 cases (90.0%) in Qi-gong group and 33 cases (55.0%) for the control group (P less than 0.01). Meconium stain in amniotic fluid was present in 12 cases (20.0%) in Qi-gong group and 29 cases (48.3%) in the control group (P less than 0.05). The incidence of abnormal hematocrit (greater than 35%) before treatment was 52.4% and decreased to 23.8% (P less than 0.05) in Qi-gong, while in the control group was 35.7% before treatment and 45.2% after treatment (P greater than 0.05). The mean value of blood E2 by RIA showed increased from 22.97 +/- 13.16 micrograms/ml to 33.74 +/- 34.01 micrograms/ml after Qi-gong treatment in 29 cases. The microscopical observation of finger nail capillaries showed various degrees of improvement of microcirculation after Qi-gong exercise for 17 cases and after a course of Qi-gong treatment for 11 cases in Qi-gong group. While for the control group, there was no changes after sit-still for some time.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2776267

  19. [Anesthetic Management of a Parturient with Eclampsia, Posterior Reversible Encephalopathy Syndrome and Pulmonary Edema due to Pregnancy-induced Hypertension].

    PubMed

    Aida, Junko; Okutani, Hiroai; Oda, Yutaka; Okutani, Ryu

    2015-08-01

    A 27-year-old woman with mental retardation was admitted to a nearby hospital for an abrupt onset of seizure. Physical examination revealed remarkable hypertension and pregnancy with estimated gestational age of 28th week. Severe pulmonary edema and hypoxia led to a diagnosis of pregnancy-induced hypertension (PIH) accompanied by eclampsia. She was orotracheally intubated because of refractory seizure and hypoxemia, and transferred to our hospital for further treatment. Besides severe hypoxia and hypercapnea, an enhanced lesion was detected in the left posterior cerebrum by brain MRI. No abnormal findings were detected in the fetus, with heart rate of 150 beats x min. She was diagnosed with posterior reversible encephalopathy syndrome (PRES) caused by PIH and emergency cesarean section under general anesthesia was scheduled. A male newborn was delivered with Apgar score of 1/4 (1/5 min), followed by starting continuous infusion of nicardipine for controlling hypertension. Chest X-P on completion of surgery revealed remarkably alleviated pulmonary edema. She received intensive treatment and continued positive pressure ventilation for four days after delivery. She recovered with no neurological deficits and her child was well without any complications. PMID:26442424

  20. Drug induced hypertension--An unappreciated cause of secondary hypertension.

    PubMed

    Grossman, Alon; Messerli, Franz H; Grossman, Ehud

    2015-09-15

    Most patients with hypertension have essential hypertension or well-known forms of secondary hypertension, such as renal disease, renal artery stenosis, or common endocrine diseases (hyperaldosteronism or pheochromocytoma). Physicians are less aware of drug induced hypertension. A variety of therapeutic agents or chemical substances may increase blood pressure. When a patient with well controlled hypertension is presented with acute blood pressure elevation, use of drug or chemical substance which increases blood pressure should be suspected. Drug-induced blood pressure increases are usually minor and short-lived, although rare hypertensive emergencies associated with use of certain drugs have been reported. Careful evaluation of prescription and non-prescription medications is crucial in the evaluation of the hypertensive individual and may obviate the need for expensive and unnecessary evaluations. Discontinuation of the offending agent will usually achieve adequate blood pressure control. When use of a chemical agent which increases blood pressure is mandatory, anti-hypertensive therapy may facilitate continued use of this agent. We summarize the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action. PMID:26096556

  1. Carbamazepine-induced hypertension: A rare case

    PubMed Central

    Kharb, Preeti; Mittal, Niti; Gupta, Mahesh C.

    2015-01-01

    A 74-year-old female with trigeminal neuralgia developed hypertension after the initiation of carbamazepine therapy. The time sequence of start of the suspected drug and onset of hypertension are consistent with the diagnosis. The hypertension did not resolve with antihypertensive therapy or dose reduction of carbamazepine. Patient recovered after the carbamazepine therapy was discontinued. The positive rechallenge and positive dechallenge showed association of carbamazepine therapy with hypertension as its adverse effect. This is a rare case that we report of carbamazepine-induced hypertension and this report may act as alerting mechanism to the health care professionals especially neurologists.

  2. Drug-induced hypertension: an unappreciated cause of secondary hypertension.

    PubMed

    Grossman, Ehud; Messerli, Franz H

    2012-01-01

    A myriad variety of therapeutic agents or chemical substances can induce either a transient or persistent increase in blood pressure, or interfere with the blood pressure-lowering effects of antihypertensive drugs. Some agents cause either sodium retention or extracellular volume expansion, or activate directly or indirectly the sympathetic nervous system. Other substances act directly on arteriolar smooth muscle or do not have a defined mechanism of action. Some medications that usually lower blood pressure may paradoxically increase blood pressure, or an increase in pressure may be encountered after their discontinuation. In general, drug-induced pressure increases are small and transient: however, severe hypertension involving encephalopathy, stroke, and irreversible renal failure have been reported. The deleterious effect of therapeutic agents is more pronounced in patients with preexisting hypertension, in those with renal failure, and in the elderly. Careful evaluation of a patient's drug regimen may identify chemically induced hypertension and obviate unnecessary evaluation and facilitate antihypertensive therapy. Once chemical-induced hypertension has been identified, discontinuation of the causative agent is recommended, although hypertension can often be managed by specific therapy and dose adjustment if continued use of the offending agent is mandatory. The present review summarizes the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action. PMID:22195528

  3. Fish Oil Supplementation does not Reduce Risks of Gestational Diabetes Mellitus, Pregnancy-Induced Hypertension, or Pre-Eclampsia: A Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Chen, Bing; Ji, Xinran; Zhang, Lei; Hou, Zhaohui; Li, Chundong; Tong, Ying

    2015-01-01

    Background The effects of gestational supplementation with fish oil on risks for gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), and pre-eclampsia (PE) have not been confirmed. In this study, a meta-analysis was performed to evaluate the effect of fish oil supplementation on these gestational complications. Material/Methods Randomized controlled human trials that investigated the effects of fish oil supplementation in pregnant women were identified by a systematic search of Medline, Embase, and Cochranes Library, and references of related reviews and studies up to December 2014. Relative risks (RRs) for GDM, PIH, and PE were the outcomes of interest. Fixed-effects or random-effects models were applied according to the heterogeneity. Results Thirteen comparisons from 11 published articles, including more than 5000 participants, were included. The results showed that fish oil supplementation was not associated with reduced risks for GDM (RR=1.06, 95% confidence interval [CI]: 0.851.32, p=0.60), PIH (RR=1.03, 95% CI: 0.891.20, p=0.66), or PE (RR=0.93, 95% CI: 0.741.16, p=0.51). No statistically significant heterogeneity was detected for the comparison of each outcome. The effects of fish oil on these gestational complications were consistent between women with low-risk and high-risk pregnancies. Conclusions Gestational supplementation with fish oil during the second or third trimester of pregnancy is not associated with reduced risks for GDM, PIH, or PE. Other possible benefits of fish oil supplementation during pregnancy warrant further evaluation. PMID:26256041

  4. The effects of smoking and hypertensive disorders on fetal growth

    PubMed Central

    Rasmussen, Svein; Irgens, Lorentz M

    2006-01-01

    Background It is well known that smoking and pregnancy induced hypertension (PIH) are associated with decreased fetal growth. It has been reported that in preeclampsia the fetal growth deficit attributable to smoking is higher, which has been contradicted in other studies. We therefore evaluated the effects on fetal growth of early- and late onset PIH and chronic hypertension and how cigarette smoking modify these effects. We also quantified the proportion of small for gestational age (SGA) cases attributable to PIH, chronic hypertension, and smoking. Methods Population-based study based on record of 215598 singleton pregnancies from the Medical Birth Registry of Norway. Results In severe preeclampsia, mild preeclampsia, transient hypertension, and normotension in term birth, odds ratios (ORs) of SGA in smokers compared with non-smokers were 1.4 (95% confidence interval 0.9, 2.2), 1.6 (1.3, 1.9), 2.3 (1.8, 3.1), and 2.0 (1.9, 2.1), respectively. For preterm births, corresponding ORs were 1.3 (0.9, 2.0), 1.8 (1.1, 3.0), 4.1 (1.9, 9.0), and 1.7 (1.4, 2.0), respectively. The effect of early onset PIH was stronger than that in term births, while the effect of smoking was equal in preterm and term newborns. Only in non-smokers who delivered at term, the rates of SGA significantly increased with the severity of PIH (ORs = 1.3 (1.1, 1.5), 1.8 (1.7, 2.0), and 2.5 (2.2, 3.0) for transient hypertension, mild-, and severe preeclampsia, respectively). The combined effects of smoking and hypertension were generally not synergistic. The effect of smoking was not stronger in women who had chronic hypertension. Nor were the effects of chronic hypertension stronger in smokers. PIH explained 21.9 and 2.5% of preterm and term cases of SGA, respectively, while smoking explained 12% of SGA cases. Conclusion The effects of hypertensive disorder and smoking were generally not synergistic, which suggest that they may exert their main actions on separate sites or work through separate mechanisms within or outside the placenta. If smoking were eliminated in pregnant women, the number of SGA cases would be reduced by 12%. PMID:16630351

  5. Mother-induced hypertension in familial dysautonomia.

    PubMed

    Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto; Kaufmann, Horacio

    2016-02-01

    Here we report the case of a patient with familial dysautonomia (a genetic form of afferent baroreflex failure), who had severe hypertension (230/149mmHg) induced by the stress of his mother taking his blood pressure. His hypertension subsided when he learnt to measure his blood pressure without his mother's involvement. The case highlights how the reaction to maternal stress becomes amplified when catecholamine release is no longer under baroreflex control. PMID:26589199

  6. A Study on Atherogenic Indices of Pregnancy Induced Hypertension Patients as Compared to Normal Pregnant Women

    PubMed Central

    Pathak, Mauchumi Saikia; Paul, Anindita

    2015-01-01

    Introduction Pregnancy induced hypertension (PIH) includes Gestational hypertension, Pre-eclampsia and Eclampsia and is one of the most common obstetric complication. Worldwide about 76,000 pregnant women die each year from pre-eclampsia and related hypertensive disorders. The aetiology of Pre-eclampsia is unknown but it is thought to be related to abnormal development of placenta. Several studies have shown the presence of reduced endothelial function in pre-eclamptic pregnancy. Endothelial dysfunction is also a feature of atherosclerosis. Aim To assess fasting lipid profile and atherogenic indices in women diagnosed with pre-eclampsia as well as in women with normal pregnancy and to correlate the findings of pre-eclamptic women with that of normal pregnant women, in an attempt to utilize the data for the development of a new clinical approach for early recognition and prevention of risk of future cardiovascular diseases in women with PIH. Materials and Methods This case-control study was conducted on 50 pre-eclampsia patients who were in third trimester of pregnancy (Case group). A control group of 50 age and gestational age matched normal pregnant women was taken. Strict inclusion and exclusion criteria were followed. Fasting Lipid profile parameters were assessed and used to calculate the atherogenic indices namely Atherogenic index of plasma (AIP), Cardiac risk ratio (CRR) and Atherogenic coefficient (AC). Statistical Analysis was done by using students t-test. Mann-Whitney U-test was used wherever applicable and correlations between the variables were estimated by Pearsons correlation coefficients. Results There was an extremely significant (p<0.0001) increase in Atherogenic indices (AIP, CRR and AC) in case group as compared to the control group. A positive and significant correlation of systolic blood pressure with AIP (r=0.3583), CRR (r=0.3137), AC (r=0.3193) was found in cases. There was a positive and significant correlation between gestational age and atherogenic indices in the case group. Conclusion Women with pre-eclampsia present abnormalities in lipid profile and these lipids turn out to be a risk factor for cardiovascular complications. Evaluation of the atherogenic indices during pregnancy may help prevent this risk. PMID:26393117

  7. [Iatrogenic and drug-induced hypertension].

    PubMed

    Mounier-Vehier, Claire; Boudghne, Fanny; Claisse, Gonzague; Delsart, Pascal

    2015-06-01

    Various toxic or drug agents can induce arterial hypertension, aggravate or limit the efficiency of anti-hypertensive drugs. Iatrogenic and drug-induced hypertension should be well known by the clinicians and the pharmacists, given the impact for driving the management of patients. In the food, an excessive alcohol consumption (more than 30 g per day) and more rarely glycerizine (active ingredient of the licorice) should be systematically looked for in front of a recent hypertension or do not respond to usual treatment. In the list of offending medicines, we must remember ethinyl estradiol contained in the contraception (oral, vaginal ring or transcutaneous patch), non steroidal anti-inflammatory drugs, immunosuppressants (cyclosporine, tacrolimus), vascular endothelial growth factor and its receptor R2 (avastin, inhibitors of receptor tyrosine kinases), recombinant human erythropoietin, sympathomimetics (nasal decongestants), anabolic steroids, bromocriptine (inhibitor of lactation), psychotropes (tricyclics antidepressants, monoamine oxydase inhibitors). The diagnosis of iatrogenic hypertensions should be systematically suspected in front of a suggestive clinical context with a meticulous food questioning because these hypertensions are partially or fully reversible after exposure stops. PMID:26298906

  8. Alcohol-induced hypertension: Mechanism and prevention

    PubMed Central

    Husain, Kazim; Ansari, Rais A; Ferder, Leon

    2014-01-01

    Epidemiological, preclinical and clinical studies established the association between high alcohol consumption and hypertension. However the mechanism through which alcohol raises blood pressure remains elusive. Several possible mechanisms have been proposed such as an imbalance of the central nervous system, impairment of the baroreceptors, enhanced sympathetic activity, stimulation of the renin-angiotensin-aldosterone system, increased cortisol levels, increased vascular reactivity due to increase in intracellular calcium levels, stimulation of the endothelium to release vasoconstrictors and loss of relaxation due to inflammation and oxidative injury of the endothelium leading to inhibition of endothelium-dependent nitric oxide production. Loss of relaxation due to inflammation and oxidative injury of the endothelium by angiotensin II leading to inhibition of endothelium-dependent nitric oxide production is the major contributors of the alcohol-induced hypertension. For the prevention of alcohol-induced hypertension is to reduce the amount of alcohol intake. Physical conditioning/exercise training is one of the most important strategies to prevent/treat chronic alcohol-induced hypertension on physiological basis. The efficacious pharmacologic treatment includes the angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARBs) which have antioxidant activity and calcium channel blockers. The most effective prevention and treatment of alcohol-induced hypertension is physical exercise and the use of ACE inhibitors or ARBs in the clinic PMID:24891935

  9. Alcohol-induced hypertension: Mechanism and prevention.

    PubMed

    Husain, Kazim; Ansari, Rais A; Ferder, Leon

    2014-05-26

    Epidemiological, preclinical and clinical studies established the association between high alcohol consumption and hypertension. However the mechanism through which alcohol raises blood pressure remains elusive. Several possible mechanisms have been proposed such as an imbalance of the central nervous system, impairment of the baroreceptors, enhanced sympathetic activity, stimulation of the renin-angiotensin-aldosterone system, increased cortisol levels, increased vascular reactivity due to increase in intracellular calcium levels, stimulation of the endothelium to release vasoconstrictors and loss of relaxation due to inflammation and oxidative injury of the endothelium leading to inhibition of endothelium-dependent nitric oxide production. Loss of relaxation due to inflammation and oxidative injury of the endothelium by angiotensin II leading to inhibition of endothelium-dependent nitric oxide production is the major contributors of the alcohol-induced hypertension. For the prevention of alcohol-induced hypertension is to reduce the amount of alcohol intake. Physical conditioning/exercise training is one of the most important strategies to prevent/treat chronic alcohol-induced hypertension on physiological basis. The efficacious pharmacologic treatment includes the angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARBs) which have antioxidant activity and calcium channel blockers. The most effective prevention and treatment of alcohol-induced hypertension is physical exercise and the use of ACE inhibitors or ARBs in the clinic. PMID:24891935

  10. Human PIH1 associates with histone H4 to mediate the glucose-dependent enhancement of pre-rRNA synthesis.

    PubMed

    Zhai, Niu; Zhao, Zhong-liang; Cheng, Mo-bin; Di, Yu-wei; Yan, Hai-xia; Cao, Chun-yu; Dai, Hui; Zhang, Ye; Shen, Yu-fei

    2012-08-01

    Ribosome biogenesis is critical in the growth of eukaryotic cells, in which the synthesis of precursor ribosomal RNA is the first and rate-limiting step. Here, we show that human PIH1 domain-containing protein 1 (PIH1) interacts directly with histone H4 and recruits the Brg1-SWI/SNF complex via SNF5 to human rRNA genes. This process is likely involved in PIH1-dependent DNase I-hypersensitive chromatin remodeling at the core promoter of the rRNA genes. PIH1 mediates the occupancy of not only the Brg1 complex but also the Pol I complex at the core promoter and enhances transcription initiation of rRNA genes. Additionally, the interaction between PIH1 and H4K16 expels TIP5, a component of the silencing nucleolar remodeling complex (NoRC), from the core region, suggesting that PIH1 is involved in the derepression of NoRC-silenced rRNA genes. These data indicate that PIH1 is a positive regulator of human rRNA genes and is of great importance for the recovery of human cells from nutrient starvation and the transition to glucose-induced exponential growth in vivo. PMID:22368283

  11. [Liquorice-induced hypertension and hypokalaemia].

    PubMed

    Nielsen, Mette Lundgren; Pareek, Manan; Andersen, Inger

    2012-04-01

    Consumption of large amounts of liquorice can cause hypertension and hypokalaemia. Liquorice contains glycyrrhetinic acid, which inhibits the enzyme 11 beta-hydroxysteroid dehydrogenase type 2, and ultimately leads to an apparent mineralocorticoid excess syndrome. This case report describes a 50 year-old woman presenting with hypertension and hypokalaemia-induced limb paresis due to chronic liquorice ingestion. The patient was treated with potassium supplementation and spironolactone. Her blood pressure and electrolyte status normalised within a month after cessation of liquorice intake. PMID:22487411

  12. Hypertension induced by adrenocortical dysfunction--hypertension in 17 alpha-hydroxylase deficiency and metopirone-induced hypertension.

    PubMed

    Saruta, T; Nakamura, R; Saito, I; Kondo, K; Ohguro, T; Yamagami, K; Kitajima, W; Oka, M; Konishi, K; Ozawa, Y; Kato, E; Matsuki, S

    1978-05-01

    Hypertension in 17 alpha-hydroxylase deficiency was studied by comparing it with hypertension in Cushing syndrome or that in primary aldosteronism. Furthermore, the role of endogenous increases of ACTH, deoxycorticosterone, and 18 alpha-hydroxy-deoxycorticosterone upon blood pressure was studied in rats by administerating metopirone. Hypertension in 17 alpha-hydroxylase deficiency was considered to be more similar to that in primary aldosteronism from the studies on renin components, pressor responses to angiotensin II and norepinephrine, and renin responses to stimulations. Plasma catecholamines were slightly decreased in 17 alpha-hydroxylase deficiency. The hypertension was alleviated by the administeration of dexamethasone in 2 of 3 patients with 17 alpha-hydroxylase deficiency. However, in the remaining one who had an accelerated hypertension and normal renin, the hypertension was not alleviated by dexamethasone. In the animal studies, hypertension induced by metopirone was accelerated by salt loading of uni-lateral nephrectomy plus salt loading. In those rats, plasma ACTH, and deoxycorticosterone were markedly increased. PMID:212619

  13. New developments in the pathogenesis of obesity-induced hypertension.

    PubMed

    Kotsis, Vasilios; Nilsson, Peter; Grassi, Guido; Mancia, Giuseppe; Redon, Josep; Luft, Frank; Schmieder, Roland; Engeli, Stefan; Stabouli, Stella; Antza, Christina; Pall, Denes; Schlaich, Markus; Jordan, Jens

    2015-08-01

    Obesity is a disorder that develops from the interaction between genotype and environment involving social, behavioral, cultural, and physiological factors. Obesity increases the risk for type 2 diabetes mellitus, hypertension, cardiovascular disease, cancer, musculoskeletal disorders, chronic kidney and pulmonary disease. Although obesity is clearly associated with an increased prevalence of hypertension, many obese individuals may not develop hypertension. Protecting factors may exist and it is important to understand why obesity is not always related to hypertension. The aim of this review is to highlight the knowledge gap for the association between obesity, hypertension, and potential genetic and racial differences or environmental factors that may protect obese patients against the development of hypertension and other co-morbidities. Specific mutations in the leptin and the melaninocortin receptor genes in animal models of obesity without hypertension, the actions of ?-melanocyte stimulating hormone, and SNS activity in obesity-related hypertension may promote recognition of protective and promoting factors for hypertension in obesity. Furthermore, gene-environment interactions may have the potential to modify gene expression and epigenetic mechanisms could also contribute to the heritability of obesity-induced hypertension. Finally, differences in nutrition, gut microbiota, exposure to sun light and exercise may play an important role in the presence or absence of hypertension in obesity. PMID:26103132

  14. Assessment of Nephroprotective Potential of Histochrome during Induced Arterial Hypertension.

    PubMed

    Agafonova, I G; Bogdanovich, R N; Kolosova, N G

    2015-12-01

    Magnetic resonance tomography was employed to verify endothelial dysfunction of renal arteries in Wistar and OXYS rats under conditions of induced arterial hypertension. Angiography revealed changes in the size and form of renal arteries of hypertensive animals. In hypertensive rats, histochrome exerted a benevolent therapeutic effect in renal arteries: it decreased BP, diminished thrombus formation in fi ne capillaries and arterioles, demonstrated the anticoagulant properties, partially improved endothelial dysfunction of small renal arteries, and up-regulated the glomerular filtration. PMID:26645289

  15. Radiation induced heart disease in hypertensive rats

    SciTech Connect

    Lauk, S.; Trott, K.R.

    1988-01-01

    Spontaneously hypertensive Wistar rats were given single doses of X rays to their heart. Irradiation decreased the blood pressure before any myocardial radiation damage was apparent. Male rats, which were more hypertensive than female rats, had a shorter survival time after local heart irradiation than female rats. Antihypertensive treatment with hydralazine did not increase the survival time. It is considered that myocardial hypertrophy is the cause of the increased susceptibility of spontaneously hypertensive rats to local heart irradiation.

  16. Spaceflight-Induced Intracranial Hypertension: An Overview

    NASA Technical Reports Server (NTRS)

    Traver, William J.

    2011-01-01

    This slide presentation is an overview of the some of the known results of spaceflight induced intracranial hypertension. Historical information from Gemini 5, Apollo, and the space shuttle programs indicated that some vision impairment was reported and a comparison between these historical missions and present missions is included. Optic Disc Edema, Globe Flattening, Choroidal Folds, Hyperopic Shifts and Raised Intracranial Pressure has occurred in Astronauts During and After Long Duration Space Flight. Views illustrate the occurrence of Optic Disc Edema, Globe Flattening, and Choroidal Folds. There are views of the Arachnoid Granulations and Venous return, and the question of spinal or venous compliance issues is discussed. The question of increased blood flow and its relation to increased Cerebrospinal fluid (CSF) is raised. Most observed on-orbit papilledema does not progress, and this might be a function of plateau homeostasis for the higher level of intracranial pressure. There are seven cases of astronauts experiencing in flight and post flight symptoms, which are summarized and follow-up is reviewed along with a comparison of the treatment options. The question is "is there other involvement besides vision," and other Clinical implications are raised,

  17. Single dose regorafenib-induced hypertensive crisis.

    PubMed

    Yilmaz, B; Kemal, Y; Teker, F; Kut, E; Demirag, G; Yucel, I

    2014-06-01

    Gastrointestinal stromal tumors (GISTs) are uncommon tumors of the gastrointestinal (GI) tract. Regorafenib is a new multikinase inhibitor and is approved for the treatment of GISTs in patients who develop resistance to imatinib and sunitinib. The most common drug-related adverse events with regorafenib are hypertension, hand-foot skin reactions, and diarrhea. Grade IV hypertensive side effect has never been reported after a single dose. In this report, we present a case of Grade IV hypertensive side effect (hypertensive crisis and seizure) after a single dose of regorafenib. A 54-year-old male normotensive GIST patient was admitted to the emergency department with seizure and encephalopathy after the first dosage of regorafenib. His blood pressure was 240/140 mmHg upon admission. After intensive treatment with nitrate and nitroprusside, his blood pressure returned to normal levels in five days. Regorafenib was discontinued, and he did not experience hypertension again. This paper reports the first case of Grade IV hypertension after the first dosage of regorafenib. We can suggest that hypertension is an idiosyncratic side effect unrelated to the dosage. PMID:24980770

  18. [Blood pressure variability-induced aggravation of hypertensive organ damages].

    PubMed

    Kai, Hisashi

    2015-11-01

    There is increasing evidence that not only the elevation of systolic and diastolic blood pressure(BP) but also the increase in BP variability (or fluctuation) are associated with hypertensive organ damages and the morbidity and mortality of cerebrovascular and cardiovascular events, as well as cognitive dysfunction. However, the molecular mechanism whereby the increase in BP variability aggravates hypertensive organ damages remains unknown. Thus, we created a rat chronic model of a combination of hypertension and large BP variability by performing bilateral sino-aortic denervation in spontaneously hypertensive rat. A series of our studies using this model revealed that large BP variability induces chronic myocardial inflammation by activating local angiotensin II and mineralocorticoid receptor systems and thereby aggravates cardiac hypertrophy and myocardial fibrosis, leading to systolic dysfunction, in hypertensive hearts. In addition, large BP variability induces the aggravation of arteriolosclerotic changes and ischemic cortical fibrosis in hypertensive kidney via local angiotensin II system. It is interesting that the initial target sites of the large BP variability are the intramyocardial arterioles in the heart and pre-glomerular arterioles in the juxtamedullary renal cortex, so called "strain vessels". Accordingly, we advocate new concept that the large BP-induced aggravation of hypertensive organ damage is attributable to "strain vessel vasculopathy". PMID:26619672

  19. Mechanisms underlying the hypertensive response induced by capsaicin.

    PubMed

    Dutta, Abhaya; Deshpande, Shripad B

    2010-11-19

    Acute ingestion of large quantity of chili peppers (rich source of capsaicin) produced hypertensive crisis in a patient. The hypertensive response was explained on the basis of decreased vasodilator substance calcitonin gene-related peptide (CGRP) from sensory nerve terminals by capsaicin. Here we present our experimental observations in anaesthetized rats regarding the mechanisms underlying hypertensive response induced by capsaicin. Our results demonstrate non-involvement of adrenergic and angiotensinergic mechanisms and also the cardiac changes in producing the response. Thus, the direct action of capsaicin on vascular smooth muscle or the activation of endothelin is proposed. PMID:20223533

  20. Melatonin prevents neonatal dexamethasone induced programmed hypertension: histone deacetylase inhibition.

    PubMed

    Wu, Ting-Hsin; Kuo, Hsuan-Chang; Lin, I-Chun; Chien, Shao-Ju; Huang, Li-Tung; Tain, You-Lin

    2014-10-01

    Adulthood hypertension can be programmed by corticosteroid exposure in early life. Oxidative stress, epigenetic regulation by histone deacetylases (HDACs), and alterations of renin-angiotensin system (RAS) are involved in the developmental programming of hypertension. We examined whether melatonin prevented neonatal dexamethasone (DEX)-induced programmed hypertension and how melatonin prevented these processes. We also examined whether HDAC inhibition by trichostatin A (TSA, a HDAC inhibitor) had similar effects. Male offspring were assigned to 5 groups (n=6/group): control, DEX, melatonin, DEX+melatonin, and DEX+TSA. Male rat pups were injected i.p. with DEX on day 1 (0.5mg/kg BW), day 2 (0.3mg/kg BW), and day 3 (0.1mg/kg BW) after birth. Melatonin was administered in drinking water at the dose of 0.01% during the lactation period. The DEX+TSA group received DEX and 0.5mg/kg TSA subcutaneous injection once daily for 1 week. All rats were killed at 16 weeks of age. Neonatal DEX exposure induced hypertension in male offspring at 16 weeks of age, which melatonin prevented. Neonatal DEX exposure decreased gene expression related to apoptosis, nephrogenesis, RAS, and sodium transporters. Yet DEX treatment increased protein levels of HDAC-1, -2, and -3 in the kidney. Melatonin therapy preserved the decreases of gene expression and decreased HDACs. Similarly, HDAC inhibition prevented DEX-induced programmed hypertension. In conclusion, melatonin therapy exerts a long-term protection against neonatal DEX-induced programmed hypertension. Its beneficial effects include alterations of RAS components and inhibition of class I HDACs. Given that the similar protective effects of melatonin and TSA, melatonin might inhibit HDACs to epigenetic regulation of hypertension-related genes to prevent programmed hypertension. PMID:25090636

  1. Functional Inducible Nitric Oxide Synthase Gene Variants Associate With Hypertension

    PubMed Central

    Nikkari, Seppo T.; Mtt, Kirsi M.; Kunnas, Tarja A.

    2015-01-01

    Abstract Increased inducible nitric oxide synthase (iNOS) activity and expression has been associated with hypertension, but less is known whether the 2 known functional polymorphic sites in the iNOS gene (g.1026 C/A (rs2779249), g.2087 G/A (rs2297518)) affect susceptibility to hypertension. The objective of this study was to investigate the association between the genetic variants of iNOS and diagnosed hypertension in a Finnish cohort. This study included 320 hypertensive cases and 439 healthy controls. All participants were 50-year-old men and women and the data were collected from the Tampere adult population cardiovascular risk study (TAMRISK). DNA was extracted from buccal swabs and iNOS single nucleotide polymorphisms (SNPs) were analyzed using KASP genotyping PCR. Data analysis was done by logistic regression. At the age of 50 years, the SNP rs2779249 (C/A) associated significantly with hypertension (P?=?0.009); specifically, subjects carrying the A-allele had higher risk of hypertension compared to those carrying the CC genotype (OR?=?1.47; CI?=?1.082.01; P?=?0.015). In addition, a 15-year follow-up period (35, 40, and 45 years) of the same individuals showed that carriers of the A-allele had more often hypertension in all of the studied age-groups. The highest risk for developing hypertension was obtained among 35-year-old subjects (odds ratio [OR] 3.83; confidence interval [CI]?=?1.2012.27; P?=?0.024). Those carrying variant A had also significantly higher readings of both systolic (P?=?0.047) and diastolic (P?=?0.048) blood pressure during the follow-up. No significant associations between rs2297518 (G/A) variants alone and hypertension were found. However, haplotype analysis of rs2779249 and rs2297518 revealed that individuals having haplotype H3 which combines both A alleles (CAGA, 19.7% of individuals) was more commonly found in the hypertensive group than in the normotensive group (OR?=?2.01; CI?=?1.293.12; P?=?0.002). In conclusion, there was a significant association between iNOS genetic variant (rs2779249) and hypertension in the genetically homogenous Finnish population. Those who carried the rare A-allele of the gene had higher risk for hypertension already at the age of 35 years. PMID:26579803

  2. Drug-Induced Ocular Hypertension and Angle-Closure Glaucoma.

    PubMed

    Badhu, Badri P; Bhattarai, Balkrishna; Sangraula, Himal P

    2013-01-01

    The objective of this study was to review the available literature on the drugs causing ocular hypertension and glaucoma. Electronic literature search was carried out using the Web sites www.pubmed.gov and www.google.com published through the year 2011. The search words were "drug induced ocular hypertension" and "drug induced glaucoma" used in combination. The articles published or translated into English were studied. Quite a significant number of drugs commonly prescribed by various physicians of different specialties can induce ocular hypertension or glaucoma. A brief account of various drugs that can induce ocular hypertension has been given in this article. Those drugs are parasympatholytics; steroids; anticholinergics, adrenergics, and antidepressants; cholinomimetics; antineoplastic agents; antipsychotic and antiparkinsonism agents; H1 and H2 receptor blockers; botulinum toxin, cardiac agents, and anticoagulants; silicone oil; sulfa drugs; and anesthetic agents. Rational use of these drugs and knowledge of their potential adverse effects can help prevent the devastating complications resulting in loss of vision and compromised quality of life. PMID:26108110

  3. Regional anesthesia in patients with pregnancy induced hypertension

    PubMed Central

    Ankichetty, Saravanan P; Chin, Ki Jinn; Chan, Vincent W; Sahajanandan, Raj; Tan, Hungling; Grewal, Anju; Perlas, Anahi

    2013-01-01

    Pregnancy induced hypertension is a hypertensive disorder, which occurs in 5% to 7% of all pregnancies. These parturients present to the labour and delivery unit ranging from gestational hypertension to HELLP syndrome. It is essential to understand the various clinical conditions that may mimic preeclampsia and the urgency of cesarean delivery, which may improve perinatal outcome. The administration of general anesthesia (GA) increases morbidity and mortality in both mother and baby. The provision of regional anesthesia when possible maintains uteroplacental blood flow, avoids the complications with GA, improves maternal and neonatal outcome. The use of ultrasound may increase the success rate. This review emphasizes on the regional anesthetic considerations when such parturients present to the labor and delivery unit. PMID:24249977

  4. Corticosteroid-induced ocular hypertension. II. An acquired form.

    PubMed Central

    Akingbehin, A O

    1982-01-01

    Thirty-five patients with unilateral closed-angle glaucoma treated by peripheral iridectomy and prophylactic peripheral iridectomy in the fellow eyes were subjected to corticosteroid provocative test in both eyes. 51% of the eyes with closed-angle glaucoma and 11% of their fellow eyes had a positive corticosteroid pressure response. The closed-angle glaucoma eyes had their fellow eyes responded differently as shown by the frequency distribution graphs and also by the difference between the corticosteroid-induced change in pressure (Wilcoxon test, z=-4.80, p less than 0.0001). These results provide evidence for an acquired form of corticosteroid-induced ocular hypertension and the possible pathogenic factors for the first time. The clinical significance of an acquired form of corticosteroid-induced ocular hypertension is discussed. PMID:7104272

  5. Placental Growth Factor Administration Abolishes Placental Ischemia-Induced Hypertension.

    PubMed

    Spradley, Frank T; Tan, Adelene Y; Joo, Woo S; Daniels, Garrett; Kussie, Paul; Karumanchi, S Ananth; Granger, Joey P

    2016-04-01

    Preeclampsia is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Placental ischemia appears central to the pathogenesis of preeclampsia because placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in humans stimulates release of hypertensive placental factors into the maternal circulation. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes and reduces bioavailable vascular endothelial growth factor and placental growth factor (PlGF), is elevated in RUPP rats and preeclampsia. Although PlGF and vascular endothelial growth factor are both natural ligands for sFlt-1, vascular endothelial growth factor also has high affinity to VEGFR2 (Flk-1) causing side effects like edema. PlGF is specific for sFlt-1. We tested the hypothesis that PlGF treatment reduces placental ischemia-induced hypertension by antagonizing sFlt-1 without adverse consequences to the mother or fetus. On gestational day 14, rats were randomized to 4 groups: normal pregnant or RUPP±infusion of recombinant human PlGF (180 μg/kg per day; AG31, a purified, recombinant human form of PlGF) for 5 days via intraperitoneal osmotic minipumps. On day 19, mean arterial blood pressure and plasma sFlt-1 were higher and glomerular filtration rate lower in RUPP than normal pregnant rats. Infusion of recombinant human PlGF abolished these changes seen with RUPP along with reducing oxidative stress. These data indicate that the increased sFlt-1 and reduced PlGF resulting from placental ischemia contribute to maternal hypertension. Our novel finding that recombinant human PlGF abolishes placental ischemia-induced hypertension, without major adverse consequences, suggests a strong therapeutic potential for this growth factor in preeclampsia. PMID:26831193

  6. Structural Basis for Phosphorylation-Dependent Recruitment of Tel2 to Hsp90 by Pih1

    PubMed Central

    Pal, Mohinder; Morgan, Marc; Phelps, SarahE.L.; Roe, S. Mark; Parry-Morris, Sarah; Downs, JessicaA.; Polier, Sigrun; Pearl, LaurenceH.; Prodromou, Chrisostomos

    2014-01-01

    Summary Client protein recruitment to the Hsp90 system depends on cochaperones that bind the client and Hsp90 simultaneously and facilitate their interaction. Hsp90 involvement in the assembly of snoRNPs, RNA polymerases, PI3-kinase-like kinases, and chromatin remodeling complexes depends on the TTT (Tel2-Tti1-Tti2), and R2TP complexesconsisting of the AAA-ATPases Rvb1 and Rvb2, Tah1 (Spagh/RPAP3 in metazoa), and Pih1 (Pih1D1 in humans)that together provide the connection to Hsp90. The biochemistry underlying R2TP function is still poorly understood. Pih1 in particular, at the heart of the complex, has not been described at a structural level, nor have the multiple protein-protein interactions it mediates been characterized. Here we present a structural and biochemical analysis of Hsp90-Tah1-Pih1, Hsp90-Spagh, and Pih1D1-Tel2 complexes that reveal a domain in Pih1D1 specific for binding CK2 phosphorylation sites, and together define the structural basis by which the R2TP complex connects the Hsp90 chaperone system to the TTT complex. PMID:24794838

  7. Familial Mineralocorticoid Induced Hypertension in the Sultanate of Oman

    PubMed Central

    Woodhouse, Nicholas JY; Elshafie, Omayma T; Ben Abid, Fatma; Doi, Suhail A

    2008-01-01

    Objectives: In Oman, many hypertensive patients with a family history of the disease respond to treatment with spironolactone, a mineralocorticoid receptor (MC-R) blocking agent thus suggesting a high prevalence of mineralocorticoid (MC) induced disease. The aim of this study was to document the prevalence of MC induced disease in patients with a positive family history of hypertension (HTN). Methods: Serum calcium, potassium, creatinine, aldosterone and renin levels were measured under standard conditions in all patients together with an abdominal ultrasound scan and an adrenal computed tomography (CT) scan in four patients. Results: In this small study, we show that 18 of the 27 patients (66%) had undetectable (suppressed) renin levels with usually normal aldosterone values (14 patients) and respond to treatment with spironoactone. Conclusion: We suggest that MC induced hypertension is likely to be common in the Middle East. In evolutionary terms, this makes sense as the ability to conserve salt in hot climates might be expected to confer a definite survival advantage. PMID:21748054

  8. Upregulated Copper Transporters in Hypoxia-Induced Pulmonary Hypertension

    PubMed Central

    Zimnicka, Adriana M.; Tang, Haiyang; Guo, Qiang; Kuhr, Frank K.; Oh, Myung-Jin; Wan, Jun; Chen, Jiwang; Smith, Kimberly A.; Fraidenburg, Dustin R.; Choudhury, Moumita S. R.; Levitan, Irena; Machado, Roberto F.; Kaplan, Jack H.; Yuan, Jason X.-J.

    2014-01-01

    Pulmonary vascular remodeling and increased arterial wall stiffness are two major causes for the elevated pulmonary vascular resistance and pulmonary arterial pressure in patients and animals with pulmonary hypertension. Cellular copper (Cu) plays an important role in angiogenesis and extracellular matrix remodeling; increased Cu in vascular smooth muscle cells has been demonstrated to be associated with atherosclerosis and hypertension in animal experiments. In this study, we show that the Cu-uptake transporter 1, CTR1, and the Cu-efflux pump, ATP7A, were both upregulated in the lung tissues and pulmonary arteries of mice with hypoxia-induced pulmonary hypertension. Hypoxia also significantly increased expression and activity of lysyl oxidase (LOX), a Cu-dependent enzyme that causes crosslinks of collagen and elastin in the extracellular matrix. In vitro experiments show that exposure to hypoxia or treatment with cobalt (CoCl2) also increased protein expression of CTR1, ATP7A, and LOX in pulmonary arterial smooth muscle cells (PASMC). In PASMC exposed to hypoxia or treated with CoCl2, we also confirmed that the Cu transport is increased using 64Cu uptake assays. Furthermore, hypoxia increased both cell migration and proliferation in a Cu-dependent manner. Downregulation of hypoxia-inducible factor 1α (HIF-1α) with siRNA significantly attenuated hypoxia-mediated upregulation of CTR1 mRNA. In summary, the data from this study indicate that increased Cu transportation due to upregulated CTR1 and ATP7A in pulmonary arteries and PASMC contributes to the development of hypoxia-induced pulmonary hypertension. The increased Cu uptake and elevated ATP7A also facilitate the increase in LOX activity and thus the increase in crosslink of extracellular matrix, and eventually leading to the increase in pulmonary arterial stiffness. PMID:24614111

  9. Brain amines in glucocorticoid-induced hypertension in the rat.

    PubMed

    Fanelli, M; Nahmod, V E; Torres, N; Santajuliana, D; Garca, S I; Finkielman, S; Pirola, C J

    1992-02-01

    A two week administration of the glucocorticoid betametasone to male Wistar rats produced a mild hypertensive state. The brain of these rats showed some significant changes in amine and metabolite content with respect to normotensive controls. Epinephrine and metanephrine were increased in the rostral ventrolateral medulla and in the preoptic area. Epinephrine also increased in the septal area. Normetanephrine decreased in the rostral ventrolateral medulla. Dopamine and homovanillic acid increased in septal and preoptic areas. Dopamine alone increased in rostral ventrolateral medulla. Serotonin and 5-hydroxyindole-3-acetic acid increased in the septal area and dorsal medulla. These changes suggest significant alterations in the aminergic activity of the brain circuitry known to regulate cardiovascular functions; the changes may play a basic role in the development and maintenance of glucocorticoid-induced hypertension. PMID:1625793

  10. Hypertension

    PubMed Central

    LePine, Todd

    2012-01-01

    Hypertension is responsible for roughly one-in-six adult deaths annually in the United States and is associated with five of the top nine causes of death.1 Ten trillion dollars is the estimated annual cost worldwide of the direct and indirect effects of hypertension.2,3 In the U.S. alone, costs estimated at almost $74 billion in 2009 placed a huge economic burden on the health care system.4 The prevalence of hypertension increases with advancing age to the point where more than half of people 60 to 69 years of age and at least three-fourths of those 70 years of age and older are affected.5 Most individuals with hypertension do not have it adequately controlled.1,6 Medication noncompliance due to avoidance of side effects is suggested to be a primary factor.6 The epidemic incidence of hypertension and its significant cost to society indicate that a well-tolerated, cost-effective approach to treatment is urgently needed. PMID:24278815

  11. Selective alpha(1)-adrenoceptor blockade prevents fructose-induced hypertension.

    PubMed

    Tran, Linda T; MacLeod, Kathleen M; McNeill, John H

    2014-07-01

    The purpose of this study was to investigate the effect of chronic treatment with prazosin, a selective ?1-adrenoceptor antagonist, on the development of hypertension in fructose-fed rats (FFR). High-fructose feeding and treatment with prazosin (1mg/kg/day via drinking water) were initiated simultaneously in male Wistar rats. Systolic blood pressure, fasted plasma parameters, insulin sensitivity, plasma norepinephrine (NE), uric acid, and angiotensin II (Ang II) were determined following 9weeks of treatment. FFR exhibited insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hypertension, as well as elevations in plasma NE and Ang II levels. Treatment with prazosin prevented the rise in blood pressure without affecting insulin levels, insulin sensitivity, uric acid, or Ang II levels, while normalizing plasma NE levels in FFR. These data suggest that over-activation of the sympathetic nervous system, specifically ?1-adrenoceptors, contributes to the development of fructose-induced hypertension, however, this over-activation does not appear to an initial, precipitating event in FFR. PMID:24682694

  12. Hypertension.

    PubMed

    Poulter, Neil R; Prabhakaran, Dorairaj; Caulfield, Mark

    2015-08-22

    Raised blood pressure is the biggest single contributor to the global burden of disease and to global mortality. The numbers of people affected and the prevalence of high blood pressure worldwide are expected to increase over the next decade. Preventive strategies are therefore urgently needed, especially in less developed countries, and management of hypertension must be optimised. Genetic advances in some rare causes of hypertension have been made lately, but the aggregate effect on blood pressure of all the genetic loci identified to date is small. Hence, intervention on key environmental determinants and effective implementation of trial-based therapies are needed. Three-drug combinations can control hypertension in about 90% of patients but only if resources allow identification of patients and drug delivery is affordable. Furthermore, assessment of optimal drug therapy for each ethnic group is needed. PMID:25832858

  13. Arginase inhibitor attenuates pulmonary artery hypertension induced by hypoxia.

    PubMed

    Chu, YanBiao; XiangLi, XiaoYing; Niu, Hu; Wang, HongChao; Jia, PingDong; Gong, WenBin; Wu, DaWei; Qin, WeiDong; Xing, ChunYan

    2016-01-01

    Hypoxia-induced pulmonary arterial hypertension (HPAH) is a refractory disease characterized by increased proliferation of pulmonary vascular smooth cells and progressive pulmonary vascular remodeling. The level of nitric oxide (NO), a potential therapeutic vasodilator, is low in PAH patients. L-arginine can be converted to either beneficial NO by nitric oxide synthases or to harmful urea by arginase. In the present study, we aimed to investigate whether an arginase inhibitor, S-(2-boronoethyl)-L-cysteine ameliorates HPAH in vivo and vitro. In a HPAH mouse model, we assessed right ventricle systolic pressure (RVSP) by an invasive method, and found that RSVP was elevated under hypoxia, but was attenuated upon arginase inhibition. Human pulmonary artery smooth muscle cells (HPASMCs) were cultured under hypoxic conditions, and their proliferative capacity was determined by cell counting and flow cytometry. The levels of cyclin D1, p27, p-Akt, and p-ERK were detected by RT-PCR or Western blot analysis. Compared to hypoxia group, arginase inhibitor inhibited HPASMCs proliferation and reduced the levels of cyclin D1, p-Akt, p-ERK, while increasing p27 level. Moreover, in mouse models, compared to control group, hypoxia increased cyclin D1 expression but reduced p27 expression, while arginase inhibitor reversed the effects of hypoxia. Taken together, these results suggest that arginase plays an important role in increased proliferation of HPASMCs induced by hypoxia and it is a potential therapeutic target for the treatment of pulmonary hypertensive disorders. PMID:26608181

  14. Major inducing factors of hypertensive complications and the interventions required to reduce their prevalence: an epidemiological study of hypertension in a rural population in China

    PubMed Central

    2011-01-01

    Background The complications of hypertension cause severe health problems in rural areas in China. We (i) screened the major factors inducing hypertensive complications and provided intervention measures; and (ii) verified the efficacy of the New Rural Cooperative Medical Scheme (NRCMS; a medical insurance scheme for rural residents) for hypertension management. Methods A survey was conducted in the villages of Yunnan (an underdeveloped province in southwest China). The NRCMS was initiated there in 2005. Data were collected through questionnaires, physical examination, electrocardiography, as well as blood and urine tests. To detect factors inducing hypertension complications, a generalized estimating equations model was developed. Multivariable logistic regression was used to analyze influencing factors for hypertension control. Results Poor management of hypertension was observed in women. Being female, old, poorly educated, a smoker, ignorant of the dangerousness of hypertension, and having uncontrolled hypertension made patients more prone to hypertension complications. Combination therapy with ?2 drugs helped control hypertension, but most rural patients disliked multidrug therapy because they considered it to be expensive and inconvenient. The NRCMS contributed little to reduce the prevalence of complications and improve control of hypertension. Conclusions The present study suggested that the NRCMS needs to be reformed to concentrate on early intervention in hypertension and to concentrate on women. To increase hypertension control in rural areas in China, compound products containing effective and inexpensive drugs (and not multidrug therapy) are needed. PMID:21569365

  15. Hypertension and associated cardiovascular abnormalities induced by chronic barium feeding.

    PubMed

    Perry, H M; Kopp, S J; Perry, E F; Erlanger, M W

    1989-01-01

    Because high barium concentrations (2-10 ppm) in human drinking water have been reported to be associated with elevated cardiovascular mortality, hypertension and other cardiovascular effects were sought in rats chronically exposed for 1-16 mo to drinking water containing 1, 10, or 100 ppm barium. From weaning, female Long-Evans rats were kept in a "low contamination" environment and fed a diet low in trace metals. Their drinking water was deionized, fortified with 5 essential trace metals, and either 0, 1, 10, or 100 ppm barium was added. Indirect systolic pressure of unanesthetized rats was measured in triplicate at 1, 2, 4, 8, 12, and 16 mo. Average systolic pressure increased significantly after exposure to 100 ppm barium for 1 mo or longer and after exposure to 10 ppm barium for 8 mo or longer. After 4 or 16 mo, barium exposure failed to alter organ weights or tissue concentrations of calcium, magnesium, sodium, or potassium; however, both 10 and 100 ppm barium resulted in significant increases in tissue barium. Rats exposed to 100 ppm Ba for 16 mo exhibited depressed rates of cardiac contraction and depressed electrical excitability in the heart. Hearts from these maximally exposed rats also had significantly lower ATP content and phosphorylation potential, as measured by 31P NMR spectroscopy. Although the barium-induced increase in the blood pressure of rats was modest, comparable mild hypertension in humans would have major health implications. PMID:2585541

  16. Evaluation of the Persistent Issues in History Laboratory for Virtual Field Experience (PIH-LVFE)

    ERIC Educational Resources Information Center

    Brush, Thomas; Saye, John; Kale, Ugur; Hur, Jung Won; Kohlmeier, Jada; Yerasimou, Theano; Guo, Lijiang; Symonette, Simone

    2009-01-01

    The Persistent Issues in History Laboratory for Virtual Field Experience (PIH-LVFE) combines a database of video cases of authentic classroom practices with multiple resources and tools to enable pre-service social studies teachers to virtually observe teachers implementing problem-based learning activities. In this paper, we present the results…

  17. Regulation of Hypoxia-induced Pulmonary Hypertension by Vascular Smooth Muscle Hypoxia-Inducible Factor-1?

    PubMed Central

    Ball, Molly K.; Waypa, Gregory B.; Mungai, Paul T.; Nielsen, Jacqueline M.; Czech, Lyubov; Dudley, V. Joseph; Beussink, Lauren; Dettman, Robert W.; Berkelhamer, Sara K.; Steinhorn, Robin H.; Shah, Sanjiv J.

    2014-01-01

    Rationale: Chronic hypoxia induces pulmonary vascular remodeling, pulmonary hypertension, and right ventricular hypertrophy. At present, little is known about mechanisms driving these responses. Hypoxia-inducible factor-1? (HIF-1?) is a master regulator of transcription in hypoxic cells, up-regulating genes involved in energy metabolism, proliferation, and extracellular matrix reorganization. Systemic loss of a single HIF-1? allele has been shown to attenuate hypoxic pulmonary hypertension, but the cells contributing to this response have not been identified. Objectives: We sought to determine the contribution of HIF-1? in smooth muscle on pulmonary vascular and right heart responses to chronic hypoxia. Methods: We used mice with homozygous conditional deletion of HIF-1? combined with tamoxifen-inducible smooth musclespecific Cre recombinase expression. Mice received either tamoxifen or vehicle followed by exposure to either normoxia or chronic hypoxia (10% O2) for 30 days before measurement of cardiopulmonary responses. Measurements and Main Results: Tamoxifen-induced smooth musclespecific deletion of HIF-1? attenuated pulmonary vascular remodeling and pulmonary hypertension in chronic hypoxia. However, right ventricular hypertrophy was unchanged despite attenuated pulmonary pressures. Conclusions: These results indicate that HIF-1? in smooth muscle contributes to pulmonary vascular remodeling and pulmonary hypertension in chronic hypoxia. However, loss of HIF-1 function in smooth muscle does not affect hypoxic cardiac remodeling, suggesting that the cardiac hypertrophy response is not directly coupled to the increase in pulmonary artery pressure. PMID:24251580

  18. Tissue angiotensinogen gene expression induced by lipopolysaccharide in hypertensive rats.

    PubMed

    Nyui, N; Tamura, K; Yamaguchi, S; Nakamaru, M; Ishigami, T; Yabana, M; Kihara, M; Ochiai, H; Miyazaki, N; Umemura, S; Ishii, M

    1997-10-01

    There is now convincing evidence that various tissues express their own tissue renin-angiotensin system, which may be regulated independently of the systemic renin-angiotensin system. However, little information is available on the regulation of the tissue renin-angiotensin system. We investigated the regulation of tissue angiotensinogen gene expression with respect to the development of hypertension. We measured basal and lipopolysaccharide-stimulated plasma angiotensinogen concentrations by radioimmunoassay and examined the expression of tissue angiotensinogen by Northern blot analysis in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at 4 and 13 weeks of age. Basal plasma angiotensinogen concentration in SHR was comparable to that in WKY at 4 weeks of age and was significantly higher than that in WKY at 13 weeks of age. Lipopolysaccharide induced a significant increase in plasma angiotensinogen concentration in both WKY and SHR at 4 and 13 weeks of age. At 4 weeks of age, the basal levels of angiotensinogen mRNA in the liver, fat, adrenal, and aorta were higher in WKY than in SHR. At 13 weeks of age, the basal levels of angiotensinogen mRNA in the fat, adrenal, aorta, spleen, and kidney were higher in WKY than in SHR, while that in the liver did not differ significantly between the two strains. At 4 weeks of age, pretreatment with lipopolysaccharide increased the angiotensinogen mRNA levels in the liver, fat, adrenal, and aorta in both WKY and SHR. At 13 weeks of age, pretreatment with lipopolysaccharide increased the angiotensinogen mRNA levels in the liver, aorta, and adrenal; decreased those in the spleen; and had no effect in the kidney in both WKY and SHR. Interestingly, lipopolysaccharide increased the angiotensinogen mRNA level in fat only in SHR, with no effect in WKY, at 13 weeks of age. Lipopolysaccharide stimulated tumor necrosis factor-a mRNA expression in fat of WKY and SHR, and the increase in tumor necrosis factor-alpha mRNA level in SHR was significantly greater than that in WKY. Therefore, the increased tumor necrosis factor-alpha mRNA expression may be involved in the increased lipopolysaccharide-induced expression of angiotensinogen gene in fat of SHR at 13 weeks of age. These data suggest that the transcriptional and probably posttranscriptional regulation of angiotensinogen mRNA differs between SHR and WKY, that the regulation of angiotensinogen gene expression is tissue-specific, and that the altered expression of the angiotensinogen gene may be involved in the development of hypertension. PMID:9336385

  19. Complement C1q-induced activation of ?-catenin signalling causes hypertensive arterial remodelling

    PubMed Central

    Sumida, Tomokazu; Naito, Atsuhiko T.; Nomura, Seitaro; Nakagawa, Akito; Higo, Tomoaki; Hashimoto, Akihito; Okada, Katsuki; Sakai, Taku; Ito, Masamichi; Yamaguchi, Toshihiro; Oka, Toru; Akazawa, Hiroshi; Lee, Jong-Kook; Minamino, Tohru; Offermanns, Stefan; Noda, Tetsuo; Botto, Marina; Kobayashi, Yoshio; Morita, Hiroyuki; Manabe, Ichiro; Nagai, Toshio; Shiojima, Ichiro; Komuro, Issei

    2015-01-01

    Hypertension induces structural remodelling of arteries, which leads to arteriosclerosis and end-organ damage. Hyperplasia of vascular smooth muscle cells (VSMCs) and infiltration of immune cells are the hallmark of hypertensive arterial remodelling. However, the precise molecular mechanisms of arterial remodelling remain elusive. We have recently reported that complement C1q activates ?-catenin signalling independent of Wnts. Here, we show a critical role of complement C1-induced activation of ?-catenin signalling in hypertensive arterial remodelling. Activation of ?-catenin and proliferation of VSMCs were observed after blood-pressure elevation, which were prevented by genetic and chemical inhibition of ?-catenin signalling. Macrophage depletion and C1qa gene deletion attenuated the hypertension-induced ?-catenin signalling, proliferation of VSMCs and pathological arterial remodelling. Our findings unveil the link between complement C1 and arterial remodelling and suggest that C1-induced activation of ?-catenin signalling becomes a novel therapeutic target to prevent arteriosclerosis in patients with hypertension. PMID:25716000

  20. Involvement of tyrosine hydroxylase upregulation in cyclosporine-induced hypertension.

    PubMed

    Shimizu, H; Kumai, T; Kobayashi, S

    2001-03-01

    To identify the mechanism of cyclosporine-induced hypertension, we studied the effect of cyclosporine on the catecholamine synthetic pathway in rats. We administered cyclosporine (10 mg/kg per day, s.c.) for 3 days to 10-week-old male Wistar rats. Systolic blood pressure increased significantly in the cyclosporine-treated group in comparison to that in the control group. Norepinephrine and epinephrine levels in the adrenal medulla and plasma of cyclosporine-treated rats were also significantly higher than levels in the control rats. Moreover, tyrosine hydroxylase (TH) activity and TH mRNA expression in the adrenal medulla of cyclosporine-treated rats were significantly elevated. Administration of the TH inhibitor alphamethyl-p-tyrosine (200 mg/kg, b.i.d., s.c.) for 3 days significantly suppressed cyclosporine-induced increases in systolic blood pressure. Phosphorylation of cyclic AMP responsive element-binding protein (CREB) and its binding activity to DNA in the nuclear fraction from the adrenal medulla of cyclosporine-treated rats were much higher than that of the control rats. Calcineurin protein expression of cyclosporine-treated rats was less than that of the control rats. These results suggest that cyclosporine increased blood pressure via activation of the catecholamine synthetic pathway due to the activation of transcription factor CREB. PMID:11325024

  1. Carotid body overactivity induces respiratory neurone channelopathy contributing to neurogenic hypertension.

    PubMed

    Moraes, Davi J A; Machado, Benedito H; Paton, Julian F R

    2015-07-15

    Why sympathetic activity rises in neurogenic hypertension remains unknown. It has been postulated that changes in the electrical excitability of medullary pre-sympathetic neurones are the main causal mechanism for the development of sympathetic overactivity in experimental hypertension. Here we review recent data suggesting that enhanced sympathetic activity in neurogenic hypertension is, at least in part, dependent on alterations in the electrical excitability of medullary respiratory neurones and their central modulation of sympatho-excitatory networks. We also present results showing a critical role for carotid body tonicity in the aetiology of enhanced central respiratory modulation of sympathetic activity in neurogenic hypertension. We propose a novel hypothesis of respiratory neurone channelopathy induced by carotid body overactivity in neurogenic hypertension that may contribute to sympathetic excess. Moreover, our data support the notion of targeting the carotid body as a potential novel therapeutic approach for reducing sympathetic vasomotor tone in neurogenic hypertension. PMID:25900825

  2. Telmisartan prevents excess-salt-induced exacerbated (malignant) hypertension in spontaneously hypertensive rats.

    PubMed

    Susic, Dinko; Fares, Hassan; Frohlich, Edward D

    2013-03-01

    The effects of angiotensin receptor blocker, diuretic, a calcium antagonist, and their combination were evaluated on the progression of cardiovascular and renal damage in spontaneously hypertensive rats (SHRs) given excess salt. To this end, 8-week male SHRs were divided into 7 groups. The control group (C) received normal NaCl (0.6%) diet. All other groups were given 8% NaCl rat chow. In addition, group 2 was given placebo (tap water alone), group 3 the angiotensin receptor antagonist telmisartan (10 mg/kg per d), group 4 received the diuretic chlorothiazide (80 mg/kg per d), group 5 was given telmisartan plus the diuretic, group 6 was given the calcium antagonist amlodipine (10 mg/kg per d), and group 7 was given telmisartan plus amlodipine. All treatments lasted for 8 weeks. Compared with controls, mean arterial pressure (MAP), renal blood flow, coronary flow reserve, minimal coronary vascular resistance, diastolic time constant, and maximal rate of ventricular pressure fall were all adversely affected by salt loading. Increased left ventricular mass with marked cardiac fibrosis was also found in the salt-overloaded SHR group. Telmisartan normalized all indices except MAP, whereas diuretic and amlodipine only partially restored cardiac functional and mass indexes. Combination therapy with telmisartan and either diuretic or amlodipine also normalized all indices including arterial pressure. These data suggest that (1) cardiovascular damage induced by excess salt in the SHRs was not pressure dependent; (2) compared with the calcium antagonist and diuretic, blockade of angiotensin receptors was extremely effective in this model. PMID:22927675

  3. Effect of magnesium on vascular reactivity in NOS inhibition-induced hypertension.

    PubMed

    Basral?, Filiz; Nas?rc?lar lker, Seher; Koer, Gnnur; lker Karadamar, P?nar; zyurt, Dilek; Cengiz, Melike; Kemal ?entrk, mit

    2015-06-01

    This study investigated the effect of magnesium on the vascular reactivity of conduit and resistance arteries in a nitric oxide synthase inhibition-induced hypertension model. The aorta and third-order branches of the mesenteric artery were dissected from normotensive control and hypertensive rats, and their constriction and dilation responses in physiological saline solution containing normal (1.2 mM) or high (4.8 mM) magnesium concentrations were examined. The responses of the vessels were evaluated using potassium chloride (KCl) and phenylephrine (Phe), acetylcholine (ACh) and sodium nitroprusside. The Phe-induced constriction response of the aortic rings increased, whereas the ACh-induced dilation response decreased, in the hypertensive group compared to controls, in the presence of a normal magnesium concentration. High magnesium did not alter these responses in either group. Both the KCl- and Phe-induced constriction responses of the mesenteric arteries increased, and the ACh-induced dilation response decreased in the hypertensive group compared to controls, in the presence of a normal magnesium concentration. High magnesium significantly decreased the KCl and Phe-induced constriction and increased the ACh-induced dilation response of the mesenteric arteries in the hypertensive group, while it did not alter these responses in controls. This study suggests that high magnesium improves vascular reactivity of resistance-, but not conduit-type arteries in the nitric oxide synthase inhibition-induced hypertension model. PMID:26395418

  4. Evaluation of docosahexaenoic acid in a dog model of hypertension induced left ventricular hypertrophy.

    PubMed

    Stanley, William C; Cox, James W; Asemu, Girma; O'Connell, Kelly A; Dabkowski, Erinne R; Xu, Wenhong; Ribeiro, Rogerio F; Shekar, Kadambari C; Hoag, Stephen W; Rastogi, Sharad; Sabbah, Hani N; Daneault, Caroline; des Rosiers, Christine

    2013-12-01

    Marine n-3 polyunsaturated fatty acids alter cardiac phospholipids and prevent cardiac pathology in rodents subjected to pressure overload. This approach has not been evaluated in humans or large animals with hypertension-induced pathological hypertrophy. We evaluated docosahexaenoic acid (DHA) in old female dogs with hypertension caused by 16 weeks of aldosterone infusion. Aldosterone-induced hypertension resulted in concentric left ventricular (LV) hypertrophy and impaired diastolic function in placebo-treated dogs. DHA supplementation increased DHA and depleted arachidonic acid in cardiac phospholipids, but did not improve LV parameters compared to placebo. Surprisingly, DHA significantly increased serum aldosterone concentration and blood pressure compared to placebo. Cardiac mitochondrial yield was decreased in placebo-treated hypertensive dogs compared to normal animals, which was prevented by DHA. Extensive analysis of mitochondrial function found no differences between DHA and placebo groups. In conclusion, DHA did not favorably impact mitochondrial or LV function in aldosterone hypertensive dogs. PMID:24065618

  5. Evaluation of Docosahexaenoic Acid in a Dog Model of Hypertension Induced Left Ventricular Hypertrophy

    PubMed Central

    Stanley, William C.; Cox, James W.; Asemu, Girma; O’Connell, Kelly A.; Dabkowski, Erinne R.; Xu, Wenhong; Ribeiro, Rogerio F.; Shekar, Kadambari C.; Hoag, Stephen W.; Rastogi, Sharad; Sabbah, Hani N.; Daneault, Caroline; des Rosiers, Christine

    2016-01-01

    Marine n-3 polyunsaturated fatty acids alter cardiac phospholipids and prevent cardiac pathology in rodents subjected to pressure overload. This approach has not been evaluated in humans or large animals with hypertension-induced pathological hypertrophy. We evaluated docosahexaenoic acid (DHA) in old female dogs with hypertension caused by 16 weeks of aldosterone infusion. Aldosterone-induced hypertension resulted in concentric LV hypertrophy and impaired diastolic function in placebo treated dogs. DHA supplementation increased DHA and depleted arachidonic acid in cardiac phospholipids, but did not improve LV parameters compared to placebo. Surprisingly, DHA significantly increased serum aldosterone concentration and blood pressure compared to placebo. Cardiac mitochondrial yield was decreased in placebo treated hypertensive dogs compared to normal animals, which was prevented by DHA. Extensive analysis of mitochondrial function found no differences between DHA and placebo groups. In conclusion, DHA did not favorably impact mitochondrial or LV function in aldosterone hypertensive dogs. PMID:24065618

  6. Pravastatin attenuates hypertension, oxidative stress and angiogenic imbalance in rat model of placental ischemia-induced hypertension

    PubMed Central

    Bauer, Ashley J; Banek, Christopher T; Needham, Karen; Gillham, Haley; Capoccia, Susan; Regal, Jean F; Gilbert, Jeffrey S

    2013-01-01

    Preeclampsia is a pregnancy-specific condition characterized by an imbalance of circulating angiogenic factors and new-onset hypertension. Although current treatment options are limited, recent studies suggest pravastatin may improve angiogenic profile and reduce blood pressure in preeclampsia. We hypothesized pravastatin would restore angiogenic balance and reduce mean arterial pressure (MAP) in rats with reduced utero-placental perfusion pressure (RUPP)-induced hypertension. Pravastatin was administered i.p. (1 mg/kg/day) in RUPP (RUPP+P) and normal pregnant rats (NP+P) from day 14-19 of pregnancy. On day 19, MAP was measured via catheter, conceptus data was recorded and tissues collected. MAP was increased (p<0.05) in RUPP compared to NP dams and pravastatin ameliorated this difference. Pravastatin attenuated decreased fetal weight and plasma VEGF and the RUPP-induced increased sFlt-1 when compared to NP dams. Pravastatin treatment did not improve angiogenic potential in RUPP serum and decreased (P<0.05) endothelial tube formation in NP rats. RUPP rats presented with indices of oxidative stress such as increased placental catalase activity and plasma TBARS along with decreased plasma total antioxidant capacity compared to NP controls and pravastatin attenuated these effects. MAP, fetal weight, plasma VEGF, and plasma sFlt-1 were unchanged in NP+P compared to NP controls. The present data indicate that treatment with pravastatin attenuates oxidative stress and lowers MAP in placental ischemia-induced hypertension, but may have negative effects on circulating angiogenic potential during pregnancy. Further studies are needed to determine if there are long-term deleterious effects on maternal or fetal health following pravastatin treatment during pregnancy-induced hypertension or preeclampsia. PMID:23460290

  7. Increased Klk9 Urinary Excretion Is Associated to Hypertension-Induced Cardiovascular Damage and Renal Alterations

    PubMed Central

    Blázquez-Medela, Ana M.; García-Sánchez, Omar; Quirós, Yaremi; Blanco-Gozalo, Victor; Prieto-García, Laura; Sancho-Martínez, Sandra M.; Romero, Miguel; Duarte, Juan M.; López-Hernández, Francisco J.; López-Novoa, José M.; Martínez-Salgado, Carlos

    2015-01-01

    Abstract Early detection of hypertensive end-organ damage and secondary diseases are key determinants of cardiovascular prognosis in patients suffering from arterial hypertension. Presently, there are no biomarkers for the detection of hypertensive target organ damage, most outstandingly including blood vessels, the heart, and the kidneys. We aimed to validate the usefulness of the urinary excretion of the serine protease kallikrein-related peptidase 9 (KLK9) as a biomarker of hypertension-induced target organ damage. Urinary, plasma, and renal tissue levels of KLK9 were measured by the Western blot in different rat models of hypertension, including angiotensin-II infusion, DOCA-salt, L-NAME administration, and spontaneous hypertension. Urinary levels were associated to cardiovascular and renal injury, assessed by histopathology. The origin of urinary KLK9 was investigated through in situ renal perfusion experiments. The urinary excretion of KLK9 is increased in different experimental models of hypertension in rats. The ACE inhibitor trandolapril significantly reduced arterial pressure and the urinary level of KLK9. Hypertension did not increase kidney, heart, liver, lung, or plasma KLK9 levels. Hypertension-induced increased urinary excretion of KLK9 results from specific alterations in its tubular reabsorption, even in the absence of overt nephropathy. KLK9 urinary excretion strongly correlates with cardiac hypertrophy and aortic wall thickening. KLK9 appears in the urine in the presence of hypertension as a result of subtle renal handling alterations. Urinary KLK9 might be potentially used as an indicator of hypertensive cardiac and vascular damage. PMID:26469898

  8. Aging exacerbates hypertension-induced cerebral microhemorrhages in mice: role of resveratrol treatment in vasoprotection

    PubMed Central

    Toth, Peter; Tarantini, Stefano; Springo, Zsolt; Tucsek, Zsuzsanna; Gautam, Tripti; Giles, Cory B; Wren, Jonathan D; Koller, Akos; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2015-01-01

    Recent studies demonstrate that aging exacerbates hypertension-induced cognitive decline, but the specific age-related mechanisms remain elusive. Cerebral microhemorrhages (CMHs) are associated with rupture of small intracerebral vessels and are thought to progressively impair neuronal function. To determine whether aging exacerbates hypertension-induced CMHs young (3months) and aged (24months) mice were treated with angiotensin II plus L-NAME. We found that the same level of hypertension leads to significantly earlier onset and increased incidence of CMHs in aged mice than in young mice, as shown by neurological examination, gait analysis, and histological assessment of CMHs in serial brain sections. Hypertension-induced cerebrovascular oxidative stress and redox-sensitive activation of matrix metalloproteinases (MMPs) were increased in aging. Treatment of aged mice with resveratrol significantly attenuated hypertension-induced oxidative stress, inhibited vascular MMP activation, significantly delayed the onset, and reduced the incidence of CMHs. Collectively, aging promotes CMHs in mice likely by exacerbating hypertension-induced oxidative stress and MMP activation. Therapeutic strategies that reduce microvascular oxidative stress and MMP activation may be useful for the prevention of CMHs, protecting neurocognitive function in high-risk elderly patients. PMID:25677910

  9. OBESITY-INDUCED HYPERTENSION: INTERACTION OF NEUROHUMORAL AND RENAL MECHANISMS

    PubMed Central

    Hall, John E.; do Carmo, Jussara M.; da Silva, Alexandre A.; Wang, Zhen; Hall, Michael E.

    2015-01-01

    Excess weight gain, especially when associated with increased visceral adiposity, is a major cause of hypertension, accounting for 65–75% of the risk for human primary (essential) hypertension. Increased renal tubular sodium reabsorption impairs pressure natriuresis and plays an important role in initiating obesity hypertension. The mediators of abnormal kidney function and increased blood pressure during development of obesity hypertension include 1) physical compression of the kidneys by fat in and around the kidneys, 2) activation of the renin-angiotensin-aldosterone system (RAAS), and 3) increased sympathetic nervous system (SNS) activity. Activation of the RAAS system is likely due, in part, to renal compression as well as SNS activation. However, obesity also causes mineralocorticoid receptor activation independent of aldosterone or angiotensin II. The mechanisms for SNS activation in obesity have not been fully elucidated but appear to require leptin and activation of the brain melanocortin system. With prolonged obesity and development of target organ injury, especially renal injury, obesity-associated hypertension becomes more difficult to control, often requiring multiple antihypertensive drugs and treatment of other risk factors, including dyslipidemia, insulin resistance and diabetes, and inflammation. Unless effective anti-obesity drugs are developed, the impact of obesity on hypertension and related cardiovascular, renal and metabolic disorders is likely to become even more important in the future as the prevalence of obesity continues to increase. PMID:25767285

  10. Deficiency of the NHE1 Gene Prevents Hypoxia-induced Pulmonary Hypertension and Vascular Remodeling

    PubMed Central

    Yu, Lunyin; Quinn, Deborah A.; Garg, Hari G.; Hales, Charles A.

    2008-01-01

    Rationale: Our previous studies found that Na+/H+ exchanger (NHE) activity played an essential role in pulmonary artery smooth muscle cell (PASMC) proliferation and in the development of hypoxia-induced pulmonary hypertension and vascular remodeling. Other investigators recently observed increased expression of the NHE isoform 1 (NHE1) gene in rodents with pulmonary hypertension induced by hypoxia. However, a causal role for the NHE1 gene in pulmonary hypertension has not been determined. Objectives: To determine the causal role of the NHE1 gene in pulmonary hypertension and vascular remodeling. Methods: We used NHE1-null mice to define the role of the NHE1 gene in the development of pulmonary hypertension and remodeling induced by hypoxia and to delineate the NHE1 regulatory pathway. Measurements and Main Results: After 2 weeks of exposure to hypoxia, in contrast to wild-type hypoxic littermates, there was no significant increase in right ventricular systolic pressure, in the ratio of right ventricular to left ventricular plus septal weight [RV/(LV + S)], or in medial wall thickness of the pulmonary arterioles in homozygous mice (NHE1?/?). There was a significant decrease in Rho kinase (ROCK1 and ROCK2) expression, accompanied by an increase in p27 expression in NHE1?/? mice. Conclusions: Our study demonstrated that deficiency of the NHE1 gene prevented the development of hypoxia-induced pulmonary hypertension and vascular remodeling in mice and revealed a novel regulatory pathway associated with NHE1 signaling. PMID:18310478

  11. Hypertension-induced cerebellar encephalopathy and hydrocephalus in a male.

    PubMed

    Lin, Kuang-Lin; Hsu, Wen-Chin; Wang, Huei-Shyong; Lui, Tai-Ngar

    2006-01-01

    Hypertensive encephalopathy is believed to be caused by an abrupt elevation in systemic blood pressure. It rarely occurs in children and can be neurologically devastating if it is not recognized and treated immediately. This report describes an 11-year-old male who presented with edema and a cerebellar lesion, with acute obstructive hydrocephalus resulting from hypertensive encephalopathy. A shunt was inserted to relieve pressure in the acute stage. The patient's hydrocephalus and cerebellar swelling subsided when his blood pressure was controlled. The cerebellar lesion had been initially diagnosed as a glioma. In children, a cerebellar lesion occurring with acute obstructive hydrocephalus and hypertensive encephalopathy is rare but reversible. Clinicians should be aware of this condition because it might be misdiagnosed as a tumor of the posterior fossa. PMID:16376285

  12. Mechanisms of phytoestrogen biochanin A-induced vasorelaxation in renovascular hypertensive rats

    PubMed Central

    Choi, Seok; Jung, Won Suk; Cho, Nam Soo; Ryu, Kwon Ho; Jun, Jae Yeoul; Shin, Byung Chul; Chung, Jong Hoon; Yeum, Cheol Ho

    2014-01-01

    Background The plant-derived estrogen biochanin A is known to cause vasodilation, but its mechanism of action in hypertension remains unclear. This study was undertaken to investigate the effects and mechanisms of biochanin A on the thoracic aorta in two-kidney, one clip (2K1C) renovascular hypertensive rats. Methods Hypertension was induced by clipping the left renal artery, and control age-matched rats were sham treated. Thoracic aortae were mounted in tissue baths to measure isometric tension. Results Biochanin A caused concentration-dependent relaxation in aortic rings from 2K1C hypertensive and sham-treated rats, which was greater in 2K1C rats than in sham rats. Biochanin A-induced relaxation was significantly attenuated by removing the endothelium in aortic rings from 2K1C rats, but not in sham rats. N?-Nitro-l-arginine methyl ester, a nitric oxide synthase inhibitor, or indomethacin, a cyclooxygenase inhibitor, did not affect the biochanin A-induced relaxation in aortic rings from 2K1C and sham rats. By contrast, treatment with glibenclamide, a selective inhibitor of adenosine triphosphate-sensitive K+ channels, or tetraethylammonium, an inhibitor of Ca2+-activated K+ channels, significantly reduced biochanin A-induced relaxation in aortic rings from both groups. However, 4-aminopyridine, a selective inhibitor of voltage-dependent K+ channels, inhibited the relaxation induced by biochanin A in 2K1C rats, whereas no significant differences were observed in sham rats. Conclusion These results suggest that the enhanced relaxation caused by biochanin A in aortic rings from hypertensive rats is endothelium dependent. Vascular smooth muscle K+ channels may be involved in biochanin A-induced relaxation in aortae from hypertensive and normotensive rats. In addition, an endothelium-derived activation of voltage-dependent K+ channels contributes, at least in part, to the relaxant effect of biochanin A in renovascular hypertension.

  13. Spice up the hypertension diet - curcumin and piperine prevent remodeling of aorta in experimental L-NAME induced hypertension

    PubMed Central

    2011-01-01

    Background Increase of blood pressure is accompanied by functional and morphological changes in the vascular wall. The presented study explored the effects of curcuma and black pepper compounds on increased blood pressure and remodeling of aorta in the rat model of experimental NO-deficient hypertension. Methods Wistar rats were administered for 6 weeks clear water or L-NAME (40 mg/kg/day) dissolved in water, piperine (20 mg/kg/day), curcumin (100 mg/kg/day) or their combination in corn oil by oral gavage. The systolic blood pressure was measured weekly. Histological slices of thoracic aorta were stained with hematoxylin and eosin, Mallory's phosphotungstic acid hematoxylin (PTAH), orcein, picrosirius red and van Gieson staining and with antibodies against smooth muscle cells actin. Microscopic pictures were digitally processed and morphometrically evaluated. Results The increase of blood pressure caused by L-NAME was partially prevented by piperine and curcumin, but the effect of their combination was less significant. Animals with hypertension had increased wall thickness and cross-sectional area of the aorta, accompanied by relative increase of PTAH positive myofibrils and decrease of elastin, collagen and actin content. Piperine was able to decrease the content of myofibrils and slightly increase actin, while curcumin also prevented elastin decrease. The combination of spices had similar effects on aortic morphology as curcumin itself. Conclusions Administration of piperine or curcumin, less their combination, is able to partially prevent the increase of blood pressure caused by chronic L-NAME administration. The spices modify the remodeling of the wall of the aorta induced by hypertension. Our results show that independent administration of curcumin is more effective in preventing negative changes in blood vessel morphology accompanying hypertensive disease. PMID:22005253

  14. beta-Adrenergic and cholinergic receptors in hypertension-induced hypertrophy

    SciTech Connect

    Vatner, D.E.; Kirby, D.A.; Homcy, C.J.; Vatner, S.F.

    1985-05-01

    Perinephritic hypertension was produced in dogs by wrapping one kidney with silk and removing the contralateral kidney 1 week later. Mean arterial pressure rose from 104 +/- 3 to 156 +/- 11 mm Hg, while left ventricular free wall weight, normalized for body weight, was increased by 49%. Muscarinic, cholinergic receptor density measured with (/sup 3/H)-quinuclidinyl benzilate, fell in hypertensive left ventricles (181 +/- 19 fmol/mg, n = 6; p less than 0.01) as compared with that found in normal left ventricles (272 +/- 16 fmol/mg, n = 8), while receptor affinity was not changed. The beta-adrenergic receptor density, measured by binding studies with (/sup 3/H)-dihydroalprenolol, rose in the hypertensive left ventricles (108 +/- 10 fmol/mg, n = 7; p less than 0.01) as compared with that found in normal left ventricles (68.6 +/- 5.2 fmol/mg, n = 15), while beta-adrenergic receptor affinity decreased in the hypertensive left ventricles (10.4 +/- 1.2 nM) compared with that found in the normal left ventricles (5.0 +/- 0.7 nM). Plasma norepinephrine levels were similar in the two groups, but myocardial norepinephrine levels were depressed (p less than 0.05) in dogs with hypertension. Moderate left ventricular hypertrophy induced by long-term aortic banding in dogs resulted in elevations in beta-adrenergic receptor density (115 +/- 14 fmol/mg) and decreases in affinity (10.4 +/- 2.2 nM) similar to those observed in the dogs with left ventricular hypertrophy induced by hypertension. Thus, these results suggest that perinephritic hypertension in the dog induces divergent effects on cholinergic and beta-adrenergic receptor density. The increased beta-adrenergic receptor density and decreased affinity may be a characteristic of left ventricular hypertrophy rather than hypertension.

  15. The renoprotective effect of shichimotsukokato on hypertension-induced renal dysfunction in spontaneously hypertensive rats.

    PubMed

    Ma, Yue; Fujimoto, Makoto; Watari, Hidetoshi; Kimura, Mari; Shimada, Yutaka

    2016-04-01

    Antihypertensive treatment is highly important to prevent the progression of chronic kidney disease. Shichimotsukokato (SKT), a traditional Japanese medicine (i.e., Kampo formula), lowered systolic blood pressure (SBP) in experimental animal models of hypertension. However, its mechanism of action has not been fully elucidated. We investigated the potential renoprotective mechanism of SKT in spontaneously hypertensive rats (SHRs). Ten-week-old SHRs were randomly divided into four groups (six rats per group). In the SHR control group, the SBP increased remarkably during the 8-week experimental period. In the SHRs, SKT extract administered orally at a daily dose of 0.45 or 0.15 g/kg significantly suppressed the increase in SBP to the same extent as telmisartan administered orally at a daily dose of 0.01 g/kg. At the end of the experiment, blood, urine, and kidney cortex tissue samples were examined. The SKT treatment significantly decreased urinary albumin excretion to nearly the same level as the telmisartan treatment. A notable loss of chloride channel 5 (ClC-5), a chloride channel in the proximal renal tubules, occurred in the SHR control group. Thus, we concluded that SKT administration significantly ameliorated this decrease. The mechanism of SKT in reducing urinary albumin excretion is mediated, at least partly, by prevention of the loss of ClC-5 in the renal cortex of SHRs. PMID:26547580

  16. NLRP3 Deficiency Improves Angiotensin II-Induced Hypertension But Not Fetal Growth Restriction During Pregnancy.

    PubMed

    Shirasuna, Koumei; Karasawa, Tadayoshi; Usui, Fumitake; Kobayashi, Motoi; Komada, Tadanori; Kimura, Hiroaki; Kawashima, Akira; Ohkuchi, Akihide; Taniguchi, Shun'ichiro; Takahashi, Masafumi

    2015-11-01

    Preeclampsia is a pregnancy-specific syndrome characterized by elevated blood pressure, proteinuria, and intrauterine growth restriction (IUGR). Although sterile inflammation appears to be involved, its pathogenesis remains unclear. Recent evidence indicates that sterile inflammation is mediated through the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes, composed of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1. Here we investigated the role of the NLRP3 inflammasomes in the pathogenesis of preeclampsia using Nlrp3(-/-) and Asc(-/-) (Nlrp3 and Asc deficient) pregnant mice. During pregnancy in mice, continuous infusion of high-dose angiotensin II (AngII) induced hypertension, proteinuria, and IUGR, whereas infusion of low-dose AngII caused hypertension alone. AngII-induced hypertension was prevented in Nlrp3(-/-) mice but not in Asc(-/-), indicating that NLRP3 contributes to gestational hypertension independently of ASC-mediated inflammasomes. Although NLRP3 deficiency had no effect on IUGR, it restored the IL-6 up-regulation in the placenta and kidney of AngII-infused mice. Furthermore, treatment with hydralazine prevented the development of gestational hypertension but not IUGR or IL-6 expression in the placenta and kidney. These findings demonstrate that NLRP3 contributes to the development of gestational hypertension independently of the inflammasomes and that IUGR and kidney injury can occur independent of blood pressure elevation during pregnancy. PMID:26360504

  17. Renal Oxidative Stress Induced by Long-Term Hyperuricemia Alters Mitochondrial Function and Maintains Systemic Hypertension

    PubMed Central

    Cristóbal-García, Magdalena; García-Arroyo, Fernando E.; Arellano-Buendía, Abraham S.; Madero, Magdalena; Rodríguez-Iturbe, Bernardo; Pedraza-Chaverrí, José; Zazueta, Cecilia; Johnson, Richard J.; Sánchez Lozada, Laura-Gabriela

    2015-01-01

    We addressed if oxidative stress in the renal cortex plays a role in the induction of hypertension and mitochondrial alterations in hyperuricemia. A second objective was to evaluate whether the long-term treatment with the antioxidant Tempol prevents renal oxidative stress, mitochondrial alterations, and systemic hypertension in this model. Long-term (11-12 weeks) and short-term (3 weeks) effects of oxonic acid induced hyperuricemia were studied in rats (OA, 750 mg/kg BW), OA+Allopurinol (AP, 150 mg/L drinking water), OA+Tempol (T, 15 mg/kg BW), or vehicle. Systolic blood pressure, renal blood flow, and vascular resistance were measured. Tubular damage (urine N-acetyl-β-D-glucosaminidase) and oxidative stress markers (lipid and protein oxidation) along with ATP levels were determined in kidney tissue. Oxygen consumption, aconitase activity, and uric acid were evaluated in isolated mitochondria from renal cortex. Short-term hyperuricemia resulted in hypertension without demonstrable renal oxidative stress or mitochondrial dysfunction. Long-term hyperuricemia induced hypertension, renal vasoconstriction, tubular damage, renal cortex oxidative stress, and mitochondrial dysfunction and decreased ATP levels. Treatments with Tempol and allopurinol prevented these alterations. Renal oxidative stress induced by hyperuricemia promoted mitochondrial functional disturbances and decreased ATP content, which represent an additional pathogenic mechanism induced by chronic hyperuricemia. Hyperuricemia-related hypertension occurs before these changes are evident. PMID:25918583

  18. Differential Phenotypes of Tissue-Infiltrating T Cells during Angiotensin II-Induced Hypertension in Mice

    PubMed Central

    Wei, Zihui; Spizzo, Iresha; Diep, Henry; Drummond, Grant R.; Widdop, Robert E.; Vinh, Antony

    2014-01-01

    Hypertension remains the leading risk factor for cardiovascular disease (CVD). Experimental hypertension is associated with increased T cell infiltration into blood pressure-controlling organs, such as the aorta and kidney; importantly in absence of T cells of the adaptive immune system, experimental hypertension is significantly blunted. However, the function and phenotype of these T cell infiltrates remains speculative and undefined in the setting of hypertension. The current study compared T cell-derived cytokine and reactive oxygen species (ROS) production from normotensive and hypertensive mice. Splenic, blood, aortic, kidney and brain T cells were isolated from C57BL/6J mice following 14-day vehicle or angiotensin (Ang) II (0.7 mg/kg/day, s.c.) infusion. T cell infiltration was increased in aorta, kidney and brain from hypertensive mice. Cytokine analysis in stimulated T cells indicated an overall Th1 pro-inflammatory phenotype, but a similar proportion (flow cytometry) and quantity (cytometric bead array) of IFN-?, TNF-?, IL-4 and IL-17 between vehicle- and Ang II- treated groups. Strikingly, elevated T cell-derived production of a chemokine, chemokine C-C motif ligand 2 (CCL2), was observed in aorta (?6-fold) and kidney in response to Ang II, but not in brain, spleen or blood. Moreover, T cell-derived ROS production in aorta was elevated ?3 -fold in Ang II-treated mice (n?=?7; P<0.05). Ang II-induced hypertension does not affect the overall T cell cytokine profile, but enhanced T cell-derived ROS production and/or leukocyte recruitment due to elevated CCL2, and this effect may be further amplified with increased infiltration of T cells. We have identified a potential hypertension-specific T cell phenotype that may represent a functional contribution of T cells to the development of hypertension, and likely several other associated vascular disorders. PMID:25501574

  19. Ketanserin in the treatment of protamine-induced pulmonary hypertension.

    PubMed Central

    van der Starre, P J; Solinas, C

    1996-01-01

    The reversal of heparin by protamine may cause severe hemodynamic deterioration, characterized by systemic hypotension, pulmonary hypertension, and bronchoconstriction. A case report is presented concerning the administration of ketanserin in the treatment of pulmonary vasoconstriction and right ventricular failure following the infusion of protamine in a patient undergoing coronary artery bypass surgery and mitral valve replacement. The potential role of serotonin in the development of this serious complication is discussed. PMID:8969033

  20. Barnidipine ameliorates the vascular and renal injury in L-NAME-induced hypertensive rats.

    PubMed

    Alp Yildirim, F Ilkay; Eker Kizilay, Deniz; Ergin, Blent; Balci Ekmeki, zlem; Topal, Gke; Kucur, Mine; Demirci Tansel, Cihan; Uyde? Do?an, B Snmez

    2015-10-01

    The present study was aimed to investigate the influence of Barnidipine treatment on early stage hypertension by determining the function and morphology of the mesenteric and renal arteries as well as the kidney in N(?)-Nitro-L-Arginine Methyl Ester (L-NAME)-induced hypertensive rats. Barnidipine (3 mg/kg/day p.o) was applied to rats after 2 weeks of L-NAME (60 mg/kg/day) administration, and continued for the next 3 weeks concomitantly with L-NAME. The systolic blood pressure (SBP) of rats was determined to decrease significantly in Barnidipine treated hypertensive group when compared to that of rats received L-NAME alone. Myograph studies demonstrated that the contractile reactivity to noradrenaline were significantly reduced in both of the resistance arteries while endothelium-dependent relaxations to acethylcholine were significantly diminished particularly in the mesenteric arteries of L-NAME-induced hypertensive rats. The impaired contractile and endothelial responses were completely restored by concomitant treatment of Barnidipine with L-NAME. Histopathological examinations verified structural alterations in the arteries as well as the kidney. Moreover, a decrease in endothelial nitric oxide synthase (eNOS) expression was presented both in the arteries and kidney of hypertensive rats which were increased following Barnidipine treatment. Elevated plasma levels of malondialdehyde (MDA) and myeloperoxidase (MPO) were also reduced in Barnidipine treated hypertensive rats. In conclusion, besides to its efficacy in reducing the elevated SBP, amelioration of vascular function, modulation of arterial and renal eNOS expressions as well as reduction of the plasma levels of oxidative and inflammatory biomarkers are possible supportive mechanisms mediating the favorable implications of Barnidipine in L-NAME-induced hypertension model. PMID:26187312

  1. Nonuniformity of CBF response to NE-or ANG II-induced hypertension in rabbits

    SciTech Connect

    Reynier-Rebuffel, A.M.; Aubineau, P.; Issertial, O.; Seylaz, J.

    1987-07-01

    The regional response of brain vasculature to moderate hypertension was investigated using two hypertensive drugs, norepinephrine (NE) and angiotensin II (ANG II), infused intravenously at low concentrations (increase in blood pressure 15-40 mmHg). Regional cerebral blood flow (rCBF) was measured in unanesthetized and anesthetized rabbits using the (/sup 14/C)ethanol saturation technique. (1) In both groups of animals, NE and ANG II induced regional differences in the flow changes as compared with controls, confirming a regional (or segmental) heterogeneity in the regulatory mechanisms to hypertension. (2) The responses to identical rises in blood pressure (BP) in most of the structures analyzed depended on the drug used. In the unanesthetized rabbits, the increase in vascular resistance induced by NE was greater than that induced by ANG II. (3) With the two drugs, there was no correlation between the flow changes in any of the structures considered and either the BP increase or the BP level in unanesthetized animals. However, these flow changes were correlated with the BP increase in anesthetized animals, although differences between the effects of NE and ANG II were again observed. This study suggests that cerebrovascular regulatory mechanisms in hypertension are probably more complex than a simple myogenic reaction. Their heterogeneity and their dependence both on the cause of hypertension and on the presence of anesthetics suggest the intervention of an integrating pathway.

  2. Supplemental calcium and risk reduction of hypertension, pregnancy-induced hypertension, and preeclampsia: an evidence-based review by the US Food and Drug Administration.

    PubMed

    Trumbo, Paula R; Ellwood, Kathleen C

    2007-02-01

    The labeling of health claims that meet the significant scientific agreement (SSA) standard (authorized health claims) and qualified health claims on conventional foods and dietary supplements requires premarket approval by the US Food and Drug Administration (FDA). FDA conducts an evidence-based review to determine whether there is sufficient evidence to support an authorized or qualified health claim. An evidence-based review was conducted on the human intervention and observational studies evaluating the role of supplemental calcium in reducing the risk of hypertension, pregnancy-induced hypertension, and preeclampsia. This review provides FDA's evaluation of the current scientific evidence on the role of supplemental calcium in reducing the risk of these three end points. Based on this evidence-based review, the agency concluded that the relationship between calcium and risk of hypertension is inconsistent and inconclusive, and the relationship between calcium and risk of pregnancy-induced hypertension and preeclampsia is highly unlikely. PMID:17345960

  3. Blockade of Salusin-? in Hypothalamic Paraventricular Nucleus Attenuates Hypertension and Cardiac Hypertrophy in Salt-induced Hypertensive Rats.

    PubMed

    Li, Hong-Bao; Qin, Da-Nian; Suo, Yu-Ping; Guo, Jing; Su, Qing; Miao, Yu-Wang; Sun, Wen-Yan; Yi, Qiu-Yue; Cui, Wei; Cheng, Kang; Zhu, Guo-Qing; Kang, Yu-Ming

    2015-10-01

    Salusin-?, a multifunctional bioactive peptide, is considered as a promising candidate biomarker for predicting cardiovascular diseases. This study was designed to determine whether inhibition of salusin-? in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by restoring neurotransmitters and cytokines. Male Sprague Dawley rats were fed with a normal salt diet (NS, 0.3%) or a high salt diet (HS, 8%) for 8 weeks to induce hypertension. Then, these rats received bilateral PVN infusion of a specific salusin-? blocker, antisalusin-? IgG (SIgG), or control IgG (CIgG) for 2 weeks. HS rats exhibited higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/bodyweight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and messenger RNA levels of cardiac atrial natriuretic peptide (ANP), and ?-myosin heavy chain. Compared with NS rats, HS rats had higher levels of glutamate, norepinephrine, tyrosine hydroxylase, proinflammatory cytokines, and lower levels of gamma-aminobutyric acid, interleukin 10, and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN, and higher plasma levels of proinflammatory cytokines. Chronic PVN infusion of SIgG attenuated all these changes in HS rats. Our findings suggest that HS rats have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between proinflammatory and anti-inflammatory cytokines in the PVN; and chronic inhibition of salusin-? in the PVN restores neurotransmitters and cytokines in the PVN, thereby attenuating hypertensive responses and cardiac hypertrophy. PMID:26038832

  4. The effect of ozone on blood pressure in DOCA-salt-induced hypertensive rats

    PubMed Central

    Akc?lar, Raziye; Aker, Sezer; ?im?ek, Hasan; Akc?lar, Ayd?n; Bayat, Zeynep; Gen, Osman

    2015-01-01

    Background: Hypertension is a risk factor for the cardiovascular diseases. Ozone as a therapeutic agent for the treatment of several disorders. We aimed to observe the effects of ozone on the blood pressure in DOCA-salt hypertensive rats. Methods: Twenty three young Sprague Dawley male rats were divided into three groups; Control (C), Hypertension (H) and Hypertension + Ozone (HO). Hypertension was induced by injection of DOCA-salt (25 mg/kg, s.c.) twice weekly, 4 weeks, whereas intraperitoneal ozone was administered (1.1 mg/kg) for 10 days. Serum endothelin-1, nitric oxide and renin levels were measured with ELISA. Blood pressures were monitored using a tail cuff system. Endothelin-1, ET receptor A and ET receptor B mRNA expression in heart and vascular tissue were assessed by quantitative reverse transcription polymerase chain reaction. Results: Blood pressure, serum endothelin-1 and ET receptor A mRNA expression levels were increased in H group, whereas serum renin, nitric oxide and ET receptor B mRNA expression levels in the heart and vascular tissue decreased compared with C and HO groups, which were counteracted by ozone treatment. Conclusion: Ozone treatment decreases blood pressure and is effective in preventing the progression of hypertensive disease, the mechanisms of which are associated with anti-vasoconstrictor effects through reducing the levels of serum endothelin-1 and ET receptor A mRNA expression in the heart and vascular tissue. PMID:26550192

  5. Resolution of pulmonary hypertension complication during venovenous perfusion-induced systemic hyperthermia application.

    PubMed

    Ballard-Croft, Cherry; Wang, Dongfang; Jones, Cameron; Wang, Jingkun; Pollock, Robert; Jubak, Bob; Topaz, Stephen; Zwischenberger, Joseph B

    2013-01-01

    We are developing a venovenous perfusion-induced systemic hyperthermia (vv-PISH) system for advanced cancer treatment. The vv-PISH system consistently delivered hyperthermia to adult healthy swine, but significant pulmonary hypertension developed during the heating phase. The goal of this study was to develop a method to prevent pulmonary hypertension. We hypothesized that pulmonary hypertension results from decreased priming solution air solubility, which causes pulmonary gas embolism. Healthy adult sheep (n = 3) were used to establish a standard vv-PISH sheep model without priming solution preheating. In subsequent sheep (n = 7), the priming solution was preheated (42-46°C) and the hyperthermia circuit flushed with CO2. All sheep survived the experiment and achieved 2 hours of 42°C hyperthermia. In the group lacking priming solution preheating, significant pulmonary hypertension (35-44 mm Hg) developed. In the sheep with priming solution preheating, pulmonary artery pressure was very stable without pulmonary hypertension. Blood electrolytes were in physiologic range, and complete blood counts were unaffected by hyperthermia. Blood chemistries revealed no significant liver or kidney damage. Our simple strategy of priming solution preheating completely resolved the problem of pulmonary hypertension as a milestone toward developing a safe and easy-to-use vv-PISH system for cancer treatment. PMID:23820278

  6. Role of the Gut Microbiome in Obstructive Sleep Apnea-Induced Hypertension.

    PubMed

    Durgan, David J; Ganesh, Bhanu P; Cope, Julia L; Ajami, Nadim J; Phillips, Sharon C; Petrosino, Joseph F; Hollister, Emily B; Bryan, Robert M

    2016-02-01

    Individuals suffering from obstructive sleep apnea (OSA) are at increased risk for systemic hypertension. The importance of a healthy gut microbiota, and detriment of a dysbiotic microbiota, on host physiology is becoming increasingly evident. We tested the hypothesis that gut dysbiosis contributes to hypertension observed with OSA. OSA was modeled in rats by inflating a tracheal balloon during the sleep cycle (10-s inflations, 60 per hour). On normal chow diet, OSA had no effect on blood pressure; however, in rats fed a high-fat diet, blood pressure increased 24 and 29 mm Hg after 7 and 14 days of OSA, respectively (P<0.05 each). Bacterial community characterization was performed on fecal pellets isolated before and after 14 days of OSA in chow and high-fat fed rats. High-fat diet and OSA led to significant alterations of the gut microbiota, including decreases in bacterial taxa known to produce the short chain fatty acid butyrate (P<0.05). Finally, transplant of dysbiotic cecal contents from hypertensive OSA rats on high-fat diet into OSA recipient rats on normal chow diet (shown to be normotensive) resulted in hypertension similar to that of the donor (increased 14 and 32 mm Hg after 7 and 14 days of OSA, respectively; P<0.05). These studies demonstrate a causal relationship between gut dysbiosis and hypertension, and suggest that manipulation of the microbiota may be a viable treatment for OSA-induced, and possibly other forms of, hypertension. PMID:26711739

  7. Antihypertensive Effect of Radix Paeoniae Alba in Spontaneously Hypertensive Rats and Excessive Alcohol Intake and High Fat Diet Induced Hypertensive Rats

    PubMed Central

    Su-Hong, Chen; Qi, Chen; Bo, Li; Jian-Li, Gao; Jie, Su; Gui-Yuan, Lv

    2015-01-01

    Radix Paeoniae Alba (Baishao, RPA) has long been used in traditional Chinese medicine formulation to treat hypertension by repression the hyperfunction of liver. However, whether the RPA itself has the antihypertensive effect or not is seldom studied. This study was to evaluate the protective effect of RPA on hypertensive rats. Alcohol in conjunction with a high fat diet- (ACHFD-) induced hypertensive rats and spontaneously hypertensive rats (SHR) was constantly received either RPA extract (25 or 75?mg/kg) or captopril (15?mg/kg) all along the experiments. As a result, RPA extract (75?mg/kg) could significantly reduce systolic blood pressure of both ACHFD-induced hypertensive rats and SHR after 9-week or 4-week treatment. In ACHFD-induced hypertensive rats, the blood pressure was significantly increased and the lipid profiles in serum including triglyceride, total cholesterol, LDL-cholesterol, and HDL-cholesterol were significantly deteriorated. Also, hepatic damage was manifested by a significant increase in alanine transaminase (ALT) and aspartate transaminase (AST) in serum. The RPA extract significantly reversed these parameters, which revealed that it could alleviate the liver damage of rats. In SHR, our result suggested that the antihypertensive active of RPA extract may be related to its effect on regulating serum nitric oxide (NO) and endothelin (ET) levels. PMID:25784949

  8. Rosiglitazone Attenuates Chronic HypoxiaInduced Pulmonary Hypertension in a Mouse Model

    PubMed Central

    Nisbet, Rachel E.; Bland, Jennifer M.; Kleinhenz, Dean J.; Mitchell, Patrick O.; Walp, Erik R.; Sutliff, Roy L.; Hart, C. Michael

    2010-01-01

    Chronic hypoxia contributes to pulmonary hypertension through complex mechanisms that include enhanced NADPH oxidase expression and reactive oxygen species (ROS) generation in the lung. Stimulation of peroxisome proliferatoractivated receptor ? (PPAR?) reduces the expression and activity of NADPH oxidase. Therefore, we hypothesized that activating PPAR? with rosiglitazone would attenuate chronic hypoxiainduced pulmonary hypertension, in part, through suppressing NADPH oxidasederived ROS that stimulate proliferative signaling pathways. Male C57Bl/6 mice were exposed to chronic hypoxia (CH, FiO2 10%) or room air for 3 or 5 weeks. During the last 10 days of exposure, each animal was treated daily by gavage with either the PPAR? ligand, rosiglitazone (10 mg/kg/d) or with an equal volume of vehicle. CH increased: (1) right ventricular systolic pressure (RVSP), (2) right ventricle weight, (3) thickness of the walls of small pulmonary vessels, (4) superoxide production and Nox4 expression in the lung, and (5) platelet-derived growth factor receptor ? (PDGFR?) expression and activity and reduced phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression. Treatment with rosiglitazone prevented the development of pulmonary hypertension at 3 weeks; reversed established pulmonary hypertension at 5 weeks; and attenuated CH-stimulated Nox4 expression and superoxide production, PDGFR? activation, and reductions in PTEN expression. Rosiglitazone also attenuated hypoxia-induced increases in Nox4 expression in pulmonary endothelial cells in vitro despite hypoxia-induced reductions in PPAR? expression. Collectively, these findings indicate that PPAR? ligands attenuated hypoxia-induced pulmonary vascular remodeling and hypertension by suppressing oxidative and proliferative signals providing novel insights for mechanisms underlying therapeutic effects of PPAR? activation in pulmonary hypertension. PMID:19520921

  9. Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model.

    PubMed

    Nisbet, Rachel E; Bland, Jennifer M; Kleinhenz, Dean J; Mitchell, Patrick O; Walp, Erik R; Sutliff, Roy L; Hart, C Michael

    2010-04-01

    Chronic hypoxia contributes to pulmonary hypertension through complex mechanisms that include enhanced NADPH oxidase expression and reactive oxygen species (ROS) generation in the lung. Stimulation of peroxisome proliferator-activated receptor gamma (PPARgamma) reduces the expression and activity of NADPH oxidase. Therefore, we hypothesized that activating PPARgamma with rosiglitazone would attenuate chronic hypoxia-induced pulmonary hypertension, in part, through suppressing NADPH oxidase-derived ROS that stimulate proliferative signaling pathways. Male C57Bl/6 mice were exposed to chronic hypoxia (CH, Fi(O2) 10%) or room air for 3 or 5 weeks. During the last 10 days of exposure, each animal was treated daily by gavage with either the PPARgamma ligand, rosiglitazone (10 mg/kg/d) or with an equal volume of vehicle. CH increased: (1) right ventricular systolic pressure (RVSP), (2) right ventricle weight, (3) thickness of the walls of small pulmonary vessels, (4) superoxide production and Nox4 expression in the lung, and (5) platelet-derived growth factor receptor beta (PDGFRbeta) expression and activity and reduced phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression. Treatment with rosiglitazone prevented the development of pulmonary hypertension at 3 weeks; reversed established pulmonary hypertension at 5 weeks; and attenuated CH-stimulated Nox4 expression and superoxide production, PDGFRbeta activation, and reductions in PTEN expression. Rosiglitazone also attenuated hypoxia-induced increases in Nox4 expression in pulmonary endothelial cells in vitro despite hypoxia-induced reductions in PPARgamma expression. Collectively, these findings indicate that PPARgamma ligands attenuated hypoxia-induced pulmonary vascular remodeling and hypertension by suppressing oxidative and proliferative signals providing novel insights for mechanisms underlying therapeutic effects of PPARgamma activation in pulmonary hypertension. PMID:19520921

  10. Hepatoprotective Effect of Silymarin (Silybum marianum) on Hepatotoxicity Induced by Acetaminophen in Spontaneously Hypertensive Rats

    PubMed Central

    Cardia, Gabriel Fernando Esteves; da Rocha, Bruno Ambrsio; Aguiar, Rafael Pazzinatto; Spironello, Ricardo Alexandre; Caparroz-Assef, Silvana Martins; Bersani-Amado, Ciomar Aparecida; Cuman, Roberto Kenji Nakamura

    2015-01-01

    This study was aimed to investigate the effect of Silymarin (SLM) on the hypertension state and the liver function changes induced by acetaminophen (APAP) in spontaneously hypertensive rat (SHR). Animals normotensive (N) or hypertensive (SHR) were treated or not with APAP (3?g/kg, oral) or previously treated with SLM. Twelve hours after APAP administration, plasmatic levels of liver function markers: alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose (GLU), gamma glutamyl transferase (?-GT), and alkaline phosphatase (ALP) of all groups, were determined. Liver injury was assessed using histological studies. Samples of their livers were then used to determine the myeloperoxidase (MPO) activity and nitric oxide (NO) production and were also sectioned for histological analysis. No differences were observed for ALT, ?-GT, and GLU levels between SHR and normotensive rats groups. However, AST and ALP levels were increased in hypertensive animals. APAP treatment promoted an increase in ALT and AST in both SHR and N. However, only for SHR, ?-GT levels were increased. The inflammatory response evaluated by MPO activity and NO production showed that SHR was more susceptible to APAP effect, by increasing leucocyte infiltration. Silymarin treatment (Legalon) restored the hepatocyte functional and histopathological alterations induced by APAP in normotensive and hypertensive animals. PMID:25821491

  11. Renal Transcriptome Analysis of Programmed Hypertension Induced by Maternal Nutritional Insults

    PubMed Central

    Tain, You-Lin; Hsu, Chien-Ning; Chan, Julie Y. H.; Huang, Li-Tung

    2015-01-01

    Maternal nutrition can affect development, leading to long-term effects on the health of offspring. The most common outcome is programmed hypertension. We examined whether alterations in renal transcriptome are responsible for generating programmed hypertension among four different models using next-generation RNA sequencing (NGS) technology. Pregnant Sprague-Dawley rats received 50% caloric restriction (CR), intraperitoneal injection of 45 mg/kg streptozotocin, 60% high-fructose (HF) diet, or 1% NaCl in drinking water to conduct CR, diabetes, HF, or high-salt models, respectively. All four models induced programmed hypertension in adult male offspring. We observed 16 shared genes in a two-week-old kidney among four different models. The identified differential expressed genes (DEGs) that are related to the regulation of blood pressure included Adrb3, Alb, Apoe, Calca, Kng1, Adm2, Guca2b, Hba2, Hba-a2, and Ppara. The peroxisome proliferator-activated receptor (PPAR) signaling pathway and glutathione metabolism pathway were shared by the CR, diabetes, and HF models. Conclusively, a variety of maternal nutritional insults induced the same phenotype—programmed hypertension with differential alterations of renal transcriptome in adult male offspring. The roles of DEGs identified by the NGS in this study deserve further clarification to develop ideal maternal dietary interventions and thus spare the next generations from the burden of hypertension. PMID:26247937

  12. Dimethylarginine dimethylaminohydrolase-1 mediates inhibitory effect of interleukin-10 on angiotensin II-induced hypertensive effects in vascular smooth muscle cells of spontaneously hypertensive rats.

    PubMed

    Kim, Hye Young; Kim, Hee Sun

    2016-01-01

    In hypertension studies, anti-inflammatory cytokine interleukin-10 (IL-10) has been shown to prevent angiotensin II (Ang II)-induced vasoconstriction and regulate vascular function by down-regulating pro-inflammatory cytokine and superoxide production in vascular cells. However, little is known about the mechanism behind the down-regulatory effect of IL-10 on Ang II-induced hypertensive mediators. In this study, we demonstrated the effects of IL-10 on expression of dimethylarginine dimethylaminohydrolase (DDAH)-1, a regulator of NO bioavailability, as well as the down-regulatory mechanism of action of IL-10 in relation to Ang II-induced hypertensive mediator expression and cell proliferation in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR). IL-10 increased DDAH-1 but not DDAH-2 expression and increased DDAH activity. Additionally, IL-10 attenuated Ang II-induced DDAH-1 inhibition in SHR VSMCs. Increased DDAH activity due to IL-10 was mediated mainly through Ang II subtype II receptor (AT2 R) and AMP-activated protein kinase (AMPK) activation. DDAH-1 induced by IL-10 partially mediated the inhibitory action of IL-10 on Ang II-induced 12-lipoxygenase (LO) and endothelin (ET)-1 expression in SHR VSMCs. In addition, the inhibitory effect of IL-10 on proliferation of Ang II-induced VSMCs was mediated partially via DDAH-1 activity. These results suggest that DDAH-1 plays a potentially important role in the anti-hypertensive activity of IL-10 during Ang II-induced hypertension. PMID:26375520

  13. Hypertension-induced reversible posterior leukoencephalopathy syndrome causing obstructive hydrocephalus.

    PubMed

    Lee, S Y; Dinesh, S K; Thomas, J

    2008-04-01

    Reversible posterior leukoencephalopathy syndrome (RPLS) is characterized clinically by headache, altered mental status, abnormal visual perception and seizures. It is associated with neuroradiological findings characterized by reversible white matter abnormalities, predominantly in the parietal-occipital areas. Since the first description in 1996, it has been recognized in an increasing number of medical conditions, including hypertensive encephalopathy, eclampsia, and immunosuppressive treatment. The rapid resolution of clinical and neuroradiologic abnormalities suggests cerebral oedema, which is thought to result from impaired cerebrovascular autoregulation and endothelial injury. We report a patient presenting with acute onset progressively worsening headache and confusion associated with uncontrolled hypertension. CT and MRI revealed acute non-communicating hydrocephalus secondary to cerebellar and pontine oedema. The patient became drowsy, so an external ventricular drain was inserted for decompression of the acute hydrocephalus, and his blood pressure was aggressively managed. The patient recovered well with complete clinical and radiological resolution. This case illustrates the reversibility of RPLS if it is diagnosed early and appropriate treatment is instituted. PMID:18249121

  14. Body fluid volumes in rats with mestranol-induced hypertension

    SciTech Connect

    Fowler, W.L. Jr.; Johnson, J.A.; Kurz, K.D.; Zeigler, D.W.; Dostal, D.E.; Payne, C.G.

    1986-07-01

    Because estrogens have been reported to produce sodium retention, this study investigated the possibility that hypertension in rats resulting from the ingestion of an estrogen used as an oral contraceptive could be due to increases in body fluid volumes. Female rats were given feed containing mestranol for 1, 3, and 6 mo; control rats were given the feed without mestranol. The mestranol-treated rats had higher arterial pressures than the controls only after 6 mo of treatment. Plasma volume, extracellular fluid volume, and total body water were measured in each rat by the distribution volumes of radioiodinated serum albumin, /sup 32/SO/sub 4/, and tritiated water, respectively. The body fluid volumes, expressed per 100 g of body weight, were not different between the mestranol-treated rats and their controls at any of the three treatment times. Due to differences in body weight and lean body mass between the mestranol-treated and the control rats, these volumes also were expressed per 100 g of lean body mass. Again, no differences were observed between the mestranol-treated rats and the control rats for any of these body fluid compartments at any of the treatment times. These studies, therefore, were unable to provide evidence that increases in body fluid volumes contributed to the elevated arterial pressure in this rat model of oral contraceptive hypertension.

  15. Total exchangeable sodium in rats with mestranol-induced hypertension

    SciTech Connect

    Abas, N. ); Johnson, J.A. )

    1989-05-01

    Rats were fed a diet containing mestranol, an orally active estrogen, while control rats were fed the same diet without mestranol. After 6 months of these diets, the rats were weighed, blood pressures were measured, and total exchangeable sodium was determined by injecting {sup 24}Na and determining the amount of {sup 24}Na in the plasma, the plasma Na concentration, and the residual {sup 24}Na in each rat. The 16 mestranol-treated rats were hypertensive (mean arterial pressure 135 {plus minus} 3 mm Hg) when compared with the 17 controls (116 {plus minus} 3 mm Hg). Total exchangeable sodium in the mestranol-treated rats averaged 39.94 {plus minus} 0.49 (SEM) mEq/kg body wt, which was very similar to the value of 39.87 {plus minus} 0.63 mEq/kg found in the control rats. Thus, no changes in total exchangeable sodium in mestranol-hypertensive rats were found in these studies.

  16. Postnatal dexamethasone-induced programmed hypertension is related to the regulation of melatonin and its receptors.

    PubMed

    Chang, Hsin-Yu; Tain, You-Lin

    2016-04-01

    Adulthood hypertension can be programmed by glucocorticoid exposure in early life. We found that maternal melatonin therapy prevents postnatal dexamethasone (DEX)-induced programmed hypertension. Melatonin acts through specific receptors, including MT1 and MT2 membrane receptors, and retinoid related orphan nuclear receptors of the RZR/ROR family. Thus we tested whether postnatal DEX-induced hypertension is related to changes of melatonin receptors in the kidney and heart, which was preserved by maternal melatonin therapy. Male neonates were assigned to four groups (n=6-8/group): control, DEX, control+melatonin (MEL), and DEX+MEL. Male rat pups were injected i.p. with DEX on d 1 (0.5mg/kg BW), d 2 (0.3mg/kg BW), and d 3 (0.1mg/kg BW) after birth. Melatonin was administered in drinking water (0.01%) during the lactation period. We found DEX group developed hypertension at 16weeks of age, which melatonin therapy prevented. Postnatal DEX treatment increased mRNA expression of MT1 and MT2, while decreased RORα and RZRβ in the kidney. These changes were prevented by melatonin therapy. Postnatal DEX decreased protein level of MT2 in the kidney, which was attenuated by melatonin therapy. Renal protein level of RORα was higher in DEX+MEL group compared to control and DEX group. Renal melatonin level was higher in the MEL and DEX+MEL groups compared to control. We concluded that melatonin therapy has long-term protection on postnatal DEX-induced programmed hypertension, which is associated with regulation on melatonin receptors in the kidney. Our findings would offer potential therapeutic approaches to prevent programmed hypertension in premature baby receiving glucocorticoids. PMID:26921678

  17. The role of NADPH oxidase in chronic intermittent hypoxia-induced pulmonary hypertension in mice.

    PubMed

    Nisbet, Rachel E; Graves, Anitra S; Kleinhenz, Dean J; Rupnow, Heidi L; Reed, Alana L; Fan, Tai-Hwang M; Mitchell, Patrick O; Sutliff, Roy L; Hart, C Michael

    2009-05-01

    Obstructive sleep apnea, characterized by intermittent periods of hypoxemia, is an independent risk factor for the development of pulmonary hypertension. However, the exact mechanisms of this disorder remain to be defined. Enhanced NADPH oxidase expression and superoxide (O2(-).) generation in the pulmonary vasculature play a critical role in hypoxia-induced pulmonary hypertension. Therefore, the current study explores the hypothesis that chronic intermittent hypoxia (CIH) causes pulmonary hypertension, in part, by increasing NADPH oxidase-derived reactive oxygen species (ROS) that contribute to pulmonary vascular remodeling and hypertension. To test this hypothesis, male C57Bl/6 mice and gp91phox knockout mice were exposed to CIH for 8 hours per day, 5 days per week for 8 weeks. CIH mice were placed in a chamber where the oxygen concentration was cycled between 21% and 10% O2 45 times per hour. Exposure to CIH for 8 weeks increased right ventricular systolic pressure (RVSP), right ventricle (RV):left ventricle (LV) + septum (S) weight ratio, an index of RV hypertrophy, and thickness of the right ventricular anterior wall as measured by echocardiography. CIH exposure also caused pulmonary vascular remodeling as demonstrated by increased muscularization of the distal pulmonary vasculature. CIH-induced pulmonary hypertension was associated with increased lung levels of the NADPH oxidase subunits, Nox4 and p22phox, as well as increased activity of platelet-derived growth factor receptor beta and its associated downstream effector, Akt kinase. These CIH-induced derangements were attenuated in similarly treated gp91phox knockout mice. These findings demonstrate that NADPH oxidase-derived ROS contribute to the development of pulmonary vascular remodeling and hypertension caused by CIH. PMID:18952568

  18. The Role of NADPH Oxidase in Chronic Intermittent Hypoxia-Induced Pulmonary Hypertension in Mice

    PubMed Central

    Nisbet, Rachel E.; Graves, Anitra S.; Kleinhenz, Dean J.; Rupnow, Heidi L.; Reed, Alana L.; Fan, Tai-Hwang M.; Mitchell, Patrick O.; Sutliff, Roy L.; Hart, C. Michael

    2009-01-01

    Obstructive sleep apnea, characterized by intermittent periods of hypoxemia, is an independent risk factor for the development of pulmonary hypertension. However, the exact mechanisms of this disorder remain to be defined. Enhanced NADPH oxidase expression and superoxide (O2?) generation in the pulmonary vasculature play a critical role in hypoxia-induced pulmonary hypertension. Therefore, the current study explores the hypothesis that chronic intermittent hypoxia (CIH) causes pulmonary hypertension, in part, by increasing NADPH oxidasederived reactive oxygen species (ROS) that contribute to pulmonary vascular remodeling and hypertension. To test this hypothesis, male C57Bl/6 mice and gp91phox knockout mice were exposed to CIH for 8 hours per day, 5 days per week for 8 weeks. CIH mice were placed in a chamber where the oxygen concentration was cycled between 21% and 10% O2 45 times per hour. Exposure to CIH for 8 weeks increased right ventricular systolic pressure (RVSP), right ventricle (RV):left ventricle (LV) + septum (S) weight ratio, an index of RV hypertrophy, and thickness of the right ventricular anterior wall as measured by echocardiography. CIH exposure also caused pulmonary vascular remodeling as demonstrated by increased muscularization of the distal pulmonary vasculature. CIH-induced pulmonary hypertension was associated with increased lung levels of the NADPH oxidase subunits, Nox4 and p22phox, as well as increased activity of platelet-derived growth factor receptor ? and its associated downstream effector, Akt kinase. These CIH-induced derangements were attenuated in similarly treated gp91phox knockout mice. These findings demonstrate that NADPH oxidasederived ROS contribute to the development of pulmonary vascular remodeling and hypertension caused by CIH. PMID:18952568

  19. The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension.

    PubMed

    Capone, Carmen; Faraco, Giuseppe; Park, Laibaik; Cao, Xian; Davisson, Robin L; Iadecola, Costantino

    2011-01-01

    Hypertension alters cerebrovascular regulation and increases the brain's susceptibility to stroke and dementia. We investigated the temporal relationships between the arterial pressure (AP) elevation induced by "slow pressor" angiotensin II (ANG II) infusion, which recapitulates key features of human hypertension, and the resulting cerebrovascular dysfunction. Minipumps delivering saline or ANG II for 14 days were implanted subcutaneously in C57BL/6 mice (n = 5/group). Cerebral blood flow was assessed by laser-Doppler flowmetry in anesthetized mice equipped with a cranial window. With ANG II (600 ng · kg(-1) · min(-1)), AP started to rise after 9 days (P < 0.05 vs. saline), remained elevated at 11-17 days, and returned to baseline at 21 days (P > 0.05). ANG II attenuated the cerebral blood flow increase induced by neural activity (whisker stimulation) or endothelium-dependent vasodilators, an effect observed before the AP elevation (7 days), as well as after the hypertension subsided (21 days). Nonpressor doses of ANG II (200 ng · kg(-1) · min(-1)) induced cerebrovascular dysfunction and oxidative stress without elevating AP (P > 0.05 vs. saline), whereas phenylephrine elevated AP without inducing cerebrovascular effects. ANG II (600 ng · kg(-1) · min(-1)) augmented neocortical reactive oxygen species (ROS) with a time course similar to that of the cerebrovascular dysfunction. Neocortical application of the ROS scavenger manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin or the NADPH oxidase peptide inhibitor gp91ds-tat attenuated ROS and cerebrovascular dysfunction. We conclude that the alterations in neurovascular regulation induced by slow pressor ANG II develop before hypertension and persist beyond AP normalization but are not permanent. The findings unveil a striking susceptibility of cerebrovascular function to the deleterious effects of ANG II and raise the possibility that cerebrovascular dysregulation precedes the elevation in AP also in patients with ANG II-dependent hypertension. PMID:20971763

  20. Myocardial blood flow during induced aortic hypertension in dogs

    SciTech Connect

    Thai, B.N.; Levesque, M.J.; Nerem, R.M.

    1986-03-01

    Myocardial blood flow was measured in anesthetized dogs during control conditions and under conditions where the aortic pressure was increased due to aortic constriction or during infusion. Blood flow was measured using the radioactive microsphere technique. Radioactive microspheres (15 m Ce-141, Sr-85, and Sc-46) were injected under control, aortic constriction and arterenol infusion in four dogs and under control conditions in two others. All microsphere injections were performed under stabilized conditions. It was found that coronary blood flow rose by 80% during aortic constriction and by 158% during arterenol infusion (P < 0.05). This increase in blood flow was not uniform throughout the heart, and higher increases were observed in the middle and apex regions of the left ventricle. Furthermore, under hypertension the increase in blood flow in LAD (left anterior descending) perfused territories was slightly higher than that in CFX (left circumflex) perfused territories.

  1. Primary hypertension-induced cerebellar encephalopathy causing obstructive hydrocephalus. Case report.

    PubMed

    Verrees, Meg; Fernandes Filho, Jose Americo; Suarez, Jose I; Ratcheson, Robert A

    2003-06-01

    Hypertension-induced encephalopathy is a recognized pathological process commonly focused in the parietal and occipital lobes of the cerebral hemispheres. The parenchyma of the posterior fossa is infrequently involved. The authors report on two cases of isolated edema of the cerebellar hemispheres, which occurred in the setting of hypertensive crisis and led to complete obstruction of or significant impingement on the fourth ventricle and potentially lethal hydrocephalus. To the best of the authors' knowledge, these are the first reported cases of hypertensive encephalopathy centered in the posterior fossa. Two patients presented with profound decreases in neurological status subsequent to development of malignant hypertension. Imaging studies revealed diffusely edematous cerebellar hemispheres with effacement of the fourth ventricle, causing dilation of the lateral and third ventricles. Following emergency placement of external ventricular drains, control of systemic blood pressure was accomplished, and neurological functioning returned to baseline. Although neurological deterioration resolved swiftly following placement of ventricular catheters and administration of diuretic agents, systemic blood pressure did not fluctuate with the release of cerebrospinal fluid and resolution of increased intracranial pressure. Decrease in systemic blood pressure lagged well behind improvement in neurological status; the patients remained morbidly hypertensive until systemic blood pressure was controlled with multiple parenteral medications. The authors hypothesize that the development of hypertension beyond the limits of cerebral autoregulation led to breakdown of the blood-brain barrier in the cerebellum and development of posterior fossa edema secondary to the focal transudation of protein and fluid. Correction of the elevated blood pressure led to amelioration of cerebellar edema. In the appropriate clinical setting, hypertension as the inciting cause of cerebellar encephalopathy should be considered. PMID:12816279

  2. Therapeutic Benefits of Induced Pluripotent Stem Cells in Monocrotaline-Induced Pulmonary Arterial Hypertension

    PubMed Central

    Huang, Wei-Chun; Ke, Meng-Wei; Cheng, Chin-Chang; Chiou, Shih-Hwa; Wann, Shue-Ren; Shu, Chih-Wen; Chiou, Kuan-Rau; Tseng, Ching-Jiunn; Pan, Hung-Wei; Mar, Guang-Yuan; Liu, Chun-Peng

    2016-01-01

    Pulmonary arterial hypertension (PAH) is characterized by progressive increases in vascular resistance and the remodeling of pulmonary arteries. The accumulation of inflammatory cells in the lung and elevated levels of inflammatory cytokines in the bloodstream suggest that inflammation may play a role in PAH. In this study, the benefits of induced pluripotent stem cells (iPSCs) and iPSC-conditioned medium (iPSC CM) were explored in monocrotaline (MCT)-induced PAH rats. We demonstrated that both iPSCs and iPSC CM significantly reduced the right ventricular systolic pressure and ameliorated the hypertrophy of the right ventricle in MCT-induced PAH rats in models of both disease prevention and disease reversal. In the prevention of MCT-induced PAH, iPSC-based therapy led to the decreased accumulation of inflammatory cells and down-regulated the expression of the IL-1β, IL-6, IL-12α, IL-12β, IL-23 and IFNγ genes in lung specimens, which implied that iPSC-based therapy may be involved in the regulation of inflammation. NF-κB signaling is essential to the inflammatory cascade, which is activated via the phosphorylation of the NF-κB molecule. Using the chemical inhibitor specifically blocked the phosphorylation of NF-κB, and in vitro assays of cultured human M1 macrophages implied that the anti-inflammation effect of iPSC-based therapy may contribute to the disturbance of NF-κB activation. Here, we showed that iPSC-based therapy could restore the hemodynamic function of right ventricle with benefits for preventing the ongoing inflammation in the lungs of MCT-induced PAH rats by regulating NF-κB phosphorylation. PMID:26840075

  3. Therapeutic Benefits of Induced Pluripotent Stem Cells in Monocrotaline-Induced Pulmonary Arterial Hypertension.

    PubMed

    Huang, Wei-Chun; Ke, Meng-Wei; Cheng, Chin-Chang; Chiou, Shih-Hwa; Wann, Shue-Ren; Shu, Chih-Wen; Chiou, Kuan-Rau; Tseng, Ching-Jiunn; Pan, Hung-Wei; Mar, Guang-Yuan; Liu, Chun-Peng

    2016-01-01

    Pulmonary arterial hypertension (PAH) is characterized by progressive increases in vascular resistance and the remodeling of pulmonary arteries. The accumulation of inflammatory cells in the lung and elevated levels of inflammatory cytokines in the bloodstream suggest that inflammation may play a role in PAH. In this study, the benefits of induced pluripotent stem cells (iPSCs) and iPSC-conditioned medium (iPSC CM) were explored in monocrotaline (MCT)-induced PAH rats. We demonstrated that both iPSCs and iPSC CM significantly reduced the right ventricular systolic pressure and ameliorated the hypertrophy of the right ventricle in MCT-induced PAH rats in models of both disease prevention and disease reversal. In the prevention of MCT-induced PAH, iPSC-based therapy led to the decreased accumulation of inflammatory cells and down-regulated the expression of the IL-1β, IL-6, IL-12α, IL-12β, IL-23 and IFNγ genes in lung specimens, which implied that iPSC-based therapy may be involved in the regulation of inflammation. NF-κB signaling is essential to the inflammatory cascade, which is activated via the phosphorylation of the NF-κB molecule. Using the chemical inhibitor specifically blocked the phosphorylation of NF-κB, and in vitro assays of cultured human M1 macrophages implied that the anti-inflammation effect of iPSC-based therapy may contribute to the disturbance of NF-κB activation. Here, we showed that iPSC-based therapy could restore the hemodynamic function of right ventricle with benefits for preventing the ongoing inflammation in the lungs of MCT-induced PAH rats by regulating NF-κB phosphorylation. PMID:26840075

  4. Resistin Induces Hypertension and Insulin Resistance in Mice via a TLR4-Dependent Pathway

    PubMed Central

    Jiang, Yun; Lu, Linfang; Hu, Youtao; Li, Qiang; An, Chaoqiang; Yu, Xiaolan; Shu, Le; Chen, Ao; Niu, Congcong; Zhou, Lei; Yang, Zaiqing

    2016-01-01

    Resistin, an adipokine involved in insulin resistance (IR) and diabetes, has recently been reported to play a role in cardiovascular events. However, its effect on blood pressure (BP) and the underlying mechanisms remain unclear. In the present study, we showed that resistin induces hypertension and IR in wild type (WT) mice, but not in tlr4−/− mice. Resistin upregulated angiotensinogen (Agt) expression in WT mice, whereas it had no effect on tlr4−/− mice, or in mice treated with the angiotensin-converting enzyme inhibitor perindopril. Real-time PCR and chromatin immunoprecipitation further confirmed that resistin activates the renin-angiotensin system (RAS) via the TLR4/P65/Agt pathway. This finding suggested an essential role of resistin in linking IR and hypertension, which may offer a novel target in clinic on the study of the association between diabetes and hypertension. PMID:26917360

  5. Resistin Induces Hypertension and Insulin Resistance in Mice via a TLR4-Dependent Pathway.

    PubMed

    Jiang, Yun; Lu, Linfang; Hu, Youtao; Li, Qiang; An, Chaoqiang; Yu, Xiaolan; Shu, Le; Chen, Ao; Niu, Congcong; Zhou, Lei; Yang, Zaiqing

    2016-01-01

    Resistin, an adipokine involved in insulin resistance (IR) and diabetes, has recently been reported to play a role in cardiovascular events. However, its effect on blood pressure (BP) and the underlying mechanisms remain unclear. In the present study, we showed that resistin induces hypertension and IR in wild type (WT) mice, but not in tlr4(-/-) mice. Resistin upregulated angiotensinogen (Agt) expression in WT mice, whereas it had no effect on tlr4(-/-) mice, or in mice treated with the angiotensin-converting enzyme inhibitor perindopril. Real-time PCR and chromatin immunoprecipitation further confirmed that resistin activates the renin-angiotensin system (RAS) via the TLR4/P65/Agt pathway. This finding suggested an essential role of resistin in linking IR and hypertension, which may offer a novel target in clinic on the study of the association between diabetes and hypertension. PMID:26917360

  6. Exercise-induced hypertension among healthy firefighters-a comparison between two different definitions.

    PubMed

    Leiba, Adi; Baur, Dorothee M; Kales, Stefanos N

    2013-01-01

    Different studies have yielded conflicting results regarding the association of hypertensive response to exercise and cardiovascular morbidity. We compared two different definitions of exaggerated hypertensive response to exercise and their association with cardio-respiratory fitness in a population of healthy firefighters. We examined blood pressure response to exercise in 720 normotensive male career firefighters. Fitness was measured as peak metabolic equivalent tasks (METs) achieved during maximal exercise treadmill tests. Abnormal hypertensive response was defined either as systolic blood pressure ? 200 mm Hg; or alternatively, as responses falling in the upper tertile of blood pressure change from rest to exertion, divided by the maximal workload achieved. Using the simple definition of a 200 mm Hg cutoff at peak exercise less fit individuals (METs ? 12) were protected from an exaggerated hypertensive response (OR 0.45, 95%CI 0.30-0.67). However, using the definition of exercise-induced hypertension that corrects for maximal workload, less fit firefighters had almost twice the risk (OR 1.8, 95%CI 1.3-2.47). Blood pressure change corrected for maximal workload is better correlated with cardiorespiratory fitness. Systolic blood pressure elevation during peak exercise likely represents an adaptive response, whereas elevation out of proportion to the maximal workload may indicate insufficient vasodilation and a maladaptive response. Prospective studies are needed to best define exaggerated blood pressure response to exercise. PMID:23246464

  7. Effects of Atorvastatin on the Hypertension-Induced Oxidative Stress in the Rat Brain

    PubMed Central

    Mohammadi, Mohammad Taghi; Amini, Reza; Jahanbakhsh, Zahra; Shekarforoush, Shahnaz

    2013-01-01

    Background: It is well known that the development of brain oxidative stress is one of the most serious complications of arterial hypertension that evokes brain tissue damage. The aim of this study was to examine the effects of atorvastatin treatment (20 mg/kg/day), as an antioxidant, to prevent the brain tissue oxidative stress in the hypertensive (HTN) rats. Methods: Experiments were performed in four groups of rats (n = 5 each group): sham, sham-treated, HTN and HTN treated. Rats were made HTN by aortic constriction above the renal arteries. After 30 days, rats were slaughtered under deep anesthesia to remove brain hemispheres. After tissue homogenization, enzyme activities of superoxide dismutase (SOD) and catalase (CAT), as well as glutathione (GSH) content and malondialdehyde (MDA) level were determined by biochemical methods. Results: In HTN rats, arterial blood pressure was increased about 40% and brain enzyme activities of SOD and CAT were significantly decreased compared with sham group. Induction of hypertension significantly decreased GSH content and increased MDA level of brain tissue. Treatment with atorvastatin enhanced the activity of SOD and prevented from GSH decrement during hypertension. Conclusion: Based on the findings of this study, treatment with atorvastatin might have saved the brain tissue of HTN rats from hypertension-induced oxidative stress. PMID:23748894

  8. Neutrophil Depletion Attenuates Placental Ischemia-Induced Hypertension in the Rat

    PubMed Central

    Regal, Jean F.; Lillegard, Kathryn E.; Bauer, Ashley J.; Elmquist, Barbara J.; Loeks-Johnson, Alex C.; Gilbert, Jeffrey S.

    2015-01-01

    Preeclampsia is characterized by reduced placental perfusion with placental ischemia and hypertension during pregnancy. Preeclamptic women also exhibit a heightened inflammatory state and greater number of neutrophils in the vasculature compared to normal pregnancy. Since neutrophils are associated with tissue injury and inflammation, we hypothesized that neutrophils are critical to placental ischemia-induced hypertension and fetal demise. Using the reduced uteroplacental perfusion pressure (RUPP) model of placental ischemia-induced hypertension in the rat, we determined the effect of neutrophil depletion on blood pressure and fetal resorptions. Neutrophils were depleted with repeated injections of polyclonal rabbit anti-rat polymorphonuclear leukocyte (PMN) antibody (antiPMN). Rats received either antiPMN or normal rabbit serum (Control) on 13.5, 15.5, 17.5, and 18.5 days post conception (dpc). On 14.5 dpc, rats underwent either Sham surgery or clip placement on ovarian arteries and abdominal aorta to reduce uterine perfusion pressure (RUPP). On 18.5 dpc, carotid arterial catheters were placed and mean arterial pressure (MAP) was measured on 19.5 dpc. Neutrophil-depleted rats had reduced circulating neutrophils from 14.5 to 19.5 dpc compared to Control, as well as decreased neutrophils in lung and placenta on 19.5 dpc. MAP increased in RUPP Control vs Sham Control rats, and neutrophil depletion attenuated this increase in MAP in RUPP rats without any effect on Sham rats. The RUPP-induced increase in fetal resorptions and complement activation product C3a were not affected by neutrophil depletion. Thus, these data are the first to indicate that neutrophils play an important role in RUPP hypertension and that cells of the innate immune system may significantly contribute to pregnancy-induced hypertension. PMID:26135305

  9. Oxidant and enzymatic antioxidant status (gene expression and activity) in the brain of chickens with cold-induced pulmonary hypertension

    NASA Astrophysics Data System (ADS)

    Hassanpour, Hossein; Khalaji-Pirbalouty, Valiallah; Nasiri, Leila; Mohebbi, Abdonnaser; Bahadoran, Shahab

    2015-11-01

    To evaluate oxidant and antioxidant status of the brain (hindbrain, midbrain, and forebrain) in chickens with cold-induced pulmonary hypertension, the measurements of lipid peroxidation, protein oxidation, antioxidant capacity, enzymatic activity, and gene expression (for catalase, glutathione peroxidase, and superoxide dismutases) were done. There were high lipid peroxidation/protein oxidation and low antioxidant capacity in the hindbrain of cold-induced pulmonary hypertensive chickens compared to control ( P < 0.05). In the hypertensive chickens, superoxide dismutase activity was decreased (forebrain, midbrain, and hindbrain), while catalase activity was increased (forebrain and midbrain) ( P < 0.05). Glutathione peroxidase activity did not change. Relative gene expression of catalase and superoxide dismutases (1 and 2) was downregulated, while glutathione peroxidase was upregulated in the brain of the cold-induced pulmonary hypertensive chickens. Probably, these situations in the oxidant and antioxidant status of the brain especially hindbrain may change its function at cardiovascular center and sympathetic nervous system to exacerbate pulmonary hypertension.

  10. Pulmonary hypertension

    MedlinePLUS

    Pulmonary arterial hypertension; Sporadic primary pulmonary hypertension; Familial primary pulmonary hypertension; Idiopathic pulmonary arterial hypertension; Primary pulmonary hypertension; PPH; Secondary pulmonary hypertension

  11. Intermittent Hypoxia-Induced Carotid Body Chemosensory Potentiation and Hypertension Are Critically Dependent on Peroxynitrite Formation.

    PubMed

    Moya, Esteban A; Arias, Paulina; Varela, Carlos; Oyarce, Mara P; Del Rio, Rodrigo; Iturriaga, Rodrigo

    2016-01-01

    Oxidative stress is involved in the development of carotid body (CB) chemosensory potentiation and systemic hypertension induced by chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea. We tested whether peroxynitrite (ONOO(-)), a highly reactive nitrogen species, is involved in the enhanced CB oxygen chemosensitivity and the hypertension during CIH. Accordingly, we studied effects of Ebselen, an ONOO(-) scavenger, on 3-nitrotyrosine immunoreactivity (3-NT-ir) in the CB, the CB chemosensory discharge, and arterial blood pressure (BP) in rats exposed to CIH. Male Sprague-Dawley rats were exposed to CIH (5% O2, 12 times/h, 8?h/day) for 7 days. Ebselen (10?mg/kg/day) was administrated using osmotic minipumps and BP measured with radiotelemetry. Compared to the sham animals, CIH-treated rats showed increased 3-NT-ir within the CB, enhanced CB chemosensory responses to hypoxia, increased BP response to acute hypoxia, and hypertension. Rats treated with Ebselen and exposed to CIH displayed a significant reduction in 3-NT-ir levels (60.8 14.9 versus 22.9 4.2?a.u.), reduced CB chemosensory response to 5% O2 (266.5 13.4 versus 168.6 16.8?Hz), and decreased mean BP (116.9 13.2 versus 82.1 5.1?mmHg). Our results suggest that CIH-induced CB chemosensory potentiation and hypertension are critically dependent on ONOO(-) formation. PMID:26798430

  12. Intermittent Hypoxia-Induced Carotid Body Chemosensory Potentiation and Hypertension Are Critically Dependent on Peroxynitrite Formation

    PubMed Central

    Moya, Esteban A.; Arias, Paulina; Varela, Carlos; Oyarce, Mara P.; Del Rio, Rodrigo; Iturriaga, Rodrigo

    2016-01-01

    Oxidative stress is involved in the development of carotid body (CB) chemosensory potentiation and systemic hypertension induced by chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea. We tested whether peroxynitrite (ONOO?), a highly reactive nitrogen species, is involved in the enhanced CB oxygen chemosensitivity and the hypertension during CIH. Accordingly, we studied effects of Ebselen, an ONOO? scavenger, on 3-nitrotyrosine immunoreactivity (3-NT-ir) in the CB, the CB chemosensory discharge, and arterial blood pressure (BP) in rats exposed to CIH. Male Sprague-Dawley rats were exposed to CIH (5% O2, 12 times/h, 8?h/day) for 7 days. Ebselen (10?mg/kg/day) was administrated using osmotic minipumps and BP measured with radiotelemetry. Compared to the sham animals, CIH-treated rats showed increased 3-NT-ir within the CB, enhanced CB chemosensory responses to hypoxia, increased BP response to acute hypoxia, and hypertension. Rats treated with Ebselen and exposed to CIH displayed a significant reduction in 3-NT-ir levels (60.8 14.9 versus 22.9 4.2?a.u.), reduced CB chemosensory response to 5% O2 (266.5 13.4 versus 168.6 16.8?Hz), and decreased mean BP (116.9 13.2 versus 82.1 5.1?mmHg). Our results suggest that CIH-induced CB chemosensory potentiation and hypertension are critically dependent on ONOO? formation. PMID:26798430

  13. Efficacy of carvedilol in reversing hypertension induced by chronic intermittent hypoxia in rats.

    PubMed

    Diogo, Lucília N; Pereira, Sofia A; Nunes, Ana R; Afonso, Ricardo A; Santos, Ana I; Monteiro, Emília C

    2015-10-15

    Animal models of chronic intermittent hypoxia (CIH) mimic the hypertension observed in patients with obstructive sleep apnoea. Antihypertensive drugs were applied to these animal models to address the physiological mechanism but not to revert established hypertension. We aimed to investigate the efficacy of carvedilol (CVDL), an unselective beta-blocker that exhibits intrinsic anti-α1-adrenergic and antioxidant activities in a rat model of CIH-induced hypertension. The variability of CVDL enantiomers in plasma concentrations was also evaluated. Wistar rats with indwelling blood pressure telemeters were exposed during their sleep period to 5.6 CIH cycles/h, 10.5 h/day, for 60 days. CVDL was administered by gavage beginning on Day 36 of the CIH period and was continued for 25 days. R-(+)-CVDL and S-(-)-CVDL plasma concentrations were monitored by HPLC. CIH significantly increased diastolic and systolic blood pressure by 25.7 and 21.6 mm Hg respectively, while no effect was observed on the heart rate (HR). CVDL administration at 10, 30 and 50 mg/kg/day promoted a significant reduction in HR but did not affect arterial pressure. The S/(R+S) ratio of CVDL enantiomers was lower in rats exposed to CIH. The blockade of the sympathetic nervous system together with the putative pleiotropic effects of CVDL did not alter the CIH-induced hypertension. Although CIH induced pharmacokinetic changes in the R/(R+S) ratio, these effects do not appear to be responsible for the inability of CVDL to reverse this particular type of hypertension. PMID:26291659

  14. Loss of functional endothelial connexin40 results in exercise-induced hypertension in mice.

    PubMed

    Morton, Susan K; Chaston, Daniel J; Howitt, Lauren; Heisler, Jillian; Nicholson, Bruce J; Fairweather, Stephen; Brer, Stefan; Ashton, Anthony W; Matthaei, Klaus I; Hill, Caryl E

    2015-03-01

    During activity, coordinated vasodilation of microcirculatory networks with upstream supply vessels increases blood flow to skeletal and cardiac muscles and reduces peripheral resistance. Endothelial dysfunction in humans attenuates activity-dependent vasodilation, resulting in exercise-induced hypertension in otherwise normotensive individuals. Underpinning activity-dependent hyperemia is an ascending vasodilation in which the endothelial gap junction protein, connexin (Cx)40, plays an essential role. Because exercise-induced hypertension is proposed as a forerunner to clinical hypertension, we hypothesized that endothelial disruption of Cx40 function in mice may create an animal model of this condition. To this end, we created mice in which a mutant Cx40T152A was expressed alongside wildtype Cx40 selectively in the endothelium. Expression of the Cx40T152A transgene in Xenopus oocytes and mouse coronary endothelial cells in vitro impaired both electric and chemical conductance and acted as a dominant-negative against wildtype Cx40, Cx43, and Cx45, but not Cx37. Endothelial expression of Cx40T152A in Cx40T152ATg mice attenuated ascending vasodilation, without effect on radial coupling through myoendothelial gap junctions. Using radiotelemetry, Cx40T152ATg mice showed an activity-dependent increase in blood pressure, which was significantly greater than in wildtype mice, but significantly less than in chronically hypertensive, Cx40knockout mice. The increase in heart rate with activity was also greater than in wildtype or Cx40knockout mice. We conclude that the endothelial Cx40T152A mutation attenuates activity-dependent vasodilation, producing a model of exercise-induced hypertension. These data highlight the importance of endothelial coupling through Cx40 in regulating blood pressure during activity. PMID:25547341

  15. Rescue Treatment with L-Citrulline Inhibits Hypoxia-Induced Pulmonary Hypertension in Newborn Pigs.

    PubMed

    Fike, Candice D; Dikalova, Anna; Kaplowitz, Mark R; Cunningham, Gary; Summar, Marshall; Aschner, Judy L

    2015-08-01

    Infants with cardiopulmonary disorders associated with hypoxia develop pulmonary hypertension. We previously showed that initiation of oral L-citrulline before and continued throughout hypoxic exposure improves nitric oxide (NO) production and ameliorates pulmonary hypertension in newborn piglets. Rescue treatments, initiated after the onset of pulmonary hypertension, better approximate clinical strategies. Mechanisms by which L-citrulline improves NO production merit elucidation. The objective of this study was to determine whether starting L-citrulline after the onset of pulmonary hypertension inhibits disease progression and improves NO production by recoupling endothelial NO synthase (eNOS). Hypoxic and normoxic (control) piglets were studied. Some hypoxic piglets received oral L-citrulline starting on Day 3 of hypoxia and continuing throughout the remaining 7 days of hypoxic exposure. Catheters were placed for hemodynamic measurements, and pulmonary arteries were dissected to assess NO production and eNOS dimer-to-monomer ratios (a measure of eNOS coupling). Pulmonary vascular resistance was lower in L-citrulline-treated hypoxic piglets than in untreated hypoxic piglets but was higher than in normoxic controls. NO production and eNOS dimer-to-monomer ratios were greater in pulmonary arteries from L-citrulline-treated than from untreated hypoxic animals but were lower than in normoxic controls. When started after disease onset, oral L-citrulline treatment improves NO production by recoupling eNOS and inhibits the further development of chronic hypoxia-induced pulmonary hypertension in newborn piglets. Oral L-citrulline may be a novel strategy to halt or reverse pulmonary hypertension in infants suffering from cardiopulmonary conditions associated with hypoxia. PMID:25536367

  16. Orotic acid induces hypertension associated with impaired endothelial nitric oxide synthesis.

    PubMed

    Choi, You-Jin; Yoon, Yujin; Lee, Kang-Yo; Kang, Yun-Pyo; Lim, Dong Kyu; Kwon, Sung Won; Kang, Keon-Wook; Lee, Seung-Mi; Lee, Byung-Hoon

    2015-04-01

    Orotic acid (OA) is an intermediate of pyrimidine nucleotide biosynthesis. Hereditary deficiencies in some enzymes associated with pyrimidine synthesis or the urea cycle induce OA accumulation, resulting in orotic aciduria. A link between patients with orotic aciduria and hypertension has been reported; however, the molecular mechanisms remain elusive. In this study, to elucidate the role of OA in vascular insulin resistance, we investigated whether OA induced endothelial dysfunction and hypertension. OA inhibited insulin- or metformin-stimulated nitric oxide (NO) production and endothelial NO synthase (eNOS) phosphorylation in human umbilical vein endothelial cells. A decreased insulin response by OA was mediated by impairment of the insulin-stimulated phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/Akt) signaling pathway in cells overexpressing the p110-PI3K catalytic subunit. Impaired effects of metformin on eNOS phosphorylation and NO production were reversed in cells transfected with constitutively active AMP-activated protein kinase. Moreover, experimental induction of orotic aciduria in rats caused insulin resistance, measured as a 125% increase in the homeostasis model assessment, and hypertension, measured as a 25% increase in systolic blood pressure. OA increased the plasma concentration of endothelin-1 by 201% and significantly inhibited insulin- or metformin-induced vasodilation. A compromised insulin or metformin response on the Akt/eNOS and AMP-activated protein kinase/eNOS pathway was observed in aortic rings of OA-fed rats. Taken together, we showed that OA induces endothelial dysfunction by contributing to vascular and systemic insulin resistance that affects insulin- or metformin-induced NO production, leading to the development of hypertension. PMID:25601987

  17. Role of the Na+/H+ exchanger 3 in angiotensin II-induced hypertension.

    PubMed

    Li, Xiao C; Shull, Gary E; Miguel-Qin, Elisa; Zhuo, Jia L

    2015-10-01

    The renal mechanisms responsible for angiotensin II (ANG II)-induced hypertension remain incompletely understood. The present study tested the hypothesis that the Na(+)/H(+) exchanger 3 (NHE3) is required for ANG II-induced hypertension in mice. Five groups of wild-type (Nhe3(+/+)) and Nhe3(-/-) mice were treated with vehicle or high pressor doses of ANG II (1.5 mg/kg/day ip, via minipump for 2 wk, or 10 pmol/min iv for 30 min). Under basal conditions, Nhe3(-/-) mice had significantly lower systolic blood pressure (SBP) and mean intra-arterial pressure (MAP) (P < 0.01), 24 h urine (P < 0.05), urinary Na(+) (P < 0.01) and urinary K(+) excretion (P < 0.01). In response to ANG II, SBP and MAP markedly increased in Nhe3(+/+) mice in a time-dependent manner, as expected (P < 0.01). However, these acute and chronic pressor responses to ANG II were significantly attenuated in Nhe3(-/-) mice (P < 0.01). Losartan blocked ANG II-induced hypertension in Nhe3(+/+) mice but induced marked mortality in Nhe3(-/-) mice. The attenuated pressor responses to ANG II in Nhe3(-/-) mice were associated with marked compensatory humoral and renal responses to genetic loss of intestinal and renal NHE3. These include elevated basal plasma ANG II and aldosterone and kidney ANG II levels, salt wasting from the intestines, increased renal AQP1, Na(+)/HCO3 (-), and Na(+)/K(+)-ATPase expression, and increased PKC?, mitogen-activated protein kinases ERK1/2, and glycogen synthase kinase 3?? signaling proteins in the proximal tubules (P < 0.01). We concluded that NHE3 in proximal tubules of the kidney, along with NHE3 in intestines, is required for maintaining basal blood pressure as well as the full development of ANG II-induced hypertension. PMID:26242933

  18. ?1-Adrenergic blockers exert antioxidant effects, reduce matrix metalloproteinase activity, and improve renovascular hypertension-induced cardiac hypertrophy.

    PubMed

    Rizzi, Elen; Guimaraes, Danielle A; Ceron, Carla S; Prado, Cibele M; Pinheiro, Lucas C; Martins-Oliveira, Alisson; Gerlach, Raquel F; Tanus-Santos, Jose E

    2014-08-01

    Hypertension induces left-ventricular hypertrophy (LVH) by mechanisms involving oxidative stress and unbalanced cardiac matrix metalloproteinase (MMP) activity. We hypothesized that ?1-adrenergic receptor blockers with antioxidant properties (nebivolol) could reverse hypertension-induced LVH more effectively than conventional ?1-blockers (metoprolol) when used at doses that exert similar antihypertensive effects. Two-kidney one-clip (2K1C) hypertension was induced in male Wistar rats. Six weeks after surgery, hypertensive and sham rats were treated with nebivolol (10 mg kg(-1)day(-1)) or metoprolol (20 mg kg(-1)day(-1)) for 4 weeks. Systolic blood pressure was monitored weekly by tail-cuff plethysmography. LV structural changes and fibrosis were studied in hematoxylin/eosin- and picrosirius-stained sections, respectively. Cardiac MMP levels and activity were determined by in situ zymography, gel zymography, and immunofluorescence. Dihydroethidium and lucigenin-derived chemiluminescence assays were used to assess cardiac reactive oxygen species (ROS) production. Nitrotyrosine levels were determined in LV samples by immunohistochemistry and green fluorescence and were evaluated using the ImageJ software. Cardiac protein kinase B/Akt (AKT) phosphorylation state was assessed by Western blot. Both ?-blockers exerted similar antihypertensive effects and attenuated hypertension-induced cardiac remodeling. Both drugs reduced myocyte hypertrophy and collagen deposition in 2K1C rats. These effects were associated with lower cardiac ROS and nitrotyrosine levels and attenuation of hypertension-induced increases in cardiac MMP-2 levels and in situ gelatinolytic activity after treatment with both ?-blockers. Whereas hypertension increased AKT phosphorylation, no effects were found with ?-blockers. In conclusion, we found evidence that two ?1-blockers with different properties attenuate hypertension-induced LV hypertrophy and cardiac collagen deposition in association with significant cardiac antioxidant effects and MMP-2 downregulation, thus suggesting a critical role for ?1-adrenergic receptors in mediating those effects. Nebivolol is not superior to metoprolol, at least with respect to their capacity to reverse hypertension-induced LVH. PMID:24933619

  19. Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice.

    PubMed

    Cero, Fadila Telarevic; Hillestad, Vigdis; Sjaastad, Ivar; Yndestad, Arne; Aukrust, Pål; Ranheim, Trine; Lunde, Ida Gjervold; Olsen, Maria Belland; Lien, Egil; Zhang, Lili; Haugstad, Solveig Bjærum; Løberg, Else Marit; Christensen, Geir; Larsen, Karl-Otto; Skjønsberg, Ole Henning

    2015-08-15

    Pulmonary hypertension is a serious condition that can lead to premature death. The mechanisms involved are incompletely understood although a role for the immune system has been suggested. Inflammasomes are part of the innate immune system and consist of the effector caspase-1 and a receptor, where nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) is the best characterized and interacts with the adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC). To investigate whether ASC and NLRP3 inflammasome components are involved in hypoxia-induced pulmonary hypertension, we utilized mice deficient in ASC and NLRP3. Active caspase-1, IL-18, and IL-1β, which are regulated by inflammasomes, were measured in lung homogenates in wild-type (WT), ASC(-/-), and NLRP3(-/-) mice, and phenotypical changes related to pulmonary hypertension and right ventricular remodeling were characterized after hypoxic exposure. Right ventricular systolic pressure (RVSP) of ASC(-/-) mice was significantly lower than in WT exposed to hypoxia (40.8 ± 1.5 mmHg vs. 55.8 ± 2.4 mmHg, P < 0.001), indicating a substantially reduced pulmonary hypertension in mice lacking ASC. Magnetic resonance imaging further supported these findings by demonstrating reduced right ventricular remodeling. RVSP of NLRP3(-/-) mice exposed to hypoxia was not significantly altered compared with WT hypoxia. Whereas hypoxia increased protein levels of caspase-1, IL-18, and IL-1β in WT and NLRP3(-/-) mice, this response was absent in ASC(-/-) mice. Moreover, ASC(-/-) mice displayed reduced muscularization and collagen deposition around arteries. In conclusion, hypoxia-induced elevated right ventricular pressure and remodeling were attenuated in mice lacking the inflammasome adaptor protein ASC, suggesting that inflammasomes play an important role in the pathogenesis of pulmonary hypertension. PMID:26071556

  20. Brain-mediated dysregulation of the bone marrow activity in angiotensin II-induced hypertension.

    PubMed

    Jun, Joo Yun; Zubcevic, Jasenka; Qi, Yanfei; Afzal, Aqeela; Carvajal, Jessica Marulanda; Thinschmidt, Jeffrey S; Grant, Maria B; Mocco, J; Raizada, Mohan K

    2012-11-01

    Oxidative stress in the brain is implicated in increased sympathetic drive, inflammatory status, and vascular dysfunctions, associated with development and establishment of hypertension. However, little is known about the mechanism of this impaired brain-vascular communication. Here, we tested the hypothesis that increased oxidative stress in the brain cardioregulatory areas, such as the paraventricular nucleus of the hypothalamus, is driven by mitochondrial reactive oxygen species and leads to increased inflammatory cells (ICs) and decreased/dysfunctional endothelial progenitor cells (EPCs), thereby compromising vasculature repair and accelerating hypertension. Chronic angiotensin II infusion resulted in elevated blood pressure and sympathetic vasomotor drive, decreased spontaneous baroreflex gain, and increased microglia activation in the paraventricular nucleus. This was associated with 46% decrease in bone marrow (BM)-derived EPCs and 250% increase in BM ICs, resulting in 5-fold decrease of EPC/IC ratio in the BM. Treatment with mitochondrial-targeted antioxidant, a scavenger of mitochondrial O(2)(-·), intracerebroventricularly but not subcutaneously attenuated angiotensin II-induced hypertension, decreased activation of microglia in the paraventricular nucleus, and normalized EPCs/ICs. This functional communication between the brain and BM was confirmed by retrograde neuronal labeling from the BM with green fluorescent protein-tagged pseudorabies virus. Administration of green fluorescent protein-tagged pseudorabies virus into the BM resulted in predominant labeling of paraventricular nucleus neurons within 3 days, with some fluorescence in the nucleus tractus solitarius, the rostral ventrolateral medulla, and subfornical organ. Taken together, these data demonstrate that inhibition of mitochondrial reactive oxygen species attenuates angiotensin II-induced hypertension and corrects the imbalance in EPCs/ICs in the BM. They suggest that an imbalance in vascular reparative and ICs may perpetuate vascular pathophysiology in this model of hypertension. PMID:23045460

  1. Oxygen radicals and substance P in perinatal hypoxia-exaggerated, monocrotaline-induced pulmonary hypertension.

    PubMed

    Chen, Kang-Hua; Lai, Yih-Loong; Chen, Mei-Jung

    2012-04-30

    Perinatal hypoxia has been observed to cause more aggressive pulmonary hypertension in human. Several mediators such as reactive oxygen species (ROS) and substance P are believed to be crucial in the mechanism of inducing pulmonary hypertension. This study was designed to test whether substance P and ROS play a role in perinatal hypoxia-exaggerated, monocrotaline (MCT)-induced pulmonary hypertension. Normoxic Wistar rats (weighing 258 9 g, n = 31) were divided into two groups: control (n = 16) and MCT (n = 15). Perinatal hypoxia Wistar rats (weighing 260 19 g, n = 49) were divided into six groups: Hypoxia (n = 8), Hypoxia+MCT (n = 8), Hypoxia+capsaicin (CP)+MCT (n = 7), Hypoxia+MCT+1,3-dimethyl-2-thiourea (DMTU)E (n = 10), Hypoxia+MCT+DMTUL (n = 9), and Hypoxia+MCT+ hexa(sulfobutyl) fullerenes (HSF) (n = 7). Rats in the control group received saline injections. MCT (60 mg/kg, s.c.) was given three weeks prior to the functional examination. Chronic capsaicin pretreatment was performed to deplete substance P. Hydroxyl radical scavenger DMTU (500 mg/kg) was intraperitoneally (i.p.) injected early (DMTUE ) or late (DMTUL ) after MCT. Antioxidant HSF (10 mg/kg, i.p.) was given once daily for three weeks following MCT. MCT treatment caused significant increases in pulmonary arterial pressure (Ppa) and substance P level in lung tissue in normoxic rats. The MCT-induced increase in pulmonary arterial blood pressure was exaggerated by perinatal hypoxia, but this exaggeration was attenuated by either capsaicin pretreatment or antioxidant administrations. These results suggest that both ROS and substance P are involved in perinatal hypoxia-augmented, MCT-induced pulmonary hypertension. PMID:22559732

  2. Central overexpression of the TRH precursor gene induces hypertension in rats: antisense reversal.

    PubMed

    Garca, S I; Porto, P I; Alvarez, A L; Martinez, V N; Shaurli, D; Finkielman, S; Pirola, C J

    1997-09-01

    Extrahypothalamic TRH participates in cardiovascular regulation and spontaneous hypertension of the rat. To investigate whether an increase in central TRH activity produces hypertension we studied the effect of the preTRH overproduction induced by I.C.V. transfection with a naked eukaryotic expression plasmid vector which encodes preTRH (pCMV-TRH). Northern blot analysis and RT-PCR showed that pCMV-TRH was transcribed in vitro and in vivo. At 24, 48, and 72 hours, pCMV-TRH (100 microg) in a significant and dose-dependent manner increased 37%, 84%, and 49%, respectively, the diencephalic TRH content and SABP (42+/-3, 50+/-2, and 22+/-2 mm Hg, respectively) with respect to the vector without the preTRH cDNA insert (V[TRH(-)]) as measured by RIA and the plethysmographic method, respectively, in awake animals. In addition, using immunohistochemistry we found that the increase of TRH was produced in circumventricular areas where the tripeptide is normally located. To further analyze the specificity of these effects we studied the actions of 23-mer sense (S), antisense (AS), and 3'self-stabilized sense (Ss) and antisense (ASs) phosphorothioate oligonucleotides against the initiation codon region. Only ASs inhibited the increase of TRH content and SABP induced by pCMV-TRH treatment. In addition, pCMV-TRH-induced hypertension seems not to be mediated by central Ang II or serum TSH. To summarize, central TRH overproduction in periventricular areas induced by I.C.V. transfection produces hypertension in rats which is reversed by specific antisense treatment. This model may help in testing effective antisense oligodeoxynucleotides against other candidate genes. PMID:9323019

  3. Experimental TIPS with spiral Z-stents in swine with and without induced portal hypertension

    SciTech Connect

    Kichikawa, Kimihiko; Saxon, Richard R.; Nishimine, Kiyoshi; Nishida, Norifumi; Uchida, Barry T.

    1997-05-15

    Purpose. To assess the suitability of spiral Z-stents for transjugular intrahepatic portosystemic shunt (TIPS) and the influence of portal hypertension on shunt patency in young swine. Methods. TIPS were established using spiral Z-stents in 14 domestic swine. In 7 animals, the portal venous pressure was normal; in the other 7, acute portal hypertension was induced by embolization of portal vein branches. Follow-up portal venography and histologic evaluations were done from 1 hr to 12 weeks after TIPS. Results. Follow-up transhepatic portal venograms showed progressive narrowing of the shunt, most priminent in the midportion of the tract. Ingrowth of liver parenchyma between the stent wires found after 3 weeks led to progressive shunt narrowing and shunt occlusion by 12 weeks. A pseudointima grew rapidly inside the stent, peaked in thickness around 4 weeks, and decreased later. Acutely created portal hypertension rapidly returned to normal and there was no difference in TIPS patency between the two groups of animals. Conclusion. Although the spiral Z-stent can be used as a device for creation of TIPS in patients with cirrhotic livers, it is associated with extensive liver ingrowth in swine that leads to rapid shunt occlusion. Portal hypertension was only transient in this model.

  4. Tetrahydrocurcumin Protects against Cadmium-Induced Hypertension, Raised Arterial Stiffness and Vascular Remodeling in Mice

    PubMed Central

    Sangartit, Weerapon; Kukongviriyapan, Upa; Donpunha, Wanida; Pakdeechote, Poungrat; Kukongviriyapan, Veerapol; Surawattanawan, Praphassorn; Greenwald, Stephen E.

    2014-01-01

    Background Cadmium (Cd) is a nonessential heavy metal, causing oxidative damage to various tissues and associated with hypertension. Tetrahydrocurcumin (THU), a major metabolite of curcumin, has been demonstrated to be an antioxidant, anti-diabetic, anti-hypertensive and anti-inflammatory agent. In this study, we investigated the protective effect of THU against Cd-induced hypertension, raised arterial stiffness and vascular remodeling in mice. Methods Male ICR mice received CdCl2 (100 mg/l) via drinking water for 8 weeks. THU was administered intragastrically at dose of 50 or 100 mg/kg/day concurrently with Cd treatment. Results Administration of CdCl2 significantly increased arterial blood pressure, blunted vascular responses to vasoactive agents, increased aortic stiffness, and induced hypertrophic aortic wall remodeling by increasing number of smooth muscle cells and collagen deposition, decreasing elastin, and increasing matrix metalloproteinase (MMP)-2 and MMP-9 levels in the aortic medial wall. Supplementation with THU significantly decreased blood pressure, improved vascular responsiveness, and reversed the structural and mechanical alterations of the aortas, including collagen and elastin deposition. The reduction on the adverse response of Cd treatment was associated with upregulated eNOS and downregulated iNOS protein expressions, increased nitrate/nitrite level, alleviated oxidative stress and enhanced antioxidant glutathione. Moreover, THU also reduced the accumulation of Cd in the blood and tissues. Conclusions Our results suggest that THU ameliorates cadmium-induced hypertension, vascular dysfunction, and arterial stiffness in mice through enhancing NO bioavailability, attenuating oxidative stress, improving vascular remodeling and decreasing Cd accumulation in other tissues. THU has a beneficial effect in moderating the vascular alterations associated with Cd exposure. PMID:25502771

  5. Carbonyl stress induces hypertension and cardio–renal vascular injury in Dahl salt-sensitive rats

    PubMed Central

    Chen, Xianguang; Mori, Takefumi; Guo, Qi; Hu, Chunyan; Ohsaki, Yusuke; Yoneki, Yoshimi; Zhu, Wanjun; Jiang, Yue; Endo, Satoshi; Nakayama, Keisuke; Ogawa, Susumu; Nakayama, Masaaki; Miyata, Toshio; Ito, Sadayoshi

    2013-01-01

    One major precursor of carbonyl stress, methylglyoxal (MG), is elevated in the plasma of chronic kidney disease (CKD) patients, and this precursor contributes to the progression of vascular injury, hypertension and renal injury in diabetic nephropathy patients. This molecule induces salt-sensitive hypertension via a reactive oxygen species-mediated pathway. We examined the role of MG in the pathogenesis of hypertension and cardio–renal injury in Dahl salt-sensitive (Dahl S) rats, which is a rat model of CKD. Nine-week-old Dahl S rats were fed a 1% NaCl diet, and 1% MG was added to their drinking water for up to 12 weeks. Blood pressure and cardio–renal injuries were compared with rats treated with tap water alone. The angiotensin II receptor blocker (ARB), candesartan (10 mg kg−1 day−1), was administered to MG Dahl S rats to determine the impact of this drug on the pathogenesis of MG-induced CKD. A progressive increase in systolic blood pressure was observed (123±1–148±5 mm Hg) after 12 weeks of MG administration. MG administration significantly increased urinary albumin excretion, glomerular sclerosis, tubular injury, myocardial collagen content and cardiac perivascular fibrosis. MG also enhanced the renal expression of Nɛ-carboxyethyl-lysine (an advanced glycation end product), 8-hydroxydeoxyguanosine (a marker of oxidative stress), macrophage (ED-1) positive cells (a marker of inflammation) and nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase activity. Candesartan treatment for 4 weeks significantly reduced these parameters. These results suggest that MG-induced hypertension and cardio–renal injury and increased inflammation and carbonyl and oxidative stress, which were partially preventable by an ARB. PMID:23364337

  6. Neuroinflammation and oxidative stress in rostral ventrolateral medulla contribute to neurogenic hypertension induced by systemic inflammation

    PubMed Central

    2012-01-01

    Background In addition to systemic inflammation, neuroinflammation in the brain, which enhances sympathetic drive, plays a significant role in cardiovascular diseases, including hypertension. Oxidative stress in rostral ventrolateral medulla (RVLM) that augments sympathetic outflow to blood vessels is involved in neural mechanism of hypertension. We investigated whether neuroinflammation and oxidative stress in RVLM contribute to hypertension following chronic systemic inflammation. Methods In normotensive Sprague-Dawley rats, systemic inflammation was induced by infusion of Escherichia coli lipopolysaccharide (LPS) into the peritoneal cavity via an osmotic minipump. Systemic arterial pressure and heart rate were measured under conscious conditions by the non-invasive tail-cuff method. The level of the inflammatory markers in plasma or RVLM was analyzed by ELISA. Protein expression was evaluated by Western blot or immunohistochemistry. Tissue level of superoxide anion (O2·-) in RVLM was determined using the oxidation-sensitive fluorescent probe dihydroethidium. Pharmacological agents were delivered either via infusion into the cisterna magna with an osmotic minipump or microinjection bilaterally into RVLM. Results Intraperitoneal infusion of LPS (1.2 mg/kg/day) for 14 days promoted sustained hypertension and induced a significant increase in plasma level of C-reactive protein, tumor necrosis factor-α (TNF-α), or interleukin-1β (IL-1β). This LPS-induced systemic inflammation was accompanied by activation of microglia, augmentation of IL-1β, IL-6, or TNF-α protein expression, and O2·- production in RVLM, all of which were blunted by intracisternal infusion of a cycloxygenase-2 (COX-2) inhibitor, NS398; an inhibitor of microglial activation, minocycline; or a cytokine synthesis inhibitor, pentoxifylline. Neuroinflammation in RVLM was also associated with a COX-2-dependent downregulation of endothelial nitric oxide synthase and an upregulation of intercellular adhesion molecule-1. Finally, the LPS-promoted long-term pressor response and the reduction in expression of voltage-gated potassium channel, Kv4.3 in RVLM were antagonized by minocycline, NS398, pentoxifylline, or a superoxide dismutase mimetic, tempol, either infused into cisterna magna or microinjected bilaterally into RVLM. The same treatments, on the other hand, were ineffective against LPS-induced systemic inflammation. Conclusion These results suggest that systemic inflammation activates microglia in RVLM to induce COX-2-dependent neuroinflammation that leads to an increase in O2·- production. The resultant oxidative stress in RVLM in turn mediates neurogenic hypertension. PMID:22958438

  7. Oral oestrogen reverses ovariectomy-induced morning surge hypertension in growth-restricted mice.

    PubMed

    Haskell, Sarah E; Peotta, Veronica; Reinking, Benjamin E; Zhang, Catherine; Zhu, Vivian; Kenkel, Elizabeth J; Roghair, Robert D

    2016-04-01

    Perinatal growth restriction (GR) is associated with heightened sympathetic tone and hypertension. We have previously shown that naturally occurring neonatal GR programmes hypertension in male but not female mice. We therefore hypothesized that intact ovarian function or post-ovariectomy (OVX) oestrogen administration protects GR female mice from hypertension. Utilizing a non-interventional model that categorizes mice with weanling weights below the tenth percentile as GR, control and GR adult mice were studied at three distinct time points: baseline, post-OVX and post-OVX with oral oestrogen replacement. OVX elicited hypertension in GR mice that was significantly exacerbated by psychomotor arousal (systolic blood pressure at light to dark transition: control 122±2; GR 119±2; control-OVX 116±3; GR-OVX 126±3 mmHg). Oestrogen partially normalized the rising blood pressure surge seen in GR-OVX mice (23±7% reduction). GR mice had left ventricular hypertrophy, and GR-OVX mice in particular had exaggerated bradycardic responses to sympathetic blockade. For GR mice, a baseline increase in baroreceptor reflex sensitivity and high frequency spectral power support a vagal compensatory mechanism, and that compensation was lost following OVX. For GR mice, the OVX-induced parasympathetic withdrawal was partially restored by oestrogen (40±25% increase in high frequency spectral power, P<0.05). In conclusion, GR alters cardiac morphology and cardiovascular regulation. The haemodynamic consequences of GR are attenuated in ovarian-sufficient or oestrogen-replete females. Further investigations are needed to define the role of hormone replacement therapy targeted towards young women with oestrogen deficiency and additional cardiovascular risk factors, including perinatal GR, cardiac hypertrophy and morning surge hypertension. PMID:26795436

  8. Hypoxia inducible factor signaling and experimental persistent pulmonary hypertension of the newborn

    PubMed Central

    Wedgwood, Stephen; Lakshminrusimha, Satyan; Schumacker, Paul T.; Steinhorn, Robin H.

    2015-01-01

    Background: Mitochondrial reactive oxygen species (ROS) levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) activity are increased in a lamb model of persistent pulmonary hypertension of the newborn (PPHN). These events can trigger hypoxia inducible factor (HIF) signaling in response to hypoxia, which has been shown to contribute to pulmonary vascular remodeling in rodent models of pulmonary hypertension. However, the role of HIF signaling in chronic intrauterine pulmonary hypertension is not well understood. Aim: To determine if HIF signaling is increased in the lamb model of PPHN, and to identify the underlying mechanisms. Results: PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs and pulmonary artery smooth muscle cells (PASMC) were isolated from control and PPHN lambs. HIF-1α expression was increased in PPHN lungs and HIF activity was increased in PPHN PASMC relative to controls. Hypoxia increased HIF activity to a greater degree in PPHN vs. control PASMC. Control PASMC were exposed to cyclic stretch at 1 Hz and 15% elongation for 24 h, as an in vitro model of vascular stress. Stretch increased HIF activity, which was attenuated by inhibition of mitochondrial complex III and NFκB. Conclusion: Increased HIF signaling in PPHN is triggered by stretch, via mechanisms involving mitochondrial ROS and NFκB. Hypoxia substantially amplifies HIF activity in PPHN vascular cells. Targeting these signaling molecules may attenuate and reverse pulmonary vascular remodeling associated with PPHN. PMID:25814954

  9. Absolute immature platelet count helps differentiate thrombotic thrombocytopenic purpura from hypertension-induced thrombotic microangiopathy.

    PubMed

    Zheng, Yan; Hong, Hong; Reeves, Hollie M; Maitta, Robert W

    2014-08-01

    ADAMTS13 activity measurement is used in the diagnostic algorithm of thrombotic thrombocytopenic purpura (TTP), but results may not be available before initiation of therapeutic plasma exchange (TPE). The immature platelet fraction (%-IPF) and the calculated absolute immature platelet count (A-IPC) represent a test of real-time thrombopoiesis, and can be performed in most laboratories using automated analyzers. Here we report on using A-IPC kinetics to exclude idiopathic TTP in a patient with severe hypertension, thrombocytopenia, and acute renal failure, which was confirmed by a normal ADAMTS13. The complete resolution of thrombocytopenia occurred once blood pressure was controlled favoring a diagnosis of hypertension-induced thrombotic microangiopathy. PMID:25130726

  10. Improvement of vascular insulin sensitivity by downregulation of GRK2 mediates exercise-induced alleviation of hypertension in spontaneously hypertensive rats.

    PubMed

    Xing, Wenjuan; Li, Youyou; Zhang, Haifeng; Mi, Chunjuan; Hou, Zuoxu; Quon, Michael J; Gao, Feng

    2013-10-15

    Exercise training lowers blood pressure and is a recommended nonpharmacological strategy and useful adjunctive therapy for hypertensive patients. Studies demonstrate that physical activity attenuates progression of hypertension. However, underlying mechanisms remain elusive. Vascular insulin resistance and endothelial dysfunction plays a critical role in the development of hypertension. The present study investigated whether long-term physical exercise starting during the prehypertensive period prevents the development of hypertension via improving vascular insulin sensitivity. Young (4 wk old) prehypertensive spontaneously hypertensive rats (SHRs) and their normotensive Wistar-Kyoto (WKY) control rats were subjected to a 10-wk free-of-loading swim training session (60 min/day, 5 days/wk). Blood pressure, mesenteric arteriolar vasorelaxation, G protein-coupled receptor kinase-2 (GRK2) expression and activity, and insulin-stimulated Akt/endothelial nitric oxide synthase (eNOS) activation were determined. SHRs had higher systolic blood pressure, systemic insulin resistance, and impaired vasodilator actions of insulin in resistance vessels when compared with WKY rats. Systolic blood pressure in SHRs postexercise was significantly lower than that in sedentary rats. Vascular insulin sensitivity in mesenteric arteries was improved after exercise training as evidenced by an increased vasodilator response to insulin. In addition, exercise downregulated vascular GRK2 expression and activity, which further increased insulin-stimulated vascular Akt/eNOS activation in exercised SHRs. Specific small interfering RNA knockdown of GRK2 in endothelium mimicked the effect of exercise-enhanced vascular insulin sensitivity. Likewise, upregulation of GRK2 by Chariot-mediated delivery opposed exercise-induced vascular insulin sensitization. Taken together, our results suggest that long-term exercise beginning at the prehypertensive stage improves vascular insulin sensitivity via downregulation of vascular GRK2 that may help to limit the progression of hypertension. PMID:23913704

  11. Improvement of vascular insulin sensitivity by downregulation of GRK2 mediates exercise-induced alleviation of hypertension in spontaneously hypertensive rats

    PubMed Central

    Xing, Wenjuan; Li, Youyou; Zhang, Haifeng; Mi, Chunjuan; Hou, Zuoxu; Quon, Michael J.

    2013-01-01

    Exercise training lowers blood pressure and is a recommended nonpharmacological strategy and useful adjunctive therapy for hypertensive patients. Studies demonstrate that physical activity attenuates progression of hypertension. However, underlying mechanisms remain elusive. Vascular insulin resistance and endothelial dysfunction plays a critical role in the development of hypertension. The present study investigated whether long-term physical exercise starting during the prehypertensive period prevents the development of hypertension via improving vascular insulin sensitivity. Young (4 wk old) prehypertensive spontaneously hypertensive rats (SHRs) and their normotensive Wistar-Kyoto (WKY) control rats were subjected to a 10-wk free-of-loading swim training session (60 min/day, 5 days/wk). Blood pressure, mesenteric arteriolar vasorelaxation, G protein-coupled receptor kinase-2 (GRK2) expression and activity, and insulin-stimulated Akt/endothelial nitric oxide synthase (eNOS) activation were determined. SHRs had higher systolic blood pressure, systemic insulin resistance, and impaired vasodilator actions of insulin in resistance vessels when compared with WKY rats. Systolic blood pressure in SHRs postexercise was significantly lower than that in sedentary rats. Vascular insulin sensitivity in mesenteric arteries was improved after exercise training as evidenced by an increased vasodilator response to insulin. In addition, exercise downregulated vascular GRK2 expression and activity, which further increased insulin-stimulated vascular Akt/eNOS activation in exercised SHRs. Specific small interfering RNA knockdown of GRK2 in endothelium mimicked the effect of exercise-enhanced vascular insulin sensitivity. Likewise, upregulation of GRK2 by Chariot-mediated delivery opposed exercise-induced vascular insulin sensitization. Taken together, our results suggest that long-term exercise beginning at the prehypertensive stage improves vascular insulin sensitivity via downregulation of vascular GRK2 that may help to limit the progression of hypertension. PMID:23913704

  12. Selective Inactivation of PTEN in Smooth Muscle Cells Synergizes With Hypoxia to Induce Severe Pulmonary Hypertension

    PubMed Central

    Horita, Henrick; Furgeson, Seth B.; Ostriker, Allison; Olszewski, Kyle A.; Sullivan, Timothy; Villegas, Leah R.; Levine, Michelle; Parr, Jane E.; Cool, Carlyne D.; Nemenoff, Raphael A.; Weiser‐Evans, Mary C. M.

    2013-01-01

    Background Pulmonary vascular remodeling in pulmonary hypertension (PH) is characterized by increased vascular smooth muscle cell (SMC) and adventitial fibroblast proliferation, small vessel occlusion, and inflammatory cell accumulation. The underlying molecular mechanisms driving progression remain poorly defined. We have focused on loss of the phosphatase PTEN in SMCs as a major driver of pathological vascular remodeling. Our goal was to define the role of PTEN in human PH and in hypoxia‐induced PH using a mouse model with inducible deletion of PTEN in SMCs. Methods and Results Staining of human biopsies demonstrated enhanced inactive PTEN selectively in the media from hypertensive patients compared to controls. Mice with induced deletion of PTEN in SMCs were exposed to normoxia or hypoxia for up to 4 weeks. Under normoxia, SMC PTEN depletion was sufficient to induce features of PH similar to those observed in wild‐type mice exposed to chronic hypoxia. Under hypoxia, PTEN depletion promoted an irreversible progression of PH characterized by increased pressure, extensive pulmonary vascular remodeling, formation of complex vascular lesions, and increased macrophage accumulation associated with synergistic increases in proinflammatory cytokines and proliferation of both SMCs and nonSMCs. Conclusions Chronic inactivation of PTEN selectively in SMC represents a critical mediator of PH progression, leading to cell autonomous events and increased production of factors correlated to proliferation and recruitment of adventitial and inflammatory cells, resulting in irreversible progression of the disease. PMID:23727701

  13. Pyk2 aggravates hypoxia-induced pulmonary hypertension by activating HIF-1?.

    PubMed

    Fukai, Kuniyoshi; Nakamura, Akihiro; Hoshino, Atsushi; Nakanishi, Naohiko; Okawa, Yoshifumi; Ariyoshi, Makoto; Kaimoto, Satoshi; Uchihashi, Motoki; Ono, Kazunori; Tateishi, Shuhei; Ikeda, Koji; Ogata, Takehiro; Ueyama, Tomomi; Matoba, Satoaki

    2015-04-15

    Pulmonary arterial hypertension (PAH) is a refractory disease characterized by uncontrolled vascular remodeling and elevated pulmonary arterial pressure. Although synthetic inhibitors of some tyrosine kinases have been used to treat PAH, their therapeutic efficacies and safeties remain controversial. Thus, the establishment of novel therapeutic targets based on the molecular pathogenesis underlying PAH is a clinically urgent issue. In the present study, we demonstrated that proline-rich tyrosine kinase 2 (Pyk2), a nonreceptor type protein tyrosine kinase, plays a crucial role in the pathogenesis of pulmonary hypertension (PH) using an animal model of hypoxia-induced PH. Resistance to hypoxia-induced PH was markedly higher in Pyk2-deficient mice than in wild-type mice. Pathological investigations revealed that medial thickening of the pulmonary arterioles, which is a characteristic of hypoxia-induced PH, was absent in Pyk2-deficient mice, suggesting that Pyk2 is involved in the hypoxia-induced aberrant proliferation of vascular smooth muscle cells in hypoxia-induced PH. In vitro experiments using human pulmonary smooth muscle cells showed that hypoxic stress increased the proliferation and migration of cells in a Pyk2-dependent manner. We also demonstrated that Pyk2 plays a crucial role in ROS generation during hypoxic stress and that this Pyk2-dependent generation of ROS is necessary for the activation of hypoxia-inducible factor-1?, a key molecule in the pathogenesis of hypoxia-induced PH. In summary, the results of the present study reveal that Pyk2 plays an important role in the pathogenesis of hypoxia-induced PH. Therefore, Pyk2 may represent a promising therapeutic target for PAH in a clinical setting. PMID:25659487

  14. Melatonin attenuates hypertension-induced renal injury partially through inhibiting oxidative stress in rats

    PubMed Central

    QIAO, YU-FENG; GUO, WEN-JUAN; LI, LU; SHAO, SHAN; QIAO, XI; SHAO, JIN-JIN; ZHANG, QIONG; LI, RONG-SHAN; WANG, LI-HUA

    2016-01-01

    The aim of the present study was to investigate the protective effects of melatonin (MLT) on hypertension-induced renal injury and identify its mechanism of action. Twenty-four healthy male Wistar rats were divided into a sham control group (n=8), which was subjected to sham operation and received vehicle treatment (physiological saline intraperitoneally at 0.1 ml/100 g), a vehicle group (n=8), which was subjected to occlusion of the left renal artery and vehicle treatment, and the MLT group (n=8), which was subjected to occlusion of the left renal artery and treated with MLT (10 mg/kg/day). Pathological features of the renal tissues were determined using hematoxylin and eosin staining and Masson staining. Urine protein, serum creatinine (Scr), superoxide dismutase (SOD) and malondialdehyde (MDA) were determined. Immunohistochemical analysis was performed to determine the expression of heme oxygenase-1 (HO-1), intercellular adhesion molecule-1 (ICAM-1), inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS). Furthermore, reverse transcription polymerase chain reaction was conducted to determine the mRNA expression of HO-1, ICAM-1, eNOS and iNOS. A marked decrease in blood pressure was noticed in the MLT group at week 4 compared with that of the vehicle group (P<0.01). Furthermore, MLT treatment attenuated the infiltration of inflammatory cells and oedema/atrophy of renal tubules. MLT attenuated hypertension-induced increases in urine protein excretion, serum creatinine and MDA as well as decreases in SOD activity in renal tissues. Furthermore, MLT attenuated hypertension-induced increases in iNOS and ICAM-1 as well as decreases in eNOS and HO-1 expression at the mRNA and protein level. In conclusion, the results of the present study indicated that MLT had protective roles in hypertension-induced renal injury. Its mechanism of action is, at least in part, associated with the inhibition of oxidative stress. PMID:26531807

  15. Melatonin attenuates hypertension-induced renal injury partially through inhibiting oxidative stress in rats.

    PubMed

    Qiao, Yu-Feng; Guo, Wen-Juan; Li, Lu; Shao, Shan; Qiao, Xi; Shao, Jin-Jin; Zhang, Qiong; Li, Rong-Shan; Wang, Li-Hua

    2016-01-01

    The aim of the present study was to investigate the protective effects of melatonin (MLT) on hypertension-induced renal injury and identify its mechanism of action. Twenty-four healthy male Wistar rats were divided into a sham control group (n=8), which was subjected to sham operation and received vehicle treatment (physiological saline intraperitoneally at 0.1ml/100g), a vehicle group (n=8), which was subjected to occlusion of the left renal artery and vehicle treatment, and the MLT group (n=8), which was subjected to occlusion of the left renal artery and treated with MLT (10mg/kg/day). Pathological features of the renal tissues were determined using hematoxylin and eosin staining and Masson staining. Urine protein, serum creatinine (Scr), superoxide dismutase (SOD) and malondialdehyde (MDA) were determined. Immunohistochemical analysis was performed to determine the expression of heme oxygenase?1 (HO?1), intercellular adhesion molecule?1 (ICAM?1), inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS). Furthermore, reverse transcription polymerase chain reaction was conducted to determine the mRNA expression of HO?1, ICAM?1, eNOS and iNOS. A marked decrease in blood pressure was noticed in the MLT group at week4 compared with that of the vehicle group (P<0.01). Furthermore, MLT treatment attenuated the infiltration of inflammatory cells and oedema/atrophy of renal tubules. MLT attenuated hypertension-induced increases in urine protein excretion, serum creatinine and MDA as well as decreases in SOD activity in renal tissues. Furthermore, MLT attenuated hypertension-induced increases in iNOS and ICAM?1 as well as decreases in eNOS and HO?1 expression at the mRNA and protein level. In conclusion, the results of the present study indicated that MLT had protective roles in hypertension?induced renal injury. Its mechanism of action is, at least in part, associated with the inhibition of oxidative stress. PMID:26531807

  16. Contribution of mitochondrial function to exercise-induced attenuation of renal dysfunction in spontaneously hypertensive rats.

    PubMed

    Gu, Qi; Zhao, Li; Ma, Yan-Ping; Liu, Jian-Dong

    2015-08-01

    It is well known that exercise training exhibits renal protective effects in animal models of hypertension and chronic renal failure. However, the mechanisms regulating these effects of exercise training remain unclear. This study aimed to investigate the role of mitochondrial function in exercise-induced attenuation of renal injury in spontaneously hypertensive rats (SHR). The adult male SHR and age-matched normotensive Wistar-Kyoto rats (WKY) were given moderate-intensity exercise for 12 weeks or treated with MitoQ10 for 8 weeks. In this work, exercise training in SHR reduced blood pressure, and effectively attenuated renal dysfunction, marked by reduced creatinine excretion, albuminuria, blood urea nitrogen, and glomerular sclerosis. Exercise training in SHR reduced MDA levels in plasma and kidneys and suppressed formation of 3-nitrotyrosine in kidneys. Exercise training suppressed mitochondrial ROS and [Formula: see text] formation, enhanced ATP formation, reduced mitochondrial swelling, and restored electron transport chain enzyme activity in kidneys of SHR. Furthermore, exercise training upregulated protein expression of uncoupling protein 2 and manganese superoxide dismutase in kidneys of SHR. In addition, treatment with mitochondria-targeted antioxidant MitoQ10 exhibited similar renal protective effects in SHR. In conclusion, chronic aerobic exercise training preserved mitochondrial function and abated oxidative stress in the kidneys of SHR, which may in part explain the protective effect of exercise on renal function and structure in hypertensive individuals. PMID:25963667

  17. Does copper enhance the antihypertensive effect of Elaeocarpus ganitrus in experimentally induced hypertensive rats?

    PubMed Central

    Barve, Kalyani H; Chodankar, Rahul

    2014-01-01

    Ayurveda, one of the traditional systems of medicine of India, reports that the seeds of Elaeocarpus ganitrus Linn. (Tilaceae) can be used for the treatment of hypertension. The main aim is to evaluate the antihypertensive effect of Elaeocarpus ganitrus (Rudraksha) seeds. Powdered seeds were extracted by maceration, overnight, using water, in copper (E1) and glass vessel (E2) and analyzed for antihypertensive activity in cadmium chloride (1 mg/kg intraperitoneally, for a period of 15 days) induced hypertensive male Wistar rats at three dose levels. E1 was administered at the dose of 5, 10, and 15 mg/kg and E2 at dose of 10, 20, and 30 mg/kg. All the data were analyzed using one way analysis of variance (ANOVA) followed by Dunnett's multiple comparison test. E1 and E2 did not show any toxicity at the dose of 5 g/kg in rats. It was found that 15 mg/kg of E1 and 30 mg/kg of E2 decreases the blood pressure by 30.20 mmHg and 28.96 mmHg, respectively, in hypertensive rats. Thus, it can be said that 15 mg/kg of E1 produced similar decrease in blood pressure as was observed with 30 mg/kg of E2. Copper ions in E1 might be additively affecting the reduction in blood pressure with the usage of Elaeocarpus ganitrus extracts. PMID:24948856

  18. Manganese porphyrin reduces retinal injury induced by ocular hypertension in rats.

    PubMed

    Dogan, Serdar; Unal, Mustafa; Ozturk, Nihal; Yargicoglu, Piraye; Cort, Aysegul; Spasojevic, Ivan; Batinic-Haberle, Ines; Aslan, Mutay

    2011-10-01

    This study aimed to clarify the possible therapeutic benefit of preferential nitric oxide synthase (NOS) inhibition and catalytic antioxidant Mn (III) meso-tetrakis (N-n-hexylpyridinium-2-yl) porphyrin (MnTnHex-2-PyP(5+)) treatment in a rat model of elevated intraocular pressure (EIOP). Rats were randomly divided into different experimental groups which received either intraperitoneal MnTnHex-2-PyP(5+) (0.1mg/kg/day), intragastric NOS inhibitor (S-methylthiourea: SMT; 5mg/kg/day) or both agents for a period of 6 weeks. Ocular hypertension was induced by unilaterally cauterizing three episcleral vessels and the unoperated eye served as control. Neuroprotective effects of given treatments were determined via electrophysiological measurements of visual evoked potentials (VEP) while retina and vitreous levels of MnTnHex-2-PyP(5+) were measured via LC-MS/MS. Latencies of all VEP components (P(1),N(1), P(2), N(2), P(3)) were significantly prolonged (p<0.05) in EIOP and returned to control levels following all three treatment protocols. Ocular hypertension significantly increased retinal protein nitration (p<0.001) which returned to baseline levels in all treated groups. NOS-2 expression and nitrate/nitrite levels were significantly greater in non-treated rats with EIOP. Retinal TUNEL staining showed apoptosis in all ocular hypertensive rats. The presented data confirm the role of oxidative injury in EIOP and highlight the protective effect of MnTnHex-2-PyP(5+) treatment and NOS inhibition in ocular hypertension. PMID:21669199

  19. Depressor effect of chymase inhibitor in mice with high salt-induced moderate hypertension.

    PubMed

    Devarajan, Sankar; Yahiro, Eiji; Uehara, Yoshinari; Habe, Shigehisa; Nishiyama, Akira; Miura, Shin-Ichiro; Saku, Keijiro; Urata, Hidenori

    2015-12-01

    The aim of the present study was to determine whether long-term high salt intake in the drinking water induces hypertension in wild-type (WT) mice and whether a chymase inhibitor or other antihypertensive drugs could reverse the increase of blood pressure. Eight-week-old male WT mice were supplied with drinking water containing 2% salt for 12 wk (high-salt group) or high-salt drinking water plus an oral chymase inhibitor (TPC-806) at four different doses (25, 50, 75, or 100 mg/kg), captopril (75 mg/kg), losartan (100 mg/kg), hydrochlorothiazide (3 mg/kg), eplerenone (200 mg/kg), or amlodipine (6 mg/kg). Control groups were given normal water with or without the chymase inhibitor. Blood pressure and heart rate gradually showed a significant increase in the high-salt group, whereas a dose-dependent depressor effect of the chymase inhibitor was observed. There was also partial improvement of hypertension in the losartan- and eplerenone-treated groups but not in the captopril-, hydrochlorothiazide-, and amlodipine-treated groups. A high salt load significantly increased chymase-dependent ANG II-forming activity in the alimentary tract. In addition, the relative contribution of chymase to ANG II formation, but not actual average activity, showed a significant increase in skin and skeletal muscle, whereas angiotensin-converting enzyme-dependent ANG II-forming activity and its relative contribution were reduced by high salt intake. Plasma and urinary renin-angiotensin system components were significantly increased in the high-salt group but were significantly suppressed in the chymase inhibitor-treated group. In conclusion, 2% salt water drinking for 12 wk caused moderate hypertension and activated the renin-angiotensin system in WT mice. A chymase inhibitor suppressed both the elevation of blood pressure and heart rate, indicating a definite involvement of chymase in salt-sensitive hypertension. PMID:26432844

  20. An Intact Median Preoptic Nucleus is Necessary for Chronic Angiotensin II-Induced Hypertension

    PubMed Central

    Ployngam, Trasida; Collister, John P.

    2007-01-01

    The median preoptic nucleus (MnPO) receives afferent input from the subfornical organ, a circumventricular organ that has been shown to be necessary in mediating the full chronic hypertensive response to angiotensin II (ANG II) administration. In addition, intravenous ANG II infusion has been shown to cause activation of a number of neurons in both the dorsal and ventral part of MnPO. Taken together, we hypothesized that the MnPO is necessary for the full hypertensive response observed during chronic ANG II-induced hypertension. To test this hypothesis, male Sprague Dawley rats were subjected to either sham (SHAM) or electrolytic lesion of both the dorsal and ventral part of the MnPO (MnPOx). During the same surgery, rats were instrumented with venous catheters, and radiotelemetric transducers for the intravenous administration of ANG II and the measurement of blood pressure and heart rate, respectively. Rats were then given a week recovery period. After 3 days of saline control infusion, ANG II was intravenously infused (10 ng ˙ kg−1˙ min−1) in both sham and MnPOx animals for 10 consecutive days, and followed by 3 recovery days. By day 7 of Ang II infusion, MAP had increased 38 ± 3 mmHg in sham lesion rats (n=6), but MAP of MnPOx rats (>90% MnPO ablated; n=5) had only increased 18 ± 2 mmHg. This trend continued through day 10 of ANG II treatment. These results support the hypothesis that the MnPO is necessary for the chronic hypertensive response to ANG II administration. PMID:17618605

  1. Renovascular hypertension identified by captopril-induced changes in the renogram

    SciTech Connect

    Geyskes, G.G.; Oei, H.Y.; Puylaert, C.B.; Mees, E.J.

    1987-05-01

    Radioisotope renography was performed in 21 patients with hypertension and unilateral renal artery stenosis with and without premedication with 25 mg of captopril, and the results were compared with the effect of percutaneous transluminal angioplasty on the blood pressure, assessed 6 weeks after angioplasty. Angioplasty caused a considerable decrease in blood pressure in 15 of the 21 patients. In 12 of these 15 patients, captopril induced changes in the time-activity curves of the affected kidney only, suggesting deterioration of the excretory function of that kidney, while the function of the contralateral kidney remained normal. After angioplasty the asymmetry in the time-activity curves diminished despite identical pretreatment with captopril. Such captopril-induced unilateral impairment of the renal function was not seen in the six patients with unilateral renal artery stenosis whose blood pressure did not change after percutaneous transluminal angioplasty or in 13 patients with hypertension and normal renal arteries. The functional impairment of the affected kidneys was characterized by a decrease of /sup 99m/Tc-diethylenetriamine pentaacetic acid uptake and a delay of /sup 131/I-hippurate excretion, while the /sup 131/I-hippurate uptake remained unaffected. These data are in agreement with a reduced glomerular filtration rate and diuresis during preservation of the renal blood flow, changes that can be expected after converting enzyme inhibition in a kidney with low perfusion and an active, renin-mediated autoregulation of the glomerular filtration rate. These data suggest that functional captopril-induced unilateral changes, shown by split renal function studies with noninvasive gamma camera scintigraphy, can be used as a diagnostic test for renovascular hypertension caused by unilateral renal artery stenosis.

  2. Diesel exhaust induced pulmonary and cardiovascular impairment: The role of hypertension intervention

    SciTech Connect

    Kodavanti, Urmila P.; Thomas, Ronald F.; Ledbetter, Allen D.; Schladweiler, Mette C.; Bass, Virginia; Krantz, Q. Todd; King, Charly; Nyska, Abraham; Richards, Judy E.; Andrews, Debora; Gilmour, M. Ian

    2013-04-15

    Exposure to diesel exhaust (DE) and associated gases is linked to cardiovascular impairments; however, the susceptibility of hypertensive individuals is poorly understood. The objectives of this study were (1) to determine cardiopulmonary effects of gas-phase versus whole-DE and (2) to examine the contribution of systemic hypertension in pulmonary and cardiovascular effects. Male Wistar Kyoto (WKY) rats were treated with hydralazine to reduce blood pressure (BP) or L-NAME to increase BP. Spontaneously hypertensive (SH) rats were treated with hydralazine to reduce BP. Control and drug-pretreated rats were exposed to air, particle-filtered exhaust (gas), or whole DE (1500 μg/m{sup 3}), 4 h/day for 2 days or 5 days/week for 4 weeks. Acute and 4-week gas and DE exposures increased neutrophils and γ-glutamyl transferase (γ-GT) activity in lavage fluid of WKY and SH rats. DE (4 weeks) caused pulmonary albumin leakage and inflammation in SH rats. Two-day DE increased serum fatty acid binding protein-3 (FABP-3) in WKY. Marked increases occurred in aortic mRNA after 4-week DE in SH (eNOS, TF, tPA, TNF-α, MMP-2, RAGE, and HMGB-1). Hydralazine decreased BP in SH while L-NAME tended to increase BP in WKY; however, neither changed inflammation nor BALF γ-GT. DE-induced and baseline BALF albumin leakage was reduced by hydralazine in SH rats and increased by L-NAME in WKY rats. Hydralazine pretreatment reversed DE-induced TF, tPA, TNF-α, and MMP-2 expression but not eNOS, RAGE, and HMGB-1. ET-1 was decreased by HYD. In conclusion, antihypertensive drug treatment reduces gas and DE-induced pulmonary protein leakage and expression of vascular atherogenic markers. - Highlights: ► Acute diesel exhaust exposure induces pulmonary inflammation in healthy rats. ► In hypertensive rats diesel exhaust effects are seen only after long term exposure. ► Normalizing blood pressure reverses lung protein leakage caused by diesel exhaust. ► Normalizing blood pressure reverses atherogenic effects of diesel exhaust. ► Diesel exhaust and hydralazine cause similar aorta effect on vascular tone markers.

  3. M₃muscarinic receptors mediate acetylcholine-induced pulmonary vasodilation in pulmonary hypertension.

    PubMed

    Orii, Ryo; Sugawara, Yasuhiko; Sawamura, Shigehito; Yamada, Yoshitsugu

    2010-10-01

    Information about the muscarinic receptor subtype(s) mediating pulmonary circulatory vasodilator responses to acetylcholine (ACh) is limited. The aim of this study was to pharmacologically characterize the muscarinic receptors associated with ACh-induced pulmonary vasodilation in a pulmonary hypertension model. Vasodilation of rabbit isolated buffer-perfused lungs in which pulmonary hypertension was induced with the thromboxane A₂ analogue U-46619 was evoked by ACh at a just maximally effective concentration (2 x 10⁻⁷ M). The effects of cumulative concentrations of three specific muscarinic receptor subtype antagonists [pirenzepine (M₁), methoctramine (M₂), and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, M₃] on ACh-induced pulmonary vasodilation were determined. Double vascular occlusion pressure was recorded to locate the muscarinic receptors within the pulmonary vasculature. Based on the 50% inhibitory concentrations (IC₅₀), the rank of order of antagonist potency was 4-DAMP > pirenzepine > methoctramine. The vascular effects of all three inhibitors were localized to the precapillary segment. These findings suggest that the vasodilator action of ACh on rabbit isolated perfused U-46619 pretreated lungs is mediated by M₃ muscarinic receptors located in the pulmonary arterial bed. PMID:21068480

  4. Protective effects of methylsulfonylmethane on hemodynamics and oxidative stress in monocrotaline-induced pulmonary hypertensive rats.

    PubMed

    Mohammadi, Sadollah; Najafi, Moslem; Hamzeiy, Hossein; Maleki-Dizaji, Nasrin; Pezeshkian, Masoud; Sadeghi-Bazargani, Homayon; Darabi, Masoud; Mostafalou, Sara; Bohlooli, Shahab; Garjani, Alireza

    2012-01-01

    Methylsulfonylmethane (MSM) is naturally occurring organic sulfur that is known as a potent antioxidant/anti-inflammatory compound. The aim of this study was to investigate the effect of MSM on hemodynamics functions and oxidative stress in rats with monocrotaline- (MCT-) induced pulmonary arterial hypertension (PAH). Wistar rats were randomly assigned to 38-days treatment. MSM was administered to rats at 100, 200, and 400?mg/kg/day doses 10 days before a single dose of 60?mg/kg, IP, MCT. Hemodynamics of ventricles were determined by Powerlab AD instrument. Blood samples were obtained to evaluate changes in the antioxidative system including activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and the level of reduced glutathione (GSH) and malondialdehyde (MDA). Improvements in cardiopulmonary hemodynamics were observed in the MSM-treated pulmonary arterial hypertensive rats, with a significant reduction in right ventricular systolic pressure (RSVP) and an increase in the mean arterial pressure (MAP). The values of CAT, SOD, GSH-px activities, and GSH were significantly lower in MCT-induced PAH (P < 0.01), but they were recovered to control levels of MSM-treated groups. Our present results suggest that long-term administration of the MSM attenuates MCT-induced PAH in rats through modulation of oxidative stress and antioxidant defense. PMID:23118745

  5. Protective Effects of Methylsulfonylmethane on Hemodynamics and Oxidative Stress in Monocrotaline-Induced Pulmonary Hypertensive Rats

    PubMed Central

    Mohammadi, Sadollah; Najafi, Moslem; Hamzeiy, Hossein; Maleki-Dizaji, Nasrin; Pezeshkian, Masoud; Sadeghi-Bazargani, Homayon; Darabi, Masoud; Mostafalou, Sara; Bohlooli, Shahab; Garjani, Alireza

    2012-01-01

    Methylsulfonylmethane (MSM) is naturally occurring organic sulfur that is known as a potent antioxidant/anti-inflammatory compound. The aim of this study was to investigate the effect of MSM on hemodynamics functions and oxidative stress in rats with monocrotaline- (MCT-) induced pulmonary arterial hypertension (PAH). Wistar rats were randomly assigned to 38-days treatment. MSM was administered to rats at 100, 200, and 400?mg/kg/day doses 10 days before a single dose of 60?mg/kg, IP, MCT. Hemodynamics of ventricles were determined by Powerlab AD instrument. Blood samples were obtained to evaluate changes in the antioxidative system including activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and the level of reduced glutathione (GSH) and malondialdehyde (MDA). Improvements in cardiopulmonary hemodynamics were observed in the MSM-treated pulmonary arterial hypertensive rats, with a significant reduction in right ventricular systolic pressure (RSVP) and an increase in the mean arterial pressure (MAP). The values of CAT, SOD, GSH-px activities, and GSH were significantly lower in MCT-induced PAH (P < 0.01), but they were recovered to control levels of MSM-treated groups. Our present results suggest that long-term administration of the MSM attenuates MCT-induced PAH in rats through modulation of oxidative stress and antioxidant defense. PMID:23118745

  6. Treatment of sunitinib-induced hypertension in solid tumor by nitric oxide donors.

    PubMed

    León-Mateos, L; Mosquera, J; Antón Aparicio, L

    2015-12-01

    Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are overexpressed in the majority of renal cell carcinomas. This characteristic has supported the rationale of targeting VEGF-driven tumour vascularization, especially in clear cell RCC. VEGF-inhibiting strategies include the use of tyrosine kinase inhibitors (sunitinib, axitinib, pazopanib, and sorafenib) and neutralizing antibodies such as bevacizumab. Hypertension (HTN) is one of the most common adverse effects of angiogenesis inhibitors. HTN observed in clinical trials appears to correlate with the potency of VEGF kinase inhibitor against VEGFR-2: agents with higher potency are associated with a higher incidence of HTN. Although the exact mechanism by tyrosine kinase inhibitors induce HTN has not yet been completely clarified, two key hypotheses have been postulated. First, some studies have pointed to a VEGF inhibitors-induced decrease in nitric oxide synthase (NOS) and nitric oxide (NO) production, that can result in vasoconstriction and increased blood pressure. VEGF, mediated by PI3K/Akt and MAPK pathway, upregulates the endothelial nitric oxide synthase enzyme leading to up-regulation of NO production. So inhibition of signaling through the VEGF pathway would lead to a decrease in NO production, resulting in an increase in vascular resistance and blood pressure. Secondly a decrease in the number of microvascular endothelial cells and subsequent depletion of normal microvessel density (rarefaction) occurs upon VEGF signaling inhibition. NO donors could be successfully used not only for the treatment of developed angiogenesis-inhibitor-induced hypertension but also for preventive effects. PMID:26386874

  7. Treatment of sunitinib-induced hypertension in solid tumor by nitric oxide donors☆

    PubMed Central

    León-Mateos, L.; Mosquera, J.; Antón Aparicio, L.

    2015-01-01

    Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are overexpressed in the majority of renal cell carcinomas. This characteristic has supported the rationale of targeting VEGF-driven tumour vascularization, especially in clear cell RCC. VEGF-inhibiting strategies include the use of tyrosine kinase inhibitors (sunitinib, axitinib, pazopanib, and sorafenib) and neutralizing antibodies such as bevacizumab. Hypertension (HTN) is one of the most common adverse effects of angiogenesis inhibitors. HTN observed in clinical trials appears to correlate with the potency of VEGF kinase inhibitor against VEGFR-2: agents with higher potency are associated with a higher incidence of HTN. Although the exact mechanism by tyrosine kinase inhibitors induce HTN has not yet been completely clarified, two key hypotheses have been postulated. First, some studies have pointed to a VEGF inhibitors-induced decrease in nitric oxide synthase (NOS) and nitric oxide (NO) production, that can result in vasoconstriction and increased blood pressure. VEGF, mediated by PI3K/Akt and MAPK pathway, upregulates the endothelial nitric oxide synthase enzyme leading to up-regulation of NO production. So inhibition of signaling through the VEGF pathway would lead to a decrease in NO production, resulting in an increase in vascular resistance and blood pressure. Secondly a decrease in the number of microvascular endothelial cells and subsequent depletion of normal microvessel density (rarefaction) occurs upon VEGF signaling inhibition. NO donors could be successfully used not only for the treatment of developed angiogenesis-inhibitor-induced hypertension but also for preventive effects. PMID:26386874

  8. Novel diallyldisulfide analogs ameliorate cardiovascular remodeling in rats with L-NAME-induced hypertension.

    PubMed

    Sharma, Dinesh Kumar; Manral, Apra; Saini, Vikas; Singh, Avninder; Srinivasan, B P; Tiwari, Manisha

    2012-09-15

    Diallyldisulfide (DADS), an active principle of garlic (Allium sativum) is known for its antihypertensive properties. The present study was designed to evaluate the effect of novel DADS analogs, against L-NAME induced hypertension in Wistar rats. The daily administration of L-NAME (50mg/kg) for six weeks along with DADS analogs (20 mg/kg) significantly decreased the elevated systolic blood pressure (SBP) and the activity of angiotensin converting enzyme (ACE) and also inhibited the decline in nitrite/nitrate (NO(x)) concentrations and cyclic guanosine monophosphate (cGMP) levels. Adverse changes such as lipid peroxidation, protein damage and a decrease in the levels of antioxidant enzymes, were rectified after the administration of DADS analogs. Oral administration of DADS analogs preserved the expression of endothelial nitric oxide synthase (eNOS). The ability of the DADS analogs to inhibit L-NAME induced hypertension was compared with Enalapril (15 mg/kg), which was taken as a standard. The DADS analogs prevented L-NAME-induced cardio toxicity, which was also reflected at the microscopic level indicative of its cardio protective effects. DADS analogs induced vasorelaxation was completely abolished by the removal of the endothelium or by pre-treatment with L-NAME, an inhibitor of nitric oxide synthase. DADS analogs inhibited the calcium influx induced by phenylephrine (0.3 ?M) and high K(+) (60mM) and this effect was completely abolished by pretreatment of L-NAME. Taken together, our results show that the DADS analogs induce vasorelaxation and have antihypertensive properties, which may be mediated through activation of eNOS. PMID:22819707

  9. Lentil polyphenol extract prevents angiotensin II-induced hypertension, vascular remodelling and perivascular fibrosis.

    PubMed

    Yao, Fanrong; Sun, Chengwen; Chang, Sam K C

    2012-02-01

    The objective of the study was to investigate whether chronic administration of the Morton lentil polyphenol extract (MLPE), which possesses rich phenolic compounds and a high antioxidant activity, had any protective effects on angiotensin II-induced hypertension. After four weeks of subcutaneous infusion of angiotensin II (200 ng kg(-1) min(-1)) in male SD rats, the water intake and mean artery pressure was significantly increased by 39.8% and 48.3%, respectively, as compared with the control. The media/lumen ratio of the small arteries in the heart and kidneys were increased by 117% and 168% by angiotensin II infusion. The perivascular fibrosis was increased by 65% and 32% in the heart and kidneys, respectively. Levels of the reactive oxygen species in the aorta was enhanced by 115.8%. In another group of rats, which received four weeks of lentil extract administration (1% freeze-dried MLPE in the drinking water), followed by another four weeks of extract administration plus angiotensin II infusion, the angiotensin II-induced enhancement in water intake and mean artery pressures decreased by 12.7% and 8.2%, respectively, as compared with the rats that received angiotensin II infusion alone. The angiotensin II-induced rats showed increases in the media/lumen ratios which were attenuated by 43.6% and 47.2% in the small arteries of heart and kidneys, respectively. Angiotensin II-induced perivascular fibrosis was attenuated by 30% and 26% in the rats that received the extract. Angiotensin II-induced rats showed reactive oxygen species levels in the aorta was reduced by 48.9%. These findings demonstrated that lentil extract attenuated angiotensin II-induced hypertension and associated pathological changes, including remodelling and perivascular fibrosis in the small resistant arteries of heart and kidneys. PMID:22159297

  10. 20-HETE induces remodeling of renal resistance arteries independent of blood pressure elevation in hypertension

    PubMed Central

    Ding, Yan; Wu, Cheng-Chia; Garcia, Victor; Dimitrova, Irina; Weidenhammer, Adam; Joseph, Gregory; Zhang, Frank; Manthati, Vijay L.; Falck, John R.; Capdevila, Jorge H.

    2013-01-01

    20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P-450 (Cyp)-derived arachidonic acid metabolite that has been shown to increase smooth muscle contractions and proliferation, stimulate endothelial dysfunction and activation, and promote hypertension. We examined if 20-HETE contributes to microvascular remodeling in hypertension. In Sprague-Dawley rats, administration of the 20-HETE biosynthesis inhibitor HET0016 or the 20-HETE antagonist N-20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) prevented 5?-dihydrotestosterone (DHT)-induced increases in blood pressure as well as abrogated DHT-induced increases in the media-to-lumen ratio (M/L), media thickness, and collagen IV deposition in renal interlobar arteries. Reserpine prevented blood pressure elevation in DHT-treated rats but did not affect microvascular remodeling (M/L, media thickness, and collagen deposition); under these conditions, treatment with the 20-HETE antagonist attenuated microvascular remodeling, suggesting that 20-HETE contributes to DHT-induced vascular remodeling independent of blood pressure elevation. In Cyp4a14?/? mice, which display androgen-driven and 20-HETE-dependent hypertension, treatment with the 20-HETE antagonist abolished remodeling of renal resistance arteries measured as media thickness (24 1 vs. 15 1 ?m) and M/L (0.29 0.03 vs. 0.17 0.01). Moreover, in Cyp4a12 transgenic mice in which the expression of Cyp4a1220-HETE synthase is driven by a tetracycline-sensitive promoter, treatment with doxycycline resulted in blood pressure elevation (140 4 vs. 92 5 mmHg) and a significant increase in remodeling of renal resistance arteries (media thickness: 23 1 vs. 16 1 ?m; M/L: 0.39 0.04 vs. 0.23 0.02); these increases were abrogated by cotreatment with 20-HEDE. This study demonstrated that 20-HETE is a key regulator of microvascular remodeling in hypertension; its effect is independent of blood pressure elevation and androgen levels. PMID:23825080

  11. Novel retro-inverso peptide inhibitor reverses angiotensin receptor autoantibody-induced hypertension in the rabbit.

    PubMed

    Li, Hongliang; Kem, David C; Zhang, Ling; Huang, Bing; Liles, Campbell; Benbrook, Alexandria; Gali, Hariprasad; Veitla, Vineet; Scherlag, Benjamin J; Cunningham, Madeleine W; Yu, Xichun

    2015-04-01

    Activating autoantibodies to the angiotensin II type 1 receptor (AT1R) have been implicated in hypertensive disorders. We investigated whether AT1R antibodies produced in immunized rabbits will activate AT1R and contribute to hypertension by a direct contractile effect on the vasculature and whether they can be blocked by a novel decoy peptide. A multiple antigenic peptide containing the AT1R epitope AFHYESQ, which is the receptor-binding epitope of AT1R-activating autoantibodies, was used to immunize 6 rabbits. AT1R antibody activity was analyzed in AT1R-transfected cells, and their contractile effects were assayed using isolated perfused rat cremaster resistance arterioles. A retro-inverso D-amino acid epitope-mimetic peptide was tested for AT1R antibody inhibition in vitro and in vivo. All immunized animals produced high AT1R antibody titers and developed elevated blood pressure. No changes in measured blood chemistry values were observed after immunization. Rabbit anti-AT1R sera induced significant AT1R activation in transfected cells and vasoconstriction in the arteriole assay, both of which were blocked by losartan and the retro-inverso D-amino acid peptide. A single intravenous bolus injection of the retro-inverso d-amino acid peptide (1 mg/kg) into immunized rabbits dropped the mean arterial pressure from 122±11 to 82±6 mm Hg. Rabbit anti-AT1R sera partially suppressed angiotensin II-induced contraction of isolated rat cremaster arterioles, and the pressor response to angiotensin II infusion was attenuated in immunized animals. In conclusion, AT1R-activating autoantibodies and the retro-inverso d-amino acid peptide, respectively, have important etiologic and therapeutic implications in hypertensive subjects who harbor these autoantibodies. PMID:25691619

  12. Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension

    SciTech Connect

    Satwiko, Muhammad Gahan; Ikeda, Koji; Nakayama, Kazuhiko; Yagi, Keiko; Hocher, Berthold; Hirata, Ken-ichi; Emoto, Noriaki

    2015-09-25

    Pulmonary arterial hypertension (PAH) is a fatal disease that eventually results in right heart failure and death. Current pharmacologic therapies for PAH are limited, and there are no drugs that could completely cure PAH. Enhanced activity of endothelin system has been implicated in PAH severity and endothelin receptor antagonists have been used clinically to treat PAH. However, there is limited experimental evidence on the direct role of enhanced endothelin system activity in PAH. Here, we investigated the correlation between endothelin-1 (ET-1) and PAH using ET-1 transgenic (ETTG) mice. Exposure to chronic hypoxia increased right ventricular pressure and pulmonary arterial wall thickness in ETTG mice compared to those in wild type mice. Of note, ETTG mice exhibited modest but significant increase in right ventricular pressure and vessel wall thickness relative to wild type mice even under normoxic conditions. To induce severe PAH, we administered SU5416, a vascular endothelial growth factor receptor inhibitor, combined with exposure to chronic hypoxia. Treatment with SU5416 modestly aggravated hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial vessel wall thickening in ETTG mice in association with increased interleukin-6 expression in blood vessels. However, there was no sign of obliterative endothelial cell proliferation and plexiform lesion formation in the lungs. These results demonstrated that enhanced endothelin system activity could be a causative factor in the development of PAH and provided rationale for the inhibition of endothelin system to treat PAH. - Highlights: • Role of endothelin-1 in pulmonary arterial hypertension (PAH) was investigated. • The endothelin-1 transgenic (ETTG) and wild type (WT) mice were analyzed. • ETTG mice spontaneously developed PAH under normoxia conditions. • SU5416 further aggravated PAH in ETTG mice. • Enhanced endothelin system activity could be a causative factor in PAH development.

  13. Effects of magnesium sulphate and nitric oxide in pulmonary hypertension induced by hypoxia in newborn piglets.

    PubMed Central

    Ryan, C A; Finer, N N; Barrington, K J

    1994-01-01

    AIM--To examine the haemodynamic effects of intravenous magnesium sulphate on an animal model of neonatal pulmonary hypertension induced by hypoxia. METHODS--The cardiac index (Q), pulmonary arterial pressure (PAP), systemic arterial pressure (SAP), and pulmonary (PVRI) and systemic (SVRI) vascular resistance indices were measured in nine newborn piglets (including three controls). Pulmonary hypertension was induced by lowering the FIO2 to 0.12-0.14, after which there was a significant increase in PAP and PVRI (37% and 142%, respectively; p < 0.01) and a significant fall in SAP and Q (30% and 33%, respectively; p < 0.01). RESULTS--Magnesium sulphate was infused intravenously as four doses of 25 mg/kg, 15 minutes apart, which resulted in a significant mean (SD) increase in serum magnesium (0.83 (0.07) mmol/l to 1.82 (0.19) mmol/l; p < 0.01). After the initial dose SAP, SVRI, PAP and PVRI decreased, but not significantly. Each subsequent dose of (50, 75, 100 mg/kg) was accompanied by further significant reductions in these variables from control baseline (p < 0.05). The PVRI:SVRI ratio remained unchanged throughout. Inhaled nitric oxide (NO) 40 ppm was administered after the last dose of magnesium sulphate. The PVRI:SVRI significantly decreased (p < 0.05), indicating that reversible pulmonary hypertension remained after a maximum dose of magnesium sulphate. CONCLUSIONS--Unlike NO, magnesium sulphate is not a selective pulmonary vasodilator and may lead to deleterious effects on systemic pressures in critically ill newborns. PMID:7820707

  14. Aldosterone acting through the central nervous system sensitizes angiotensin II-induced hypertension.

    PubMed

    Xue, Baojian; Zhang, Zhongming; Roncari, Camila F; Guo, Fang; Johnson, Alan Kim

    2012-10-01

    Previous studies have shown that preconditioning rats with a nonpressor dose of angiotensin II (Ang II) sensitizes the pressor response produced by later treatment with a higher dose of Ang II and that Ang II and aldosterone (Aldo) can modulate each other's pressor effects through actions involving the central nervous system. The current studies tested whether Aldo can cross-sensitize the pressor actions of Ang II to enhance hypertension by employing an induction-delay-expression experimental design. Male rats were implanted for telemetered blood pressure recording. During induction, subpressor doses of either subcutaneous or intracerebroventricular Aldo were delivered for 1 week. Rats were then rested for 1 week (delay) to assure that any exogenous Aldo was metabolized. After this, Ang II was given subcutaneously for 2 weeks (expression). During induction and delay, Aldo had no sustained effect on blood pressure. However, during expression, Ang II-induced hypertension was greater in the groups receiving subcutaneous or intracerebroventricular Aldo during induction in comparison with those groups receiving vehicle. Central administration of mineralocorticoid receptor antagonist blocked sensitization. Brain tissue collected at the end of delay and expression showed increased mRNA expression of several renin-angiotensin-aldosterone system components in cardiovascular-related forebrain regions of cross-sensitized rats. Cultured subfornical organ neurons preincubated with Aldo displayed greater increases in [Ca2+]i after Ang II treatment, and there was a greater Fra-like immunoreactivity present at the end of expression in cardiovascular-related forebrain structures. Taken together, these results indicate that Aldo pretreatment cross-sensitizes the development of Ang II-induced hypertension probably by mechanisms that involve the central nervous system. PMID:22949534

  15. Metalloproteinase Inhibition Protects against Reductions in Circulating Adrenomedullin during Lead-induced Acute Hypertension.

    PubMed

    Nascimento, Regina A; Mendes, Gabryella; Possomato-Vieira, Jose S; Gonalves-Rizzi, Victor Hugo; Kushima, Hlio; Delella, Flavia K; Dias-Junior, Carlos A

    2015-06-01

    Intoxication with lead (Pb) results in increased blood pressure by mechanisms involving matrix metalloproteinases (MMPs). Recent findings have revealed that MMP type two (MMP-2) seems to cleave vasoactive peptides. This study examined whether MMP-2 and MMP-9 levels/activities increase after acute intoxication with low lead concentrations and whether these changes were associated with increases in blood pressure and circulating endothelin-1 or with reductions in circulating adrenomedullin and calcitonin gene-related peptide (CGRP). Here, we expand previous findings and examine whether doxycycline (a MMPs inhibitor) affects these alterations. Wistar rats received intraperitoneally (i.p.) 1st dose 8 ?g/100 g of lead (or sodium) acetate, a subsequent dose of 0.1 ?g/100 g to cover daily loss and treatment with doxycycline (30 mg/kg/day) or water by gavage for 7 days. Similar whole-blood lead levels (9 ?g/dL) were found in lead-exposed rats treated with either doxycycline or water. Lead-induced increases in systolic blood pressure (from 143 2 to 167 3 mmHg) and gelatin zymography of plasma samples showed that lead increased MMP-9 (but not MMP-2) levels. Both lead-induced increased MMP-9 activity and hypertension were blunted by doxycycline. Doxycycline also prevented lead-induced reductions in circulating adrenomedullin. No significant changes in plasma levels of endothelin-1 or CGRP were found. Lead-induced decreases in nitric oxide markers and antioxidant status were not prevented by doxycycline. In conclusion, acute lead exposure increases blood pressure and MMP-9 activity, which were blunted by doxycycline. These findings suggest that MMP-9 may contribute with lead-induced hypertension by cleaving the vasodilatory peptide adrenomedullin, thereby inhibiting adrenomedullin-dependent lowering of blood pressure. PMID:25308714

  16. Ocular Hypertension

    MedlinePLUS

    ... News Ask an Eye M.D. Espaol Ocular Hypertension What Is Ocular Hypertension? Ocular Hypertension Causes Ocular ... Hypertension Diagnosis Ocular Hypertension Treatment What Is Ocular Hypertension? Written by: Kierstan Boyd Reviewed by: J Kevin ...

  17. Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension.

    PubMed

    Satwiko, Muhammad Gahan; Ikeda, Koji; Nakayama, Kazuhiko; Yagi, Keiko; Hocher, Berthold; Hirata, Ken-ichi; Emoto, Noriaki

    2015-09-25

    Pulmonary arterial hypertension (PAH) is a fatal disease that eventually results in right heart failure and death. Current pharmacologic therapies for PAH are limited, and there are no drugs that could completely cure PAH. Enhanced activity of endothelin system has been implicated in PAH severity and endothelin receptor antagonists have been used clinically to treat PAH. However, there is limited experimental evidence on the direct role of enhanced endothelin system activity in PAH. Here, we investigated the correlation between endothelin-1 (ET-1) and PAH using ET-1 transgenic (ETTG) mice. Exposure to chronic hypoxia increased right ventricular pressure and pulmonary arterial wall thickness in ETTG mice compared to those in wild type mice. Of note, ETTG mice exhibited modest but significant increase in right ventricular pressure and vessel wall thickness relative to wild type mice even under normoxic conditions. To induce severe PAH, we administered SU5416, a vascular endothelial growth factor receptor inhibitor, combined with exposure to chronic hypoxia. Treatment with SU5416 modestly aggravated hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial vessel wall thickening in ETTG mice in association with increased interleukin-6 expression in blood vessels. However, there was no sign of obliterative endothelial cell proliferation and plexiform lesion formation in the lungs. These results demonstrated that enhanced endothelin system activity could be a causative factor in the development of PAH and provided rationale for the inhibition of endothelin system to treat PAH. PMID:26275708

  18. Endogenous biosynthesis of arachidonic acid epoxides in humans: Increased formation in pregnancy-induced hypertension

    SciTech Connect

    Catella, F.; Lawson, J.A.; Fitzgerald, D.J.; FitzGerald, G.A. )

    1990-08-01

    Arachidonic acid is metabolized by means of P450 isoenzyme(s) to form epoxyeicosatrienoic acids (EETs) and their corresponding dihydroxy derivatives (DHETs). In the present study, we established the presence in human urine of 8,9-, 11,12-, and 14,15-EETs and their corresponding DHETs by developing quantitative assays and using negative ion, chemical ionization GC/MS and octadeuterated internal standards. Urinary excretion of 8,9- and 11,12-DHET increased in healthy pregnant women compared with nonpregnant female volunteers. By contrast, excretion of 11,12-DHET and 14,15-DHET, but not the 8,9-DHET regioisomer, increased even further in patients with pregnancy-induced hypertension. Intravenous administration of (3H)14,15-EET to three dogs markedly increased its DHET in plasma. The terminal half-life ranged from 7.9-12.3 min and the volume of distribution (3.5-5.3 liters) suggested limited distribution outside the plasma compartment. Negligible radioactivity was detected in urine; this fact infers that under physiological circumstances, urinary DHETs largely derive from the kidney. That P450 metabolites of arachidonic acid are formed in humans supports the hypothesis that these metabolites contribute to the physiological response to normal pregnancy and the pathophysiology of pregnancy-induced hypertension.

  19. The effect of magnesium sulfate on maternal and fetal blood flow in pregnancy-induced hypertension.

    PubMed

    Belfort, M A; Saade, G R; Moise, K J

    1993-10-01

    The purpose of this study was to evaluate the effects of magnesium sulfate on maternal and fetal blood flow in pregnancy-induced hypertension. Twelve patients with pregnancy-induced hypertension were prospectively studied with transcranial pulsed Doppler and transabdominal color flow Doppler before and after infusion of a 6 gram intravenous loading dose of magnesium sulfate. The maternal vessels studied included the middle cerebral, common carotid, and internal carotid arteries. The fetal vessels studied included the middle cerebral, renal, and umbilical arteries. In addition the maternal circulation in the placental base plate was imaged. The results of this descriptive study suggest that a 6 gram loading dose of magnesium sulfate significantly vasodilates the vascular bed distal to the maternal middle cerebral artery, and increases blood velocity in this distribution. There was no significant change in pulsatility index or blood velocity in the central large vessels of the head and neck. There were no acute effects noted in the fetal or placental vessels evaluated. PMID:8213097

  20. Beneficial effects of diminished production of hydrogen sulfide or carbon monoxide on hypertension and renal injury induced by NO withdrawal

    PubMed Central

    Wesseling, Sebastiaan; Fledderus, Joost O; Verhaar, Marianne C; Joles, Jaap A

    2015-01-01

    Background and Purpose Whether NO, carbon monoxide (CO) and hydrogen sulfide (H2S) compensate for each other when one or more is depleted is unclear. Inhibiting NOS causes hypertension and kidney injury. Both global depletion of H2S by cystathionine γ-lyase (CSE) gene deletion and low levels of exogenous H2S cause hypertension. Inhibiting CO-producing enzyme haeme oxygenase-1 (HO-1) makes rodents hypersensitive to hypertensive stimuli. We hypothesized that combined inhibition of NOS and HO-1 exacerbates hypertension and renal injury, but how combined inhibition of NOS and CSE affect hypertension and renal injury was unclear. Experimental Approach Rats were treated with inhibitors of NOS (L-nitroarginine; LNNA), CSE (DL-propargylglycine; PAG), or HO-1 (tin protoporphyrin; SnPP) singly for 1 or 4 weeks or in combinations for 4 weeks. Key Results LNNA always reduced NO, decreased H2S and increased CO after 4 weeks. PAG abolished H2S, always enhanced CO and reduced NO, but not when used in combination with other inhibitors. SnPP always increased NO, enhanced H2S and inhibited CO after 1 week. Rats treated with LNNA, but not PAG and SnPP, rapidly developed hypertension followed by renal dysfunction. LNNA-induced hypertension was ameliorated and renal dysfunction prevented by all additional treatments. Renal HO-1 expression was increased by LNNA in injured tubules and increased in all tubules by all other treatments. Conclusions and Implications The amelioration of LNNA-induced hypertension and renal injury by additional inhibition of H2S and/or CO-producing enzymes appeared to be associated with secondary increases in renal CO or NO production. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6 PMID:24597655

  1. Hemodynamic basis for the limited renal injury in rats with angiotensin II-induced hypertension

    PubMed Central

    Griffin, Karen A.; Picken, Maria M.; Licea-Vargas, Hector; Long, Jianrui; Williamson, Geoffrey A.; Bidani, Anil K.

    2014-01-01

    ANG II is thought to increase the susceptibility to hypertension-induced renal disease (HIRD) via blood pressure (BP)-dependent and BP-independent pathways; however, the quantitative relationships between BP and HIRD have not been examined in ANG II-infused hypertensive rats. We compared the relationship between radiotelemetrically measured BP and HIRD in Sprague-Dawley rats (Harlan) chronically administered ANG II (300500 ngkg?1min?1, n = 19) for 4 wk versus another commonly employed pharmacological model of hypertension induced by the chronic administration of N?-nitro-l-arginine methyl ester (l-NAME, 50 mgkg?1min?1, n = 23). Despite the significantly higher average systolic BP associated with ANG II (191.1 3.2 mmHg) versus l-NAME (179.9 2.5 mmHg) administration, the level of HIRD was very modest in the ANG II versus l-NAME model as evidenced by significantly less glomerular injury (6.6 1.3% vs. 11.3 1.5%, respectively), tubulointerstitial injury (0.3 0.1 vs. 0.7 0.1 injury score, respectively), proteinuria (66.3 10.0 vs. 117.5 10.1 mg/day, respectively), and serum creatinine levels (0.5 0.04 vs. 0.9 0.07 mg/dl, respectively). Given that HIRD severity is expected to be a function of renal microvascular BP transmission, BP-renal blood flow (RBF) relationships were examined in additional conscious rats administered ANG II (n = 7) or l-NAME (n = 8). Greater renal vasoconstriction was observed during ANG II versus l-NAME administration (41% vs. 23% decrease in RBF from baseline). Moreover, administration of ANG II, but not l-NAME, led to a unique BP-RBF pattern in which the most substantial decreases in RBF were observed during spontaneous increases in BP. We conclude that the hemodynamic effects of ANG II may mediate the strikingly low susceptibility to HIRD in the ANG II-infused model of hypertension in rats. PMID:25477472

  2. Pulmonary Hypertension

    MedlinePLUS

    MENU Return to Web version Pulmonary Hypertension Overview What is pulmonary hypertension? "Pulmonary" means "in the lungs," and "hypertension" means "high blood pressure." Pulmonary hypertension is an increase ...

  3. Protective effects of hydrogen-rich saline on monocrotaline-induced pulmonary hypertension in a rat model

    PubMed Central

    2011-01-01

    Background Hydrogen-rich saline has been reported to have antioxidant and anti-inflammatory effects and effectively protect against organ damage. Oxidative stress and inflammation contribute to the pathogenesis and/or development of pulmonary hypertension. In this study, we investigated the effects of hydrogen-rich saline on the prevention of pulmonary hypertension induced by monocrotaline in a rat model. Methods In male Sprague-Dawley rats, pulmonary hypertension was induced by subcutaneous administration of monocrotaline at a concentration of 6 mg/100 g body weight. Hydrogen-rich saline (5 ml/kg) or saline was administred intraperitoneally once daily for 2 or 3 weeks. Severity of pulmonary hypertension was assessed by hemodynamic index and histologic analysis. Malondialdehyde and 8-hydroxy-desoxyguanosine level, and superoxide dismutase activity were measured in the lung tissue and serum. Levels of pro-inflammatory cytokines (tumor necrosis factor-?, interleukin-6) in serum were determined with enzyme-linked immunosorbent assay. Results Hydrogen-rich saline treatment improved hemodynamics and reversed right ventricular hypertrophy. It also decreased malondialdehyde and 8-hydroxy-desoxyguanosine levels, and increased superoxide dismutase activity in the lung tissue and serum, accompanied by a decrease in pro-inflammatory cytokines. Conclusions These results suggest that hydrogen-rich saline ameliorates the progression of pulmonary hypertension induced by monocrotaline in rats, which may be associated with its antioxidant and anti-inflammatory effects. PMID:21375753

  4. Oxidant and enzymatic antioxidant status (gene expression and activity) in the brain of chickens with cold-induced pulmonary hypertension.

    PubMed

    Hassanpour, Hossein; Khalaji-Pirbalouty, Valiallah; Nasiri, Leila; Mohebbi, Abdonnaser; Bahadoran, Shahab

    2015-11-01

    To evaluate oxidant and antioxidant status of the brain (hindbrain, midbrain, and forebrain) in chickens with cold-induced pulmonary hypertension, the measurements of lipid peroxidation, protein oxidation, antioxidant capacity, enzymatic activity, and gene expression (for catalase, glutathione peroxidase, and superoxide dismutases) were done. There were high lipid peroxidation/protein oxidation and low antioxidant capacity in the hindbrain of cold-induced pulmonary hypertensive chickens compared to control (P?hypertensive chickens, superoxide dismutase activity was decreased (forebrain, midbrain, and hindbrain), while catalase activity was increased (forebrain and midbrain) (P?induced pulmonary hypertensive chickens. Probably, these situations in the oxidant and antioxidant status of the brain especially hindbrain may change its function at cardiovascular center and sympathetic nervous system to exacerbate pulmonary hypertension. PMID:25939899

  5. Transient Receptor Potential Melastatin 7 Cation Channel Kinase: New Player in Angiotensin II-Induced Hypertension.

    PubMed

    Antunes, Tayze T; Callera, Glaucia E; He, Ying; Yogi, Alvaro; Ryazanov, Alexey G; Ryazanova, Lillia V; Zhai, Alexander; Stewart, Duncan J; Shrier, Alvin; Touyz, Rhian M

    2016-04-01

    Transient receptor potential melastatin 7 (TRPM7) is a bifunctional protein comprising a magnesium (Mg(2+))/cation channel and a kinase domain. We previously demonstrated that vasoactive agents regulate vascular TRPM7. Whether TRPM7 plays a role in the pathophysiology of hypertension and associated cardiovascular dysfunction is unknown. We studied TRPM7 kinase-deficient mice (TRPM7Δkinase; heterozygous for TRPM7 kinase) and wild-type (WT) mice infused with angiotensin II (Ang II; 400 ng/kg per minute, 4 weeks). TRPM7 kinase expression was lower in heart and aorta from TRPM7Δkinase versus WT mice, effects that were further reduced by Ang II infusion. Plasma Mg(2+) was lower in TRPM7Δkinase versus WT mice in basal and stimulated conditions. Ang II increased blood pressure in both strains with exaggerated responses in TRPM7Δkinase versus WT groups (P<0.05). Acetylcholine-induced vasorelaxation was reduced in Ang II-infused TRPM7Δkinase mice, an effect associated with Akt and endothelial nitric oxide synthase downregulation. Vascular cell adhesion molecule-1 expression was increased in Ang II-infused TRPM7 kinase-deficient mice. TRPM7 kinase targets, calpain, and annexin-1, were activated by Ang II in WT but not in TRPM7Δkinase mice. Echocardiographic and histopathologic analysis demonstrated cardiac hypertrophy and left ventricular dysfunction in Ang II-treated groups. In TRPM7 kinase-deficient mice, Ang II-induced cardiac functional and structural effects were amplified compared with WT counterparts. Our data demonstrate that in TRPM7Δkinase mice, Ang II-induced hypertension is exaggerated, cardiac remodeling and left ventricular dysfunction are amplified, and endothelial function is impaired. These processes are associated with hypomagnesemia, blunted TRPM7 kinase expression/signaling, endothelial nitric oxide synthase downregulation, and proinflammatory vascular responses. Our findings identify TRPM7 kinase as a novel player in Ang II-induced hypertension and associated vascular and target organ damage. PMID:26928801

  6. Activation of central PPAR-γ attenuates angiotensin II-induced hypertension.

    PubMed

    Yu, Yang; Xue, Bao-Jian; Wei, Shun-Guang; Zhang, Zhi-Hua; Beltz, Terry G; Guo, Fang; Johnson, Alan Kim; Felder, Robert B

    2015-08-01

    Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-γ in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that the activation of brain PPAR-γ might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg per minute) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR-γ agonist pioglitazone (3 nmol/h) or the PPAR-γ antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-γ mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-γ DNA-binding activity was reduced. mRNA for interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2, and angiotensin II type 1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA-binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-γ to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension. PMID:26101342

  7. New Insights on the Maternal Diet Induced-Hypertension: Potential Role of the Phenotypic Plasticity and Sympathetic-Respiratory Overactivity

    PubMed Central

    Costa-Silva, João H.; de Brito-Alves, José L.; Barros, Monique Assis de V.; Nogueira, Viviane Oliveira; Paulino-Silva, Kássya M.; de Oliveira-Lira, Allan; Nobre, Isabele G.; Fragoso, Jéssica; Leandro, Carol G.

    2015-01-01

    Systemic arterial hypertension (SAH) is an important risk factor for cardiovascular disease and affects worldwide population. Current environment including life style coupled with genetic programming have been attributed to the rising incidence of hypertension. Besides, environmental conditions during perinatal development such as maternal malnutrition can program changes in the integration among renal, neural, and endocrine system leading to hypertension. This phenomenon is termed phenotypic plasticity and refers to the adjustment of a phenotype in response to environmental stimuli without genetic change, following a novel or unusual input during development. Human and animal studies indicate that fetal exposure to an adverse maternal environment may alter the renal morphology and physiology that contribute to the development of hypertension. Recently, it has been shown that the maternal protein restriction alter the central control of SAH by a mechanism that include respiratory dysfunction and enhanced sympathetic-respiratory coupling at early life, which may contribute to adult hypertension. This review will address the new insights on the maternal diet induced-hypertension that include the potential role of the phenotypic plasticity, specifically the perinatal protein malnutrition, and sympathetic-respiratory overactivity. PMID:26635631

  8. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension

    PubMed Central

    McMurtry, M. Sean; Archer, Stephen L.; Altieri, Dario C.; Bonnet, Sebastien; Haromy, Alois; Harry, Gwyneth; Bonnet, Sandra; Puttagunta, Lakshmi; Michelakis, Evangelos D.

    2005-01-01

    Pulmonary arterial hypertension (PAH) is characterized by genetic and acquired abnormalities that suppress apoptosis and enhance cell proliferation in the vascular wall, including downregulation of the bone morphogenetic protein axis and voltage-gated K+ (Kv) channels. Survivin is an inhibitor of apoptosis protein, previously thought to be expressed primarily in cancer cells. We found that survivin was expressed in the pulmonary arteries (PAs) of 6 patients with PAH and rats with monocrotaline-induced PAH, but not in the PAs of 3 patients and rats without PAH. Gene therapy with inhalation of an adenovirus carrying a phosphorylation-deficient survivin mutant with dominant-negative properties reversed established monocrotaline-induced PAH and prolonged survival by 25%. The survivin mutant lowered pulmonary vascular resistance, RV hypertrophy, and PA medial hypertrophy. Both in vitro and in vivo, inhibition of survivin induced PA smooth muscle cell apoptosis, decreased proliferation, depolarized mitochondria, caused efflux of cytochrome c in the cytoplasm and translocation of apoptosis-inducing factor into the nucleus, and increased Kv channel current; the opposite effects were observed with gene transfer of WT survivin, both in vivo and in vitro. Inhibition of the inappropriate expression of survivin that accompanies human and experimental PAH is a novel therapeutic strategy that acts by inducing vascular mitochondria-dependent apoptosis. PMID:15931388

  9. Purinergic P2Y6 receptors heterodimerize with angiotensin AT1 receptors to promote angiotensin II-induced hypertension.

    PubMed

    Nishimura, Akiyuki; Sunggip, Caroline; Tozaki-Saitoh, Hidetoshi; Shimauchi, Tsukasa; Numaga-Tomita, Takuro; Hirano, Katsuya; Ide, Tomomi; Boeynaems, Jean-Marie; Kurose, Hitoshi; Tsuda, Makoto; Robaye, Bernard; Inoue, Kazuhide; Nishida, Motohiro

    2016-01-01

    The angiotensin (Ang) type 1 receptor (AT1R) promotes functional and structural integrity of the arterial wall to contribute to vascular homeostasis, but this receptor also promotes hypertension. In our investigation of how Ang II signals are converted by the AT1R from physiological to pathological outputs, we found that the purinergic P2Y6 receptor (P2Y6R), an inflammation-inducible G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR), promoted Ang II-induced hypertension in mice. In mice, deletion of P2Y6R attenuated Ang II-induced increase in blood pressure, vascular remodeling, oxidative stress, and endothelial dysfunction. AT1R and P2Y6R formed stable heterodimers, which enhanced G protein-dependent vascular hypertrophy but reduced ?-arrestin-dependent AT1R internalization. Pharmacological disruption of AT1R-P2Y6R heterodimers by the P2Y6R antagonist MRS2578 suppressed Ang II-induced hypertension in mice. Furthermore, P2Y6R abundance increased with age in vascular smooth muscle cells. The increased abundance of P2Y6R converted AT1R-stimulated signaling in vascular smooth muscle cells from ?-arrestin-dependent proliferation to G protein-dependent hypertrophy. These results suggest that increased formation of AT1R-P2Y6R heterodimers with age may increase the likelihood of hypertension induced by Ang II. PMID:26787451

  10. Angiotensin-II-induced reactive oxygen species along the SFO-PVN-RVLM pathway: implications in neurogenic hypertension.

    PubMed

    Braga, V A; Medeiros, I A; Ribeiro, T P; França-Silva, M S; Botelho-Ono, M S; Guimarães, D D

    2011-09-01

    Neurogenic hypertension has been the subject of extensive research worldwide. This review is based on the premise that some forms of neurogenic hypertension are caused in part by the formation of angiotensin-II (Ang-II)-induced reactive oxygen species along the subfornical organ-paraventricular nucleus of the hypothalamus-rostral ventrolateral medulla pathway (SFO-PVN-RVLM pathway). We will discuss the recent contribution of our laboratory and others regarding the mechanisms by which neurons in the SFO (an important circumventricular organ) are activated by Ang-II, how the SFO communicates with two other important areas involved in sympathetic activity regulation (PVN and RVLM) and how Ang-II-induced reactive oxygen species participate along the SFO-PVN-RVLM pathway in the pathogenesis of neurogenic hypertension. PMID:21755262

  11. NaCl-induced hypertensive rat model of non-insulin-dependent diabetes: role of sympathetic modulation.

    PubMed

    Mozaffari, M S; Patel, C; Warren, B K; Schaffer, S W

    2000-05-01

    Systemic hypertension is common in individuals with non-insulin-dependent diabetes (NIDD) and, in this population, markedly increases the risk for cardiovascular complications. The aims of this study were to develop a rat model of combined NaCl-induced hypertension and NIDD, and to determine the contribution of the sympathetic nervous system to the development of the manifest hypertension. Two-day old male Wistar-Kyoto rats were injected with either streptozotocin (90 mg/kg, ip; NIDD) or vehicle (citrate buffer; control). At 4 weeks of age, the animals underwent either a right nephrectomy or a sham operation. Animals in each group were further subdivided, with one group maintained on normal (0.72 %) NaCl diet whereas the other was placed on a high (8%)-NaCl diet. At 6 months of age, diabetes was confirmed by glucose tolerance testing. Hemodynamic parameters were measured in the freely moving animal (ia) before and after the administration of prazosin (peripheral alpha1-adrenergic antagonist, iv) or clonidine (central alpha2-adrenergic agonist). The NIDD rat displayed a higher (P < .05) blood glucose concentration than the nondiabetic control rat during the glucose tolerance test. Elevated dietary NaCl significantly increased mean arterial pressure (MAP) in the uninephrectomized, but not the sham-operated groups. Acute administration of prazosin resulted in a significantly greater reduction in MAP of both hypertensive groups than of their normotensive counterparts. Moreover, clonidine caused a significant reduction in MAP of the hypertensive control rat but not in the normotensive controls. By contrast, both the hypertensive NIDD and the normotensive NIDD rats showed a similar reduction in MAP in response to clonidine administration. The data suggest that the combination of uninephrectomy and dietary NaCl excess confers hypertension on the NIDD rat. Moreover, enhancement of the sympathetic pathway plays an important role in the regulation of arterial pressure in the hypertensive NIDD rat. PMID:10826407

  12. Inactivation of p53 Is Sufficient to Induce Development of Pulmonary Hypertension in Rats

    PubMed Central

    Jacquin, S.; Rincheval, V.; Mignotte, B.; Richard, S.; Humbert, M.; Mercier, O.; Londoo-Vallejo, A.; Fadel, E.; Eddahibi, S.

    2015-01-01

    Objective Pulmonary artery smooth muscle cells (PA-SMCs) in pulmonary arterial hypertension (PAH) show similarities to cancer cells. Due to the growth-suppressive and pro-apoptotic effects of p53 and its inactivation in cancer, we hypothesized that the p53 pathway could be altered in PAH. We therefore explored the involvement of p53 in the monocrotaline (MCT) rat model of pulmonary hypertension (PH) and the pathophysiological consequences of p53 inactivation in response to animal treatment with pifithrin-? (PFT, an inhibitor of p53 activity). Methods and Results PH development was assessed by pulmonary arterial pressure, right ventricular hypertrophy and arterial wall thickness. The effect of MCT and PFT on lung p53 pathway expression was evaluated by western blot. Fourteen days of daily PFT treatment (2.2 mg/kg/day), similar to a single injection of MCT (60 mg/kg), induced PH and aggravated MCT-induced PH. In the first week after MCT administration and prior to PH development, p53, p21 and MDM2 protein levels were significantly reduced; whereas PFT administration effectively altered the protein level of p53 targets. Anti-apoptotic and pro-proliferative effects of PFT were revealed by TUNEL and MTT assays on cultured human PA-SMCs treated with 50 ?M PFT. Conclusions Pharmacological inactivation of p53 is sufficient to induce PH with a chronic treatment by PFT, an effect related to its anti-apoptotic and pro-proliferative properties. The p53 pathway was down-regulated during the first week in the rat MCT model. These in vivo experiments implicate the p53 pathway at the initiation stages of PH pathogenesis. PMID:26121334

  13. Myocyte cytoskeletal disorganization and right heart failure in hypoxia-induced neonatal pulmonary hypertension.

    PubMed

    Lemler, M S; Bies, R D; Frid, M G; Sastravaha, A; Zisman, L S; Bohlmeyer, T; Gerdes, A M; Reeves, J T; Stenmark, K R

    2000-09-01

    Previous studies have demonstrated that environmentally or genetically induced changes in the intracellular proteins that compose the cytoskeleton can contribute to heart failure. Because neonatal right ventricular myocytes are immature and are in the process of significant cytoskeletal change, we hypothesized that they may be particularly susceptible to pressure stress. Newborn calves exposed to hypobaric hypoxia (barometric pressure = 430 mmHg) for 14 days developed severe pulmonary hypertension (pulmonary arterial pressure = 101 +/- 6 vs. 27 +/- 1 mmHg) and right heart failure compared with age-matched controls. Light microscopy showed partial loss of myocardial striations in the failing neonatal right but not left ventricles and in neither ventricle of adolescent cattle dying of altitude-induced right heart failure. In neonatal calves, immunohistochemical analysis of the cytoskeletal proteins (vinculin, metavinculin, desmin, vimentin, and cadherin) showed selectively, within the failing right ventricles, patchy areas characterized by loss and disorganization of costameres and intercalated discs. Within myocytes from the failing ventricles, vinculin and desmin were observed to redistribute diffusely within the cytosol, metavinculin appeared in disorganized clumps, and vimentin immunoreactivity was markedly decreased. Western blot analysis of the failing right ventricular myocardium showed, compared with control, vinculin and desmin to be little changed in total content but redistributed from insoluble (structural) to soluble (cytosolic) fractions; metavinculin total content was markedly decreased, tubulin content increased, particularly in the structural fraction, and cadherin total content and distribution were unchanged. We conclude that hypoxic pulmonary hypertensive-induced neonatal right ventricular failure is associated with disorganization of the cytoskeletal architecture. PMID:10993804

  14. Effect of Lysyl Oxidase Inhibition on Angiotensin II-Induced Arterial Hypertension, Remodeling, and Stiffness

    PubMed Central

    Eberson, Lance S.; Sanchez, Pablo A.; Majeed, Beenish A.; Tawinwung, Supannikar; Secomb, Timothy W.; Larson, Douglas F.

    2015-01-01

    It is well accepted that angiotensin II (Ang II) induces altered vascular stiffness through responses including both structural and material remodeling. Concurrent with remodeling is the induction of the enzyme lysyl oxidase (LOX) through which ECM proteins are cross-linked. The study objective was to determine the effect of LOX mediated cross-linking on vascular mechanical properties. Three-month old mice were chronically treated with Ang II with or without the LOX blocker, β -aminopropionitrile (BAPN), for 14 days. Pulse wave velocity (PWV) from Doppler measurements of the aortic flow wave was used to quantify in vivo vascular stiffness in terms of an effective Young’s modulus. The increase in effective Young’s modulus with Ang II administration was abolished with the addition of BAPN, suggesting that the material properties are a major controlling element in vascular stiffness. BAPN inhibited the Ang II induced collagen cross-link formation by 2-fold and PWV by 44% (P<0.05). Consistent with this observation, morphometric analysis showed that BAPN did not affect the Ang II mediated increase in medial thickness but significantly reduced the adventitial thickness. Since the hypertensive state contributes to the measured in vivo PWV stiffness, we removed the Ang II infusion pumps on Day 14 and achieved normal arterial blood pressures. With pump removal we observed a decrease of the PWV in the Ang II group to 25% above that of the control values (P=0.002), with a complete return to control values in the Ang II plus BAPN group. In conclusion, we have shown that the increase in vascular stiffness with 14 day Ang II administration results from a combination of hypertension-induced wall strain, adventitial wall thickening and Ang II mediated LOX ECM cross-linking, which is a major material source of vascular stiffening, and that the increased PWV was significantly inhibited with co-administration of BAPN. PMID:25875748

  15. Calorie Restriction Attenuates Monocrotaline-induced Pulmonary Arterial Hypertension in Rats.

    PubMed

    Ding, Mingge; Lei, Jingyi; Qu, Yinxian; Zhang, Huan; Xin, Weichuan; Ma, Feng; Liu, Shuwen; Li, Zhichao; Jin, Faguang; Fu, Enqing

    2015-06-01

    Calorie restriction (CR) is one of the most effective nonpharmacological interventions protecting against cardiovascular disease, such as hypertension in the systemic circulation. However, whether CR could attenuate pulmonary arterial hypertension (PAH) is largely unknown. The PAH model was developed by subjecting the rats to a single subcutaneous injection of monocrotaline. CR lowered mean pulmonary arterial pressure (mPAP) and reduced vascular remodeling and right ventricular hypertrophy in PAH rats. Meanwhile, CR attenuated endothelial dysfunction as evidenced by increased relaxation in response to acetylcholine. The beneficial effects of CR were associated with restored sirtuin-1 (SIRT1) expression and endothelial nitric oxide synthase (eNOS) phosphorylation and reduced eNOS acetylation in pulmonary arteries of PAH rats. To further clarify the role of SIRT1 in the protective effects of CR, adenoviral vectors for overexpression of SIRT1 were administered intratracheally at 1 day before monocrotaline injection. Overexpression of SIRT1 exhibited similar beneficial effects on mPAP and endothelial function, and increased eNOS phosphorylation and reduced eNOS acetylation in the absence of CR. Moreover, SIRT1 overexpression attenuated the increase in mPAP in hypoxia-induced PAH animals. Overall, the present data demonstrate that CR may serve as an effective treatment of PAH, and targeting the SIRT1/eNOS pathway may improve treatment of PAH. PMID:25636073

  16. Lead Poisoning-Induced Hypertensive Crisis Managed by Prazosin: A Case Report

    PubMed Central

    Dadpour, Bita; Mehrpour, Omid; Etemad, Leila; Moshiri, Mohammad

    2013-01-01

    Introduction Chronic lead exposure is known to be a risk factor for hypertension (HTN). No specific medication is recommended for the treatment of lead-induced hypertension (LIHTN). Case Presentation Our patient was a male admitted with the chief complaint of chronic abdominal pain. His whole blood lead level was reported to be 1961 g/L. He also mentioned a previous history of HTN managed by propranolol (10 mg, TDS). He discharged himself by giving written consent and 19 days later, he was re-admitted due to high blood pressure of 220/140 mmHg. His Blood pressure (BP) was decreased to 180/110 mmHg with sublingual captopril; but, in maintenance therapy, higher doses of captopril could not further decrease BP. Amlodipine was tried which was discontinued due to the patient intolerance. Prazosin was then administered in gradual increasing doses up to 1 mg twice a day and captopril was tapered. Conclusions We would like to suggest that LIHTN may better be managed by alpha blockers compared with converting enzyme inhibitors PMID:24349754

  17. Cerebral microvascular inflammation in DOCA salt-induced hypertension: role of angiotensin II and mitochondrial superoxide

    PubMed Central

    Rodrigues, Stephen F; Granger, Daniel Neil

    2012-01-01

    Angiotensin II-mediated hypertension (HTN) is accompanied by a pro-inflammatory and pro-thrombotic state in the cerebral microvasculature. Whether comparable phenotypic changes are elicited in other models of HTN remains unclear. Using wild-type mice with deoxycorticosterone acetate (DOCA) salt-induced HTN and intravital microscopy, we observed significant increases in the adhesion of both leukocytes and platelets in cerebral venules, compared with uninephrectomized control mice, without an accompanying increase in bloodbrain barrier permeability. The cellcell interactions in hypertensive mice were more pronounced after ischemic stroke, but no difference in infarct size was detected. The blood cell recruitment was largely prevented in the following groups of DOCA salt mice: losartan (angiotensin II AT1 receptor blocker) treated, AT1 receptor knockout mice, tempol (a membrane-permeable oxygen radical scavenger) treated, and mito-TEMPO (a mitochondria-targeted antioxidant) treated. A similar pattern of protection was noted in mice subjected to ischemic stroke. The blunted cell recruitment responses were not accompanied by reductions in blood pressure (BP). These findings implicate mitochondria-derived oxygen radicals and angiotensin II in the cerebral inflammation associated with DOCA salt HTN and suggests that BP per se is not a critical determinant of the phenotypic changes that accompany HTN, even after ischemic stroke. PMID:21971354

  18. Glucocorticoid-induced hypertension in rats: role of the central muscarinic cholinergic system.

    PubMed

    Torres, N; Fanelli, M; Alvarez, A L; Santajuliana, D; Finkielman, S; Pirola, C J

    1991-05-01

    Betamethasone was administered on alternate days to rats, and the role of the central cholinergic system in the development of hypertension assessed. After 15 days of treatment the systolic blood pressure of treated rats was significantly higher than that of control rats. Peripheral administration of atropine but not of methyl atropine reduced systolic pressure in glucocorticoid-treated rats and had no effect in controls. Therefore, [3H]quinuclidinyl benzylate binding, sodium-dependent high-affinity choline uptake and choline acetyltransferase studies were performed in the septal area, anteroventrolateral medulla (AVLM), anterior hypothalamic preoptic area (AH/PO) and hypothalamus. The density of muscarinic receptors was increased in the hypothalamus and AVLM of treated rats without significant changes in affinity. Choline acetyltransferase activity significantly decreased in the AVLM and increased in the AH/PO. In addition, a decrease in the hypothalamus and an increase in the AH/PO of sodium-dependent high-affinity choline uptake was observed in glucocorticoid-treated rats. These results suggest the presence of an enhanced muscarinic cholinergic activity in several brain nuclei in rats with glucocorticoid-induced hypertension. This activation could be due to pre- and post-synaptic hypersensitivity. PMID:2040860

  19. CYP450 4A Inhibition Attenuates O2 Induced Arteriolar Constriction in Chronic but not Acute Goldblatt Hypertension

    PubMed Central

    Kunert, Mary Pat; Friesma, Jill; Falck, John R.; Lombard, Julian H.

    2009-01-01

    We explored the role of 20-hydroxy-5Z, 8Z, 11Z, 14Z-eicosatetraenoic acid (20-HETE) in oxygen-induced vasoconstriction in a normal renin form of hypertension [the 1 kidney-1 clip Goldblatt hypertensive rat (1K1C)] and a high renin form of hypertension [the 2 kidney-1 clip Goldblatt hypertensive rat (2K1C)]. A silver clip was placed around the left renal artery of adult Sprague-Dawley males. The right kidney was removed in the 1K1C group and left intact in the 2K1C group. Arteriolar responses to elevation of O2 concentration in the superfusion solution from 0% O2 to 21% O2 were determined in the in situ cremaster muscle before and after inhibition of cytochrome P450 4A ?-hydroxylase (CYP450 4A) with N-methyl-sulfonyl-12, 12-dibromododec-11-enamide (DDMS). Arteriolar constriction to elevated PO2 was enhanced in the chronic 1K1C but not the acute 1K1C or 2K1C. DDMS eliminated O2-induced arteriolar constriction in the 9 week 1K1C, but had no effect in the 2 wk 1K1C, and only partially inhibited O2-induced constriction of arterioles in the 4 wk 2K1C rat. These findings indicate that although the CYP4A/20-HETE system contributes to arteriolar constriction in response to elevated PO2 in the established stage of 1K1C renovascular hypertension, physiological alterations in other mechanisms are the primary determinants of O2-induced constriction of arterioles in the early and developing stages of 1K1C and 2K1C hypertension. PMID:19761780

  20. Elevated Transglutaminase 2 Activity is Associated with Hypoxia-Induced Experimental Pulmonary Hypertension in Mice

    PubMed Central

    DiRaimondo, Thomas R.; Klock, Cornelius; Warburton, Rod; Herrera, Zachary; Penumatsa, Krishna; Toksoz, Deniz; Hill, Nicholas; Khosla, Chaitan; Fanburg, Barry

    2013-01-01

    Previous studies in human patients and animal models have suggested that transglutaminase 2 (TG2) is upregulated in pulmonary hypertension (PH), a phenomenon that appears to be associated with the effects of serotonin (5-hydroxytryptamine; 5-HT) in this disease. Using chemical tools to interrogate and inhibit TG2 activity in vivo, we have shown that pulmonary TG2 undergoes marked post-translational activation in a mouse model of hypoxia-induced PH. We have also identified irreversible fluorinated TG2 inhibitors that may find use as non-invasive positron emission tomography probes for diagnosis and management of this debilitating, lifelong disorder. Pharmacological inhibition of TG2 attenuated the elevated right ventricular pressure but had no effect on hypertrophy of the right ventricle of the heart. A longitudinal study of pulmonary TG2 activity in PH patients is warranted. PMID:24152195

  1. CYP4A2-Induced Hypertension is 20-HETE and Angiotensin II-Dependent

    PubMed Central

    Sodhi, Komal; Wu, Cheng-Chia; Cheng, Jennifer; Gotlinger, Katherine; Inoue, Kazuyoshi; Goli, Mohan; Falck, John R.; Abraham, Nader G.; Schwartzman, Michal L.

    2010-01-01

    We have previously shown that increased vascular endothelial expression of CYP4A2 leads to 20-HETE-dependent hypertension. The renin-angiotensin system (RAS) is a key regulator of blood pressure. In this study, we examined possible interactions between 20-HETE and RAS. In normotensive (1103 mmHg) Sprague Dawley rats transduced with a lentivirus expressing the CYP4A2 cDNA under the control of an endothelial-specific promoter (VECAD-4A2), systolic blood pressure increased rapidly, reaching 1391, 1453 and 1502 mmHg at 3, 5 and 10 days after transduction; blood pressure remained elevated, thereafter, with maximum levels of 1633 mmHg. Treatment with lisinopril, losartan or the 20-HETE antagonist 20-hydroxyeicosa-6(Z), 15(Z)-dienoic acid (20-HEDE) decreased blood pressure to control values, but blood pressure returned to its high levels after cessation of treatment. Endothelial-specific overexpression of CYP4A2 resulted in increased expression of vascular angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) and increased levels of plasma and tissue Angiotensin II; all were attenuated by treatment with HET0016, an inhibitor of 20-HETE synthesis, or with 20-HEDE. In cultured endothelial cells, 20-HETE specifically and potently induced ACE expression without altering the expression of ACE2, angiotensinogen or angiotensin II receptors. This is the first study to demonstrate that 20-HETE, a key constrictor eicosanoid in the microcirculation, induces ACE and AT1R expression and increases Angiotensin II levels, suggesting that the mechanisms by which 20-HETE promotes hypertension include activation of RAS that is likely initiated at the level of ACE induction. PMID:20837888

  2. The Beneficial Effect of Suramin on Monocrotaline-Induced Pulmonary Hypertension in Rats

    PubMed Central

    Izikki, Mohamed; Mercier, Olaf; Lecerf, Florence; Lubert Guin, Lauriane; Hoang, Eric; Dorfmller, Peter; Perros, Frdric; Humbert, Marc; Simonneau, Gerald; Dartevelle, Philippe; Fadel, Elie; Eddahibi, Saadia

    2013-01-01

    Background Pulmonary hypertension (PH) is a progressive disorder characterized by an increase in pulmonary artery pressure and structural changes in the pulmonary vasculature. Several observations indicate that growth factors play a key role in PH by modulating pulmonary artery smooth muscle cell (PA-SMC) function. In rats, established monocrotaline-induced PH (MCT-PH) can be reversed by blocking platelet-derived growth factor receptors (PDGF-R), epidermal growth factor receptors (EGF-R), or fibroblast growth factor receptors (FGF-R). All these receptors belong to the receptor tyrosine kinase (RTK) family. Methods and Results We evaluated whether RTK blockade by the nonspecific growth factor inhibitor, suramin, reversed advanced MCT-PH in rats via its effects on growth-factor signaling pathways. We found that suramin inhibited RTK and ERK1/2 phosphorylation in cultured human PA-SMCs. Suramin inhibited PA-SMC proliferation induced by serum, PDGF, FGF2, or EGF in vitro and ex vivo. Treatment with suramin from day 1 to day 21 after monocrotaline injection attenuated PH development, as shown by lower values for pulmonary artery pressure, right ventricular hypertrophy, and distal vessel muscularization on day 21 compared to control rats. Treatment with suramin from day 21 to day 42 after monocrotaline injection reversed established PH, thereby normalizing the pulmonary artery pressure values and vessel structure. Suramin treatment suppressed PA-SMC proliferation and attenuated both the inflammatory response and the deposition of collagen. Conclusions RTK blockade by suramin can prevent MCT-PH and reverse established MCT-PH in rats. This study suggests that an anti-RTK strategy that targets multiple RTKs could be useful in the treatment of pulmonary hypertension. PMID:24143201

  3. Heme oxygenase induction attenuates TNF-?-induced hypertension in pregnant rodents

    PubMed Central

    George, Eric M.; Stout, Jacob M.; Stec, David E.; Granger, Joey P.

    2015-01-01

    Pre-eclampsia is a hypertensive disorder of pregnancy initiated by placental insufficiency and chronic ischemia. In response, several pathways activated in the placenta are responsible for the maternal syndrome, including increased production of the anti-angiogenic protein, sFlt-1, and inflammatory cytokines, especially tumor necrosis factor-alpha (TNF-?). Previous studies have demonstrated that heme oxygenase (HO) induction can block TNF-? pathways in vitro and attenuate placental ischemia-induced sFlt-1 in vivo. Here, we investigated whether HO-1 induction could attenuate TNF-?-induced hypertension in pregnant rats. In response to TNF-? infusion (100 ng/day i.p.), maternal mean arterial pressure (MAP) increased vs. control animals (104 3 vs. 119 3 mmHg). HO-1 induction had no effect in control animals, but significantly decreased MAP in TNF-?-infused animals (108 2 mmHg). Placental vascular endothelial growth factor (VEGF) was decreased in response to TNF-? infusion (92 4 vs. 76 2 pg/mg). Placental sFlt-1 was increased by TNF-? infusion (758 45 vs. 936 46 pg/mg, p < 0.05), which trended to normalization by HO-1 induction (779 98 pg/mg). In contrast, HO-1 induction had no significant effect on placental VEGF in TNF-?-infused animals. Taken together, these data suggest that one of the key mechanisms by which HO exerts cytoprotective actions in the placenta during inflammation due to chronic ischemia is through suppression of sFlt-1. Further work elucidating the bioactive metabolites of HO-1 in innate inflammatory responses to placental ischemia is warranted. PMID:26347650

  4. Maternal Melatonin Therapy Rescues Prenatal Dexamethasone and Postnatal High-Fat Diet Induced Programmed Hypertension in Male Rat Offspring

    PubMed Central

    Tain, You-Lin; Sheen, Jiunn-Ming; Yu, Hong-Ren; Chen, Chih-Cheng; Tiao, Mao-Meng; Hsu, Chien-Ning; Lin, Yu-Ju; Kuo, Kuang-Che; Huang, Li-Tung

    2015-01-01

    Prenatal dexamethasone (DEX) exposure and high-fat (HF) intake are linked to hypertension. We examined whether maternal melatonin therapy prevents programmed hypertension synergistically induced by prenatal DEX plus postnatal HF in adult offspring. We also examined whether DEX and melatonin causes renal programming using next-generation RNA sequencing (NGS) technology. Pregnant Sprague-Dawley rats received intraperitoneal dexamethasone (0.1 mg/kg) or vehicle from gestational day 16 to 22. In the melatonin-treatment groups (M), rats received 0.01% melatonin in drinking water during their entire pregnancy and lactation. Male offspring were assigned to five groups: control, DEX, HF, DEX+HF, and DEX+HF+M. Male offspring in the HF group were fed a HF diet from weaning to 4 months of age. Prenatal DEX and postnatal HF diet synergistically induced programmed hypertension in adult offspring, which melatonin prevented. Maternal melatonin treatment modified over 3000 renal transcripts in the developing offspring kidney. Our NGS data indicate that PPAR signaling and fatty acid metabolism are two significantly regulated pathways. In addition, maternal melatonin therapy elicits longstanding alterations on renal programming, including regulation of the melatonin signaling pathway and upregulation of Agtr1b and Mas1 expression in the renin-angiotensin system (RAS), to protect male offspring against programmed hypertension. Postnatal HF aggravates prenatal DEX induced programmed hypertension in adult offspring, which melatonin prevented. The protective effects of melatonin on programmed hypertension is associated with regulation of the RAS and melatonin receptors. The long-term effects of maternal melatonin therapy on renal transcriptome require further clarification. PMID:26696906

  5. Pulmonary Hypertension

    PubMed Central

    Newman, John H.

    2005-01-01

    The modern era in cardiopulmonary medicine began in the 1940s, when Cournand and Richards pioneered right-heart catheterization. Until that time, no direct measurement of central vascular pressure had been performed in humans. Right-heart catheterization ignited an explosion of insights into function and dysfunction of the pulmonary circulation, cardiac performance, ventilationperfusion relationships, lungheart interactions, valvular function, and congenital heart disease. It marked the beginnings of angiocardiography with its diagnostic implications for diseases of the left heart and peripheral circulation. Pulmonary hypertension was discovered to be the consequence of a large variety of diseases that either raised pressure downstream of the pulmonary capillaries, induced vasoconstriction, increased blood flow to the lung, or obstructed the pulmonary vessels, either by embolism or in situ fibrosis. Hypoxic vasoconstriction was found to be a major cause of acute and chronic pulmonary hypertension, and surprising vasoreactivity of the pulmonary vascular bed was discovered to be present in many cases of severe pulmonary hypertension, initially in mitral stenosis. Diseases as disparate as scleroderma, cystic fibrosis, kyphoscoliosis, sleep apnea, and sickle cell disease were found to have shared consequences in the pulmonary circulation. Some of the achievements of Cournand and Richards and their scientific descendents are discussed in this article, including success in the diagnosis and treatment of idiopathic pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, and management of hypoxic pulmonary hypertension. PMID:15994464

  6. Role of digitalis-like substance in the hypertension of streptozotocin-induced diabetes and simulated weightlessness in rats

    NASA Technical Reports Server (NTRS)

    Pamnani, M. B.; Chen, S.; Haddy, F. J.; Yuan, C.; Mo, Z.

    1998-01-01

    We have examined the role of plasma Na+-K+ pump inhibitor (SPI) in the hypertension of streptozotocin induced insulin dependent diabetes (IDDM) in reduced renal mass rats. The increase in blood pressure (BP) was associated with an increase in extracellular fluid volume (ECFV), and SPI and a decrease in myocardial Na+,K+ATPase (NKA) activity, suggesting that increased SPI, which inhibits cardiovascular muscle (CVM) cell NKA activity, may be involved in the mechanism of IDDM-hypertension. In a second study, using prolonged suspension resulted in a decrease in cardiac NKA activity, suggesting that cardiovascular deconditioning following space flight might in part result from insufficient SPI.

  7. Structural and functional prevention of hypoxia-induced pulmonary hypertension by individualized exercise training in mice.

    PubMed

    Weissmann, Norbert; Peters, Dorothea M; Klpping, Christina; Krger, Karsten; Pilat, Christian; Katta, Susmitha; Seimetz, Michael; Ghofrani, Hossein A; Schermuly, Ralph T; Witzenrath, Martin; Seeger, Werner; Grimminger, Friedrich; Mooren, Frank C

    2014-06-01

    Pulmonary hypertension (PH) is a disease with a poor prognosis characterized by a vascular remodeling process and an increase in pulmonary vascular resistance. While a variety of reports demonstrated that exercise training exerts beneficial effects on exercise performance and quality of life in PH patients, it is not known how physical exercise affects vascular remodeling processes occurring in hypoxia-induced PH. Therefore, we investigated the effect of individualized exercise training on the development of hypoxia-induced PH in mice. Training effects were compared with pharmacological treatment with the phosphodiesterase 5 inhibitor Sildenafil or a combination of training plus Sildenafil. Trained mice who received Sildenafil showed a significantly improved walking distance (from 88.9 8.1 to 146.4 13.1 m) and maximum oxygen consumption (from 93.3 2.9 to 105.5 2.2% in combination with Sildenafil, to 102.2 3.0% with placebo) compared with sedentary controls. Right ventricular systolic pressure, measured by telemetry, was at the level of healthy normoxic animals, whereas right heart hypertrophy did not benefit from training. Most interestingly, the increase in small pulmonary vessel muscularization was prevented by training. Respective counterregulatory processes were detected for the nitric oxide-soluble guanylate cyclase-phosphodiesterase system. We conclude that individualized daily exercise can prevent vascular remodeling in hypoxia-induced PH. PMID:24705723

  8. Predictive factor and antihypertensive usage of tyrosine kinase inhibitor-induced hypertension in kidney cancer patients.

    PubMed

    Izumi, Kouji; Itai, Shingo; Takahashi, Yoshiko; Maolake, Aerken; Namiki, Mikio

    2014-07-01

    Hypertension (HT) is the common adverse event associated with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKI). The present study was performed to identify the predictive factors of TKI-induced HT and to determine the classes of antihypertensive agents (AHTA) that demonstrate optimal efficacy against this type of HT. The charts of 50 cases of patients that had received VEGFR-TKI treatment were retrospectively examined. The association between patient background and TKI-induced HT, and the effect of administering AHTA were analyzed. High systolic blood pressure at baseline was identified to be a predictive factor for HT. In addition, there was no difference observed between calcium channel blockers (CCBs) and angiotensin receptor II blockers (ARBs) as first-line AHTA for the control of HT. The findings of the present study may aid with predicting the onset of TKI-induced HT, as well as for its management via the primary use of either CCBs or ARBs. PMID:24959266

  9. Cerium oxide nanoparticles attenuate monocrotaline induced right ventricular hypertrophy following pulmonary arterial hypertension

    PubMed Central

    Kolli, Madhukar B.; Manne, Nandini D.P.K.; Para, Radhakrishna; Nalabotu, Siva K.; Nandyala, Geeta; Shokuhfar, Tolou; He, Kun; Hamlekhan, Azhang; Ma, Jane Y.; Wehner, Paulette S.; Dornon, Lucy; Arvapalli, Ravikumar; Rice, Kevin M.; Blough, Eric R.

    2016-01-01

    Cerium oxide (CeO2) nanoparticles have been posited to exhibit potent anti-oxidant activity which may allow for the use of these materials in biomedical applications. Herein, we investigate whether CeO2 nanoparticle administration can diminish right ventricular (RV) hypertrophy following four weeks of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Male Sprague Dawley rats were randomly divided into three groups: control, MCT only (60 mg/kg), or MCT + CeO2 nanoparticle treatment (60 mg/kg; 0.1 mg/kg). Compared to the control group, the RV weight to body weight ratio was 45% and 22% higher in the MCT and MCT + CeO2 groups, respectively (p < 0.05). Doppler echocardiography demonstrated that CeO2 nanoparticle treatment attenuated monocrotaline-induced changes in pulmonary flow and RV wall thickness. Paralleling these changes in cardiac function, CeO2 nanoparticle treatment also diminished MCT-induced increases in right ventricular (RV) cardiomyocyte cross sectional area, β-myosin heavy chain, fibronectin expression, protein nitrosylation, protein carbonylation and cardiac superoxide levels. These changes with treatment were accompanied by a decrease in the ratio of Bax/Bcl2, diminished caspase-3 activation and reduction in serum inflammatory markers. Taken together, these data suggest that CeO2 nanoparticle administration may attenuate the hypertrophic response of the heart following PAH. PMID:25224369

  10. Alterations in phenylephrine-induced contractions and the vascular expression of Na+,K+-ATPase in ouabain-induced hypertension

    PubMed Central

    Rossoni, Luciana V; Salaices, Mercedes; Marín, Jesús; Vassallo, Dalton V; Alonso, María J

    2002-01-01

    Hypertension development, phenylephrine-induced contraction and Na+,K+-ATPase functional activity and protein expression in aorta (AO), tail (TA) and superior mesenteric (SMA) arteries from ouabain- (25 μg day−1, s.c., 5 weeks) and vehicle-treated rats were evaluated.Ouabain treatment increased systolic blood pressure (127±1 vs 160±2 mmHg, n=24, 35; P<0.001) while the maximum response to phenylephrine was reduced (P<0.01) in AO (102.8±3.9 vs 67.1±10.1% of KCl response, n=12, 9) and SMA (82.5±7.5 vs 52.2±5.8%, n=12, 9).Endothelium removal potentiated the phenylephrine response to a greater extent in segments from ouabain-treated rats. Thus, differences of area under the concentration-response curves (dAUC) in endothelium-denuded and intact segments for control and ouabain-treated rats were, respectively: AO, 56.6±9.6 vs 198.3±18.3 (n=9, 7); SMA, 85.5±15.4 vs 165.4±24.8 (n=6, 6); TA, 13.0±6.1 vs 39.5±10.4% of the corresponding control AUC (n=6, 6); P<0.05.The relaxation to KCl (1 – 10 mM) was similar in segments from both groups. Compared to controls, the inhibition of 0.1 mM ouabain on KCl relaxation was greater in AO (dAUC: 64.8±4.6 vs 84.0±5.1%, n=11, 14; P<0.05), similar in SMA (dAUC: 39.1±3.9 vs 43.3±7.8%, n=6, 7; P>0.05) and smaller in TA (dAUC: 62.1±5.5 vs 41.4±8.2%, n=12, 13; P<0.05) in ouabain-treated rats.Protein expression of both α1 and α2 isoforms of Na+,K+-ATPase was augmented in AO, unmodified in SMA and reduced in TA from ouabain-treated rats.These results suggest that chronic administration of ouabain induces hypertension and regional vascular alterations, the latter possibly as a consequence of the hypertension. PMID:11834625

  11. Endothelin-1-induced contraction is impaired in the tail artery of renal hypertensive rats.

    PubMed

    Linder, Aurea Elizabeth; Bendhack, Lusiane Maria

    2002-07-01

    The contraction induced by endothelin-1 (ET-1) was evaluated in tail arteries from normotensive two-kidney (2K) and hypertensive two-kidney-one-clip (2K-1C) rats. Since the maximal effect induced by ET-1 (0.1-30 or 100 nmol/l) was lower in 2K-1C (1.11 +/- 0.10 g) than in 2K (1.46 +/- 0.14 g) tail arteries, we evaluated the possible mechanisms involved in this blunted response. The sensitivity and efficacy of ET-1 were not affected by endothelium removal in either group. ET-1 failed to induce contraction of 2K and 2K-1C arteries in Ca(2+)-free medium. The contractile response induced by 10 nmol/l ET-1 was similarly inhibited by 0.1 microM nifedipine in arteries from 2K (81.6 +/- 3.3%) and 2K-1C (81.3 +/- 3.8%) rats. The effect of nifedipine was not potentiated by 10 mumol/l SK&F 96365. The cytosolic Ca2+ concentration ([Ca2+]c) was similarly increased by 30 nmol/l ET-1 in smooth muscle cells isolated from tail arteries of 2K (30.80 +/- 11.94 nmol/l) and 2K-1C (54.06 +/- 10.98 nmol/l) rats. In conclusion, the blunted contraction induced by ET-1 in 2K-1C tail arteries was not dependent on the endothelium or on decreased Ca2+ influx through channels sensitive to nifedipine or SK&F 96365. Since the increase of [Ca2+]c upon stimulation with ET-1 was similar in 2K and 2K-1C tail artery cells, probably the sensitivity to Ca2+ is decreased in 2K-1C tail arteries. PMID:12616994

  12. Microtubule proliferation in right ventricular myocytes of rats with monocrotaline-induced pulmonary hypertension

    PubMed Central

    Stones, Rachel; Benoist, David; Peckham, Michelle; White, Ed

    2013-01-01

    Microtubules are components of the cardiac cytoskeleton that can proliferate in response to pressure-overload in animal and human heart failure. We wished to test whether there was a proliferation of the microtubule cytoskeleton in the right ventricle of rats with pulmonary hypertension induced by monocrotaline (MCT) and whether this contributed to contractile dysfunction. Male Wistar rats were injected with 60mg/kg of MCT in saline or an equivalent volume of saline (CON). MCT produced clinical signs of heart failure within 4weeks of injection. Expression of right ventricular mRNA for ?-tubulin was measured by real-time reverse transcription polymerase chain reaction. Free and polymerised fractions of ?-tubulin protein were assessed using Western blot analysis and immunofluorescence microscopy was used to assess tyrosinated and acetylated (stabilized) microtubules. Right ventricular myocyte contraction was measured in response to the microtubule de-polymeriser colchicine (10?mol/l for at least 1h). Compared to CON, in MCT right ventricles there was a small but statistically significant increase in the expression of mRNA for ?-tubulin (P<0.001); total (P<0.05) and polymerised fraction (P<0.01) of ?-tubulin protein and level of acetylated tubulin (P<0.01). However colchicine treatment did not increase the contraction of MCT myocytes (P>0.05) or affect their response to increased stimulation frequency. Our observations support the hypothesis that microtubule proliferation is a common response to pulmonary hypertension in failing right ventricles but suggest that the effect this has on contraction depends upon the specific experimental or clinical conditions that prevail and the subsequent level of microtubule proliferation. PMID:23261965

  13. Effect of deoxycorticosterone acetate-salt-induced hypertension on diabetic peripheral neuropathy in alloxan-induced diabetic WBN/Kob rats

    PubMed Central

    Ozaki, Kiyokazu; Hamano, Hiroko; Matsuura, Tetsuro; Narama, Isao

    2015-01-01

    The relationship between hypertension and diabetic peripheral neuropathy (DPN) has recently been reported in clinical research, but it remains unclear whether hypertension is a risk factor for DPN. To investigate the effects of hypertension on DPN, we analyzed morphological features of peripheral nerves in diabetic rats with hypertension. Male WBN/Kob rats were divided into 2 groups: alloxan-induced diabetic rats with deoxycorticosterone acetate-salt (DOCA-salt) treatment (ADN group) and nondiabetic rats with DOCA-salt treatment (DN group). Sciatic, tibial (motor) and sural (sensory) nerves were subjected to qualitative and quantitative histomorphological analysis. Systolic blood pressure in the two groups exhibited a higher value (>140 mmHg), but there was no significant difference between the two groups. Endoneurial blood vessels in both groups presented endothelial hypertrophy and narrowing of the vascular lumen. Electron microscopically, duplication of basal lamina surrounding the endothelium and pericyte of the endoneurial vessels was observed, and this lesion appeared to be more frequent and severe in the ADN group than the DN group. Many nerve fibers of the ADN and DN groups showed an almost normal appearance, whereas morphometrical analysis of the tibial nerve showed a significant shift to smaller fiber and myelin sizes in the ADN group compared with DN group. In sural nerve, the fiber and axon-size significantly shifted to a smaller size in ADN group compared with the DN group. These results suggest that combined diabetes and hypertension could induce mild peripheral nerve lesions with vascular changes. PMID:26989296

  14. Activation of peroxisome proliferator-activated receptor ? ameliorates monocrotaline-induced pulmonary arterial hypertension in rats

    PubMed Central

    XIE, XINMING; WANG, GUIZUO; ZHANG, DEXIN; ZHANG, YONGHONG; ZHU, YANTING; LI, FANGWEI; LI, SHAOJUN; LI, MANXIANG

    2015-01-01

    Activation of peroxisome proliferator-activated receptor ? (PPAR?) suppresses the proliferation of pulmonary artery smooth muscle cells (PASMCs) and vascular remodeling in rats and humans, and therefore improves the development of pulmonary arterial hypertension (PAH). However, molecular mechanisms underlying these effects have not been completely understood. In the present study, the effects of PPAR? activation in monocrotaline (MCT)-induced pulmonary artery remodeling in rats were investigated. Eighteen Sprague-Dawley (SD) rats were randomly assigned into three groups (n=6): Control (Con), PAH and PAH treated with rosiglitazone (MCT + Rosi). The right ventricular systolic pressure (RVSP), the ratio of the right to left ventricle plus septum weight [RV/(LV + S)], the percentage of medial wall thickness (%MT) and wall area (%WA) were used to evaluate the development of PAH. Tissue morphology was measured using hematoxylin and eosin staining. The protein levels of the phosphatase and tensin homologue deleted on chromosome ten (PTEN), Akt (ser473) phosphorylation (p-Akt) and total Akt in intrapulmonary arteries were determined by western blot analysis. MCT treatment significantly increased the RVSP, which was reduced by rosiglitazone treatment. The ratio of RV/(LV + S), %MT and %WA induced by MCT were similarly inhibited, which was associated with the increase of PTEN expression and the inhibition of Akt phosphorylation levels by rosiglitazone. In conclusion, activation of PPAR? ameliorates the proliferation of PASMCs and vascular remodeling by regulating the PTEN/PI3K/Akt pathway, suggesting that the activation of PPAR? has potential benefits for PAH. PMID:26171162

  15. Effect of dietary tyrosine supplementation on development of deoxycorticosterone acetate (DOCA)-induced hypertension in rats

    SciTech Connect

    Henley, W.N.; Fregly, M.J.; Mihally, M.A.; Wilson, K.M.; Hathaway, S.

    1986-03-01

    Adult male Sprague-Dawley rats were unilaterally nephrectomized, given 0.15M NaCl to drink, and assigned to 1 or 4 groups: (a) control diet (CD); (b) CD plus DOCA (39 ..mu..g/rat/day); (c) CD supplemented with 2.5% 1-tyrosine (Tyr); and (d) Tyr plus DOCA. DOCA significantly elevated systolic blood pressure (SBP) within 2 weeks (P < 0.05); however, Tyr for 8 weeks failed to affect SBP. Direct measurement of BP confirmed these findings. Tyrosine also failed to affect the enhanced vascular reactivity (change in MBP to phenylephrine) noted in DOCA-treated rats. Although ineffective in these regards, Tyr alone induced both significant elevations in urinary excretion of free dopamine (week 1, 3, 5, 7) and a significant decrease in urinary free norepinephrine excretion (week 1). Tyr induced significant prolongations in the time-courses of metabolic and cardiovascular responses to the beta-adrenergic agonist, isoproterenol. The binding (B/sub max/) of /sup 3/H-yohimbine in cerebral cortical membranes was also reduced. Thus, chronic excess of precursor can affect the function of the adrenergic system, but these effects do not include mitigation of DOCA-salt hypertension.

  16. Iptakalim attenuates hypoxia-induced pulmonary arterial hypertension in rats by endothelial function protection.

    PubMed

    Zhu, Rong; Bi, Li-Qing; Wu, Su-Ling; Li, Lan; Kong, Hui; Xie, Wei-Ping; Wang, Hong; Meng, Zi-Li

    2015-08-01

    The present study aimed to investigate the protective effects of iptakalim, an adenosine triphosphate (ATP)-sensitive potassium channel opener, on the inflammation of the pulmonary artery and endothelial cell injury in a hypoxia-induced pulmonary arterial hypertension (PAH) rat model. Ninety-six Sprague-Dawley rats were placed into normobaric hypoxia chambers for four weeks and were treated with iptakalim (1.5 mg/kg/day) or saline for 28 days. The right ventricle systolic pressures (RVSP) were measured and small pulmonary arterial morphological alterations were analyzed with hematoxylin and eosin staining. Enzyme-linked immunosorbent assay (ELISA) was performed to analyze the content of interleukin (IL)-1β and IL-10. Immunohistochemical analysis for ED1(+) monocytes was performed to detect the inflammatory cells surrounding the pulmonary arterioles. Western blot analysis was performed to analyze the expression levels of platelet endothelial cell adhesion molecule-1 (PECAM-1) and endothelial nitric oxide synthase (eNOS) in the lung tissue. Alterations in small pulmonary arteriole morphology and the ultrastructure of pulmonary arterial endothelial cells were observed via light and transmission electron microscopy, respectively. Iptakalim significantly attenuated the increase in mean pulmonary artery pressure, RVSP, right ventricle to left ventricle plus septum ratio and small pulmonary artery wall remodeling in hypoxia-induced PAH rats. Iptakalim also prevented an increase in IL-1β and a decrease in IL-10 in the peripheral blood and lung tissue, and alleviated inflammatory cell infiltration in hypoxia-induced PAH rats. Furthermore, iptakalim enhanced PECAM-1 and eNOS expression and prevented the endothelial cell injury induced by hypoxic stimuli. Iptakalim suppressed the pulmonary arteriole and systemic inflammatory responses and protected against the endothelial damage associated with the upregulation of PECAM-1 and eNOS, suggesting that iptakalim may represent a potential therapeutic agent for PAH. PMID:25936382

  17. An inducible transgenic mouse model for familial hypertension with hyperkalaemia (Gordon's syndrome or pseudohypoaldosteronism type II).

    PubMed

    Chowdhury, Jabed A; Liu, Che-Hsiung; Zuber, Annie M; O'Shaughnessy, Kevin M

    2013-06-01

    Mutations in the novel serine/threonine WNK [With No lysine (=K)] kinases WNK1 and WNK4 cause PHAII (pseudohypoaldosteronism type II or Gordon's syndrome), a rare monogenic syndrome which causes hypertension and hyperkalaemia on a background of a normal glomerular filtration rate. Current animal models for PHAII recapitulate some aspects of the disease phenotype, but give no clues to how rapidly the phenotype emerges or whether it is reversible. To this end we have created an inducible PHAII transgenic animal model that expresses a human disease-causing WNK4 mutation, WNK4 Q565E, under the control of the Tet-On system. Several PHAII inducible transgenic mouse lines were created, each with differing TG (transgene) copy numbers and displaying varying degrees of TG expression (low, medium and high). Each of these transgenic lines demonstrated similar elevations of BP (blood pressure) and plasma potassium after 4 weeks of TG induction. Withdrawal of doxycycline switched off mutant TG expression and the disappearance of the PHAII phenotype. Western blotting of microdissected kidney nephron segments confirmed that expression of the thiazide-sensitive NCC (Na?-Cl? co-transporter) was increased, as expected, in the distal convoluted tubule when transgenic mice were induced with doxycycline. The kidneys of these mice also do not show the morphological changes seen in the previous transgenic model expressing the same mutant form of WNK4. This inducible model shows, for the first time, that in vivo expression of a mutant WNK4 protein is sufficient to cause the rapid and reversible appearance of a PHAII disease phenotype in mice. PMID:23336180

  18. Cilnidipine lowered psychological stress-induced increase in blood pressure in a hypertensive man: a case report

    PubMed Central

    Hayashida, Sota; Oka, Takakazu; Tsuji, Sadatoshi

    2007-01-01

    Background In some hypertensive patients, psychological stress makes blood pressure difficult to control and causes physical symptoms such as headache or dizziness. We report the case of a hypertensive man whose psychological stress-induced increase in blood pressure was attenuated by cilnidipine. Case Presentation The patient (a 72-year-old man) had hypertension and was on antihypertensive therapy. When mentally concentrating, he experienced occipital headaches and dizziness, and despite thorough testing, no abnormality was found. He was subsequently referred to our department. The mirror drawing test (MDT), a psychological stress test, increased blood pressure by about 40 mmHg, and the patient described occipital headache. Plasma noradrenaline level also increased from 212 to 548 pg/ml. We therefore switched the patient from nifedipine, an L-type calcium (Ca) channel blocker, to cilnidipine, an L-type/N-type Ca channel blocker with suppressive effects on sympathetic activity. Cilnipidine attenuated MDT-induced an increase in blood pressure and plasma noradrenaline level and prevented the development of headache during testing. Conclusion These findings suggest that cilnidipine is a useful antihypertensive agent for hypertensive patients in whom psychological stress causes marked fluctuations in blood pressure. PMID:17900335

  19. The chloride intracellular channel 5A stimulates podocyte Rac1, protecting against hypertension-induced glomerular injury.

    PubMed

    Tavasoli, Mahtab; Li, Laiji; Al-Momany, Abass; Zhu, Lin-Fu; Adam, Benjamin A; Wang, Zhixiang; Ballermann, Barbara J

    2016-04-01

    Glomerular capillary hypertension elicits podocyte remodeling and is a risk factor for the progression of glomerular disease. Ezrin, which links podocalyxin to actin in podocytes, is activated through the chloride intracellular channel 5A (CLIC5A)-dependent phosphatidylinositol 4,5 bisphosphate (PI[4,5]P2) accumulation. Because Rac1 is involved in podocyte actin remodeling and can promote PI[4,5]P2 production we determined whether CLIC5A-dependent PI[4,5]P2 generation and ezrin activation are mediated by Rac1. In COS7 cells, CLIC5A expression stimulated Rac1 but not Cdc42 or Rho activity. CLIC5A also stimulated phosphorylation of the Rac1 effector Pak1 in COS7 cells and in cultured mouse podocytes. CLIC5A-induced PI[4,5]P2 accumulation and Pak1 and ezrin phosphorylation were all Rac1 dependent. In DOCA/Salt hypertension, phosphorylated Pak increased in podocytes of wild-type, but not CLIC5-deficient mice. In DOCA/salt hypertensive mice lacking CLIC5, glomerular capillary microaneurysms were more frequent and albuminuria was greater than in wild-type mice. Thus, augmented hypertension-induced glomerular capillary injury in mice lacking CLIC5 results from abrogation of Rac1-dependent Pak and ezrin activation, perhaps reducing the tensile strength of the podocyte actin cytoskeleton. PMID:26924049

  20. Pulmonary Artery Denervation Reduces Pulmonary Artery Pressure and Induces Histological Changes in an Acute Porcine Model of Pulmonary Hypertension

    PubMed Central

    Arnold, Nadine D.; Chang, William; Watson, Oliver; Swift, Andrew J.; Condliffe, Robin; Elliot, Charlie A.; Kiely, David G.; Suvarna, S. Kim; Gunn, Julian; Lawrie, Allan

    2015-01-01

    Background— Pulmonary arterial hypertension is a devastating disease with high morbidity and mortality and limited treatment options. Recent studies have shown that pulmonary artery denervation improves pulmonary hemodynamics in an experimental model and in an early clinical trial. We aimed to evaluate the nerve distribution around the pulmonary artery, to determine the effect of radiofrequency pulmonary artery denervation on acute pulmonary hypertension induced by vasoconstriction, and to demonstrate denervation of the pulmonary artery at a histological level. Methods and Results— Histological evaluation identified a circumferential distribution of nerves around the proximal pulmonary arteries. Nerves were smaller in diameter, greater in number, and located in closer proximity to the luminal aspect of the pulmonary arterial wall beyond the pulmonary artery bifurcation. To determine the effect of pulmonary arterial denervation acute pulmonary hypertension was induced in 8 pigs by intravenous infusion of thromboxane A2 analogue. Animals were assigned to either pulmonary artery denervation, using a prototype radiofrequency catheter and generator, or a sham procedure. Pulmonary artery denervation resulted in reduced mean pulmonary artery pressure and pulmonary vascular resistance and increased cardiac output. Ablation lesions on the luminal surface of the pulmonary artery were accompanied by histological and biochemical alteration in adventitial nerves and correlated with improved hemodynamic parameters. Conclusions— Pulmonary artery denervation offers the possibility of a new treatment option for patients with pulmonary arterial hypertension. Further work is required to determine the long-term efficacy and safety. PMID:26553697

  1. Veratric acid, a phenolic acid attenuates blood pressure and oxidative stress in L-NAME induced hypertensive rats.

    PubMed

    Saravanakumar, Murugesan; Raja, Boobalan

    2011-12-01

    The present study was undertaken to assess the antihypertensive and antioxidant effects of veratric acid on N(?)-nitro-L arginine methyl ester (L-NAME) induced hypertensive rats. Hypertension was induced in adult male albino rats of the Wistar strain, weighing 180-220 g, by oral administration of the L-NAME (40 mg/kg body weight/day) in drinking water for 4 weeks. Rats were treated with various doses of veratric acid (20, 40, 80 mg/kg/day) for four weeks. Hypertension was manifested by considerably increased systolic and diastolic blood pressure and the toxic effect of L-NAME was determined using lipid peroxidative markers (thiobarbituric acid reactive substances and lipid hydroperoxides). We also assessed the activities of enzymatic antioxidants (superoxide dismutase, catalase, and glutathione peroxidase) and measured the levels of non-enzymatic antioxidants (vitamin-C, vitamin-E and reduced glutathione) levels in erythrocytes, plasma and tissues and plasma nitric oxide metabolites (nitrite/nitrate). Oral administration of veratric acid at the dosage of 40 mg/kg considerably decreased systolic and diastolic blood pressure, lipid peroxidation products; increased plasma nitric oxide levels and showed no toxicity which was measured using hepatic and renal function markers when compared to other doses of veratric acid (20, 80 mg/kg). In addition, histopathological findings of veratric acid treated hypertensive rat heart confirmed the biochemical findings of this study. These results suggest that veratric acid decreased the blood pressure, significantly restored nitric oxide, enzymatic and non-enzymatic antioxidants and reduced lipid peroxidation products and thus exhibits antihypertensive and antioxidant effects against l-NAME induced hypertension. PMID:21937012

  2. ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause.

    PubMed

    Pollow, Dennis P; Romero-Aleshire, Melissa J; Sanchez, Jessica N; Konhilas, John P; Brooks, Heddwen L

    2015-12-15

    Premenopausal females are resistant to the development of hypertension, and this protection is lost after the onset of menopause, resulting in a sharp increase in disease onset and severity. However, it is unknown how a fluctuating ovarian hormone environment during the transition from perimenopause to menopause impacts the onset of hypertension, and whether interventions during perimenopause prevent disease onset after menopause. A gradual transition to menopause was induced by repeated daily injections of 4-vinylcyclohexene diepoxide (VCD). ANG II (800 ngkg(-1)min(-1)) was infused into perimenopausal and menopausal female mice for 14 days. A separate cohort of mice received 17?-estradiol replacement during perimenopause. ANG II infusion produced significantly higher mean arterial pressure (MAP) in menopausal vs. cycling females, and 17?-estradiol replacement prevented this increase. In contrast, MAP was not significantly different when ANG II was infused into perimenopausal and cycling females, suggesting that female resistance to ANG II-induced hypertension is intact during perimenopause. ANG II infusion caused a significant glomerular hypertrophy, and hypertrophy was not impacted by hormonal status. Expression levels of aquaporin-2 (AQP2), a collecting duct protein, have been suggested to reflect blood pressure. AQP2 protein expression was significantly downregulated in the renal cortex of the ANG II-infused menopause group, where blood pressure was increased. AQP2 expression levels were restored to control levels with 17?-estradiol replacement. This study indicates that the changing hormonal environment in the VCD model of menopause impacts the severity of ANG II-induced hypertension. These data highlight the utility of the ovary-intact VCD model of menopause as a clinically relevant model to investigate the physiological mechanisms of hypertension that occur in women during the transition into menopause. PMID:26491098

  3. Anti-pressor effects of whole body exposure to static magnetic field on pharmacologically induced hypertension in conscious rabbits.

    PubMed

    Okano, Hideyuki; Ohkubo, Chiyoji

    2003-02-01

    Acute effects of whole body exposure to static magnetic field (SMF) on pharmacologically induced hypertension in a conscious rabbit were evaluated. Hypertensive and vasoconstrictive actions were induced by norepinephrine (NE) or a nonselective nitric oxide synthase (NOS) inhibitor, N(omega)-nitro-l-arginine methyl ester (l-NAME). The hemodynamics in a central artery of the ear lobe was measured continuously and analyzed by penetrating microphotoelectric plethysmography (MPPG). Concurrently, blood pressure (BP) changes in a central artery, contralateral to that of the MPPG measured ear lobe, were monitored. Magnetic flux densities were 5.5 mT (Bmax), the magnetic gradient peaked in the throat at the level of approximately 0.09 mT/mm, and the duration of exposure was 30 min. The results demonstrated that under normal physiological conditions without treatment of pharmacological agents, there were no statistically significant differences in the hemodynamics and BP changes between the sham and the SMF exposure alone. Under pharmacologically induced hypertensive conditions, the whole body exposure to nonuniform SMF with peak magnetic gradient in the carotid sinus baroreceptor significantly attenuated the vasoconstriction and suppressed the elevation of BPs. These findings suggest that antipressor effects of the SMF on the hemodynamics under NE or l-NAME induced high vascular tone might be, in part, dependent on modulation of NE mediated response in conjunction with alteration in NOS activity, thereby modulating BPs. PMID:12524681

  4. Protective Effect of Enalapril against Methionine-Enriched Diet-Induced Hypertension: Role of Endoplasmic Reticulum and Oxidative Stress

    PubMed Central

    Zhou, Yanfen; Zhao, Lianyou; Zhang, Zhimin; Lu, Xuanhao

    2015-01-01

    In the present study, we investigated the effect of methionine-enriched diet (MED) on blood pressure in rats and examined the protective effect of enalapril, a widely used angiotensin converting enzyme inhibitors (ACEi) class antihypertensive drug. The results showed that MED induced significant increase of SBP and Ang II-induced contractile response in aortae of rats. MED significantly increased plasma levels of homocysteine (Hcy) and ACE. In addition, MED increased the phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor 2 (eIF2α) and expression of activating transcription factor 3 (ATF3) and ATF6 in aortae of rats, indicating the occurrence of endoplasmic reticulum (ER) stress. Moreover, MED resulted in oxidative stress as evidenced by significant increase of TBARS level and decrease of superoxide dismutase and catalase activities. Administration of enalapril could effectively inhibit these pathological changes induced by MED in rats. These results demonstrated that ACE-mediated ER stress and oxidative stress played an important role in high Hcy-induced hypertension and MED may exert a positive loop between the activation of ACE and accumulation of Hcy, aggravating the pathological condition of hypertension. The data provide novel insights into the mechanism of high Hcy-associated hypertension and the therapeutic efficiency of enalapril. PMID:26640794

  5. Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs.

    PubMed

    Grasemann, Hartmut; Dhaliwal, Rupinder; Ivanovska, Julijana; Kantores, Crystal; McNamara, Patrick J; Scott, Jeremy A; Belik, Jaques; Jankov, Robert P

    2015-03-15

    Arginase is an enzyme that limits substrate L-arginine bioavailability for the production of nitric oxide by the nitric oxide synthases and produces L-ornithine, which is a precursor for collagen formation and tissue remodeling. We studied the pulmonary vascular effects of arginase inhibition in an established model of repeated systemic bleomycin sulfate administration in neonatal rats that results in pulmonary hypertension and lung injury mimicking the characteristics typical of bronchopulmonary dysplasia. We report that arginase expression is increased in the lungs of bleomycin-exposed neonatal rats and that treatment with the arginase inhibitor amino-2-borono-6-hexanoic acid prevented the bleomycin-induced development of pulmonary hypertension and deposition of collagen. Arginase inhibition resulted in increased L-arginine and L-arginine bioavailability and increased pulmonary nitric oxide production. Arginase inhibition also normalized the expression of inducible nitric oxide synthase, and reduced bleomycin-induced nitrative stress while having no effect on bleomycin-induced inflammation. Our data suggest that arginase is a promising target for therapeutic interventions in neonates aimed at preventing lung vascular remodeling and pulmonary hypertension. PMID:25595650

  6. Right ventricular cyclic nucleotide signaling is decreased in hyperoxia-induced pulmonary hypertension in neonatal mice.

    PubMed

    Heilman, Rachel P; Lagoski, Megan B; Lee, Keng Jin; Taylor, Joann M; Kim, Gina A; Berkelhamer, Sara K; Steinhorn, Robin H; Farrow, Kathryn N

    2015-06-15

    Pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) affect 25-35% of premature infants with significant bronchopulmonary dysplasia (BPD), increasing morbidity and mortality. We sought to determine the role of phosphodiesterase 5 (PDE5) in the right ventricle (RV) and left ventricle (LV) in a hyperoxia-induced neonatal mouse model of PH and RVH. After birth, C57BL/6 mice were placed in room air (RA) or 75% O2 (CH) for 14 days to induce PH and RVH. Mice were euthanized at 14 days or recovered in RA for 14 days or 42 days prior to euthanasia at 28 or 56 days of age. Some pups received sildenafil or vehicle (3 mg·kg(-1)·dose(-1) sc) every other day from P0. RVH was assessed by Fulton's index [RV wt/(LV + septum) wt]. PDE5 protein expression was analyzed via Western blot, PDE5 activity was measured by commercially available assay, and cGMP was measured by enzyme-linked immunoassay. Hyperoxia induced RVH in mice after 14 days, and RVH did not resolve until 56 days of age. Hyperoxia increased PDE5 expression and activity in RV, but not LV + S, after 14 days. PDE5 expression normalized by 28 days of age, but PDE5 activity did not normalize until 56 days of age. Sildenafil given during hyperoxia prevented RVH, decreased RV PDE5 activity, and increased RV cGMP levels. Mice with cardiac-specific overexpression of PDE5 had increased RVH in RA. These findings suggest normal RV PDE5 function is disrupted by hyperoxia, and elevated PDE5 contributes to RVH and remodeling. Therefore, in addition to impacting the pulmonary vasculature, sildenafil also targets PDE5 in the neonatal mouse RV and decreases RVH. PMID:25862831

  7. Valproic acid prevents the deregulation of lipid metabolism and renal renin-angiotensin system in L-NAME induced nitric oxide deficient hypertensive rats.

    PubMed

    Rajeshwari, Thiyagarajan; Raja, Boobalan; Manivannan, Jeganathan; Silambarasan, Thangarasu; Dhanalakshmi, Thanikkodi

    2014-05-01

    The present study was aimed to investigate the antihyperlipidemic and renoprotective potential of valproic acid against N(?)-nitro-L arginine methyl ester hydrochloride (L-NAME) induced hypertension in male albino Wistar rats. In hypertensive rats, mean arterial pressure (MAP), kidney weight, levels of oxidative stress markers in tissues were increased. Dyslipidemia was also observed in hypertensive rats. Moreover, enzymatic and nonenzymatic antioxidant network also deregulated in tissues. Valproic acid (VPA) supplementation daily for four weeks brought back all the above parameters to near normal level and showed no toxicity which was established using serum hepatic marker enzyme activities and renal function markers. Moreover the up regulated expression of renin-angiotensin system (RAS) components were also attenuated by VPA treatment. All the above outcomes were confirmed by the histopathological examination. These results suggest that VPA has enough potential to attenuate hypertension, dyslipidemia and renal damage in nitric oxide deficiency induced hypertension. PMID:24705342

  8. Hypoxia-induced glucose-6-phosphate dehydrogenase overexpression and -activation in pulmonary artery smooth muscle cells: implication in pulmonary hypertension

    PubMed Central

    Chettimada, Sukrutha; Gupte, Rakhee; Rawat, Dhwajbahadur; Gebb, Sarah A.; McMurtry, Ivan F.

    2014-01-01

    Severe pulmonary hypertension is a debilitating disease with an alarmingly low 5-yr life expectancy. Hypoxia, one of the causes of pulmonary hypertension, elicits constriction and remodeling of the pulmonary arteries. We now know that pulmonary arterial remodeling is a consequence of hyperplasia and hypertrophy of pulmonary artery smooth muscle (PASM), endothelial, myofibroblast, and stem cells. However, our knowledge about the mechanisms that cause these cells to proliferate and hypertrophy in response to hypoxic stimuli is still incomplete, and, hence, the treatment for severe pulmonary arterial hypertension is inadequate. Here we demonstrate that the activity and expression of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, are increased in hypoxic PASM cells and in lungs of chronic hypoxic rats. G6PD overexpression and -activation is stimulated by H2O2. Increased G6PD activity contributes to PASM cell proliferation by increasing Sp1 and hypoxia-inducible factor 1α (HIF-1α), which directs the cells to synthesize less contractile (myocardin and SM22α) and more proliferative (cyclin A and phospho-histone H3) proteins. G6PD inhibition with dehydroepiandrosterone increased myocardin expression in remodeled pulmonary arteries of moderate and severe pulmonary hypertensive rats. These observations suggest that altered glucose metabolism and G6PD overactivation play a key role in switching the PASM cells from the contractile to synthetic phenotype by increasing Sp1 and HIF-1α, which suppresses myocardin, a key cofactor that maintains smooth muscle cell in contractile state, and increasing hypoxia-induced PASM cell growth, and hence contribute to pulmonary arterial remodeling and pathogenesis of pulmonary hypertension. PMID:25480333

  9. Nox2-Induced Production of Mitochondrial Superoxide in Angiotensin II-Mediated Endothelial Oxidative Stress and Hypertension

    PubMed Central

    Dikalov, Sergey I.; Bikineyeva, Alfiya; Hilenski, Lula; Lassgue, Bernard; Griendling, Kathy K.; Harrison, David G.; Dikalova, Anna E.

    2014-01-01

    Abstract Aims: Angiotensin II (AngII)-induced superoxide (O2?) production by the NADPH oxidases and mitochondria has been implicated in the pathogenesis of endothelial dysfunction and hypertension. In this work, we investigated the specific molecular mechanisms responsible for the stimulation of mitochondrial O2? and its downstream targets using cultured human aortic endothelial cells and a mouse model of AngII-induced hypertension. Results: Western blot analysis showed that Nox2 and Nox4 were present in the cytoplasm but not in the mitochondria. Depletion of Nox2, but not Nox1, Nox4, or Nox5, using siRNA inhibits AngII-induced O2? production in both mitochondria and cytoplasm. Nox2 depletion in gp91phox knockout mice inhibited AngII-induced cellular and mitochondrial O2? and attenuated hypertension. Inhibition of mitochondrial reverse electron transfer with malonate, malate, or rotenone attenuated AngII-induced cytoplasmic and mitochondrial O2? production. Inhibition of the mitochondrial ATP-sensitive potassium channel (mitoK+ATP) with 5-hydroxydecanoic acid or specific PKC? peptide antagonist (EAVSLKPT) reduced AngII-induced H2O2 in isolated mitochondria and diminished cytoplasmic O2?. The mitoK+ATP agonist diazoxide increased mitochondrial O2?, cytoplasmic c-Src phosphorylation and cytoplasmic O2? suggesting feed-forward regulation of cellular O2? by mitochondrial reactive oxygen species (ROS). Treatment of AngII-infused mice with malate reduced blood pressure and enhanced the antihypertensive effect of mitoTEMPO. Mitochondria-targeted H2O2 scavenger mitoEbselen attenuated redox-dependent c-Src and inhibited AngII-induced cellular O2?, diminished aortic H2O2, and reduced blood pressure in hypertensive mice. Innovation and Conclusions: These studies show that Nox2 stimulates mitochondrial ROS by activating reverse electron transfer and both mitochondrial O2? and reverse electron transfer may represent new pharmacological targets for the treatment of hypertension. Antioxid. Redox Signal. 20, 281294. PMID:24053613

  10. Effect of age on insulin-induced endothelin release and vasoreactivity in hypertriglyceridemic and hypertensive rats.

    PubMed

    Rubio, Mara Esther; Baos, Guadalupe; Daz, Eulises; Guarner, Vernica

    2006-03-01

    In the present paper, the age-related changes in the vasoconstrictive endothelin-mediated response to insulin in aortas of normal and hypertensive, hypertriglyceridemic, hyperinsulinemic (HTG) rats were studied. To develop HTG rats, weanling male Wistar animals were given 30% sucrose in their drinking water for 4, 6, 12 and 18 months. Blood pressure was increased in HTG rats for up to 12 months showing a maximum at 6 months (138.9+/-0.8 mmHg). In vitro contractions were elicited with 40 mM KCl in the presence and absence 50 microU/ml insulin and of endothelin-receptor antagonists BQ123 and BQ788. Tension development to KCl was not modified during aging in control rats but was increased at 4 and 6 months in HTG rats. Increased endothelin release induced by insulin remained constant in normal rats, while in HTG rats it was higher than in controls at all ages. ET(A) blocker participation alone increased during aging in control rats while both receptor blockers participated in HTG rats. Our results suggest that the vasoconstrictive capacity to KCl plus insulin decreases during aging and that this decrease is greater in HTG rats. The participation of endothelin receptors in the aging process differs in control and HTG rats. PMID:16427233

  11. Rhodiola-water extract induces ?-endorphin secretion to lower blood pressure in spontaneously hypertensive rats.

    PubMed

    Lee, Wei-Jing; Chung, Hsien-Hui; Cheng, Yung-Ze; Lin, Hung Jung; Cheng, Juei-Tang

    2013-10-01

    Rhodiola rosea (Rhodiola) is grown at high altitudes and northern latitudes. It is mainly used clinically as an adaptogen, but antihypertensive effects have been reported for the extract. These have not been well investigated, so in the present study, we evaluated the effect of Rhodiola-water extract on blood pressure in spontaneously hypertensive rats (SHRs) and investigated the potential mechanism(s) for this action. In conscious male SHRs, systolic blood pressure (SBP) and heart rate were recorded using the tail-cuff method. Plasma ?-endorphin was measured by enzyme-linked immunosorbent assay. Rhodiola-water extract decreased SBP in SHRs in a dose-dependent manner, and this action was more significant than that in normal group named Wistar-Kyoto (WKY) rats. This reduction of SBP in SHRs was inhibited by pretreatment with the selective opioid ?-receptor antagonist, cyprodime, but not by naloxonazine, an antagonist specific to opioid ?1-receptor. Also, the SBP-lowering action of Rhodiola-water extract was attenuated in adrenalectomized SHRs. Moreover, Rhodiola-water extract dose-dependently increased ?-endorphin release in SHRs, and the elevation of ?-endorphin in SHRs was higher than that in WKY. Thus, we suggest that Rhodiola-water extract can induce release of ?-endorphin to lower SBP in SHRs. PMID:23192943

  12. Does pregnancy-induced hypertension affect the electrophysiology of the heart?

    PubMed

    Gazi, E; Gencer, M; Temiz, A; Barutcu, A; Altun, B; Gungor, A N C; Hacivelioglu, S; Uysal, A; Cosar, E

    2016-02-01

    Pregnancy-induced hypertension (PIHT) increases both maternal and neonatal mortality and morbidity in pregnant women. We sought to investigate the electrocardiographic findings in pregnant women with PIHT. Seventeen pregnant women (29.4 5 years) with PIHT and 24 pregnant women (27.3 6.1 years) with normal blood pressure (control group) were included in the study. A 12-lead surface electrocardiogram was used to evaluate the electrocardiographic parameters. Pregnant women with PIHT had higher blood pressure (p = 0.001). The Tp-e interval was longer in PIHT pregnant women at 83.5 7.8 ms versus 75.8 8.4 ms in the control group (p = 0.007). The Tp-e/QTc ratio was higher in pregnant women with PIHT than that in healthy controls (0.19 0.02 vs. 0.18 0.02, respectively). This study demonstrated that Pd, QTd and the P wave durations were similar in the PIHT pregnant women and control group, but the Tp-e and Tp-e/QTc ratio were higher in pregnant women with PIHT than in normotensive pregnant women. PMID:26366512

  13. Effect of Domperidone on the Bromocriptine-Induced Antihypertensive Action in Hypertensive Patients.

    PubMed

    Luchsinger, Augusta; Velasco, Manuel; Arbona, Ester; Forte, Pablo; Gmez, Juanita; Sukerman, Moiss; Urbina, Adalberto; Pieretti, Otto Hernndez

    1995-06-01

    Dopaminergic receptors have been involved in the cardiovascular and renin-angiotensin systems (RAS). We have recently reported that bromocriptine is an effective antihypertensive drug by stimulating DA(2) dopaminergic receptors. However, the nature of the dopaminergic receptors in RAS has not been established. Ten outpatients with essential hypertension were treated at the Vargas Hospital with bromocriptine (BR) (11.25 mg day(minus sign1)), a DA(2) dopaminergic agonist, for a 2-week period, after which an oral dose of 30 mg day(minus sign1) of domperidone (DO), a peripheric DA(2) dopaminergic antagonist, was added for 2 additional weeks. The active period was preceeded by a 2-week placebo period. Bromocriptine decreased blood pressure (BP) significantly by 19/9 mm Hg (systolic/diastolic BP). Bromocriptine did not cause heart rate (HR) changes. Bromocriptine decreased plasma aldosterone (ALD) without altering plasma renin activity (PRA). Domperidone partially blocked bromocriptine-induced antihypertensive submaximal treadmill effects and reversed ALD decrease. Exercise response was not significantly altered by BR + DO. We conclude the following: (1) BR is an effective antihypertensive agent; (2) BR seems to be acting at both the central and peripheric nervous systems, and (3) the nature of the dopaminergic receptor involved in renin secretion does not seem to be DA(2). PMID:11850682

  14. Sleep and Pregnancy-Induced Hypertension: A Possible Target for Intervention?

    PubMed Central

    Haney, Alyssa; Buysse, Daniel J.; Okun, Michele

    2013-01-01

    Sleep disturbances in the general population are associated with elevated blood pressure. This may be due to several mechanisms, including sympathetic activation and hypothalamic-pituitary-adrenal (HPA) axis disturbance. Elevated blood pressure in pregnancy can have devastating effects on both maternal and fetal health and is associated with increased risk for preeclampsia and poor delivery outcomes. Preliminary evidence suggests that mechanisms linking sleep and blood pressure in the general population may also hold in the pregnant population. However, the effects of disturbed sleep on physiologic mechanisms that may directly influence blood pressure in pregnancy have not been well studied. The role that sleep disturbance plays in gestational blood pressure elevation and its subsequent consequences warrant further investigation. This review evaluates the current literature on sleep disturbance and elevated blood pressure in pregnancy and proposes possible treatment interventions. Citation: Haney A; Buysse DJ; Okun M. Sleep and pregnancy-induced hypertension: a possible target for intervention? J Clin Sleep Med 2013;9(12):1349-1356. PMID:24340300

  15. Relation between calcium and cardiovascular reactivity in mineralocorticoid-induced hypertension in the rat.

    PubMed Central

    Berthelot, A.; Gairard, A.; Goyault, M.; Pernot, F.

    1980-01-01

    1 Previous work has shown that parathyroidectomy (PTX) decreases cardiovascular reactivity to noradrenaline in Sprague-Dawley rats with mineralocorticoid-induced (D) hypertension. 2. In order to explain this diminution of cardiovascular reactivity, we studied in vivo the influence of serum calcium levels on the cardiac and vascular response to noradrenaline (500 ng/kg). We used rats with or without parathyroids but fed a standard or a high-calcium (+Ca) diet that re-established a serum calcium level of about 100 mg/l. Work was performed in vagotomized, anaesthetized rats after ganglionic blockage with pentolinium and atropine sulphate. 3 Cardiac output was unchanged in all the experimental groups after 11 weeks of mineralocorticoid treatment. The enhancing effect of noradrenaline was not modified. 4. Since a serum calcium level of about 100 mg/l was sufficient to re-establish vascular reactivity to exogenous noradrenaline in the PTX-D rats, parathyroid hormone was not necessary. 5 The total and lanthanum-resistant calcium fractions of the walls of the aorta were reduced in the PTX-D rats. When serum calcium levels were re-established at about 100 mg/l, there was no difference between PTX-D and D rats. 6 It is postulated that the decreased storage of calcium in vascular smooth muscle cells of PTX-D rats depresses the vascular effect of noradrenaline. PMID:7426838

  16. Cold-restraint induced gastric lesions in normotensive and spontaneously hypertensive rats

    SciTech Connect

    Athey, G.R.; Iams, S.G.

    1981-02-23

    Spontaneously hypertensive (SHR) rats and normotensive Wistar-Kyoto (WKY) rats were subjected to 2 hr of cold-restraint stress at 4-6/sup o/C following a 24 hr fast. WKY rats had a significantly greater incidence and degree of ulceration of the gastric glandular mucosa than did SHR rats. Mean arterial pressure, obtained from a chronic arterial cannula, fell during 2 hr of cold-restraint stress in both SHR and WKY rats. Heart rate was unchanged in WKY but fell significantly in SHR. Plasma norepinephrine (NE) and epinephrine (E), determined by radioenzymatic assay, increased significantly following stress. Increased levels of NE remained similar for both SHR and WKY rats, while post-stress levels of E for the SHR rats greatly exceeded E levels for WKY rats. A greater degree of hypothermia was also noted in SHR rats. Decreased stress induced ulcerogenesis in the SHR may be due to the well-known altered hemodynamic and autonomic nervous system reactivity in this strain or other factors not yet discovered.

  17. Contribution of elastin and collagen to the pathogenesis of monocrotaline induced pulmonary hypertension

    SciTech Connect

    Todorovich, L.; Johnson, D.; Ranger, P.; Keeley, F.; Rabinovitch, M.

    1986-03-01

    Male Sprague-Dawley rats were selected randomly for subcutaneous injections, 24 with monocrotaline (M) (60mg/kg) and 24 with an equivolume of saline, and studied 8, 16 or 28 days later. The right (RV) and left ventricle with septum (LV + S) were separated and weighed. The pulmonary artery (PA) was assessed by light and electron microscopy. Synthesis of elastin collagen and non-collagenous proteins was determined by measuring incorporations of /sup 3/H-valine, /sup 14/C-OH-proline and /sup 14/C-proline respectively. Total content of elastin was determined by weight of residue after CNBr digestion, and of collagen by total OH-proline content in SDS and CNBr extracts. At 16 days, the M injected rats developed a 6-fold increase in PA elastin synthesis and a 2-fold increase in medial wall thickness. Ultrastructural changes included increased microtubules and golgi apparatus in endothelium, decreased proportion of mature elastin in subendothelium and increased ground substance in media. By 28 days, M rats showed a progressive increase in PA elastin and collagen synthesis, greater than 20-fold, and in medial wall thickness, 3-fold. This was associated with a 2-fold increase in total elastin in proportion to the increase in PA weight and the development of RV hypertrophy (RV/LV + S increased more than 2-fold). Progressive irreversible pulmonary hypertension induced by M may be related to continuing stimulation of PA elastin and collagen synthesis.

  18. Altered lymphatic function and architecture in salt-induced hypertension assessed by near-infrared fluorescence imaging

    NASA Astrophysics Data System (ADS)

    Kwon, Sunkuk; Agollah, Germaine D.; Chan, Wenyaw; Sevick-Muraca, Eva M.

    2012-08-01

    The lymphatic system plays an important role in maintaining the fluid homeostasis between the blood vascular and interstitial tissue compartment and there is recent evidence that its transport capabilities may regulate blood pressure in salt-induced hypertension. Yet, there is little known how the lymphatic contractile function and architecture responds to dietary salt-intake. Thus, we longitudinally characterized lymphatic contractile function and vessel remodeling noninvasively using dynamic near-infrared fluorescence imaging in animal models of salt-induced hypertension. The lymphatics of mice and rats were imaged following intradermal injection of indocyanine green to the ear tip or the base of the tail before and during two weeks of either a high salt diet (HSD) or normal chow. Our noninvasive imaging data demonstrated dilated lymphatic vessels in the skin of mice and rats on a HSD as compared to their baseline levels. In addition, our dynamic imaging results showed increased lymphatic contraction frequency in HSD-fed mice and rats. Lymphatic contractile function and vessel remodeling occurs in response to salt-induced hypertension suggesting a possible role for the lymphatics in the regulation of vascular blood pressure.

  19. Purinergic contraction of the rat vas deferens in L-NAME-induced hypertension: effect of sildenafil.

    PubMed

    Gur, Serap; Sikka, Suresh C; Knight, Gillian E; Burnstock, Geoffrey; Hellstrom, Wayne J G

    2010-05-01

    Hypertension (HTN) is a risk factor for erectile dysfunction, but its effect on vas deferens (VD) contractility and the ejaculatory response has not been delineated. NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, was used for induction of nitric oxide (NO)-deficient HTN. Our aim was to evaluate the effects of L-NAME-induced HTN on rat VD contractility and to determine whether sildenafil affects VD contractility. A total of 36 male rats were divided into (1) control, (2) L-NAME-HTN, (3) sildenafil treated L-NAME-HTN groups. Group 2 was treated with L-NAME (40 mg kg(-1) per day) in drinking water for 4 weeks. Group 3 received sildenafil (1.5 mg kg(-1) per day, by oral gavage) concomitantly with L-NAME. The prostatic portion of the VD was subjected to electrical field stimulation (EFS, 1-20 Hz), and the P2X(1) agonist alpha,beta-methylene ATP (alpha,beta-meATP, 100 micromol L(-1)-1 micromol L(-1)) and the alpha1-adrenoceptor agonist phenylephrine (Phe, 100 micromol L(-1)-1 mmol L(-1)) were used to construct concentration-response curves. These experiments were repeated in the presence of P2X receptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS, 30 micromol L(-1)). VD contractions in response to EFS, alpha,beta-meATP and Phe were significantly enhanced by L-NAME. Sildenafil treatment in the L-NAME group improved the contractile response of VD to EFS (20 Hz). In the presence of PPADS, the enhanced contractile response of VD to EFS and alpha,beta-meATP in hypertensive rats was reversed. In the rat model of chronic NO depletion, the purinergic and adrenergic components and EFS affect VD contractility. The VD contractile response may be mediated more by the purinergic system than the adrenergic system, and sildenafil may alter the ejaculatory response in men with PE. PMID:20305675

  20. Atorvastatin ameliorates arsenic-induced hypertension and enhancement of vascular redox signaling in rats

    SciTech Connect

    Sarath, Thengumpallil Sasindran; Waghe, Prashantkumar; Gupta, Priyanka; Choudhury, Soumen; Kannan, Kandasamy; Pillai, Ayyappan Harikrishna; Harikumar, Sankaran Kutty; Mishra, Santosh Kumar; Sarkar, Souvendra Nath

    2014-11-01

    Chronic arsenic exposure has been linked to elevated blood pressure and cardiovascular diseases, while statins reduce the incidence of cardiovascular disease predominantly by their low density lipoprotein-lowering effect. Besides, statins have other beneficial effects, including antioxidant and anti-inflammatory activities. We evaluated whether atorvastatin, a widely used statin, can ameliorate arsenic-induced increase in blood pressure and alteration in lipid profile and also whether the amelioration could relate to altered NO and ROS signaling. Rats were exposed to sodium arsenite (100 ppm) through drinking water for 90 consecutive days. Atorvastatin (10 mg/kg bw, orally) was administered once daily during the last 30 days of arsenic exposure. On the 91st day, blood was collected for lipid profile. Western blot of iNOS and eNOS protein, NO and 3-nitrotyrosine production, Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation, lipid peroxidation and antioxidants were evaluated in thoracic aorta. Arsenic increased systolic, diastolic and mean arterial blood pressure, while it decreased HDL-C and increased LDL-C, total cholesterol and triglycerides in serum. Arsenic down-regulated eNOS and up-regulated iNOS protein expression and increased basal NO and 3-nitrotyrosine level. Arsenic increased aortic Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation and lipid peroxidation. Further, arsenic decreased the activities of superoxide dismutase, catalase, and glutathione peroxidase and depleted aortic GSH content. Atorvastatin regularized blood pressure, improved lipid profile and attenuated arsenic-mediated redox alterations. The results demonstrate that atorvastatin has the potential to ameliorate arsenic-induced hypertension by improving lipid profile, aortic NO signaling and restoring vascular redox homeostasis. - Highlights: • Arsenic increased systolic, diastolic and mean arterial blood pressure and caused dyslipidemia. • Arsenic increased both oxidative and nitrosative stress in thoracic aorta. • Atorvastatin regularized blood pressure, improved lipid profile and restored redox homeostasis.

  1. Ruscogenin exerts beneficial effects on monocrotaline-induced pulmonary hypertension by inhibiting NF-?B expression

    PubMed Central

    Zhu, Rong; Bi, Liqing; Kong, Hui; Xie, Weiping; Hong, Yongqing; Wang, Hong

    2015-01-01

    This study aims to examine the effect of ruscogenin on pulmonary arterial hypertension (PAH) and to determine the mechanism underlying this effect. We isolated pulmonary vascular smooth muscle cells (PVSMCs) from the pulmonary artery of the rats; the PVSMCs were cultured in vitro and then were treated with platelet-derived growth factor (PDGF), PDGF + ruscogenin, or PDGF + ruscogenin + parthenolide. We randomized Sprague-Dawley rats into five groups as follows: control group, PAH group, low-dose group, medium-dose group, and high-dose group; the rats in the low-, medium-, and high-dose groups received the vehicle and ruscogenin 0.1, 0.4, and 0.7 mg/kg, respectively, from day 1 to day 21 after injection of monocrotaline (MCT). We measured the mean pulmonary arterial pressure (mPAP), right ventricular systolic pressure (RVSP), and medial wall thickness of the pulmonary artery (PAWT). We examined the levels of the nuclear factor kappa B (NF-?B) protein by using immunohistochemistry and western blot analysis, and the mRNA levels of NF-?B in PVSMCs were evaluated using real-time polymerase chain reaction (PCR). The mPAP, RVSP, and PAWT and the protein and mRNA levels of NF-?B were significantly higher in the PAH model group than in the control group (P < 0.05). Ruscogenin induced a significant dose-dependent decrease in the mPAP, RVSP, and PAWT and in the NF-?B expression in the PAH group (P < 0.05), which suggests that ruscogenin will also exert dose-dependent effects on MCT-induced PAH through the inhibition of NF-?B. PMID:26722401

  2. Pioglitazone alleviates cardiac and vascular remodelling and improves survival in monocrotaline induced pulmonary arterial hypertension.

    PubMed

    Behringer, Arnica; Trappiel, Manuela; Berghausen, Eva Maria; Ten Freyhaus, Henrik; Wellnhofer, Ernst; Odenthal, Margarete; Blaschke, Florian; Er, Fikret; Gassanov, Natig; Rosenkranz, Stephan; Baldus, Stephan; Kappert, Kai; Caglayan, Evren

    2016-04-01

    Pulmonary arterial hypertension (PAH) is a fatal disease with limited therapeutic options. Pathophysiological changes comprise obliterative vascular remodelling of small pulmonary arteries, elevated mean pulmonary arterial systolic pressure (PASP) due to elevated resistance of pulmonary vasculature, adverse right ventricular remodelling, and heart failure. Recent findings also indicate a role of increased inflammation and insulin resistance underlying the development of PAH. We hypothesized that treatment of this condition with the peroxisome proliferator-activated receptor-γ (PPARγ) activator pioglitazone, known to regulate the expression of different genes addressing insulin resistance, inflammatory changes, and vascular remodelling, could be a beneficial approach. PAH was induced in adult rats by a single subcutaneous injection of monocrotaline (MCT). Pioglitazone was administered for 2 weeks starting 3 weeks after MCT-injection. At day 35, hemodynamics, organ weights, and -indices were measured. We performed morphological and molecular characterization of the pulmonary vasculature, including analysis of the degree of muscularization, proliferation rates, and medial wall thickness of the small pulmonary arteries. Furthermore, markers of cardiac injury, collagen content, and cardiomyocyte size were analyzed. Survival rates were monitored throughout the experimental period. Pioglitazone treatment improved survival, reduced PASP, muscularization of small pulmonary arteries, and medial wall thickness. Further, MCT-induced right ventricular hypertrophy and fibrosis were attenuated. This was accompanied with reduced cardiac expression of brain natriuretic peptide, as well as decreased cardiomyocyte size. Finally, pulmonary macrophage content and osteopontin gene expression were attenuated. Based on the beneficial impact of pioglitazone, activation of PPARγ might be a promising treatment option in PAH. PMID:26742933

  3. Pregnancy-Induced Hypertensive Disorders before and after a National Economic Collapse: A Population Based Cohort Study

    PubMed Central

    Eirksdttir, Vds Helga; Valdimarsdttir, Unnur Anna; sgeirsdttir, Tinna Laufey; Hauksdttir, Arna; Lund, Sigrn Helga; Bjarnadttir, Ragnheiur Ingibjrg; Cnattingius, Sven; Zoga, Helga

    2015-01-01

    Background Data on the potential influence of macroeconomic recessions on maternal diseases during pregnancy are scarce. We aimed to assess potential change in prevalence of pregnancy-induced hypertensive disorders (preeclampsia and gestational hypertension) during the first years of the major national economic recession in Iceland, which started abruptly in October 2008. Methods and Findings Women whose pregnancies resulted in live singleton births in Iceland in 20052012 constituted the study population (N = 35,211). Data on pregnancy-induced hypertensive disorders were obtained from the Icelandic Medical Birth Register and use of antihypertensive drugs during pregnancy, including ?-blockers and calcium channel blockers, from the Icelandic Medicines Register. With the pre-collapse period as reference, we used logistic regression analysis to assess change in pregnancy-induced hypertensive disorders and use of antihypertensives during the first four years after the economic collapse, adjusting for demographic and pregnancy characteristics, taking aggregate economic indicators into account. Compared with the pre-collapse period, we observed an increased prevalence of gestational hypertension in the first year following the economic collapse (2.4% vs. 3.9%; adjusted odds ratio [aOR] 1.47; 95 percent confidence interval [95%CI] 1.131.91) but not in the subsequent years. The association disappeared completely when we adjusted for aggregate unemployment rate (aOR 1.04; 95% CI 0.741.47). Similarly, there was an increase in prescription fills of ?-blockers in the first year following the collapse (1.9% vs.3.1%; aOR 1.43; 95% CI 1.071.90), which disappeared after adjusting for aggregate unemployment rate (aOR 1.05; 95% CI 0.721.54). No changes were observed for preeclampsia or use of calcium channel blockers between the pre- and post-collapse periods. Conclusions Our data suggest a transient increased risk of gestational hypertension and use of ?-blockers among pregnant women in Iceland in the first and most severe year of the national economic recession. PMID:26379126

  4. Central Renin-Angiotensin System Activation and Inflammation Induced by High-Fat Diet Sensitize Angiotensin II-Elicited Hypertension.

    PubMed

    Xue, Baojian; Thunhorst, Robert L; Yu, Yang; Guo, Fang; Beltz, Terry G; Felder, Robert B; Johnson, Alan Kim

    2016-01-01

    Obesity has been shown to promote renin-angiotensin system activity and inflammation in the brain and to be accompanied by increased sympathetic activity and blood pressure. Our previous studies demonstrated that administration of a subpressor dose of angiotensin (Ang) II sensitizes subsequent Ang II-elicited hypertension. The present study tested whether high-fat diet (HFD) feeding also sensitizes the Ang II-elicited hypertensive response and whether HFD-induced sensitization is mediated by an increase in renin-angiotensin system activity and inflammatory mechanisms in the brain. HFD did not increase baseline blood pressure, but enhanced the hypertensive response to Ang II compared with a normal-fat diet. The sensitization produced by the HFD was abolished by concomitant central infusions of either a tumor necrosis factor-? synthesis inhibitor, pentoxifylline, an Ang II type 1 receptor blocker, irbesartan, or an inhibitor of microglial activation, minocycline. Furthermore, central pretreatment with tumor necrosis factor-? mimicked the sensitizing action of a central subpressor dose of Ang II, whereas central pentoxifylline or minocycline abolished this Ang II-induced sensitization. Real-time quantitative reverse transcription-polymerase chain reaction analysis of lamina terminalis tissue indicated that HFD feeding, central tumor necrosis factor-?, or a central subpressor dose of Ang II upregulated mRNA expression of several components of the renin-angiotensin system and proinflammatory cytokines, whereas inhibition of Ang II type 1 receptor and of inflammation reversed these changes. The results suggest that HFD-induced sensitization of Ang II-elicited hypertension is mediated by upregulation of the brain renin-angiotensin system and of central proinflammatory cytokines. PMID:26573717

  5. Conditional knockout of collecting duct bradykinin B2 receptors exacerbates angiotensin II-induced hypertension during high salt intake.

    PubMed

    Kopkan, Libor; Huskov, Zuzana; Jchov, rka; ?ervenkov, Lenka; ?ervenka, Lud?k; Saifudeen, Zubaida; El-Dahr, Samir S

    2016-01-01

    We elucidated the role of collecting duct kinin B2 receptor (B2R) in the development of salt-sensitivity and angiotensin II (ANG II)-induced hypertension. To this end, we used a Cre-Lox recombination strategy to generate mice lacking Bdkrb2 gene for B2R in the collecting duct (Hoxb7-Cre(tg/+):Bdkrb2(flox/flox)). In 3 groups of control (Bdkrb2(flox/flox)) and 3 groups of UB(Bdkrb2-/-) mice, systolic blood pressure (SBP) responses to high salt intake (4 or 8% NaCl; HS) were monitored by radiotelemetry in comparison with standard salt diet (0.4% NaCl) prior to and during subcutaneous ANG II infusion (1000?ng/min/kg) via osmotic minipumps. High salt intakes alone for 2 weeks did not alter SBP in either strain. ANG II significantly increased SBP equally in control (121??2 to 156??3?mmHg) and UB(Bdkrb2-/-) mice (120??2 to 153??2?mmHg). The development of ANG II-induced hypertension was exacerbated by 4%HS in both control (125??3 to 164??5?mmHg) and UB(Bdkrb2-/-) mice (124??2 to 162??3?mmHg) during 2 weeks. Interestingly, 8%HS caused a more profound and earlier ANG II-induced hypertension in UB(Bdkrb2-/-) (129??2 to 166??3?mmHg) as compared to control (128??2 to 158??2?mmHg) and it was accompanied by body weight loss and increased mortality. In conclusion, targeted inactivation of B2R in the renal collecting duct does not cause salt-sensitivity; however, collecting duct B2R attenuates the hypertensive actions of ANG II under conditions of very high salt intake. PMID:26151827

  6. Constriction rate variation produced by partial ligation of the portal vein at pre-hepatic portal hypertension induced in rats

    PubMed Central

    RODRIGUES, Daren Athi Boy; da SILVA, Aline Riquena; SERIGIOLLE, Leonardo Carvalho; FIDALGO, Ramiro de Sousa; FAVERO, Sergio San Gregorio; LEME, Pedro Luiz Squilacci

    2014-01-01

    Background Partial portal vein ligation causes an increase in portal pressure that remains stable even after the appearance of collateral circulation, with functional adaptation to prolonged decrease in portal blood flow. Aim To assess whether different constriction rates produced by partial ligation of the vein interfere with the results of this experimental model in rats. Methods Three groups of five rats each were used; in group 1 (sham-operated), dissection and measurement of portal vein diameters were performed. Portal hypertension was induced by partial portal vein ligation, reducing its size to 0.9 mm in the remaining 10 animals, regardless of the initial diameter of the veins. Five animals with portal hypertension (group 2) underwent reoperation after 15 days and the rats in group 3 after 30 days. The calculation of the constriction rate was performed using a specific mathematical formula (1 - ? r 2 / ? R2) x 100% and the statistical analysis with the Student t test. Results The initial diameter of the animal's portal vein was 2.06 mm, with an average constriction rate of the 55.88%; although the diameter of the veins and the constriction rate in group 2 were lower than in group 3 (2.06 mm - 55,25% and 2.08 mm - 56.51%, respectively), portal hypertension was induced in all rats and no significant macroscopic differences were found between the animals that were reoperated after 15 days and after 30 days respectively, being the shorter period considered enough for the evaluation. Comparing the initial diameter of the vein and the rate of constriction performed in groups 2 and 3, no statistic significance was found (p>0.05). Conclusion Pre-hepatic portal hypertension in rat can be induced by the reduction of the portal vein diameter to 0.9 mm, regardless the initial diameter of the vein and the vessel constriction rate. PMID:25626939

  7. Role of copper transport protein Antioxidant-1 in Angiotensin II-induced hypertension: A key regulator of Extracellular SOD

    PubMed Central

    Ozumi, Kiyoshi; Sudhahar, Varadarajan; Kim, Ha Won; Chen, Gin-Fu; Kohno, Takashi; Finney, Lydia; Vogt, Stefan; McKinney, Ronald D.; Ushio-Fukai, Masuko; Fukai, Tohru

    2012-01-01

    Extracellular superoxide dismutase (SOD3) is a secretory copper enzyme involved in protecting angiotensin II (Ang II)-induced hypertension. We previously found that Ang II upregulates SOD3 expression and activity as a counter-regulatory mechanism; however, underlying mechanisms are unclear. Antioxidant-1 (Atox1) is shown to act as a copper-dependent transcription factor as well as copper chaperone for SOD3 in vitro, but its role in Ang II-induced hypertension in vivo is unknown. Here we show that Ang II infusion increases Atox1 expression as well as SOD3 expression and activity in aortas of wild-type mice, which are inhibited in mice lacking Atox1. Accordingly, Ang II increases vascular O2? production, reduces endothelium-dependent vasodilation and increases vasoconstriction in mesenteric arterioles to a greater extent in Atox1?/? than in wild-type mice. This contributes to augmented hypertensive response to Ang II in Atox1?/? mice. In cultured vascular smooth muscle cells, Ang II promotes translocation of Atox1 to the nucleus, thereby increasing SOD3 transcription by binding to Atox1 responsive element in the SOD3 promoter. Furthermore, Ang II increases Atox1 binding to the copper exporter ATP7A which obtains copper from Atox1 as well as translocation of ATP7A to plasma membranes where it colocalizes with SOD3. As its consequence, Ang II decreases vascular copper levels, which is inhibited in Atox1?/? mice. In summary, Atox1 functions to prevent Ang II-induced endothelial dysfunction and hyper-contraction in resistant vessels as well as hypertension in vivo by reducing extracellular O2? levels via increasing vascular SOD3 expression and activity. PMID:22753205

  8. Molecular mechanisms of hypoxia-inducible factor-induced pulmonary arterial smooth muscle cell alterations in pulmonary hypertension.

    PubMed

    Veith, Christine; Schermuly, Ralph T; Brandes, Ralf P; Weissmann, Norbert

    2016-03-01

    Oxygen (O2 ) is essential for the viability and function of most metazoan organisms and thus is closely monitored at both the organismal and the cellular levels. However, alveoli often encounter decreased O2 levels (hypoxia), leading to activation of physiological or pathophysiological responses in the pulmonary arteries. Such changes are achieved by activation of transcription factors. The hypoxia-inducible factors (HIFs) are the most prominent hypoxia-regulated transcription factors in this regard. HIFs bind to hypoxia-response elements (HREs) in the promoter region of target genes, whose expression and translation allows the organism, amongst other factors, to cope with decreased environmental O2 partial pressure (pO2 ). However, prolonged HIF activation can contribute to major structural alterations, especially in the lung, resulting in the development of pulmonary hypertension (PH). PH is characterized by a rise in pulmonary arterial pressure associated with pulmonary arterial remodelling, concomitant with a reduced intravascular lumen area. Patients with PH develop right heart hypertrophy and eventually die from right heart failure. Thus, understanding the molecular mechanisms of HIF regulation in PH is critical for the identification of novel therapeutic strategies. This review addresses the relationship of hypoxia and the HIF system with pulmonary arterial dysfunction in PH. We particularly focus on the cellular and molecular mechanisms underlying the HIF-driven pathophysiological processes. PMID:26228924

  9. Hypertension induced by omega-3 polyunsaturated fatty acid deficiency is alleviated by alpha-linolenic acid regardless of dietary source.

    PubMed

    Begg, Denovan P; Sinclair, Andrew J; Stahl, Lauren A; Premaratna, Shirmila D; Hafandi, Ahmad; Jois, Mark; Weisinger, Richard S

    2010-08-01

    Omega-3 polyunsaturated fatty acid deficiency, particularly during the prenatal period, can cause hypertension in later life. This study examined the effect of different sources of alpha-linolenic acid (canola oil or flaxseed oil) in the prevention of hypertension and other metabolic symptoms induced by an omega-3 fatty acid-deficient diet. Dams were provided one of three experimental diets from 1 week before mating. Diets were either deficient (10% safflower oil-DEF) or sufficient (7% safflower oil+3% flaxseed oil-SUF-F; or 10% canola oil-SUF-C) in omega-3 fatty acids. The male offspring were continued on the maternal diet from weaning for the duration of the study. Body weight, ingestive behaviors, blood pressure, body composition, metabolic rate, plasma leptin and brain fatty acids were all assessed. The DEF animals were hypertensive at 24 weeks of age compared with SUF-F or SUF-C animals; this was not evident at 12 weeks. These results suggest that different sources of ALA are effective in preventing hypertension related to omega-3 fatty acid deficiency. However, there were other marked differences between the DEF and, in particular, the SUF-C phenotype including lowered body weight, adiposity, leptin and food intake in SUF-C animals. SUF-F animals also had lower, but less marked reductions in adiposity and leptin compared with DEF animals. The differences observed between DEF, SUF-F and SUF-C phenotypes indicate that body fat and leptin may be involved in omega-3 fatty acid deficiency hypertension. PMID:20520615

  10. Inhibition of neutral sphingomyelinase decreases elevated levels of inducible nitric oxide synthase and apoptotic cell death in ocular hypertensive rats

    SciTech Connect

    Aslan, Mutay; Basaranlar, Goksun; Unal, Mustafa; Ciftcioglu, Akif; Derin, Narin; Mutus, Bulent

    2014-11-01

    Endoplasmic reticulum (ER) stress and excessive nitric oxide production via induction of inducible nitric oxide synthase (NOS2) have been implicated in the pathogenesis of neuronal retinal cell death in ocular hypertension. Neutral sphingomyelinase (N-SMase)/ceramide pathway can regulate NOS2 expression, hence this study determined the role of selective neutral sphingomyelinase (N-SMase) inhibition on retinal NOS2 levels, ER stress, apoptosis and visual evoked potentials (VEPs) in a rat model of elevated intraocular pressure (EIOP). NOS2 expression and retinal protein nitration were significantly greater in EIOP and significantly decreased with N-SMase inhibition. A significant increase was observed in retinal ER stress markers pPERK, CHOP and GRP78 in EIOP, which were not significantly altered by N-SMase inhibition. Retinal TUNEL staining showed increased apoptosis in all EIOP groups; however N-SMase inhibition significantly decreased the percent of apoptotic cells in EIOP. Caspase-3, -8 and -9 activities were significantly increased in EIOP and returned to baseline levels following N-SMase inhibition. Latencies of all VEP components were significantly prolonged in EIOP and shortened following N-SMase inhibition. Data confirm the role of nitrative injury in EIOP and highlight the protective effect of N-SMase inhibition in EIOP via down-regulation of NOS2 levels and nitrative stress. - Highlights: • Inhibition of N-SMase decreases NOS2 levels in ocular hypertension. • Inhibition of N-SMase decreases protein nitration in ocular hypertension. • Inhibition of N-SMase decreases caspase activation in ocular hypertension. • Inhibition of N-SMase decreases apoptosis in ocular hypertension.

  11. Insight into molecular mechanisms of ultrafine carbon particle induced cardiovascular impairments in spontaneously hypertensive rats.

    EPA Science Inventory

    Rationale: Exposure to ambient particulate matter is a risk factor for cardiopulmonary disease as identified in several epidemiological studies. Radio telemetric analysis detected increased heart rate and blood pressure in Spontaneously Hypertensive Rats (SHR) following inhalatio...

  12. Blood volume increase in salt-induced pulmonary hypertension, heart failure and ascites in broiler and White Leghorn chickens.

    PubMed Central

    Mirsalimi, S M; O'Brien, P J; Julian, R J

    1993-01-01

    In this study we tested the hypothesis that excess dietary salt produces an expansion of extracellular fluid volume which may be associated with pulmonary hypertension-induced right ventricular failure in chickens with rapid growth rates. One-week-old broiler and White Leghorn chickens were given 0.5% salt in their drinking water for three weeks. Saline water had a minimal effect on White Leghorns. The hypothesis appears to be correct since salt-treatment in broilers resulted in up to 30% expansion in blood volume and there was 50% mortality from pulmonary hypertension-induced right ventricular failure and ascites. There was marked (up to 88% in some broilers) right ventricular hypertrophy, an indicator of pulmonary hypertension. There was less left ventricular hypertrophy as shown by an increase in the ratio of the right to total ventricle weight. There was up to 32% decrease in growth rate. There was renal hypertrophy in the salt-treated birds as shown by a higher kidney to body weight ratio. PMID:8490804

  13. Optical cryoimaging of rat kidney and the effective role of chromosome 13 in salt-induced hypertension

    NASA Astrophysics Data System (ADS)

    Salehpour, F.; Yang, C.; Kurth, T.; Cowley, A. W.; Ranji, M.

    2015-03-01

    The objective of this work is to assess oxidative stress levels in salt-sensitive hypertension animal model using 3D optical cryoimager to image mitochondrial redox ratio. We studied Dahl salt-induced (SS) rats, and compared the results with a consomic SS rat strain (SSBN13). The SSBN13 strain was developed by the introgression of chromosome from the Brown Norway (BN) rat into the salt-sensitive (SS) genetic background and exhibits significant protection from salt induced hypertension1 . These two groups were fed on a high salt diet of 8.0% NaCl for one week. Mitochondrial redox ratio (NADH/FAD=NADH RR), was used as a quantitative marker of the oxidative stress in kidney tissue. Maximum intensity projected images and their corresponding histograms in each group were acquired from each kidney group. The result showed a 49% decrease in mitochondrial redox ratio of SS compared to SSBN13 translated to an increase in the level of oxidative stress of the tissue. Therefore, the results quantify oxidative stress levels and its effect on mitochondrial redox in salt sensitive hypertension.

  14. Protective actions of estrogen on angiotensin II-induced hypertension: role of central nitric oxide.

    PubMed

    Xue, Baojian; Singh, Minati; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2009-11-01

    The present study tested the hypotheses that 1) nitric oxide (NO) is involved in attenuated responses to ANG II in female mice, and 2) there is differential expression of neuronal NO synthase (nNOS) in the subfornical organ (SFO) and paraventricular nucleus (PVN) in response to systemic infusions of ANG II in males vs. females. Aortic blood pressure (BP) was measured in conscious mice with telemetry implants. N(G)-nitro-l-arginine methyl ester (l-NAME; 100 microg x kg(.-1)day(-1)), an inhibitor of NOS, was administrated into the lateral cerebral ventricle for 14 days before and during ANG II pump implantation. Central infusion of l-NAME augmented the pressor effects of systemic ANG II in females (Delta21.5 + or - 2.2 vs. Delta9.2 + or - 1.5 mmHg) but not in males (Delta29.4 + or - 2.5 vs. Delta30.1 + or - 2.5 mmHg). Central administration of N(5)-(1-imino-3-butenyl)-l-ornithine (l-VNIO), a selective nNOS inhibitor, also significantly potentiated the increase in BP induced by ANG II in females (Delta17.5 + or - 3.2 vs. Delta9.2 + or - 1.5 mmHg). In gonadectomized mice, central l-NAME infusion did not affect the pressor response to ANG II in either males or females. Ganglionic blockade after ANG II infusion resulted in a greater reduction in BP in central l-NAME- or l-VNIO-treated females compared with control females. Western blot analysis of nNOS protein expression indicated that levels were approximately 12-fold higher in both the SFO and PVN of intact females compared with those in intact males. Seven days of ANG II treatment resulted in a further increase in nNOS protein expression only in intact females (PVN, to approximately 51-fold). Immunohistochemical studies revealed colocalization of nNOS and estrogen receptors in the SFO and PVN. These results suggest that NO attenuates the increase in BP induced by ANG II through reduced sympathetic outflow in females and that increased nNOS protein expression associated with the presence of female sex hormones plays a protective role against ANG II-induced hypertension in female mice. PMID:19734362

  15. Eukaryotic elongation factor 2 kinase mediates monocrotaline-induced pulmonary arterial hypertension via reactive oxygen species-dependent vascular remodeling.

    PubMed

    Kameshima, Satoshi; Kazama, Kyosuke; Okada, Muneyoshi; Yamawaki, Hideyuki

    2015-05-15

    Pulmonary arterial (PA) hypertension (PAH) is a progressive and lethal disease that is caused by increased vascular contractile reactivity and structural remodeling. These changes contribute to increasing pulmonary peripheral vascular resistance, finally leading to right heart failure and death. Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca(2+)/calmodulin-dependent protein kinase. We previously revealed that eEF2K protein increases in the mesenteric artery from spontaneously hypertensive rats and partly mediates the development of hypertension via a promotion of ROS-dependent vascular inflammatory responses and proliferation and migration of vascular smooth muscle cells. However, a role of eEF2K in the pathogenesis of PAH is unknown. In the present study, we tested the hypothesis that eEF2K may be involved in the pathogenesis of PAH. PAH was induced by a single intraperitoneal injection of monocrotaline (MCT; 60 mg/kg) to rats. A specific eEF2K inhibitor, A-484954 (2.5 mg·kg(-1)·day(-1)), was intraperitoneally injected for 14 days. Long-term A-484954 treatment inhibited MCT-induced increased PA pressure. It was revealed that A-484954 inhibited MCT-induced PA hypertrophy and fibrosis but not impairment of endothelium-dependent and -independent relaxation. Furthermore, A-484954 inhibited MCT-induced NADPH oxidase-1 expression and ROS generation as well as matrix metalloproteinase-2 activation. In conclusion, the present results suggest that eEF2K at least partly mediates MCT-induced PAH via stimulation of vascular structural remodeling perhaps through NADPH oxidase-1/ROS/matrix metalloproteinase-2 pathway. PMID:25770246

  16. Human immunodeficiency virus-1 transgene expression increases pulmonary vascular resistance and exacerbates hypoxia-induced pulmonary hypertension development.

    PubMed

    Porter, Kristi M; Walp, Erik R; Elms, Shawn C; Raynor, Robert; Mitchell, Patrick O; Guidot, David M; Sutliff, Roy L

    2013-01-01

    Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary arterial resistance and vessel remodeling. Patients living with human immunodeficiency virus-1 (HIV-1) have an increased susceptibility to develop severe pulmonary hypertension (PH) irrespective of their CD4+ lymphocyte counts. While the underlying cause of HIV-PAH remains unknown, the interaction of HIV-1 proteins with the vascular endothelium may play a critical role in HIV-PAH development. Hypoxia promotes PH in experimental models and in humans, but the impact of HIV-1 proteins on hypoxia-induced pulmonary vascular dysfunction and PAH has not been examined. Therefore, we hypothesize that the presence of HIV-1 proteins and hypoxia synergistically augment the development of pulmonary vascular dysfunction and PH. We examined the effect of HIV-1 proteins on pulmonary vascular resistance by measuring pressure-volume relationships in isolated lungs from wild-type (WT) and HIV-1 Transgenic (Tg) rats. WT and HIV-1 Tg rats were exposed to 10% O2 for four weeks to induce experimental pulmonary hypertension to assess whether HIV-1 protein expression would impact the development of hypoxia-induced PH. Our results demonstrate that HIV-1 protein expression significantly increased pulmonary vascular resistance (PVR). HIV-1 Tg mice demonstrated exaggerated pulmonary vascular responses to hypoxia as evidenced by greater increases in right ventricular systolic pressures, right ventricular hypertrophy and vessel muscularization when compared to wild-type controls. This enhanced PH was associated with enhanced expression of HIF-1? and PCNA. In addition, in vitro studies reveal that medium from HIV-infected monocyte derived macrophages (MDM) potentiates hypoxia-induced pulmonary artery endothelial proliferation. These results indicate that the presence of HIV-1 proteins likely impact pulmonary vascular resistance and exacerbate hypoxia-induced PH. PMID:23662175

  17. Identification of a Novel Mucin Gene HCG22 Associated With Steroid-Induced Ocular Hypertension

    PubMed Central

    Jeong, Shinwu; Patel, Nitin; Edlund, Christopher K.; Hartiala, Jaana; Hazelett, Dennis J.; Itakura, Tatsuo; Wu, Pei-Chang; Avery, Robert L.; Davis, Janet L.; Flynn, Harry W.; Lalwani, Geeta; Puliafito, Carmen A.; Wafapoor, Hussein; Hijikata, Minako; Keicho, Naoto; Gao, Xiaoyi; Argeso, Pablo; Allayee, Hooman; Coetzee, Gerhard A.; Pletcher, Mathew T.; Conti, David V.; Schwartz, Stephen G.; Eaton, Alexander M.; Fini, M. Elizabeth

    2015-01-01

    Purpose. The pathophysiology of ocular hypertension (OH) leading to primary open-angle glaucoma shares many features with a secondary form of OH caused by treatment with glucocorticoids, but also exhibits distinct differences. In this study, a pharmacogenomics approach was taken to discover candidate genes for this disorder. Methods. A genome-wide association study was performed, followed by an independent candidate gene study, using a cohort enrolled from patients treated with off-label intravitreal triamcinolone, and handling change in IOP as a quantitative trait. Results. An intergenic quantitative trait locus (QTL) was identified at chromosome 6p21.33 near the 5? end of HCG22 that attained the accepted statistical threshold for genome-level significance. The HCG22 transcript, encoding a novel mucin protein, was expressed in trabecular meshwork cells, and expression was stimulated by IL-1, and inhibited by triamcinolone acetate and TGF-?. Bioinformatic analysis defined the QTL as an approximately 4 kilobase (kb) linkage disequilibrium block containing 10 common single nucleotide polymorphisms (SNPs). Four of these SNPs were identified in the National Center for Biotechnology Information (NCBI) GTEx eQTL browser as modifiers of HCG22 expression. Most are predicted to disrupt or improve motifs for transcription factor binding, the most relevant being disruption of the glucocorticoid receptor binding motif. A second QTL was identified within the predicted signal peptide of the HCG22 encoded protein that could affect its secretion. Translation, O-glycosylation, and secretion of the predicted HCG22 protein was verified in cultured trabecular meshwork cells. Conclusions. Identification of two independent QTLs that could affect expression of the HCG22 mucin gene product via two different mechanisms (transcription or secretion) is highly suggestive of a role in steroid-induced OH. PMID:25813999

  18. Downregulation of vascular soluble guanylate cyclase induced by high salt intake in spontaneously hypertensive rats

    PubMed Central

    Kagota, Satomi; Tamashiro, Akiko; Yamaguchi, Yu; Sugiura, Reiko; Kuno, Takayoshi; Nakamura, Kazuki; Kunitomo, Masaru

    2001-01-01

    Cyclic guanosine monophosphate (cyclic GMP)-mediated mechanism plays an important role in vasodilatation and blood pressure regulation. We investigated the effects of high salt intake on the nitric oxide (NO)??cyclic GMP signal transduction pathway regulating relaxation in aortas of spontaneously hypertensive rats (SHR).Four-week-old SHR and normotensive Wistar-Kyoto rats (WKY) received a normal salt diet (0.3% NaCl) or a high salt diet (8% NaCl) for 4 weeks.In aortic rings from SHR, endothelium-dependent relaxations in response to acetylcholine (ACh), adenosine diphosphate (ADP) and calcium ionophore A23187 were significantly impaired by the high salt intake. The endothelium-independent relaxations in response to sodium nitroprusside (SNP) and nitroglycerin were also impaired, but that to 8-bromo-cyclic GMP remained unchanged. On the other hand, high salt diet had no significant effects on the relaxations of aortic rings from WKY.In aortas from SHR, the release of NO stimulated by ACh was significantly enhanced, whereas the production of cyclic GMP induced by either ACh or SNP was decreased by the high salt intake.Western blot analysis showed that the protein level of endothelial NO synthase (eNOS) was slightly increased, whereas that of soluble guanylate cyclase (sGC) was dramatically reduced by the high salt intake.These results indicate that in SHR, excessive dietary salt can result in downregulation of sGC followed by decreased cyclic GMP production, which leads to impairment of vascular relaxation in responses to NO. It is notable that chronic high salt intake impairs the sGC/cyclic GMP pathway but not the eNOS/NO pathway. PMID:11606313

  19. The role of sustained release isosorbide mononitrate on corticosteroid-induced hypertension in healthy human subjects.

    PubMed

    Williamson, P M; Ong, S L H; Whitworth, J A; Kelly, J J

    2015-12-01

    There is evidence implicating abnormalities in the nitric oxide (NO) pathway in the development of glucocorticoid-induced hypertension (GC-HT). In humans, a reduction in NO availability during cortisol treatment has been observed. This study examined whether the NO donation may reverse the elevated blood pressure (BP) observed with cortisol treatment. A randomised double-blind, placebo-controlled, crossover study was undertaken in eight healthy men to address the effect of co-administration of isosorbide mononitrate (ISMN, 60?mg single dose, day 5) with cortisol (200?mg per day, days 1-6) and then compared with placebo (single dose, day 5) with cortisol. After a 2-week washout period, subjects crossed over to the alternate treatment. BP measurements were obtained using a mercury sphygmomanometer. Tonometry was used to estimate central pressures. There was a significant rise in mean arterial pressure with cortisol: 803 vs 893?mm?Hg (day 1 vs day 5, cortisol+ISMN phase, P<0.001) and 813 vs 893?mm?Hg (day 1 vs day 5, cortisol+placebo phase, P<0.01). ISMN significantly decreased aortic augmentation index: -17.33.2 vs 1.83.5%, (differences calculated from day 5-day 1, cortisol/ISMN vs cortisol+placebo, P<0.001). These results demonstrated that GC-HT can be modified by co-administration of exogenous NO donors, consistent with the hypothesis that GC-HT is accompanied by reduced NO activity in humans. PMID:25810066

  20. Evaluation of Exercise-Induced Hypertension Post Endovascular Stenting of Coarctation of Aorta

    PubMed Central

    Mortazaeian, Hojat; Moghadam, Mohammad Yoosef Aarabi; Ghaderian, Mehdi; Davary, Paridokht Nakhostin; Meraji, Mohmood; Mohammadi, Akbar Shah

    2010-01-01

    Background: Coarctation of the aorta (COA) is a defect that accounts for 58% of all congenital heart diseases. Balloon angioplasty as a treatment for COA is increasingly performed, with endovascular stents having been proposed as a means of improving the efficacy and safety of the procedure. The aim of this study was to evaluate the systolic blood pressure gradient at rest and during maximal exercise at follow-up in patients post endovascular stenting of COA. Methods: Thirteen patients (4 native and 9 re-coarctation cases of COA after surgery or balloon angioplasty) with a mean age of 11.1 4.7 years underwent endovascular stenting between November 2007 and December 2009 via standard techniques for native COA as an alternative to surgical repair. Doppler echocardiography was performed pre and post stenting. Resting and exercise assessment of blood pressure was performed at follow-up. Results: Post stent implantation, no angiographic major complications were evident. Systolic blood pressure gradient decreased from 42 8.8 mm Hg before stent placement to 7 10 mm Hg at follow-up (p value < 0.001). Peak Doppler pressure gradient decreased from 30 14 mm Hg to 14 10 mm Hg at follow-up (p value < 0.007). One case of exercise-induced hypertension was seen in patients. Conclusion: Endovascular stenting for native COA in older children and post-surgical COA repair in patients with residual COA and re-coarctation is a reasonable alternative to surgical correction. During early follow-up, stenting effectively alleviates the aortic arch obstruction with normalization of the systemic blood pressure both at rest and during maximal exercise. PMID:23074582

  1. Vascular Smooth Muscle Sirtuin-1 Protects Against Aortic Dissection During Angiotensin IIInduced Hypertension

    PubMed Central

    Fry, Jessica L; Shiraishi, Yasunaga; Turcotte, Raphal; Yu, Xunjie; Gao, Yuan Z; Akiki, Rachid; Bachschmid, Markus; Zhang, Yanhang; Morgan, Kathleen G; Cohen, Richard A; Seta, Francesca

    2015-01-01

    Background Sirtuin-1 (SirT1), a nicotinamide adenine dinucleotide+dependent deacetylase, is a key enzyme in the cellular response to metabolic, inflammatory, and oxidative stresses; however, the role of endogenous SirT1 in the vasculature has not been fully elucidated. Our goal was to evaluate the role of vascular smooth muscle SirT1 in the physiological response of the aortic wall to angiotensin II, a potent hypertrophic, oxidant, and inflammatory stimulus. Methods and Results Mice lacking SirT1 in vascular smooth muscle (ie, smooth muscle SirT1 knockout) had drastically high mortality (70%) caused by aortic dissection after angiotensin II infusion (1mg/kg per day) but not after an equipotent dose of norepinephrine, despite comparable blood pressure increases. Smooth muscle SirT1 knockout mice did not show any abnormal aortic morphology or blood pressure compared with wild-type littermates. Nonetheless, in response to angiotensin II, aortas from smooth muscle SirT1 knockout mice had severely disorganized elastic lamellae with frequent elastin breaks, increased oxidant production, and aortic stiffness compared with angiotensin IItreated wild-type mice. Matrix metalloproteinase expression and activity were increased in the aortas of angiotensin IItreated smooth muscle SirT1 knockout mice and were prevented in mice overexpressing SirT1 in vascular smooth muscle or with use of the oxidant scavenger tempol. Conclusions Endogenous SirT1 in aortic smooth muscle is required to maintain the structural integrity of the aortic wall in response to oxidant and inflammatory stimuli, at least in part, by suppressing oxidant-induced matrix metalloproteinase activity. SirT1 activators could potentially be a novel therapeutic approach to prevent aortic dissection and rupture in patients at risk, such as those with hypertension or genetic disorders, such as Marfans syndrome. PMID:26376991

  2. Endogenous hydrogen peroxide in the hypothalamic paraventricular nucleus regulates neurohormonal excitation in high salt-induced hypertension.

    PubMed

    Zhang, Meng; Qin, Da-Nian; Suo, Yu-Ping; Su, Qing; Li, Hong-Bao; Miao, Yu-Wang; Guo, Jing; Feng, Zhi-Peng; Qi, Jie; Gao, Hong-Li; Mu, Jian-Jun; Zhu, Guo-Qing; Kang, Yu-Ming

    2015-06-15

    Reactive oxygen species (ROS) in the brain plays an important role in the progression of hypertension and hydrogen peroxide (H2O2) is a major component of ROS. The aim of this study is to explore whether endogenous H2O2 changed by polyethylene glycol-catalase (PEG-CAT) and aminotriazole (ATZ) in the hypothalamic paraventricular nucleus (PVN) regulates neurotransmitters, renin-angiotensin system (RAS), and cytokines, and whether subsequently affects the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in high salt-induced hypertension. Male Sprague-Dawley rats received a high-salt diet (HS, 8% NaCl) or a normal-salt diet (NS, 0.3% NaCl) for 10 weeks. Then rats were treated with bilateral PVN microinjection of PEG-CAT (0.2 i.u./50nl), an analog of endogenous catalase, the catalase inhibitor ATZ (10nmol/50nl) or vehicle. High salt-fed rats had significantly increased MAP, RSNA, plasma norepinephrine (NE) and pro-inflammatory cytokines (PICs). In addition, rats with high-salt diet had higher levels of NOX-2, NOX-4 (subunits of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), interleukin-1beta (IL-1β), glutamate and NE, and lower levels of gamma-aminobutyric acid (GABA) and interleukin-10 (IL-10) in the PVN than normal diet rats. Bilateral PVN microinjection of PEG-CAT attenuated the levels of RAS and restored the balance of neurotransmitters and cytokines, while microinjection of ATZ into the PVN augmented those changes occurring in hypertensive rats. Our findings demonstrate that ROS component H2O2 in the PVN regulating MAP and RSNA are partly due to modulate neurotransmitters, renin-angiotensin system, and cytokines within the PVN in salt-induced hypertension. PMID:25891026

  3. CNS neuroplasticity and salt-sensitive hypertension induced by prior treatment with subpressor doses of ANG II or aldosterone.

    PubMed

    Clayton, Sarah C; Zhang, Zhongming; Beltz, Terry; Xue, Baojian; Johnson, Alan Kim

    2014-06-15

    Although sensitivity to high dietary NaCl is regarded to be a risk factor for cardiovascular disease, the causes of salt-sensitive hypertension remain elusive. Previously, we have shown that rats pretreated with subpressor doses of either ANG II or aldosterone (Aldo) show sensitized hypertensive responses to a mild pressor dose of ANG II when tested after an intervening delay. The current studies investigated whether such treatments will induce salt sensitivity. In studies employing an induction-delay-expression experimental design, male rats were instrumented for chronic mean arterial pressure (MAP) recording. In separate experiments, ANG II, Aldo, or vehicle was delivered either subcutaneously or intracerebroventricularly during the induction. There were no sustained differences in BP during the delay prior to being given 2% saline. While consuming 2% saline during the expression, both ANG II- and Aldo-pretreated rats showed significantly greater hypertension. When hexamethonium was used to assess autonomic control of MAP, no differences in the decrease of MAP in response to ganglionic blockade were detected during the induction. However, during the expression, the fall was greater in sensitized rats. In separate experiments, brain tissue that was collected at the end of delay showed increases in message or activation of putative markers of neuroplasticity (i.e., brain-derived neurotrophic factor, p38 mitogen-activated protein kinase, and cAMP response element-binding protein). These experiments demonstrate that prior administration of nonpressor doses of either ANG II or Aldo will induce salt sensitivity. Collectively, our findings indicate that treatment with subpressor doses of ANG II and Aldo initiate central neuroplastic changes that are involved in hypertension of different etiologies. PMID:24694383

  4. CNS neuroplasticity and salt-sensitive hypertension induced by prior treatment with subpressor doses of ANG II or aldosterone

    PubMed Central

    Clayton, Sarah C.; Zhang, Zhongming; Beltz, Terry; Xue, Baojian

    2014-01-01

    Although sensitivity to high dietary NaCl is regarded to be a risk factor for cardiovascular disease, the causes of salt-sensitive hypertension remain elusive. Previously, we have shown that rats pretreated with subpressor doses of either ANG II or aldosterone (Aldo) show sensitized hypertensive responses to a mild pressor dose of ANG II when tested after an intervening delay. The current studies investigated whether such treatments will induce salt sensitivity. In studies employing an induction-delay-expression experimental design, male rats were instrumented for chronic mean arterial pressure (MAP) recording. In separate experiments, ANG II, Aldo, or vehicle was delivered either subcutaneously or intracerebroventricularly during the induction. There were no sustained differences in BP during the delay prior to being given 2% saline. While consuming 2% saline during the expression, both ANG II- and Aldo-pretreated rats showed significantly greater hypertension. When hexamethonium was used to assess autonomic control of MAP, no differences in the decrease of MAP in response to ganglionic blockade were detected during the induction. However, during the expression, the fall was greater in sensitized rats. In separate experiments, brain tissue that was collected at the end of delay showed increases in message or activation of putative markers of neuroplasticity (i.e., brain-derived neurotrophic factor, p38 mitogen-activated protein kinase, and cAMP response element-binding protein). These experiments demonstrate that prior administration of nonpressor doses of either ANG II or Aldo will induce salt sensitivity. Collectively, our findings indicate that treatment with subpressor doses of ANG II and Aldo initiate central neuroplastic changes that are involved in hypertension of different etiologies. PMID:24694383

  5. Estrogen receptor-beta (ERβ) in the PVN and RVLM plays an essential protective role in aldosterone/salt-induced hypertension in female rats

    PubMed Central

    Xue, Baojian; Zhang, Zhongming; Beltz, Terry G; Johnson, Ralph F; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2013-01-01

    The identification of the specific estrogen receptor (ER) subtypes that are involved in estrogen protection from hypertension and their specific locations in the CNS is critical to our understanding and design of effective estrogen replacement therapies in women. Using selective ER agonists and recombinant adeno-associated virus (AAV) carrying small interference (si) RNA to silence either ERα (AAV-siRNA-ERα) or ERβ (AAV-siRNA-ERβ), the present study investigated regional specificity of different ER subtypes in the protective actions of estrogen in aldosterone (Aldo)-induced hypertension. Intracerebroventricular (icv) infusions of either DPN, a selective ERβ agonist, or PPT, a selective ERα agonist, attenuated Aldo/NaCl-induced hypertension in ovariectomized rats. In contrast, icv injections of siRNA-ERα or siRNA-ERβ augmented Aldo-induced hypertension in intact females. Site specific PVN or RVLM injections of siRNA-ERβ augmented Aldo-induced hypertension. However, rats with PVN or RVLM injections of siRNA-ERα did not significantly increase BP induced by Aldo. RT-PCR analyses of the PVN and RVLM of siRNA injected rat confirmed a marked reduction in the expression of ERα and ERβ. In cultured PVN neurons, silencing either ERα or ERβ by culturing PVN neurons with siRNA-ERα or siRNA-ERβ enhanced Aldo-induced ROS production. Ganglionic blockade after Aldo infusion showed an increase in sympathetic activity in ERβ knockdown rats. These results indicate that both PVN and RVLM ERβ, but not ERα in these nuclei, contribute to the protective effects of estrogen against Aldo-induced hypertension. The brain regions responsible for the protective effects of estrogen interaction with ERα in Aldo-induced hypertension still need to be determined. PMID:23608653

  6. Onset and Regression of Pregnancy-Induced Cardiac Alterations in Gestationally Hypertensive Mice: The Role of the Natriuretic Peptide System.

    PubMed

    Ventura, Nicole M; Li, Terry Y; Tse, M Yat; Andrew, R David; Tayade, Chandrakant; Jin, Albert Y; Pang, Stephen C

    2015-12-01

    Pregnancy induces cardiovascular adaptations in response to increased volume overload. Aside from the hemodynamic changes that occur during pregnancy, the maternal heart also undergoes structural changes. However, cardiac modulation in pregnancies complicated by gestational hypertension is incompletely understood. The objectives of the current investigation were to determine the role of the natriuretic peptide (NP) system in pregnancy and to assess alterations in pregnancy-induced cardiac hypertrophy between gestationally hypertensive and normotensive dams. Previously we have shown that mice lacking the expression of atrial NP (ANP; ANP(-/-)) exhibit a gestational hypertensive phenotype. In the current study, female ANP(+/+) and ANP(-/-) mice were mated with ANP(+/+) males. Changes in cardiac size and weight were evaluated across pregnancy at Gestational Days 15.5 and 17.5 and Postnatal Days 7, 14, and 28. Nonpregnant mice were used as controls. Physical measurement recordings and histological analyses demonstrated peak cardiac hypertrophy occurring at 14 days postpartum in both ANP(+/+) and ANP(-/-) dams with little to no change during pregnancy. Additionally, left ventricular expression of the renin-angiotensin system (RAS) and NP system was quantified by real-time quantitative polymerase chain reaction. Up-regulation of Agt and AT1a genes was observed late in pregnancy, while Nppa and Nppb genes were significantly up-regulated postpartum. Our data suggest that pregnancy-induced cardiac hypertrophy may be influenced by the RAS throughout gestation and by the NP system postpartum. Further investigations are required to gain a complete understanding of the mechanistic aspects of pregnancy-induced cardiac hypertrophy. PMID:26536903

  7. Oxidative stress-dependent activation of collagen synthesis is induced in human pulmonary smooth muscle cells by sera from patients with scleroderma-associated pulmonary hypertension.

    PubMed

    Boin, Francesco; Erre, Gian Luca; Posadino, Anna Maria; Cossu, Annalisa; Giordo, Roberta; Spinetti, Gaia; Passiu, Giuseppe; Emanueli, Costanza; Pintus, Gianfranco

    2014-01-01

    Pulmonary arterial hypertension is a major complication of systemic sclerosis. Although oxidative stress, intima hyperplasia and a progressive vessel occlusion appear to be clearly involved, the fine molecular mechanisms underpinning the onset and progression of systemic sclerosis-associated pulmonary arterial hypertension remain largely unknown. Here we shows for the first time that an increase of NADPH-derived reactive oxygen species production induced by sera from systemic sclerosis patients with pulmonary arterial hypertension drives collagen type I promoter activity in primary human pulmonary artery smooth muscle cells, suggesting that antioxidant-based therapies should be considered in the treatment of systemic sclerosis-associated vascular diseases. PMID:25085432

  8. Oxidative stress-dependent activation of collagen synthesis is induced in human pulmonary smooth muscle cells by sera from patients with scleroderma-associated pulmonary hypertension

    PubMed Central

    2014-01-01

    Pulmonary arterial hypertension is a major complication of systemic sclerosis. Although oxidative stress, intima hyperplasia and a progressive vessel occlusion appear to be clearly involved, the fine molecular mechanisms underpinning the onset and progression of systemic sclerosis-associated pulmonary arterial hypertension remain largely unknown. Here we shows for the first time that an increase of NADPH-derived reactive oxygen species production induced by sera from systemic sclerosis patients with pulmonary arterial hypertension drives collagen type I promoter activity in primary human pulmonary artery smooth muscle cells, suggesting that antioxidant-based therapies should be considered in the treatment of systemic sclerosis-associated vascular diseases. PMID:25085432

  9. Intrarenal Angiotensin-Converting Enzyme Induces Hypertension in Response to Angiotensin I Infusion

    PubMed Central

    Billet, Sandrine; Kim, Catherine; Satou, Ryousuke; Fuchs, Sebastien; Bernstein, Kenneth E.; Navar, L. Gabriel

    2011-01-01

    The contribution of the intrarenal renin-angiotensin system to the development of hypertension is incompletely understood. Here, we used targeted homologous recombination to generate mice that express angiotensin-converting enzyme (ACE) in the kidney tubules but not in other tissues. Mice homozygous for this genetic modification (ACE 9/9 mice) had low BP levels, impaired ability to concentrate urine, and variable medullary thinning. In accord with the ACE distribution, these mice also had reduced circulating angiotensin II and high plasma renin concentration but maintained normal kidney angiotensin II levels. In response to chronic angiotensin I infusions, ACE 9/9 mice displayed increased kidney angiotensin II, enhanced rate of urinary angiotensin II excretion, and development of hypertension. These findings suggest that intrarenal ACE-derived angiotensin II formation, even in the absence of systemic ACE, increases kidney angiotensin II levels and promotes the development of hypertension. PMID:21115616

  10. Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension

    PubMed Central

    Claude, Caroline; Mougenot, Nathalie; Bechaux, Julia; Hadri, Lahouaria; Brockschnieder, Damian; Clergue, Michel; Atassi, Fabrice; Lompr, Anne-Marie; Hulot, Jean-Sbastien

    2015-01-01

    The ATP-binding cassette transporter MRP4 (encoded by ABCC4) regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells. MRP4/ABCC4 deficient mice display a reduction in smooth muscle cells proliferation and a prevention of pulmonary hypertension in response to hypoxia. We aimed to study gene transfer of a MRP4/ABCC4 silencing RNA via intratracheal delivery of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed 35 days later. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >1011 DRP/animal) as compared to AAV1.control. The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension. PMID:26052533

  11. Role of the NADPH oxidases in the subfornical organ in angiotensin II-induced hypertension.

    PubMed

    Lob, Heinrich E; Schultz, David; Marvar, Paul J; Davisson, Robin L; Harrison, David G

    2013-02-01

    Reactive oxygen species and the NADPH oxidases contribute to hypertension via mechanisms that remain undefined. Reactive oxygen species produced in the central nervous system have been proposed to promote sympathetic outflow, inflammation, and hypertension, but the contribution of the NADPH oxidases to these processes in chronic hypertension is uncertain. We therefore sought to identify how NADPH oxidases in the subfornical organ (SFO) of the brain regulate blood pressure and vascular inflammation during sustained hypertension. We produced mice with loxP sites flanking the coding region of the NADPH oxidase docking subunit p22(phox). SFO-targeted injections of an adenovirus encoding cre-recombinase markedly diminished p22(phox), Nox2, and Nox4 mRNA in the SFO, as compared with a control adenovirus encoding red-fluorescent protein injection. Increased superoxide production in the SFO by chronic angiotensin II infusion (490 ng/kg min(-1) × 2 weeks) was blunted in adenovirus encoding cre-recombinase-treated mice, as detected by dihydroethidium fluorescence. Deletion of p22(phox) in the SFO eliminated the hypertensive response observed at 2 weeks of angiotensin II infusion compared with control adenovirus encoding red-fluorescent protein-treated mice (mean arterial pressures=97 ± 15 versus 154 ± 6 mm Hg, respectively; P=0.0001). Angiotensin II infusion also promoted marked vascular inflammation, as characterized by accumulation of activated T-cells and other leukocytes, and this was prevented by deletion of the SFO p22(phox). These experiments definitively identify the NADPH oxidases in the SFO as a critical determinant of the blood pressure and vascular inflammatory responses to chronic angiotensin II, and further support a role of reactive oxygen species in central nervous system signaling in hypertension. PMID:23248154

  12. Giant left Atrial Myxoma Induces Mitral Valve Obstruction and Pulmonary Hypertension

    PubMed Central

    Mashhadi, Mahpaekar; Peter, Sanjeeth

    2016-01-01

    Atrial myxomas are the commonest benign primary tumours of the heart. They are generally 2 to 6 cm in size. Depending on their size and site may result in mitral valve obstruction which may lead to pulmonary hypertension. Clinical symptoms may suggest the presence of a myxoma but echocardiography is the mainstay of diagnosis and confirmation is by histopathology. A well-formed, organized thrombus is a common differential. The report of an unusually large left atrial myxoma that occurred in a 54-year-old male causing mitral valve obstruction and pulmonary hypertension is presented here. PMID:26894077

  13. Plasma Cardiotrophin-1 as a Marker of Hypertension and Diabetes-Induced Target Organ Damage and Cardiovascular Risk

    PubMed Central

    Gamella-Pozuelo, Luis; Fuentes-Calvo, Isabel; Gmez-Marcos, Manuel A.; Recio-Rodriguez, Jos I.; Agudo-Conde, Cristina; Fernndez-Martn, Jos L.; Cannata-Anda, Jorge B.; Lpez-Novoa, Jos M.; Garca-Ortiz, Luis; Martnez-Salgado, Carlos

    2015-01-01

    Abstract The search for biomarkers of hypertension and diabetes-induced damage to multiple target organs is a priority. We analyzed the correlation between plasma cardiotrophin-1 (CT-1), a chemokine that participates in cardiovascular remodeling and organ fibrosis, and a wide range of parameters currently used to diagnose morphological and functional progressive injury in left ventricle, arteries, and kidneys of diabetic and hypertensive patients, in order to validate plasma levels of CT-1 as clinical biomarker. This is an observational study with 93 type 2-diabetic patients, 209 hypertensive patients, and 82 healthy controls in which we assessed the following parameters: plasma CT-1, basal glycaemia, systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), left ventricular hypertrophy (LVH by electrocardiographic indexes), peripheral vascular disease (by pulse wave velocityPWV, carotid intima-media thicknessC-IMT, and ankle-brachial indexABI), and renal impairment (by microalbuminuria, albumin/creatinine urinary ratio, plasma creatinine concentrations, and glomerular filtration rate). Hypertensive or diabetic patients have higher plasma CT-1 than control patients. CT-1 positively correlates with basal glycaemia, SBP, DBP, PP, LVH, arterial damage (increased IMT, decreased ABI), and early renal damage (microalbuminuria, elevated albumin/creatinine ratio). CT-1 also correlates with increased 10-year cardiovascular risk. Multiple linear regression analysis confirmed that CT-1 was associated with arterial injury assessed by PWV, IMT, ABI, and cardiac damage evaluated by Cornell voltage duration product. Increases in plasma CT-1 are strongly related to the intensity of several parameters associated to target organ damage supporting further investigation of its diagnostic capacity as single biomarker of cardiovascular injury and risk and, possibly, of subclinical renal damage. PMID:26222851

  14. Effect of angiotensin II-induced arterial hypertension on the voltage-dependent contractions of mouse arteries.

    PubMed

    Fransen, Paul; Van Hove, Cor E; Leloup, Arthur J A; Schrijvers, Dorien M; De Meyer, Guido R Y; De Keulenaer, Gilles W

    2016-02-01

    Arterial hypertension (AHT) affects the voltage dependency of L-type Ca(2+) channels in cardiomyocytes. We analyzed the effect of angiotensin II (AngII)-induced AHT on L-type Ca(2+) channel-mediated isometric contractions in conduit arteries. AHT was induced in C57Bl6 mice with AngII-filled osmotic mini-pumps (4weeks). Normotensive mice treated with saline-filled osmotic mini-pumps were used for comparison. Voltage-dependent contractions mediated by L-type Ca(2+) channels were studied in vaso-reactive studies in vitro in isolated aortic and femoral arteries by using extracellular K(+) concentration-response (KDR) experiments. In aortic segments, AngII-induced AHT significantly sensitized isometric contractions induced by elevated extracellular K(+) and depolarization. This sensitization was partly prevented by normalizing blood pressure with hydralazine, suggesting that it was caused by AHT rather than by direct AngII effects on aortic smooth muscle cells. The EC50 for extracellular K(+) obtained in vitro correlated significantly with the rise in arterial blood pressure induced by AngII in vivo. The AHT-induced sensitization persisted when aortic segments were exposed to levcromakalim or to inhibitors of basal nitric oxide release. Consistent with these observations, AngII-treatment also sensitized the vaso-relaxing effects of the L-type Ca(2+) channel blocker diltiazem during K(+)-induced contractions. Unlike aorta, AngII-treatment desensitized the isometric contractions to depolarization in femoral arteries pointing to vascular bed specific responses of arteries to hypertension. AHT affects the voltage-dependent L-type Ca(2+) channel-mediated contraction of conduit arteries. This effect may contribute to the decreased vascular compliance in AHT and explain the efficacy of Ca(2+) channel blockers to reduce vascular stiffness and central blood pressure in AHT. PMID:26432297

  15. Differential gene expression of three nitric oxide synthases is consistent with increased nitric oxide in the hindbrain of broilers with cold-induced pulmonary hypertension.

    PubMed

    Hassanpour, H; Nikoukar, Z; Nasiri, L; Bahadoran, S

    2015-01-01

    Quantitative real-time PCR and Griess reaction were conducted to evaluate gene expression of nitric oxide synthases (eNOS, nNOS and iNOS) and nitric oxide (NO) production in the hindbrain, midbrain, forebrain of chickens with cold-induced pulmonary hypertension. The ratio of the right to total ventricular weight of heart as an indication of pulmonary hypertension was increased in the cold stress groups of chickens at 42 d of age. In the pulmonary hypertensive chickens, production of NO was increased in the hindbrain but was unchanged in the forebrain and midbrain. Relative gene expression of eNOS and nNOS was upregulated in the three segments of brain, whereas the iNOS transcript was downregulated in the forebrain and midbrain of the cold-induced pulmonary hypertensive chickens. It is concluded that in the chickens with cold-induced pulmonary hypertension, variations of nNOS, eNOS and iNOS gene expression would lead to overproduction of NO in the hindbrain, whereas the variations in the expression of these genes did not result in an elevation of NO in the forebrain and midbrain. It is suggested that high levels of NO in the hindbrain excites neural mechanisms involved in pulmonary hypertension. PMID:26053227

  16. Estrogen regulation of the brain renin-angiotensin system in protection against angiotensin II-induced sensitization of hypertension

    PubMed Central

    Zhang, Zhongming; Beltz, Terry G.; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2014-01-01

    This study investigated sex differences in the sensitization of angiotensin (ANG) II-induced hypertension and the role of central estrogen and ANG-(1–7) in this process. Male and female rats were implanted for telemetered blood pressure (BP) recording. A subcutaneous subpressor dose of ANG II was given alone or concurrently with intracerebroventricular estrogen, ANG-(1–7), an ANG-(1–7) receptor antagonist A-779 or vehicle for 1 wk (induction). After a 1-wk rest (delay), a pressor dose of ANG II was given for 2 wk (expression). In males and ovariectomized females, subpressor ANG II had no sustained effect on BP during induction, but produced an enhanced hypertensive response to the subsequent pressor dose of ANG II during expression. Central administration of estrogen or ANG-(1–7) during induction blocked ANG II-induced sensitization. In intact females, subpressor ANG II treatment produced a decrease in BP during induction and delay, and subsequent pressor ANG II treatment given during expression produced only a slight but significant increase in BP. However, central blockade of ANG-(1–7) by intracerebroventricular infusion of A-779 during induction restored the decreased BP observed in females during induction and enhanced the pressor response to the ANG II treatment during expression. RT-PCR analyses indicated that estrogen given during induction upregulated mRNA expression of the renin-angiotensin system (RAS) antihypertensive components, whereas both central estrogen and ANG-(1–7) downregulated mRNA expression of RAS hypertensive components in the lamina terminalis. The results indicate that females are protected from ANG II-induced sensitization through central estrogen and its regulation of brain RAS. PMID:24858844

  17. A Critical Role of the mTOR/eIF2α Pathway in Hypoxia-Induced Pulmonary Hypertension

    PubMed Central

    Wang, Ai-ping; Li, Xiao-hui; Yang, Yong-mei; Li, Wen-qun; Zhang, Wang; Hu, Chang-ping; Zhang, Zheng; Li, Yuan-jian

    2015-01-01

    Enhanced proliferation of pulmonary arterial vascular smooth muscle cells (PASMCs) is a key pathological component of vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Mammalian targeting of rapamycin (mTOR) signaling has been shown to play a role in protein translation and participate in the progression of pulmonary hypertension. Eukaryotic translation initiation factor-2α (eIF2α) is a key factor in regulation of cell growth and cell cycle, but its role in mTOR signaling and PASMCs proliferation remains unknown. Pulmonary hypertension (PH) rat model was established by hypoxia. Rapamycin was used to treat rats as an mTOR inhibitor. Proliferation of primarily cultured rat PASMCs was induced by hypoxia, rapamycin and siRNA of mTOR and eIF2α were used in loss-of-function studies. The expression and activation of eIF2α, mTOR and c-myc were analyzed. Results showed that mTOR/eIF2α signaling was significantly activated in pulmonary arteries from hypoxia exposed rats and PASMCs cultured under hypoxia condition. Treatment with mTOR inhibitor for 21 days attenuated vascular remodeling, suppressed mTOR and eIF2α activation, inhibited c-myc expression in HPH rats. In hypoxia-induced PASMCs, rapamycin and knockdown of mTOR and eIF2α by siRNA significantly abolished proliferation and increased c-myc expression. These results suggest a critical role of the mTOR/eIF2αpathway in hypoxic vascular remodeling and PASMCs proliferation of HPH. PMID:26120832

  18. Central endogenous angiotensin-(1–7) protects against aldosterone/NaCl-induced hypertension in female rats

    PubMed Central

    Zhang, Zhongming; Johnson, Ralph F.; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2013-01-01

    In comparison to male rodents, females are protected against angiotensin (ANG) II- and aldosterone (Aldo)-induced hypertension. However, the mechanisms underlying this protective effect are not well understood. ANG-(1–7) is formed from ANG II by angiotensin-converting enzyme 2 (ACE2) and has an antihypertensive effect in the central nervous system (CNS). The present study tested the hypothesis that central ANG-(1–7) plays an important protective role in attenuating the development of Aldo/NaCl-hypertension in female rats. Systemic infusion of Aldo into intact female rats with 1% NaCl as their sole drinking fluid resulted in a slight increase in blood pressure (BP). Intracerebroventricular (icv) infusion of A-779, an ANG-(1–7) receptor (Mas-R) antagonist, significantly augmented the pressor effects of Aldo/NaCl. In contrast, systemic Aldo/NaCl induced a significant increase in BP in ovariectomized (OVX) female rats, and central infusion of ANG-(1–7) significantly attenuated this Aldo/NaCl pressor effect. The inhibitory effect of ANG-(1–7) on the Aldo/NaCl pressor effect was abolished by concurrent infusion of A-779. RT-PCR analyses showed that there was a corresponding change in mRNA expression of several renin-angiotensin system components, estrogen receptors and an NADPH oxidase subunit in the lamina terminalis. Taken together these results suggest that female sex hormones regulate an antihypertensive axis of the brain renin-angiotensin system involving ACE2/ANG-(1–7)/Mas-R that plays an important counterregulatory role in protecting against the development of Aldo/NaCl-induced hypertension. PMID:23812385

  19. Prolonged Subcutaneous Administration of Oxytocin Accelerates Angiotensin II-Induced Hypertension and Renal Damage in Male Rats

    PubMed Central

    Phie, James; Haleagrahara, Nagaraja; Newton, Patricia; Constantinoiu, Constantin; Sarnyai, Zoltan; Chilton, Lisa; Kinobe, Robert

    2015-01-01

    Oxytocin and its receptor are synthesised in the heart and blood vessels but effects of chronic activation of this peripheral oxytocinergic system on cardiovascular function are not known. In acute studies, systemic administration of low dose oxytocin exerted a protective, preconditioning effect in experimental models of myocardial ischemia and infarction. In this study, we investigated the effects of chronic administration of low dose oxytocin following angiotensin II-induced hypertension, cardiac hypertrophy and renal damage. Angiotensin II (40 μg/Kg/h) only, oxytocin only (20 or 100 ng/Kg/h), or angiotensin II combined with oxytocin (20 or 100 ng/Kg/h) were infused subcutaneously in adult male Sprague-Dawley rats for 28 days. At day 7, oxytocin or angiotensin-II only did not change hemodynamic parameters, but animals that received a combination of oxytocin and angiotensin-II had significantly elevated systolic, diastolic and mean arterial pressure compared to controls (P < 0.01). Hemodynamic changes were accompanied by significant left ventricular cardiac hypertrophy and renal damage at day 28 in animals treated with angiotensin II (P < 0.05) or both oxytocin and angiotensin II, compared to controls (P < 0.01). Prolonged oxytocin administration did not affect plasma concentrations of renin and atrial natriuretic peptide, but was associated with the activation of calcium-dependent protein phosphatase calcineurin, a canonical signalling mechanism in pressure overload-induced cardiovascular disease. These data demonstrate that oxytocin accelerated angiotensin-II induced hypertension and end-organ renal damage, suggesting caution should be exercised in the chronic use of oxytocin in individuals with hypertension. PMID:26393919

  20. Ameliorative Effect of Hydroethanolic Leaf Extract of Byrsocarpus coccineus in Alcohol- and Sucrose-Induced Hypertension in Rats

    PubMed Central

    Akindele, Abidemi J.; Iyamu, Endurance A.; Dutt, Prabhu; Satti, Naresh K.; Adeyemi, Olufunmilayo O.

    2014-01-01

    Hypertension remains a major health problem worldwide considering the prevalence of morbidity and mortality. Plants remain a reliable source of efficacious and better tolerated drugs and botanicals. This study was designed to investigate the effect of the chemo-profiled hydroethanolic leaf extract of Byrsocarpus coccineus in ethanol- and sucrose-induced hypertension. Groups of rats were treated orally (p.o.) with distilled water (10 ml/kg), ethanol (35%; 3 g/kg), sucrose (5-7%), and B. coccineus (100, 200, and 400 mg/kg), and nifedipine together with ethanol and sucrose separately for 8 weeks. At the end of the treatment period, blood pressure and heart rate of rats were determined. Blood was collected for serum biochemical parameters and lipid profile assessment, and the liver, aorta, kidney, and heart were harvested for estimation of in vivo antioxidants and malondialdehyde (MDA). Results obtained in this study showed that B. coccineus at the various doses administered reduced the systolic, diastolic, and arterial blood pressure elevated by ethanol and sucrose. Also, the extract reversed the reduction in catalase (CAT), reduced glutathione (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD) induced by ethanol and sucrose. The level of MDA was reduced compared to the ethanol- and sucrose-induced hypertensive group. With respect to lipid profile, administration of B. coccineus at the various doses reduced the levels of triglycerides, low-density lipoprotein (LDL), cholesterol, and atherogenic indices, compared to the ethanol and sucrose groups. In conclusion the hydroethanolic leaf extract of B. coccineus exerted significant antihypertensive effect and this is probably related to the antioxidant property and improvement of lipid profile observed in this study. PMID:25161923

  1. Estrogen regulation of the brain renin-angiotensin system in protection against angiotensin II-induced sensitization of hypertension.

    PubMed

    Xue, Baojian; Zhang, Zhongming; Beltz, Terry G; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2014-07-15

    This study investigated sex differences in the sensitization of angiotensin (ANG) II-induced hypertension and the role of central estrogen and ANG-(1-7) in this process. Male and female rats were implanted for telemetered blood pressure (BP) recording. A subcutaneous subpressor dose of ANG II was given alone or concurrently with intracerebroventricular estrogen, ANG-(1-7), an ANG-(1-7) receptor antagonist A-779 or vehicle for 1 wk (induction). After a 1-wk rest (delay), a pressor dose of ANG II was given for 2 wk (expression). In males and ovariectomized females, subpressor ANG II had no sustained effect on BP during induction, but produced an enhanced hypertensive response to the subsequent pressor dose of ANG II during expression. Central administration of estrogen or ANG-(1-7) during induction blocked ANG II-induced sensitization. In intact females, subpressor ANG II treatment produced a decrease in BP during induction and delay, and subsequent pressor ANG II treatment given during expression produced only a slight but significant increase in BP. However, central blockade of ANG-(1-7) by intracerebroventricular infusion of A-779 during induction restored the decreased BP observed in females during induction and enhanced the pressor response to the ANG II treatment during expression. RT-PCR analyses indicated that estrogen given during induction upregulated mRNA expression of the renin-angiotensin system (RAS) antihypertensive components, whereas both central estrogen and ANG-(1-7) downregulated mRNA expression of RAS hypertensive components in the lamina terminalis. The results indicate that females are protected from ANG II-induced sensitization through central estrogen and its regulation of brain RAS. PMID:24858844

  2. Central endogenous angiotensin-(1-7) protects against aldosterone/NaCl-induced hypertension in female rats.

    PubMed

    Xue, Baojian; Zhang, Zhongming; Johnson, Ralph F; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2013-09-01

    In comparison to male rodents, females are protected against angiotensin (ANG) II- and aldosterone (Aldo)-induced hypertension. However, the mechanisms underlying this protective effect are not well understood. ANG-(1-7) is formed from ANG II by angiotensin-converting enzyme 2 (ACE2) and has an antihypertensive effect in the central nervous system (CNS). The present study tested the hypothesis that central ANG-(1-7) plays an important protective role in attenuating the development of Aldo/NaCl-hypertension in female rats. Systemic infusion of Aldo into intact female rats with 1% NaCl as their sole drinking fluid resulted in a slight increase in blood pressure (BP). Intracerebroventricular (icv) infusion of A-779, an ANG-(1-7) receptor (Mas-R) antagonist, significantly augmented the pressor effects of Aldo/NaCl. In contrast, systemic Aldo/NaCl induced a significant increase in BP in ovariectomized (OVX) female rats, and central infusion of ANG-(1-7) significantly attenuated this Aldo/NaCl pressor effect. The inhibitory effect of ANG-(1-7) on the Aldo/NaCl pressor effect was abolished by concurrent infusion of A-779. RT-PCR analyses showed that there was a corresponding change in mRNA expression of several renin-angiotensin system components, estrogen receptors and an NADPH oxidase subunit in the lamina terminalis. Taken together these results suggest that female sex hormones regulate an antihypertensive axis of the brain renin-angiotensin system involving ACE2/ANG-(1-7)/Mas-R that plays an important counterregulatory role in protecting against the development of Aldo/NaCl-induced hypertension. PMID:23812385

  3. Delivery of imatinib-incorporated nanoparticles into lungs suppresses the development of monocrotaline-induced pulmonary arterial hypertension.

    PubMed

    Akagi, Satoshi; Nakamura, Kazufumi; Miura, Daiji; Saito, Yukihiro; Matsubara, Hiromi; Ogawa, Aiko; Matoba, Tetsuya; Egashira, Kensuke; Ito, Hiroshi

    2015-05-13

    Platelet-derived growth factor (PDGF) is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Imatinib, a PDGF-receptor tyrosine kinase inhibitor, improved hemodynamics, but serious side effects and drug discontinuation are common when treating PAH. A drug delivery system using nanoparticles (NPs) enables the reduction of side effects while maintaining the effects of the drug. We examined the efficacy of imatinib-incorporated NPs (Ima-NPs) in a rat model and in human PAH-pulmonary arterial smooth muscle cells (PASMCs). Rats received a single intratracheal administration of PBS, FITC-NPs, or Ima-NPs immediately after monocrotaline injection. Three weeks after monocrotaline injection, intratracheal administration of Ima-NPs suppressed the development of pulmonary hypertension, small pulmonary artery remodeling, and right ventricular hypertrophy in the rat model of monocrotaline-induced PAH. We also examined the effects of imatinib and Ima-NPs on PDGF-induced proliferation of human PAH-PASMCs by (3)H-thymidine incorporation. Imatinib and Ima-NPs significantly inhibited proliferation after 24 hours of treatment. Ima-NPs significantly inhibited proliferation compared with imatinib at 24 hours after removal of these drugs. Delivery of Ima-NPs into lungs suppressed the development of MCT-induced PAH by sustained antiproliferative effects on PAS-MCs. PMID:25902888

  4. Combined inhibition of 20-hydroxyeicosatetraenoic acid formation and of epoxyeicosatrienoic acids degradation attenuates hypertension and hypertension-induced end-organ damage in Ren-2 transgenic rats

    PubMed Central

    ?ertkov Chbov, V?ra; Walkowska, Agnieszka; Kompanowska-Jezierska, Elzbieta; Sadowski, Janusz; Kujal, Petr; Vernerov, Zdena; Va?ourkov, Zdenka; Kopkan, Libor; Kramer, Herbert J.; Falck, John R.; Imig, John D.; Hammock, Bruce D.; Van??kov, Ivana; ?ervenka, Lud?k

    2010-01-01

    Recent studies have shown that the renal cytochrome P-450 metabolites of arachidonic acid: the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE), and the vasodilator epoxyeicosatrienoic acids (EETs) play an important role in the pathophysiology of angiotensin II (ANG II)-dependent forms of hypertension and the associated target organ damage. The present studies were performed in Ren-2 renin transgenic rats (TGR) to evaluate the effects of chronic selective inhibition of 20-HETE formation or elevation of the level of EETs, alone or in combination, on the course of hypertension and hypertension-associated end-organ damage. Both young (30 days of age) prehypertensive TGR and adult (190 days of age) TGR with established hypertension were examined. Normotensive Hannover Sprague-Dawley (HanSD) rats served as controls. The rats were treated with N-methylsulfonyl-12,12-dibromododec-11-enamide to inhibit 20-HETE formation and/or with N-cyclohexyl-N-dodecyl urea to inhibit soluble epoxide hydrolase and prevent degradation of EETs. Inhibition in TGR rats of 20-HETE formation combined with enhanced bioavailability of EETs attenuated the development of hypertension, cardiac hypertrophy, proteinuria, glomerular hypertrophy and sclerosis as well as renal tubulointerstitial injury. This was also associated with an attenuation of the responsiveness of the systemic and renal vascular beds to ANG II without modifying their responses to norepinephrine. Our data suggest that altered production and/or action of 20-HETE and EETs plays a permissive role in the development of hypertension and hypertension-associated end-organ damage in this model of ANG II-dependent hypertension. This information provides a basis for a search of new therapeutic approaches to the treatment of hypertension. PMID:20050826

  5. Prenatal programming of pulmonary hypertension induced by chronic hypoxia or ductal ligation in sheep

    PubMed Central

    2013-01-01

    Abstract Pulmonary hypertension of the newborn is caused by a spectrum of functional and structural abnormalities of the cardiopulmonary circuit. The existence of multiple etiologies and an incomplete understanding of the mechanisms of disease progression have hindered the development of effective therapies. Animal models offer a means of gaining a better understanding of the fundamental basis of the disease. To that effect, a number of experimental animal models are being used to generate pulmonary hypertension in the fetus and newborn. In this review, we compare the mechanisms associated with pulmonary hypertension caused by two such models: in utero ligation of the ductus arteriosus and chronic perinatal hypoxia in sheep fetuses and newborns. In this manner, we make direct comparisons between ductal ligation and chronic hypoxia with respect to the associated mechanisms of disease, since multiple studies have been performed with both models in a single species. We present evidence that the mechanisms associated with pulmonary hypertension are dependent on the type of stress to which the fetus is subjected. Such an analysis allows for a more thorough evaluation of the disease etiology, which can help focus clinical treatments. The final part of the review provides a clinical appraisal of current treatment strategies and lays the foundation for developing individualized therapies that depend on the causative factors. PMID:25006393

  6. Diesel Exhaust-Induced Pulmonary and Cardiovascular Impairment: The Role of Hypertension Intervention

    EPA Science Inventory

    BackgroundExposure to diesel exhaust (DE) particles and associated gases is linked to cardiovascular impairments; however the susceptibility of hypertensive individuals is less well understood. Objective1) To determine cardiopulmonary effects of gas-phase versus whole-DE, and 2...

  7. Sex differences in angiotensin II- and aldosterone-induced hypertension: the central protective effects of estrogen

    PubMed Central

    Xue, Baojian; Hay, Meredith

    2013-01-01

    Premenopausal women have lower blood pressure and a reduced incidence of cardiovascular disease compared with age-matched men. Similar sex differences have been seen across species and in multiple animal models of hypertension. While important progress over the last decade has been made in elucidating some of the mechanisms underlying these differences, there are still significant gaps in our knowledge. Understanding the cellular and molecular mechanisms responsible for sex differences in hypertension will be important for developing sex-specific therapies targeted toward the prevention and treatment of hypertension. Female sex hormones, especially estrogen, have been demonstrated to modulate the renin-angiotensin-aldosterone system (RAAS) and to have beneficial effects on cardiovascular function through actions not only on the kidney, heart, and vasculature, but also on the central nervous system (CNS). This review primarily focuses on the central regulatory actions of estrogen on brain nuclei involved in blood pressure regulation and the interactions between estrogen and the RAAS in the CNS by which estrogen plays an important protective role against the development of hypertension. PMID:23883676

  8. Diesel Exhaust-Induced Pulmonary and Cardiovascular Impairment: The Role of Hypertension Intervention

    EPA Science Inventory

    Background–Exposure to diesel exhaust (DE) particles and associated gases is linked to cardiovascular impairments; however the susceptibility of hypertensive individuals is less well understood. Objective–1) To determine cardiopulmonary effects of gas-phase versus whole-DE, and 2...

  9. Pulmonary hypertension in hydralazine induced systemic lupus erythematosus: association with C4 null allele.

    PubMed Central

    Asherson, R A; Benbow, A G; Speirs, C J; Jackson, N; Hughes, G R

    1986-01-01

    A patient who developed pulmonary hypertension and systemic lupus erythematosus as a complication of hydralazine therapy is reported. She was a slow acetylator and in addition was found to have a null allele at the C4A locus. PMID:3767464

  10. Sensory CGRP depletion by capsaicin exacerbates hypoxia-induced pulmonary hypertension in rats.

    PubMed

    Tjen-A-Looi, S; Kraiczi, H; Ekman, R; Keith, I M

    1998-04-24

    Pulmonary hypertension is a debilitating disease that occurs among infants and adults. One of many etiologies is airway hypoxia. We previously demonstrated a role of endogenous calcitonin gene-related peptide (CGRP), a potent vasodilator, in ameliorating the pulmonary vascular pressor response to chronic hypoxia and related changes in the lungs and heart. This study evaluates the role of endogenous sensory CGRP in hypoxic pulmonary hypertension and examines the intrinsic neural microcircuitry. Rats were pretreated with capsaicin i.p. to deplete pulmonary sensory C-fiber stores of CGRP and substance P and placed in hypobaric hypoxia (10% O2, 16 days) or normoxia together with sham controls. Hypoxia increased pulmonary artery pressure, right-ventricular weight, arterial medial thickness, elasticized capillaries, endothelial cell density, lung water and hematocrit in control rats. Capsaicin augmented pulmonary artery pressure and right-ventricular hypertrophy in hypoxia, and medial thickness and endothelial cell density both in normoxia and hypoxia. Because of the limited effects on these parameters by substance P and other capsaicin-sensitive lung agents, our results suggest that sensory CGRP deficit severely exacerbates pathological signs of hypoxic pulmonary hypertension. A neural microcircuitry consistent with an axon reflex pathway is outlined histochemically. We conclude that endogenous CGRP modulates pulmonary vascular tone in hypoxic pulmonary hypertension which requires intact primary sensory fibers. PMID:9657352

  11. Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice

    PubMed Central

    Beetz, Nadine; Harrison, Michael D.; Brede, Marc; Zong, Xiangang; Urbanski, Michal J.; Sietmann, Anika; Kaufling, Jennifer; Barrot, Michel; Seeliger, Mathias W.; Vieira-Coelho, Maria Augusta; Hamet, Pavel; Gaudet, Daniel; Seda, Ondrej; Tremblay, Johanne; Kotchen, Theodore A.; Kaldunski, Mary; Nsing, Rolf; Szabo, Bela; Jacob, Howard J.; Cowley, Allen W.; Biel, Martin; Stoll, Monika; Lohse, Martin J.; Broeckel, Ulrich; Hein, Lutz

    2009-01-01

    Hypertension and its complications represent leading causes of morbidity and mortality. Although the cause of hypertension is unknown in most patients, genetic factors are recognized as contributing significantly to an individuals lifetime risk of developing the condition. Here, we investigated the role of the G protein regulator phosducin (Pdc) in hypertension. Mice with a targeted deletion of the gene encoding Pdc (Pdc/ mice) had increased blood pressure despite normal cardiac function and vascular reactivity, and displayed elevated catecholamine turnover in the peripheral sympathetic system. Isolated postganglionic sympathetic neurons from Pdc/ mice showed prolonged action potential firing after stimulation with acetylcholine and increased firing frequencies during membrane depolarization. Furthermore, Pdc/ mice displayed exaggerated increases in blood pressure in response to post-operative stress. Candidate genebased association studies in 2 different human populations revealed several SNPs in the PDC gene to be associated with stress-dependent blood pressure phenotypes. Individuals homozygous for the G allele of an intronic PDC SNP (rs12402521) had 1215 mmHg higher blood pressure than those carrying the A allele. These findings demonstrate that PDC is an important modulator of sympathetic activity and blood pressure and may thus represent a promising target for treatment of stress-dependent hypertension. PMID:19959875

  12. Sex differences in angiotensin II- and aldosterone-induced hypertension: the central protective effects of estrogen.

    PubMed

    Xue, Baojian; Johnson, Alan Kim; Hay, Meredith

    2013-09-01

    Premenopausal women have lower blood pressure and a reduced incidence of cardiovascular disease compared with age-matched men. Similar sex differences have been seen across species and in multiple animal models of hypertension. While important progress over the last decade has been made in elucidating some of the mechanisms underlying these differences, there are still significant gaps in our knowledge. Understanding the cellular and molecular mechanisms responsible for sex differences in hypertension will be important for developing sex-specific therapies targeted toward the prevention and treatment of hypertension. Female sex hormones, especially estrogen, have been demonstrated to modulate the renin-angiotensin-aldosterone system (RAAS) and to have beneficial effects on cardiovascular function through actions not only on the kidney, heart, and vasculature, but also on the central nervous system (CNS). This review primarily focuses on the central regulatory actions of estrogen on brain nuclei involved in blood pressure regulation and the interactions between estrogen and the RAAS in the CNS by which estrogen plays an important protective role against the development of hypertension. PMID:23883676

  13. Pulmonary vascular efflux of norepinephrine in Dahl rats susceptible or resistant to salt-induced hypertension

    SciTech Connect

    Metting, P.J.; Duggan, J.M.

    1988-06-01

    The purpose of these studies was to determine whether the accumulation of norepinephrine by the pulmonary circulation is altered in the Dahl model of genetic hypertension. Pulmonary norepinephrine accumulation was evaluated by performing a compartmental analysis of the efflux of L-(/sup 3/H)norepinephrine from perfused lungs after inhibition of the norepinephrine-metabolizing enzymes. The lungs were isolated from Dahl salt-hypertension-susceptible (S) and salt-hypertension-resistant (R) rats that had been on a high sodium diet for 3 weeks. In both S and R rats, norepinephrine was accumulated into a single compartment with an efflux half-time of approximately 23 min, in addition to its distribution in the extracellular space. The size of the extracellular space was significantly increased in the S rats, but there was no difference in the size of the compartment of L-(/sup 3/H)norepinephrine efflux between S (6.4 +/- 1.2 ml/g) and R (3.7 +/- 0.7 ml/g) rats. These data indicate that impaired accumulation and efflux of norepinephrine by the lungs does not contribute to the pathogenesis of hypertension in Dahl S rats.

  14. PRENATAL TESTOSTERONE EXPOSURE INDUCES HYPERTENSION IN ADULT FEMALES VIA ANDROGEN RECEPTOR-DEPENDENT PKCδ-MEDIATED MECHANISM

    PubMed Central

    Hankins, Gary D.; Yallampalli, Chandra; Sathishkumar, Kunju

    2014-01-01

    Prenatal exposure to excess testosterone induces hyperandrogenism in adult females and predisposes them to hypertension. We tested whether androgens induce hypertension through transcriptional regulation and signaling of protein kinase C (PKC) in the mesenteric arteries. Pregnant Sprague-Dawley rats were injected with vehicle or testosterone propionate (0.5mg/kg/day from gestation day 15–19, subcutaneously) and their 6-month-old adult female offspring were examined. Plasma testosterone levels (0.84±0.04 vs 0.42±0.09 ng/ml) and blood pressures (111.6± 1.3 vs 104.5 ± 2.4 mmHg) were significantly higher in prenatal testosterone-exposed rats compared to controls. This was accompanied with enhanced expression of PKCδ mRNA (1.5-fold) and protein (1.7-fold) in the mesenteric arteries of prenatal testosterone-exposed rats. In addition, mesenteric artery contractile responses to PKC activator—phorbol-12,13-dibutyrate—was significantly greater in prenatal testosterone-exposed rats. Treatment with androgen receptor antagonist flutamide (10 mg/kg, subcutaneously, twice-daily for 10 days) significantly attenuated hypertension, PKCδ expression, and the exaggerated vasoconstriction in prenatal testosterone-exposed rats. In vitro exposure of testosterone to cultured mesenteric artery smooth muscle cells dose-dependently upregulated PKCδ expression. Analysis of PKCδ gene revealed a putative androgen responsive element in the promoter upstream to the transcription start site and an enhancer element in intron-1. Chromatin-immunoprecipitation assays showed that androgen receptors bind to these elements in response to testosterone stimulation. Furthermore, luciferase reporter assays showed that the enhancer element is highly responsive to androgens and treatment with flutamide reverses reporter activity. Our studies identified a novel androgen-mediated mechanism for the control of PKCδ expression via transcriptional regulation that controls vasoconstriction and blood pressure. PMID:25489059

  15. Prenatal testosterone exposure induces hypertension in adult females via androgen receptor-dependent protein kinase C?-mediated mechanism.

    PubMed

    Blesson, Chellakkan S; Chinnathambi, Vijayakumar; Hankins, Gary D; Yallampalli, Chandra; Sathishkumar, Kunju

    2015-03-01

    Prenatal exposure to excess testosterone induces hyperandrogenism in adult females and predisposes them to hypertension. We tested whether androgens induce hypertension through transcriptional regulation and signaling of protein kinase C (PKC) in the mesenteric arteries. Pregnant Sprague-Dawley rats were injected with vehicle or testosterone propionate (0.5 mg/kg per day from gestation days 15 to 19, SC) and their 6-month-old adult female offspring were examined. Plasma testosterone levels (0.840.04 versus 0.420.09 ng/mL) and blood pressures (111.61.3 versus 104.52.4 mm Hg) were significantly higher in prenatal testosterone-exposed rats compared with controls. This was accompanied with enhanced expression of PKC? mRNA (1.5-fold) and protein (1.7-fold) in the mesenteric arteries of prenatal testosterone-exposed rats. In addition, mesenteric artery contractile responses to PKC activator, phorbol-12,13-dibutyrate, was significantly greater in prenatal testosterone-exposed rats. Treatment with androgen receptor antagonist flutamide (10 mg/kg, SC, BID for 10 days) significantly attenuated hypertension, PKC? expression, and the exaggerated vasoconstriction in prenatal testosterone-exposed rats. In vitro exposure of testosterone to cultured mesenteric artery smooth muscle cells dose dependently upregulated PKC? expression. Analysis of PKC? gene revealed a putative androgen responsive element in the promoter upstream to the transcription start site and an enhancer element in intron-1. Chromatin immunoprecipitation assays showed that androgen receptors bind to these elements in response to testosterone stimulation. Furthermore, luciferase reporter assays showed that the enhancer element is highly responsive to androgens and treatment with flutamide reverses reporter activity. Our studies identified a novel androgen-mediated mechanism for the control of PKC? expression via transcriptional regulation that controls vasoconstriction and blood pressure. PMID:25489059

  16. Clinical relevance of the glucocorticoid receptor gene polymorphisms in glucocorticoidinduced ocular hypertension and primary open angle glaucoma

    PubMed Central

    Wang, Xiu-Qing; Duan, Zhao-Xia; He, Xiang-Ge; Zhou, Xi-Yuan

    2015-01-01

    AIM To avoid the side effects of ocular hypertension of glucocorticoid (GC) usage in eye, we must identify susceptible individuals, which exists in about one-third of all population. Further, the majority of all primary open angle glaucoma (POAG) patients show this phenotype. Glucocorticoid receptor (GR) regulates C responsiveness in trabecular meshwork (TM) cells. In this study, single nucleotide polymorphism (SNP) genotyping was used to determine whether there are differences in the BclI (rs41423247) and N363S (rs6195) polymorphisms of the GR gene in healthy and POAG patients, and glucocorticoid-induced ocular hypertension (GIOH) populations. METHODS Three hundred and twenty-seven unrelated Chinese adults, including 111 normal controls, 117 GIOH subjects and 99 POAG patients, were recruited. DNA samples were prepared and the BclI and N363S polymorphisms were screened using real-time polymerase chain reaction (RT-PCR)-restriction fragment length polymorphism (RFLP) analysis. Frequencies of the BclI and N363S polymorphisms were determined and compared using Fisher's exact test and the Chi-squared test. RESULTS Only the BclI polymorphism was identified in the Chinese Han population. The frequency of the G allele was 21.6 % in normal controls, 18.3% in GIOH patients, and 13.64% in the POAG patients. There was no significant difference in polymorphism or allele frequency in the 3 groups. Furthermore, no N363S polymorphism was found in the study subjects. CONCLUSION The BclI polymorphisms in GR gene had no association with GIOH and POAG patients, and N363S polymorphism might not exist in the Chinese Han population. Therefore, the BclI polymorphism might not be responsible for the development of GC-induced ocular hypertension or POAG. PMID:25709928

  17. Role of oxidative stress, inflammation, nitric oxide and transforming growth factor-beta in the protective effect of diosgenin in monocrotaline-induced pulmonary hypertension in rats.

    PubMed

    Ahmed, Lamiaa A; Obaid, Al Arqam Z; Zaki, Hala F; Agha, Azza M

    2014-10-01

    Pulmonary hypertension is a progressive disease of various origins that is associated with right ventricular dysfunction. In the present study, the protective effect of diosgenin was investigated in monocrotaline-induced pulmonary hypertension in rats. Pulmonary hypertension was induced by a single subcutaneous injection of monocrotaline (60 mg/kg). Diosgenin (100 mg/kg) was given by oral administration once daily for 3 weeks. At the end of the experiment, mean arterial blood pressure, electrocardiography and echocardiography were recorded. Rats were then sacrificed and serum was separated for determination of total nitrate/nitrite level. Right ventricles and lungs were isolated for estimation of oxidative stress markers, tumor necrosis factor-alpha, total nitrate/nitrite and transforming growth factor-beta contents. Myeloperoxidase and caspase-3 activities in addition to endothelial and inducible nitric oxide synthase protein expression were also determined. Moreover, histological analysis of pulmonary arteries and cardiomyocyte cross-sectional area was performed. Diosgenin treatment provided a significant improvement toward preserving hemodynamic changes and alleviating oxidative stress, inflammatory and apoptotic markers induced by monocrotaline in rats. Furthermore, diosgenin therapy prevented monocrotaline-induced changes in nitric oxide production, endothelial and inducible nitric oxide synthase protein expression as well as histological analysis. These findings support the beneficial effect of diosgenin in pulmonary hypertension induced by monocrotaline in rats. PMID:25062790

  18. Crocetin reduces the oxidative stress induced reactive oxygen species in the stroke-prone spontaneously hypertensive rats (SHRSPs) brain.

    PubMed

    Yoshino, Fumihiko; Yoshida, Ayaka; Umigai, Naofumi; Kubo, Koya; Lee, Masaichi-Chang-Il

    2011-11-01

    Crocetin is a natural carotenoid compound of gardenia fruits and saffron, which has various effects in biological systems. In this study, we investigated the antioxidant effects of crocetin on reactive oxygen species such as hydroxyl radical using in vitro X-band electron spin resonance and spin trapping. Crocetin significantly inhibited hydroxyl radical generation compared with the control. Moreover, we performed electron spin resonance computed tomography ex vivo with the L-band electron spin resonance imaging system and determined the electron spin resonance signal decay rate in the isolated brain of stroke-prone spontaneously hypertensive rats, a high-oxidative stress model. Crocetin significantly reduced oxidative stress in the isolated brain by acting as a scavenger of reactive oxygen species, especially hydroxyl radical, as demonstrated by in vitro and ex vivo electron spin resonance analysis. The distribution of crocetin was also determined in the plasma and the brain of stroke-prone spontaneously hypertensive rats using high-performance liquid chromatography. After oral administration, crocetin was detected at high levels in the plasma and the brain. Our results suggest that crocetin may participate in the prevention of reactive oxygen species-induced disease due to a reduction of oxidative stress induced by reactive oxygen species in the brain. PMID:22128217

  19. Renoprotective mechanisms of pirfenidone in hypertension-induced renal injury: through anti-fibrotic and anti-oxidative stress pathways.

    PubMed

    Ji, Xu; Naito, Yukiko; Weng, Huachun; Ma, Xiao; Endo, Kosuke; Kito, Naoko; Yanagawa, Nariaki; Yu, Yang; Li, Jie; Iwai, Naoharu

    2013-01-01

    Pirfenidone (PFD) is a novel anti-fibrotic agent that targets TGF?. However, the mechanisms underlying its renoprotective properties in hypertension-induced renal injury are poorly understood. We investigated the renoprotective properties of PFD and clarified its renoprotective mechanisms in a rat hypertension-induced renal injury model. Dahl salt-sensitive rats were fed a high-salt diet with or without 1% PFD for 6 weeks. During the administration period, we examined the effects of PFD on blood pressure and renal function. After the administration, the protein levels of renal TGF?, Smad2/3, TNF?, MMP9, TIMP1, and catalase were examined. In addition, total serum antioxidant activity was measured. Compared to untreated rats, PFD treatment significantly attenuated blood pressure and proteinuria. Histological study showed that PFD treatment improved renal fibrosis. PFD may exert its anti-fibrotic effects via the downregulation of TGF?-Smad2/3 signaling, improvement of MMP9/TIMP1 balance, and suppression of fibroblast proliferation. PFD treatment also increased catalase expression and total serum antioxidant activity. In contrast, PFD treatment did not affect the expression of TNF? protein, macrophage or T-cell infiltration, or plasma interleukin 1? levels. PFD prevents renal injury via its anti-fibrotic and anti-oxidative stress mechanisms. Clarifying the renoprotective mechanisms of PFD will help improve treatment for chronic renal diseases. PMID:24389407

  20. Captopril attenuates hypertension and renal injury induced by the vascular endothelial growth factor inhibitor sorafenib

    PubMed Central

    Nagasawa, Tasuku; Khan, Abdul Hye; Imig, John D

    2013-01-01

    SUMMARY Vascular endothelial growth factor inhibitors (VEGFi) are known to cause hypertension and renal injury that severely limits their use as an anticancer therapy. We hypothesized that the angiotensin-converting enzyme inhibitor captopril not only prevents hypertension, but also decreases renal injury caused by the VEGFi sorafenib.Rats were administered sorafenib (20 mg/kg per day) alone or in combination with captopril (40 mg/kg per day) for 4 weeks. Sorafenib administration increased blood pressure, which plateaued by day 10.Concurrent treatment with captopril for 4 weeks resulted in a 30 mmHg decrease in blood pressure compared with sorafenib alone (155 5 vs 182 6 mmHg, respectively; P < 0.05). Furthermore, concurrent captopril treatment reduced albuminuria by 50% compared with sorafenib alone (20 8 vs 42 9 mg/day, respectively; P < 0.05) and reduced nephrinuria by eightfold (280 96 vs 2305 665 ?g/day, respectively; P < 0.05). Glomerular injury, thrombotic micro-angiopathy and tubular cast formation were also decreased in captopril-treated rats administered sorafenib. Renal autoregulatory efficiency was determined by evaluating the afferent arteriolar constrictor response to ATP. Sorafenib administration attenuated the vasoconstriction to ATP, whereas concurrent captopril treatment improved ATP reactivity.In conclusion, captopril attenuated hypertension and renal injury and improved renal autoregulatory capacity in rats administered sorafenib. These findings indicate that captopril treatment, in addition to alleviating the detrimental side-effect of hypertension, decreases the renal injury associated with anticancer VEGFi therapies such as sorafenib. PMID:22443474

  1. Schistosome-induced cholangiocyte proliferation and osteopontin secretion correlate with fibrosis and portal hypertension in human and murine schistosomiasis mansoni.

    PubMed

    Pereira, Thiago A; Syn, Wing-Kin; Machado, Mariana V; Vidigal, Paula V; Resende, Vivian; Voieta, Izabela; Xie, Guanhua; Otoni, Alba; Souza, Márcia M; Santos, Elisângela T; Chan, Isaac S; Trindade, Guilherme V M; Choi, Steve S; Witek, Rafal P; Pereira, Fausto E; Secor, William E; Andrade, Zilton A; Lambertucci, José Roberto; Diehl, Anna Mae

    2015-11-01

    Schistosomiasis is a major cause of portal hypertension worldwide. It associates with portal fibrosis that develops during chronic infection. The mechanisms by which the pathogen evokes these host responses remain unclear. We evaluated the hypothesis that schistosome eggs release factors that directly stimulate liver cells to produce osteopontin (OPN), a pro-fibrogenic protein that stimulates hepatic stellate cells to become myofibroblasts. We also investigated the utility of OPN as a biomarker of fibrosis and/or severity of portal hypertension. Cultured cholangiocytes, Kupffer cells and hepatic stellate cells were treated with soluble egg antigen (SEA); OPN production was quantified by quantitative reverse transcriptase polymerase chain reaction (qRTPCR) and ELISA; cell proliferation was assessed by BrdU (5-bromo-2'-deoxyuridine). Mice were infected with Schistosoma mansoni for 6 or 16 weeks to cause early or advanced fibrosis. Liver OPN was evaluated by qRTPCR and immunohistochemistry (IHC) and correlated with liver fibrosis and serum OPN. Livers from patients with schistosomiasis mansoni (early fibrosis n=15; advanced fibrosis n=72) or healthy adults (n=22) were immunostained for OPN and fibrosis markers. Results were correlated with plasma OPN levels and splenic vein pressures. SEA-induced cholangiocyte proliferation and OPN secretion (P<0.001 compared with controls). Cholangiocytes were OPN (+) in Schistosoma-infected mice and humans. Liver and serum OPN levels correlated with fibrosis stage (mice: r=0.861; human r=0.672, P=0.0001) and myofibroblast accumulation (mice: r=0.800; human: r=0.761, P=0.0001). Numbers of OPN (+) bile ductules strongly correlated with splenic vein pressure (r=0.778; P=0.001). S. mansoni egg antigens stimulate cholangiocyte proliferation and OPN secretion. OPN levels in liver and blood correlate with fibrosis stage and portal hypertension severity. PMID:26201095

  2. Schistosome-induced cholangiocyte proliferation and osteopontin secretion correlate with fibrosis and portal hypertension in human and murine schistosomiasis mansoni

    PubMed Central

    Pereira, ThiagoA.; Syn, Wing-Kin; Machado, MarianaV.; Vidigal, PaulaV.; Resende, Vivian; Voieta, Izabela; Xie, Guanhua; Otoni, Alba; Souza, MrciaM.; Santos, ElisngelaT.; Chan, IsaacS.; Trindade, GuilhermeV.M.; Choi, SteveS.; Witek, RafalP.; Pereira, FaustoE.; Secor, WilliamE.; Andrade, ZiltonA.; Lambertucci, JosRoberto

    2015-01-01

    Schistosomiasis is a major cause of portal hypertension worldwide. It associates with portal fibrosis that develops during chronic infection. The mechanisms by which the pathogen evokes these host responses remain unclear. We evaluated the hypothesis that schistosome eggs release factors that directly stimulate liver cells to produce osteopontin (OPN), a pro-fibrogenic protein that stimulates hepatic stellate cells to become myofibroblasts. We also investigated the utility of OPN as a biomarker of fibrosis and/or severity of portal hypertension. Cultured cholangiocytes, Kupffer cells and hepatic stellate cells were treated with soluble egg antigen (SEA); OPN production was quantified by quantitative reverse transcriptase polymerase chain reaction (qRTPCR) and ELISA; cell proliferation was assessed by BrdU (5-bromo-2'-deoxyuridine). Mice were infected with Schistosoma mansoni for 6 or 16weeks to cause early or advanced fibrosis. Liver OPN was evaluated by qRTPCR and immunohistochemistry (IHC) and correlated with liver fibrosis and serum OPN. Livers from patients with schistosomiasis mansoni (early fibrosis n=15; advanced fibrosis n=72) or healthy adults (n=22) were immunostained for OPN and fibrosis markers. Results were correlated with plasma OPN levels and splenic vein pressures. SEA-induced cholangiocyte proliferation and OPN secretion (P<0.001 compared with controls). Cholangiocytes were OPN (+) in Schistosoma-infected mice and humans. Liver and serum OPN levels correlated with fibrosis stage (mice: r=0.861; human r=0.672, P=0.0001) and myofibroblast accumulation (mice: r=0.800; human: r=0.761, P=0.0001). Numbers of OPN (+) bile ductules strongly correlated with splenic vein pressure (r=0.778; P=0.001). S. mansoni egg antigens stimulate cholangiocyte proliferation and OPN secretion. OPN levels in liver and blood correlate with fibrosis stage and portal hypertension severity. PMID:26201095

  3. Decreased creatine kinase is linked to diastolic dysfunction in rats with right heart failure induced by pulmonary artery hypertension

    PubMed Central

    Fowler, Ewan D.; Benoist, David; Drinkhill, Mark J.; Stones, Rachel; Helmes, Michiel; Wst, Rob C.I.; Stienen, Ger J.M.; Steele, Derek S.; White, Ed

    2015-01-01

    Our objective was to investigate the role of creatine kinase in the contractile dysfunction of right ventricular failure caused by pulmonary artery hypertension. Pulmonary artery hypertension and right ventricular failure were induced in rats by monocrotaline and compared to saline-injected control animals. In vivo right ventricular diastolic pressurevolume relationships were measured in anesthetized animals; diastolic forcelength relationships in single enzymatically dissociated myocytes and myocardial creatine kinase levels by Western blot. We observed diastolic dysfunction in right ventricular failure indicated by significantly steeper diastolic pressurevolume relationships in vivo and diastolic forcelength relationships in single myocytes. There was a significant reduction in creatine kinase protein expression in failing right ventricle. Dysfunction also manifested as a shorter diastolic sarcomere length in failing myocytes. This was associated with a Ca2+-independent mechanism that was sensitive to cross-bridge cycling inhibition. In saponin-skinned failing myocytes, addition of exogenous creatine kinase significantly lengthened sarcomeres, while in intact healthy myocytes, inhibition of creatine kinase significantly shortened sarcomeres. Creatine kinase inhibition also changed the relatively flat contraction amplitudestimulation frequency relationship of healthy myocytes into a steeply negative, failing phenotype. Decreased creatine kinase expression leads to diastolic dysfunction. We propose that this is via local reduction in ATP:ADP ratio and thus to Ca2+-independent force production and diastolic sarcomere shortening. Creatine kinase inhibition also mimics a definitive characteristic of heart failure, the inability to respond to increased demand. Novel therapies for pulmonary artery hypertension are needed. Our data suggest that cardiac energetics would be a potential ventricular therapeutic target. PMID:26116865

  4. Structure/Function Analysis of Protein-Protein Interactions Developed by the Yeast Pih1 Platform Protein and Its Partners in Box C/D snoRNP Assembly.

    PubMed

    Quinternet, Marc; Rothé, Benjamin; Barbier, Muriel; Bobo, Claude; Saliou, Jean-Michel; Jacquemin, Clémence; Back, Régis; Chagot, Marie-Eve; Cianférani, Sarah; Meyer, Philippe; Branlant, Christiane; Charpentier, Bruno; Manival, Xavier

    2015-08-28

    In eukaryotes, nucleotide post-transcriptional modifications in RNAs play an essential role in cell proliferation by contributing to pre-ribosomal RNA processing, ribosome assembly and activity. Box C/D small nucleolar ribonucleoparticles catalyze site-specific 2'-O-methylation of riboses, one of the most prevalent RNA modifications. They contain one guide RNA and four core proteins and their in vivo assembly requires numerous factors including (HUMAN/Yeast) BCD1/Bcd1p, NUFIP1/Rsa1p, ZNHIT3/Hit1p, the R2TP complex composed of protein PIH1D1/Pih1p and RPAP3/Tah1p that bridges the R2TP complex to the HSP90/Hsp82 chaperone and two AAA+ ATPases. We show that Tah1p can stabilize Pih1p in the absence of Hsp82 activity during the stationary phase of growth and consequently that the Tah1p:Pih1p interaction is sufficient for Pih1p stability. This prompted us to establish the solution structure of the Tah1p:Pih1p complex by NMR. The C-terminal tail S93-S111 of Tah1p snakes along Pih1p264-344 folded in a CS domain to form two intermolecular β-sheets and one covering loop. However, a thorough inspection of the NMR and crystal structures revealed structural differences that may be of functional importance. In addition, our NMR and isothermal titration calorimetry data revealed the formation of direct contacts between Pih1p257-344 and the Hsp82MC domain in the presence of Tah1p. By co-expression in Escherichia coli, we demonstrate that Pih1p has two other direct partners, the Rsa1p assembly factor and the Nop58p core protein, and in vivo and in vitro experiments mapped the required binding domains. Our data suggest that these two interactions are mutually exclusive. The implication of this finding for box C/D small nucleolar ribonucleoparticle assembly is discussed. PMID:26210662

  5. Endothelial expression of human cytochrome P450 epoxygenases lowers blood pressure and attenuates hypertension-induced renal injury in mice

    PubMed Central

    Lee, Craig R.; Imig, John D.; Edin, Matthew L.; Foley, Julie; DeGraff, Laura M.; Bradbury, J. Alyce; Graves, Joan P.; Lih, Fred B.; Clark, James; Myers, Page; Perrow, A. Ligon; Lepp, Adrienne N.; Kannon, M. Alison; Ronnekleiv, Oline K.; Alkayed, Nabil J.; Falck, John R.; Tomer, Kenneth B.; Zeldin, Darryl C.

    2010-01-01

    Renal cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) regulate sodium transport and blood pressure. Although endothelial CYP-derived EETs are potent vasodilators, their contribution to the regulation of blood pressure remains unclear. Consequently, we developed transgenic mice with endothelial expression of the human CYP2J2 and CYP2C8 epoxygenases to increase endothelial EET biosynthesis. Compared to wild-type littermate controls, an attenuated afferent arteriole constrictor response to endothelin-1 and enhanced dilator response to acetylcholine was observed in CYP2J2 and CYP2C8 transgenic mice. CYP2J2 and CYP2C8 transgenic mice demonstrated modestly, but not significantly, lower mean arterial pressure under basal conditions compared to wild-type controls. However, mean arterial pressure was significantly lower in both CYP2J2 and CYP2C8 transgenic mice during coadministration of N-nitro-l-arginine methyl ester and indomethacin. In a separate experiment, a high-salt diet and subcutaneous angiotensin II was administered over 4 wk. The angiotensin/high-salt-induced increase in systolic blood pressure, proteinuria, and glomerular injury was significantly attenuated in CYP2J2 and CYP2C8 transgenic mice compared to wild-type controls. Collectively, these data demonstrate that increased endothelial CYP epoxygenase expression attenuates afferent arteriolar constrictor reactivity and hypertension-induced increases in blood pressure and renal injury in mice. We conclude that endothelial CYP epoxygenase function contributes to the regulation of blood pressure.Lee, C. R., Imig, J. D., Edin, M. E., Foley, J., DeGraff, L. M., Bradbury, J. A., Graves, J. P., Lih, F. B., Clark, J., Myers, P., Perrow, A. L., Lepp, A. N., Kannon, M. A., Ronnekleiv, O. K., Alkayed, N. J., Falck, J. R., Tomer, K. B., Zeldin, D. C. Endothelial expression of human cytochrome P450 epoxygenases lowers blood pressure and attenuates hypertension-induced renal injury in mice. PMID:20495177

  6. Genetic knockdown of estrogen receptor-alpha in the subfornical organ augments ANG II-induced hypertension in female mice

    PubMed Central

    Zhang, Zhongming; Beltz, Terry G.; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2014-01-01

    The present study tested the hypotheses that 1) ERα in the brain plays a key role in the estrogen-protective effects against ANG II-induced hypertension, and 2) that the subfornical organ (SFO) is a key site where ERα mediates these protective actions. In this study, a “floxed” ERα transgenic mouse line (ERαflox) was used to create models in which ERα was knocked down in the brain or just in the SFO. Female mice with ERα ablated in the nervous system (Nestin-ERα− mice) showed greater increases in blood pressure (BP) in response to ANG II. Furthermore, females with ERα knockdown specifically in the SFO [SFO adenovirus-Cre (Ad-Cre) injected ERαflox mice] also showed an enhanced pressor response to ANG II. Immunohistochemical (IHC), RT-PCR, and Western blot analyses revealed a marked reduction in the expression of ERα in nervous tissues and, in particular, in the SFO. These changes were not present in peripheral tissues in Nestin-ERα− mice or Ad-Cre-injected ERαflox mice. mRNA expression of components of the renin-angiotensin system in the lamina terminalis were upregulated in Nestin-ERα− mice. Moreover, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction of BP in Nestin-ERα− mice or SFO Ad-Cre-injected mice, suggesting that knockdown of ERα in the nervous system or the SFO alone augments central ANG II-induced increase in sympathetic tone. The results indicate that interfering with the action of estrogen on SFO ERα is sufficient to abolish the protective effects of estrogen against ANG II-induced hypertension. PMID:25552661

  7. Genetic knockdown of estrogen receptor-alpha in the subfornical organ augments ANG II-induced hypertension in female mice.

    PubMed

    Xue, Baojian; Zhang, Zhongming; Beltz, Terry G; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2015-03-15

    The present study tested the hypotheses that 1) ERα in the brain plays a key role in the estrogen-protective effects against ANG II-induced hypertension, and 2) that the subfornical organ (SFO) is a key site where ERα mediates these protective actions. In this study, a "floxed" ERα transgenic mouse line (ERα(flox)) was used to create models in which ERα was knocked down in the brain or just in the SFO. Female mice with ERα ablated in the nervous system (Nestin-ERα(-) mice) showed greater increases in blood pressure (BP) in response to ANG II. Furthermore, females with ERα knockdown specifically in the SFO [SFO adenovirus-Cre (Ad-Cre) injected ERα(flox) mice] also showed an enhanced pressor response to ANG II. Immunohistochemical (IHC), RT-PCR, and Western blot analyses revealed a marked reduction in the expression of ERα in nervous tissues and, in particular, in the SFO. These changes were not present in peripheral tissues in Nestin-ERα(-) mice or Ad-Cre-injected ERα(flox) mice. mRNA expression of components of the renin-angiotensin system in the lamina terminalis were upregulated in Nestin-ERα(-) mice. Moreover, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction of BP in Nestin-ERα(-) mice or SFO Ad-Cre-injected mice, suggesting that knockdown of ERα in the nervous system or the SFO alone augments central ANG II-induced increase in sympathetic tone. The results indicate that interfering with the action of estrogen on SFO ERα is sufficient to abolish the protective effects of estrogen against ANG II-induced hypertension. PMID:25552661

  8. Fatty acid nitroalkenes ameliorate glucose intolerance and pulmonary hypertension in high-fat diet-induced obesity

    PubMed Central

    Kelley, Eric E.; Baust, Jeff; Bonacci, Gustavo; Golin-Bisello, Franca; Devlin, Jason E.; St. Croix, Claudette M.; Watkins, Simon C.; Gor, Sonia; Cantu-Medellin, Nadiezhda; Weidert, Eric R.; Frisbee, Jefferson C.; Gladwin, Mark T.; Champion, Hunter C.; Freeman, Bruce A.; Khoo, Nicholas K.H.

    2014-01-01

    Aims Obesity is a risk factor for diabetes and cardiovascular diseases, with the incidence of these disorders becoming epidemic. Pathogenic responses to obesity have been ascribed to adipose tissue (AT) dysfunction that promotes bioactive mediator secretion from visceral AT and the initiation of pro-inflammatory events that induce oxidative stress and tissue dysfunction. Current understanding supports that suppressing pro-inflammatory and oxidative events promotes improved metabolic and cardiovascular function. In this regard, electrophilic nitro-fatty acids display pleiotropic anti-inflammatory signalling actions. Methods and results It was hypothesized that high-fat diet (HFD)-induced inflammatory and metabolic responses, manifested by loss of glucose tolerance and vascular dysfunction, would be attenuated by systemic administration of nitrooctadecenoic acid (OA-NO2). Male C57BL/6j mice subjected to a HFD for 20 weeks displayed increased adiposity, fasting glucose, and insulin levels, which led to glucose intolerance and pulmonary hypertension, characterized by increased right ventricular (RV) end-systolic pressure (RVESP) and pulmonary vascular resistance (PVR). This was associated with increased lung xanthine oxidoreductase (XO) activity, macrophage infiltration, and enhanced expression of pro-inflammatory cytokines. Left ventricular (LV) end-diastolic pressure remained unaltered, indicating that the HFD produces pulmonary vascular remodelling, rather than LV dysfunction and pulmonary venous hypertension. Administration of OA-NO2 for the final 6.5 weeks of HFD improved glucose tolerance and significantly attenuated HFD-induced RVESP, PVR, RV hypertrophy, lung XO activity, oxidative stress, and pro-inflammatory pulmonary cytokine levels. Conclusions These observations support that the pleiotropic signalling actions of electrophilic fatty acids represent a therapeutic strategy for limiting the complex pathogenic responses instigated by obesity. PMID:24385344

  9. Aldehyde dehydrogenase 2 partly mediates hypotensive effect of nitrite on L-NAME-induced hypertension in normoxic rat.

    PubMed

    Sonoda, Kunihiro; Ohtake, Kazuo; Kubo, Yoshinori; Uchida, Hiroyuki; Uchida, Masaki; Natsume, Hideshi; Kobayashi, Miya; Kobayashi, Jun

    2014-01-01

    Nitrite has become a topic of interest in the field of medical research because of its potential therapeutic role as an alternative source of nitric oxide (NO). While the bioconversion of nitrite to NO occurs via either nonenzymatic or enzymatic reduction under acidic or hypoxic conditions, little is known about its conversion to NO under normoxic conditions. Because of a recent report of aldehyde dehydrogenase 2 (ALDH2)-catalyzed glyceryl trinitrate (GTN) vasorelaxation by denitration of GTN to 1,2-glyceryl dinitrate (1,2-GDN) and nitrite, we therefore investigated a catalytic activity of ALDH2 for nitrite reduction and subsequent effect on N(?)-nitro-l-arginine methyl ester (l-NAME)-induced hypertension in normoxic rat. Male Sprague-Dawley rats treated with l-NAME in drinking water for 3 weeks developed hypertension with significantly reduced plasma levels of nitrite and nitrate. The intravenous injection of sodium nitrite lowered the arterial pressure in a dose-dependent manner (17, 50 and 150 ?mol/kg). Pretreatment with ALDH2 inhibitors (cyanamide and chloral hydrate) partially inhibited the hypotensive responses to sodium nitrite. In addition, cyanamide significantly delayed the nitrite clearance from plasma and most of the organs examined during the experimental period. These results suggest that ALDH2 may be at least in part involved in nitrite-mediated hypotensive effects and nitrite catalysis in many organs of normoxic rats. PMID:24164360

  10. Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension

    PubMed Central

    2011-01-01

    Background Involvement of inflammation in pulmonary hypertension (PH) has previously been demonstrated and recently, immune-modulating dendritic cells (DCs) infiltrating arterial lesions in patients suffering from idiopathic pulmonary arterial hypertension (IPAH) and in experimental monocrotaline-induced PH have been reported. Occurrence of perivascular inflammatory cells could be linked to local increase of oxidative stress (OS), as it has been shown for systemic atherosclerosis. The impact of OS on vascular remodeling in PH is still to be determined. We hypothesized, that augmented blood-flow could increase OS and might thereby contribute to DC/inflammatory cell-recruitment and smooth-muscle-cell-proliferation. Methods We applied a monocrotaline-induced PH-model and combined it with permanent flow-challenge. Thirty Sprague-Dawley rats were assigned to following groups: control, monocrotaline-exposure (MCT), monocrotaline-exposure/pneumonectomy (MCT/PE). Results Hemodynamic exploration demonstrated most severe effects in MCT/PE, corresponding in histology to exuberant medial and adventitial remodeling of pulmonary muscular arteries, and intimal remodeling of smaller arterioles; lung-tissue PCR evidenced increased expression of DCs-specific fascin, CD68, proinflammatory cytokines (IL-6, RANTES, fractalkine) in MCT/PE and to a lesser extent in MCT. Major OS enzyme NOX-4 was maximal in MCT/PE. Antioxidative stress enzymes Mn-SOD and glutathion-peroxidase-1 were significantly elevated, while HO-1 showed maximal expression in MCT with significant decrease in MCT/PE. Catalase was decreased in MCT and MCT/PE. Expression of NOX-4, but also of MN-SOD in MCT/PE was mainly attributed to a highly increased number of interstitial and perivascular CXCR4/SDF1 pathway-recruited mast-cells. Stress markers malonedialdehyde and nitrotyrosine were produced in endothelial cells, medial smooth muscle and perivascular leucocytes of hypertensive vasculature. Immunolabeling for OX62, CD68 and actin revealed adventitial and medial DC- and monocyte-infiltration; in MCT/PE, medial smooth muscle cells were admixed with CD68+/vimentin+ cells. Conclusion Our experimental findings support a new concept of immunologic responses to increased OS in MCT/PE-induced PAH, possibly linking recruitment of dendritic cells and OS-producing mast-cells to characteristic vasculopathy. PMID:21906276

  11. Acute and chronic antihypertensive effects of Cinnamomum zeylanicum stem bark methanol extract in L-NAME-induced hypertensive rats

    PubMed Central

    2013-01-01

    Background Previous study showed that the aqueous extract of the stem bark of Cinnamomum zeylanicum possesses antihypertensive and vasodilatory properties. The present work investigates the acute and chronic antihypertensive effects of the methanol extract of Cinnamomum zeylanicum stem bark (MECZ) in L-NAME-induced hypertensive rats. Methods The acute antihypertensive effects of MECZ (5, 10 and 20 mg/kg) administered intravenously were evaluated in rats in which acute arterial hypertension has been induced by intravenous administration of L-NAME (20 mg/kg). For chronic antihypertensive effects, animals were treated with L-NAME (40 mg/kg/day) plus the vehicle or L-NAME (40 mg/kg/day) in combination with captopril (20 mg/kg/day) or MECZ (300 mg/kg/day) and compared with control group receiving only distilled water. All drugs were administered per os and at the end of the experiment that lasted for four consecutive weeks, blood pressure was measured by invasive method and blood samples were collected for the determination of the lipid profile. The heart and aorta were collected, weighed and used for both histological analysis and determination of NO tissue content. Results Acute intravenous administration of C. zeylanicum extract (5, 10 and 20 mg/kg) to L-NAME-induced hypertensive rats provoked a long-lasting decrease in blood pressure. Mean arterial blood pressure decreased by 12.5%, 26.6% and 30.6% at the doses of 5, 10 and 20 mg/kg, respectively. In chronic administration, MECZ and captopril significantly prevented the increase in blood pressure and organs weights, as well as tissue histological damages and were able to reverse the depletion in NO tissues concentration. The MECZ also significantly lower the plasma level of triglycerides (38.1%), total cholesterol (32.1%) and LDL-cholesterol (75.3%) while increasing that of HDL-cholesterol (58.4%) with a significant low atherogenic index (1.4 versus 5.3 for L-NAME group). Conclusion MECZ possesses antihypertensive and organ protective effects that may result from its ability to increase the production of the endogenous NO and/or to regulate dyslipidemia. PMID:23368533

  12. Heme-arginate suppresses phospholipase C and oxidative stress in the mesenteric arterioles of mineralcorticoid-induced hypertensive rats.

    PubMed

    Ndisang, Joseph Fomusi; Jadhav, Ashok

    2010-04-01

    Induction of heme-oxygenase (HO) is an important cellular defense mechanism against oxidative and inflammatory insults. We analyzed the effects of the HO inducer, heme-arginate, on the phospholipase C (PLC)/inositol-triphosphate (IP(3)) pathway in the mesenteric arterioles of uninephrectomized (UnX) deoxycorticosterone acetate (DOCA)-salt hypertensive rats, which is a volume-overload model characterized by elevated endothelin (ET-1) and mineralocorticoid-induced oxidative/inflammatory insults. Our study included the following groups: (A) controls [(i) surgery-free Sprague-Dawley (SD) rats, (ii) UnX-Sham, (iii) UnX-Salt (0.9% NaCl+0.2% KCl) and (iv) UnX-DOCA)]; (B) UnX-DOCA-salt hypertensive rats; (C) UnX-DOCA-salt+heme-arginate; (D) UnX-DOCA-salt+heme-arginate+chromium mesoporphyrin (CrMP), the HO inhibitor; (E) UnX-DOCA-salt+CrMP (F); SD+heme-arginate, (G) UnX-DOCA-salt+vehicle dissolving heme-arginate and CrMP and (H) normal-SD+heme-arginate. Quantitative reverse transcriptase PCR, western blot, enzyme immunoassay and spectrophotometric analyses were used. Heme-arginate enhanced mesenteric arteriole HO-1, HO activity, cyclic guanosine monophosphate (cGMP) and anti-oxidants including bilirubin, ferritin, superoxide dismutase with potentiation of the total anti-oxidant capacity. Correspondingly, oxidative/inflammatory mediators such as 8-isoprostane, nuclear-factor kappaB (NF-kappaB) and ET-1 were markedly reduced. Furthermore, heme-arginate suppressed PLC activity, attenuated IP(3) and reduced resting intracellular calcium. The effects of heme-arginate were nullified by the HO inhibitor, with aggravation of oxidative/inflammatory insults. In heme-arginate-treated SD rats, the HO system was potentiated to a lesser magnitude and the suppression of ET-1, PLC, IP(3) and NF-kappaB were less accentuated, suggesting greater selectivity of HO against the ET-1-PLC-IP(3)-NF-kappaB destructive axis in the pathological condition of mineralocorticoid-induced hypertension. Given that ET-1 stimulates PLC and IP(3), which in turn activates NF-kappaB, the concomitant reduction of ET-1, PLC, IP(3) and NF-kappaB alongside the corresponding decline of resting intracellular calcium may account for the reduction of blood pressure and attenuation of oxidative/inflammatory injury by heme-arginate. PMID:20203687

  13. A new rat model of portal hypertension induced by intraportal injection of microspheres

    PubMed Central

    Li, Xiang-Nong; Benjamin, IS; Alexander, B

    1998-01-01

    AIM: To produce a new rat model of portal hypertension by intraportal injection of microspheres. METHODS: Measured aliquots of single or different-sized microspheres (15, 40, 80?m) were injected into the portal vein to block intrahepatic portal radicals. The resultant changes in arterial,portal,hepatic venous and splenic pulp pressures were monitored. The liver and lungs were excised for histological examination. RESULTS: Portal venous pressure was elevated from basal value of 0.89-1.02 kPa to a steady-state of 1.98-3.19 kPa following the sequential injections of single- or different-sized microspheres, with a markedly lowered mean arterial pressure. However, a small-dose injection of 80 ?m microspheres (1.8 105) produced a steady-state portal venous pressure of 2.53 0.17 kPa, and all rats showed normal arterial pressures. In addition, numerous microspheres were found in the lungs in all experimental groups. CONCLUSION: Portal hypertension can be reproduced in rats by intraportal injection of microspheres at a small dose of 80 ?m (1.8 105). Intrahepatic portal-systemic shunts probably exist in the normal rat liver. PMID:11819236

  14. Amlodipine induces a flow and pressure-independent vasoactive effect on the brachial artery in hypertension.

    PubMed Central

    Megnien, J L; Levenson, J; Del-Pino, M; Simon, A

    1995-01-01

    1. The objectives of this study were to study the flow-dependent arterial reactivity and pressure-independent arterial compliance of the calcium antagonist amlodipine in hypertensive men. 2. Twenty-one hypertensive patients were randomized to receive 2 months treatment with placebo (n = 10) or 5-10 mg amlodipine (n = 11) once a day. Non-invasive measurement of brachial artery mean blood pressure, diameter and flow (pulsed Doppler) and compliance (arterial mechanography and logarithmic elastic model) were obtained before and after drug administration. Vasoreactivity was studied by means of response of the brachial artery during exclusion of the hand and hyperaemia post-ischaemia. 3. Compared with placebo, amlodipine reduced mean blood pressure (% change +/- s.e. mean 11 +/- 1% vs 4 +/- 3%, P < 0.05), and increased arterial compliance at prevailing pressure (44 +/- 13%, vs 1 +/- 8%, P < 0.05) and at isobaric pressure (26 +/- 10% vs -3 +/- 6%, P < 0.05). A significant % change increase from baseline in brachial artery diameter between placebo and amlodipine was observed at rest (-2 +/- 3 vs 8 +/- 3%; P < 0.05), after wrist occlusion (-3 +/- 3 vs 6 +/- 2%; P < 0.05) and during reactive hyperaemia (-5 +/- 3 vs 18 +/- 5%; P < 0.05). No significant differences between amlodipine and placebo groups were observed in blood velocity after forearm manoeuvres before and after treatment. 4. No differences were observed between groups in brachial flow-dependent vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7654482

  15. Critical role of matrix metalloproteinase-9 in acute cold exposure-induced stroke in renovascular hypertensive rats.

    PubMed

    Li, Chunguang; Li, Xiangpen; Shen, Qingyu; Li, Yi; He, Lei; Li, Mei; Tang, Yamei; Wang, Yidong; He, Qingyu; Peng, Ying

    2013-11-01

    Our objectives are to investigate the role of MMP-9 in cold exposure-induced stroke and assess the preventive effect of doxycycline, a total of 200 rats were assigned to a control group, sham group, 2-kidney, 2-clip (2K-2C) group, and doxycycline-received 2K-2C group (2K-2C+doxy) (N=50, each), and subsequently, each group were randomly assigned to 2 groups: acute cold exposure (ACE) and nonacute cold exposure (NACE) (N=25, each). After the blood pressure was stabilized, rats were maintained on a 12-h light (22C)/dark (4C) cycle (ACE group) or a 12-h light (22C)/dark (22C) cycle (NACE group) for 3 cycles. The results showed that ACE upregulated Ang II and MMP-9 protein levels in brains and aortas and considerably enhanced stroke incidence in 2K-2C rats. In contrast, doxycycline treatment prevented upregulation of MMP-9 protein expression and activity in brains and aortas in response to ACE and significantly decreased stroke incidence. These findings suggest that cold exposure-induced MMP-9 via activation of RAS might play a critical role in the initiation of cold exposure-induced stroke during chronic hypertension and doxycycline shows protective effects against cold exposure-induced stroke. PMID:23800500

  16. Cytochrome P4501A1 is Required for Vascular Dysfunction and Hypertension Induced by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    National Health and Nutrition Examination Survey data show an association between hypertension and exposure to dioxin-like halogenated aromatic hydrocarbons (HAH). Further, chronic exposure of mice to the prototypical HAH, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces reactive oxygen species (...

  17. Exercise-Induced Pulmonary Artery Hypertension in a Patient with Compensated Cardiac Disease: Hemodynamic and Functional Response to Sildenafil Therapy

    PubMed Central

    Nikolaidis, Lazaros; Memon, Nabeel

    2015-01-01

    We describe the case of a 54-year-old man who presented with exertional dyspnea and fatigue that had worsened over the preceding 2 years, despite a normally functioning bioprosthetic aortic valve and stable, mild left ventricular dysfunction (left ventricular ejection fraction, 0.45). His symptoms could not be explained by physical examination, an extensive biochemical profile, or multiple cardiac and pulmonary investigations. However, abnormal cardiopulmonary exercise test results and a right heart catheterization—combined with the use of a symptom-limited, bedside bicycle ergometer—revealed that the patient's exercise-induced pulmonary artery hypertension was out of proportion to his compensated left heart disease. A trial of sildenafil therapy resulted in objective improvements in hemodynamic values and functional class. PMID:25873799

  18. Androgen-dependent hypertension is mediated by 20-HETE-induced vascular dysfunction: Role of IkappaB kinase

    PubMed Central

    Wu, Cheng-Chia; Cheng, Jennifer; Zhang, Frank Fan; Gotlinger, Katherine H.; Kelkar, Mukul; Zhang, Yilun; Jat, Jawahar L.; Falck, John R.; Schwartzman, Michal L.

    2011-01-01

    Increased vascular synthesis of 20-HETE is associated with increased vascular contraction, endothelial dysfunction and endothelial activation; all are believed to account for 20-HETE pro-hypertensive properties. We previously demonstrated that the 20-HETE-dependent inhibition of NO production is mediated through I?B kinase (IKK) suggesting a cross talk between 20-HETE-mediated endothelial dysfunction and activation. In this study, we examined the temporal relationship among blood pressure, endothelial dysfunction and endothelial activation and the role of IKK in the rat model of androgen-driven 20-HETE-mediated hypertension. In Sprague-Dawley rats treated with 5?-dihydrotestosterone (DHT), renal vascular 20-HETE levels increased by day 2 of treatment from 17.72.4 to 57.79.7 ng/mg, while blood pressure elevation reached significance by day 3 (132.71.7 vs 117.20.8 mmHg). In renal interlobar arteries, when compared to vehicle, DHT treatment increased the sensitivity to phenylephrine-induced vasoconstriction by 3.5-fold, decreased acetylcholine-induced vasorelaxation and increased NF-kB activity, all of which were attenuated by treatment with the 20-HETE antagonist, 20-HEDE. Co-treatment with parthenolide, an IKK inhibitor, attenuated the androgen-dependent 20-HETE-mediated elevation in blood pressure (from 133.73.1 to 109.83.0 mmHg). In addition, parthenolide treatment negated 20-HETE-mediated inhibition of the relaxing response to acetylcholine and 20-HETE-mediated increase in vascular NF-kB activity. These findings suggest that inhibition of IKK attenuates the androgen-dependent 20-HETE-mediated increase in blood pressure by inhibiting both 20-HETE-dependent endothelial activation and dysfunction. PMID:21321301

  19. Water deprivation-induced sodium appetite and differential expression of encephalic c-Fos immunoreactivity in the spontaneously hypertensive rat.

    PubMed

    Pereira-Derderian, Daniela T B; Vendramini, Regina C; Menani, José V; De Luca, Laurival A

    2010-05-01

    The spontaneously hypertensive rat (SHR) has an intense consumption of NaCl solution. Water deprivation (WD) followed by water intake to satiety induces partial rehydration (PR)-the WD-PR protocol-and sodium appetite. In the present work, WD produced similar water intake and no alterations in arterial pressure among spontaneously hypertensive rat (SHR), Wistar-Kyoto, and Holtzman strains. It also increased the number of cells with positive c-Fos immunoreactivity (Fos-IR) in the lamina terminalis and in the hypothalamic supraoptic (SON) and paraventricular (parvocellular, PVNp) nucleus in these strains. The WD and WD-PR produced similar alterations in all strains in serum osmolality and protein, plasma renin activity, and sodium balance. The SHR ingested about 10 times more 0.3 M NaCl than normotensives strains in the sodium appetite test that follows WD-PR. After WD-PR, the Fos-IR persisted, elevated in the lamina terminalis of all strains but notably in the subfornical organ of the SHR. The WD-PR reversed Fos-IR in the SON of all strains and in the PVNp of SHR. It induced Fos-IR in the area postrema and in the nucleus of the solitary tract (NTS), dorsal raphe, parabrachial (PBN), pre-locus coeruleus (pre-LC), suprachiasmatic, and central amygdalar nucleus of all strains. This effect was bigger in the caudal-NTS, pre-LC, and medial-PBN of SHRs. The results indicate that WD-PR increases cell activity in the forebrain and hindbrain areas that control sodium appetite in the rat. They also suggest that increased cell activity in facilitatory brain areas precedes the intense 0.3 M NaCl intake of the SHR in the sodium appetite test. PMID:20200133

  20. Maternal use of cyclobenzaprine (Flexeril) may induce ductal closure and persistent pulmonary hypertension in neonates.

    PubMed

    Moreira, Alvaro; Barbin, Clay; Martinez, Hugo; Aly, Ashraf; Fonseca, Rafael

    2014-07-01

    A full-term male infant presented shortly after birth with respiratory distress. An echocardiogram done within the first hour of life showed an elevated pulmonary artery pressure, an associated right ventricular hypertrophy without a patent ductus arteriosus. The patient was treated for persistent pulmonary hypertension with favorable response. Maternal history was unremarkable except for chronic low back pain treated with cyclobenzaprine (Flexeril). A proposed mechanism for cyclobenzaprine includes inhibition of norepinephrine and serotonin reuptake, factors known to inhibit prostaglandin and nitric oxide. These two factors are the leading causes of in-utero ductal closure. This report is the first to indicate that cyclobenzaprine use during late pregnancy should be considered a potential cause of early ductal closure. PMID:24102182

  1. Hypertension - overview

    MedlinePLUS

    If left untreated, hypertension can lead to the thickening of arterial walls causing its lumen, or blood passage way, to narrow in diameter. ... the narrowed arterial openings. In addition, people with hypertension may be more susceptible to stroke.

  2. Malignant hypertension

    MedlinePLUS

    ... hypertension; Arteriolar nephrosclerosis; Nephrosclerosis - arteriolar; Hypertension - malignant; High blood pressure - malignant ... affects a small number of people with high blood pressure, including children and adults. It is more common ...

  3. Pulmonary Hypertension

    MedlinePLUS

    ... page from the NHLBI on Twitter. What Is Pulmonary Hypertension? Pulmonary hypertension (PULL-mun-ary HI-per-TEN-shun), or PH, is increased pressure in the pulmonary arteries. These arteries carry blood from your heart ...

  4. Collecting duct-specific knockout of renin attenuates angiotensin II-induced hypertension

    PubMed Central

    Stuart, Deborah; Rees, Sara; Hoek, Alfred Van; Sigmund, Curt D.; Kohan, Donald E.

    2014-01-01

    The physiological and pathophysiological significance of collecting duct (CD)-derived renin, particularly as it relates to blood pressure (BP) regulation, is unknown. To address this question, we generated CD-specific renin knockout (KO) mice and examined BP and renal salt and water excretion. Mice containing loxP-flanked exon 1 of the renin gene were crossed with mice transgenic for aquaporin-2-Cre recombinase to achieve CD-specific renin KO. Compared with controls, CD renin KO mice had 70% lower medullary renin mRNA and 90% lower renin mRNA in microdissected cortical CD. Urinary renin levels were significantly lower in KO mice (45% of control levels) while plasma renin concentration was significantly higher in KO mice (63% higher than controls) during normal-Na intake. While no observable differences were noted in BP between the two groups with varying Na intake, infusion of angiotensin II at 400 ngkg?1min?1 resulted in an attenuated hypertensive response in the KO mice (mean arterial pressure 111 4 mmHg in KO vs. 128 3 mmHg in controls). Urinary renin excretion and epithelial Na+ channel (ENaC) remained significantly lower in the KO mice following ANG II infusion compared with controls. Furthermore, membrane-associated ENaC protein levels were significantly lower in KO mice following ANG II infusion. These findings suggest that CD renin modulates BP in ANG II-infused hypertension and these effects are associated with changes in ENaC expression. PMID:25122048

  5. Calcium/Calmodulin-Dependent Kinase II Inhibition in Smooth Muscle Reduces Angiotensin II–Induced Hypertension by Controlling Aortic Remodeling and Baroreceptor Function

    PubMed Central

    Prasad, Anand M; Morgan, Donald A; Nuno, Daniel W; Ketsawatsomkron, Pimonrat; Bair, Thomas B; Venema, Ashlee N; Dibbern, Megan E; Kutschke, William J; Weiss, Robert M; Lamping, Kathryn G; Chapleau, Mark W; Sigmund, Curt D; Rahmouni, Kamal; Grumbach, Isabella M

    2015-01-01

    Background Multifunctional calcium/calmodulin-dependent kinase II (CaMKII) is activated by angiotensin II (Ang II) in cultured vascular smooth muscle cells (VSMCs), but its function in experimental hypertension has not been explored. The aim of this study was to determine the impact of CaMKII inhibition selectively in VSMCs on Ang II hypertension. Methods and Results Transgenic expression of a CaMKII peptide inhibitor in VSMCs (TG SM-CaMKIIN model) reduced the blood pressure response to chronic Ang II infusion. The aortic depressor nerve activity was reset in hypertensive versus normotensive wild-type animals but not in TG SM-CaMKIIN mice, suggesting that changes in baroreceptor activity account for the blood pressure difference between genotypes. Accordingly, aortic pulse wave velocity, a measure of arterial wall stiffness and a determinant of baroreceptor activity, increased in hypertensive versus normotensive wild-type animals but did not change in TG SM-CaMKIIN mice. Moreover, examination of blood pressure and heart rate under ganglionic blockade revealed that VSMC CaMKII inhibition abolished the augmented efferent sympathetic outflow and renal and splanchnic nerve activity in Ang II hypertension. Consequently, we hypothesized that VSMC CaMKII controls baroreceptor activity by modifying arterial wall remodeling in Ang II hypertension. Gene expression analysis in aortas from normotensive and Ang II–infused mice revealed that TG SM-CaMKIIN aortas were protected from Ang II–induced upregulation of genes that control extracellular matrix production, including collagen. VSMC CaMKII inhibition also strongly altered the expression of muscle contractile genes under Ang II. Conclusions CaMKII in VSMCs regulates blood pressure under Ang II hypertension by controlling structural gene expression, wall stiffness, and baroreceptor activity. PMID:26077587

  6. Salidroside attenuates chronic hypoxia-induced pulmonary hypertension via adenosine A2a receptor related mitochondria-dependent apoptosis pathway.

    PubMed

    Huang, Xiaoying; Zou, Lizhen; Yu, Xiaoming; Chen, Mayun; Guo, Rui; Cai, Hui; Yao, Dan; Xu, Xiaomei; Chen, Yanfan; Ding, Cheng; Cai, Xueding; Wang, Liangxing

    2015-05-01

    Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial remodeling mainly due to excess cellular proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Salidroside, an active ingredient isolated from Rhodiola rosea is proposed to exert protective effects against PAH. However, the function of salidroside in PAH has not been investigated systematically and the underlying mechanisms are not clear. To investigate the effects of salidroside on PAH, the mice in chronic hypoxia model of PAH were given by an increasing concentration of salidroside (0, 16 mg/kg, 32 mg/kg, and 64 mg/kg). After salidroside treatment, the chronic hypoxia-induced right ventricular hypertrophy and pulmonary arterial remodeling were attenuated, suggesting a protective role played by salidroside in PAH. To explore the potential mechanisms, the apoptosis of PASMCs after salidroside treatment under hypoxia conditions were determined in vivo and in vitro, and also the mitochondria-dependent apoptosis factors, Bax, Bcl-2, cytochrome C, and caspase 9 were examined. The results revealed that salidroside reversed hypoxia-induced cell apoptosis resistance at least partially via a mitochondria-dependent pathway. In addition, salidroside upregulated the expression of adenosine A2a receptor (A2aR) in lung tissues of mice and in PASMCs in vitro after hypoxia exposure. Combined the evidence above, we conclude that salidroside can attenuate chronic hypoxia-induced PAH by promoting PASMCs apoptosis via an A2aR related mitochondria dependent pathway. PMID:25772255

  7. Role of miR206 in genistein-induced rescue of pulmonary hypertension in monocrotaline model.

    PubMed

    Sharma, Salil; Umar, Soban; Centala, Alexander; Eghbali, Mansoureh

    2015-12-15

    Pulmonary hypertension (PH) is a progressive lung disease associated with proliferation of smooth muscle cells and constriction of lung microvasculature, leading to increased pulmonary arterial pressure, right ventricular failure, and death. We have previously shown that genistein rescues preexisting established PH by significantly improving lung and heart function. (Matori H, Umar S, Nadadur RD, Sharma S, Partow-Navid R, Afkhami M, Amjedi M, Eghbali M. Hypertension 60: 425-430, 2012). Here, we have examined the role of microRNAs (miRs) in the rescue action of genistein in monocrotaline (MCT)-induced PH in rats. Our miR microarray analysis on the lung samples from control, PH, and genistein-rescue group revealed that miR206, which was robustly upregulated to ?11-fold by PH, was completely normalized to control levels by genistein treatment. Next, we examined whether knockdown of miR206 could reverse preexisting established PH. PH was induced in male rats by 60 mg/kg of MCT, and rats received three intratracheal doses of either miR206 antagomir (10 mg/kg body wt) or scrambled miR control at days 17, 21, and 26. Knockdown of miR206 resulted in significant improvement in the cardiopulmonary function, as right ventricular pressure was significantly reduced to 38.6 3.61 mmHg from 61.2 5.4 mmHg in PH, and right ventricular hypertrophy index was decreased to 0.35 0.04 from 0.59 0.037 in PH. Knockdown of miR206 reversed PH-induced pulmonary vascular remodeling in vivo and was associated with restoration of PH-induced loss of capillaries in the lungs and induction of vascular endothelial growth factor A expression. In conclusion, miR206 antagomir therapy improves cardiopulmonary function and structure and rescues preexisting severe PH in MCT rat model possibly by stimulating angiogenesis in the lung. PMID:26472874

  8. Maternal diet during gestation and lactation modifies the severity of salt-induced hypertension and renal injury in Dahl salt-sensitive rats.

    PubMed

    Geurts, Aron M; Mattson, David L; Liu, Pengyuan; Cabacungan, Erwin; Skelton, Meredith M; Kurth, Theresa M; Yang, Chun; Endres, Bradley T; Klotz, Jason; Liang, Mingyu; Cowley, Allen W

    2015-02-01

    Environmental exposure of parents or early in life may affect disease development in adults. We found that hypertension and renal injury induced by a high-salt diet were substantially attenuated in Dahl SS/JrHsdMcwiCrl (SS/Crl) rats that had been maintained for many generations on the grain-based 5L2F diet compared with SS/JrHsdMcwi rats (SS/Mcw) maintained on the casein-based AIN-76A diet (mean arterial pressure, 116±9 versus 154±25 mm Hg; urinary albumin excretion, 23±12 versus 170±80 mg/d). RNAseq analysis of the renal outer medulla identified 129 and 82 genes responding to a high-salt diet uniquely in SS/Mcw and SS/Crl rats, respectively, along with minor genetic differences between the SS substrains. The 129 genes responding to salt in the SS/Mcw strain included numerous genes with homologs associated with hypertension, cardiovascular disease, or renal disease in human. To narrow the critical window of exposure, we performed embryo-transfer experiments in which single-cell embryos from 1 colony (SS/Mcw or SS/Crl) were transferred to surrogate mothers from the other colony, with parents and surrogate mothers maintained on their respective original diet. All offspring were fed the AIN-76A diet after weaning. Salt-induced hypertension and renal injury were substantially exacerbated in rats developed from SS/Crl embryos transferred to SS/Mcw surrogate mothers. Conversely, salt-induced hypertension and renal injury were significantly attenuated in rats developed from SS/Mcw embryos transferred to SS/Crl surrogate mothers. Together, the data suggest that maternal diet during the gestational-lactational period has substantial effects on the development of salt-induced hypertension and renal injury in adult SS rats. PMID:25452472

  9. The effect of hydroalcoholic extract of Ferula foetida stems on blood pressure and oxidative stress in dexamethasone-induced hypertensive rats

    PubMed Central

    Safaeian, Leila; Ghannadi, Alireza; Javanmard, Shaghayegh Haghjoo; Vahidian, Mohammad Hadi

    2015-01-01

    Ferula foetida (Bunge) Regel. is one of the most widespread and important Ferula species with nutritional and medicinal applications. Some phytochemicals with helpful cardiovascular effects have been isolated from Ferula species. The present study was designed to evaluate the effects of hydroalcoholic extract of the stems of F. foetida in dexamethasone (Dex)-induced hypertension in rats. Hypertension was induced by subcutaneous injection of Dex (30 µg/kg) for 14 days. In a prevention study, rats received oral F. foetida extract (200, 400 and 800 mg/kg) for 4 days prior to Dex administration and during the test period (Days 1-18). In a treatment study, F. foetida extract was administered from day 8 to 14. Systolic blood pressure (SBP) was evaluated using tail-cuff method. The thymus weight was measured as an indicator of glucocorticoid activity. The hydrogen peroxide (H2O2) concentration and ferric reducing antioxidant power (FRAP) were measured in plasma samples. Dex-induced hypertensive rats showed significant increases in SBP and in plasma H2O2 and decreases in the body and thymus weights and in FRAP value (P<0.001). Administration of F. foetida extract significantly prevented and reversed hypertension at all doses. It also increased plasma FRAP value (P<0.001) but failed to decrease plasma H2O2 concentration. These results suggest antihypertensive and antioxidant effects of F. foetida stem extract in Dex-induced hypertension. More investigations are needed to elucidate the exact mechanism of antihypertensive effect of this traditional phytomedicine. PMID:26600859

  10. Eosinophils are necessary for pulmonary arterial remodeling in a mouse model of eosinophilic inflammation-induced pulmonary hypertension.

    PubMed

    Weng, M; Baron, D M; Bloch, K D; Luster, A D; Lee, J J; Medoff, B D

    2011-12-01

    There is increasing evidence that inflammation plays a pivotal role in the pathogenesis of some forms of pulmonary hypertension (PH). We recently demonstrated that deficiency of adiponectin (APN) in a mouse model of PH induced by eosinophilic inflammation increases pulmonary arterial remodeling, pulmonary pressures, and the accumulation of eosinophils in the lung. Based on these data, we hypothesized that APN deficiency exacerbates PH indirectly by increasing eosinophil recruitment. Herein, we examined the role of eosinophils in the development of inflammation-induced PH. Elimination of eosinophils in APN-deficient mice by treatment with anti-interleukin-5 antibody attenuated pulmonary arterial muscularization and PH. In addition, we observed that transgenic mice that are devoid of eosinophils also do not develop pulmonary arterial muscularization in eosinophilic inflammation-induced PH. To investigate the mechanism by which APN deficiency increased eosinophil accumulation in response to an allergic inflammatory stimulus, we measured expression levels of the eosinophil-specific chemokines in alveolar macrophages isolated from the lungs of mice with eosinophilic inflammation-induced PH. In these experiments, the levels of CCL11 and CCL24 were higher in macrophages isolated from APN-deficient mice than in macrophages from wild-type mice. Finally, we demonstrate that the extracts of eosinophil granules promoted the proliferation of pulmonary arterial smooth muscle cells in vitro. These data suggest that APN deficiency may exacerbate PH, in part, by increasing eosinophil recruitment into the lung and that eosinophils could play an important role in the pathogenesis of inflammation-induced PH. These results may have implications for the pathogenesis and treatment of PH caused by vascular inflammation. PMID:21908591

  11. TRPV4 channel contributes to serotonin-induced pulmonary vasoconstriction and the enhanced vascular reactivity in chronic hypoxic pulmonary hypertension

    PubMed Central

    Xia, Yang; Fu, Zhenzhen; Hu, Jinxing; Huang, Chun; Paudel, Omkar; Cai, Shaoxi; Liedtke, Wolfgang

    2013-01-01

    Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive channel in pulmonary arterial smooth muscle cells (PASMCs). Its upregulation by chronic hypoxia is associated with enhanced myogenic tone, and genetic deletion of trpv4 suppresses the development of chronic hypoxic pulmonary hypertension (CHPH). Here we further examine the roles of TRPV4 in agonist-induced pulmonary vasoconstriction and in the enhanced vasoreactivity in CHPH. Initial evaluation of TRPV4-selective antagonists HC-067047 and RN-1734 in KCl-contracted pulmonary arteries (PAs) of trpv4?/? mice found that submicromolar HC-067047 was devoid of off-target effect on pulmonary vasoconstriction. Inhibition of TRPV4 with 0.5 ?M HC-067047 significantly reduced the sensitivity of serotonin (5-HT)-induced contraction in wild-type (WT) PAs but had no effect on endothelin-1 or phenylephrine-activated response. Similar shift in the concentration-response curve of 5-HT was observed in trpv4?/? PAs, confirming specific TRPV4 contribution to 5-HT-induced vasoconstriction. 5-HT-induced Ca2+ response was attenuated by HC-067047 in WT PASMCs but not in trpv4?/? PASMCs, suggesting TRPV4 is a major Ca2+ pathway for 5-HT-induced Ca2+ mobilization. Nifedipine also attenuated 5-HT-induced Ca2+ response in WT PASMCs but did not cause further reduction in the presence of HC-067047, suggesting interdependence of TRPV4 and voltage-gated Ca2+ channels in the 5-HT response. Chronic exposure (34 wk) of WT mice to 10% O2 caused significant increase in 5-HT-induced maximal contraction, which was partially reversed by HC-067047. In concordance, the enhancement of 5-HT-induced contraction was significantly reduced in PAs of CH trpv4?/? mice and HC-067047 had no further effect on the 5-HT induced response. These results suggest unequivocally that TRPV4 contributes to 5-HT-dependent pharmaco-mechanical coupling and plays a major role in the enhanced pulmonary vasoreactivity to 5-HT in CHPH. PMID:23739180

  12. Role of angiotensin II in plasma PAI-1 changes induced by imidapril or candesartan in hypertensive patients with metabolic syndrome.

    PubMed

    Fogari, Roberto; Zoppi, Annalisa; Mugellini, Amedeo; Maffioli, Pamela; Lazzari, Pierangelo; Derosa, Giuseppe

    2011-12-01

    To evaluate the relationship between plasma plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) changes during treatment with imidapril and candesartan in hypertensive patients with metabolic syndrome. A total of 84 hypertensive patients with metabolic syndrome were randomized to imidapril 10?mg or candesartan 16?mg for 16 weeks. At weeks 4 and 8, there was a dose titration to imidapril 20?mg and candesartan 32?mg in nonresponders (systolic blood pressure (SBP) >140 and/or diastolic blood pressure (DBP) >90?mm?Hg). We evaluated, at baseline and after 2, 4, 8, 12 and 16 weeks, clinic blood pressure, Ang II and PAI-1 antigen. Both imidapril and candesartan induced a similar SBP/DBP reduction (-19.4/16.8 and -19.5/16.3?mm?Hg, respectively, P<0.001 vs. baseline). Both drugs decreased PAI-1 antigen after 4 weeks of treatment, but only the PAI-1 lowering effect of imidapril was sustained throughout the 16 weeks (-9.3?ng?ml(-1), P<0.01 vs. baseline), whereas candesartan increased PAI-1 (+6.5?ng?ml(-1), P<0.05 vs. baseline and P<0.01 vs. imidapril). Imidapril significantly decreased Ang II levels (-14.6?pg?ml(-1) at week 16, P<0.05 vs. baseline), whereas candesartan increased them (+24.2?pg?ml(-1), P<0.01 vs. baseline and vs. imidapril). In both groups there was a positive correlation between Ang II and PAI-1 changes (r=0.61, P<0.001 at week 16 for imidapril, and r=0.37, P<0.005 at week 16 for candesartan). Imidapril reduced plasma PAI-1 and Ang II levels, whereas candesartan increased them. This suggests that the different effect of angiotensin-converting enzyme inhibitors and Ang II blockers on Ang II production has a role in their different influence on fibrinolysis. PMID:21814211

  13. ApoA-I Mimetic Peptide 4F Rescues Pulmonary Hypertension by Inducing MicroRNA-193-3p

    PubMed Central

    Sharma, Salil; Umar, Soban; Potus, Francois; Iorga, Andrea; Wong, Gabriel; Meriwether, David; Breuils-Bonnet, Sandra; Mai, Denise; Navab, Kaveh; Ross, David; Navab, Mohamad; Provencher, Steeve; Fogelman, Alan M.; Bonnet, Sébastien; Reddy, Srinivasa T.; Eghbali, Mansoureh

    2014-01-01

    Background Pulmonary Arterial Hypertension (PAH) is a chronic lung disease associated with severe pulmonary vascular changes. A pathogenic role of oxidized lipids such as hydroxyeicosatetraenoic acids (HETEs) and hydroxyoctadecadienoic acids (HODEs) is well established in vascular disease. Apolipoprotein A-I (apoA-I) mimetic peptides including 4F have been reported to reduce levels of these oxidized lipids and improve vascular disease. However, the role of oxidized lipids in the progression of PAH and the therapeutic action of 4F in PAH is not well established. Methods and Results We studied two different rodent models of Pulmonary Hypertension (PH); a monocrotaline (MCT) rat model and a hypoxia mouse model. Plasma levels of HETEs and HODEs were significantly elevated in PH. 4F treatment reduced these levels and rescued pre-existing PH in both models. MicroRNA analysis revealed that miR193-3p (miR193) was significantly downregulated in the lung tissue and in serum from both PAH patients and in PH rodents. In-vivo miR193 overexpression in the lungs rescued pre-existing PH and resulted in downregulation of lipoxygenases and insulin-like growth factor-1 receptor. 4F restored PH-induced miR193 expression via transcription factor retinoid X receptor alpha (RXRα). Conclusions These studies establish the importance of microRNAs as downstream effectors of an apoA-I mimetic peptide in the rescue of PH and suggest that treatment with apoA-I mimetic peptides, or miR193 may have therapeutic value. PMID:24963038

  14. N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats

    PubMed Central

    2014-01-01

    Background The outcome of patients suffering from pulmonary arterial hypertension (PAH) are predominantly determined by the response of the right ventricle to the increase afterload secondary to high vascular pulmonary resistance. However, little is known about the effects of the current available or experimental PAH treatments on the heart. Recently, inflammation has been implicated in the pathophysiology of PAH. N-acetylcysteine (NAC), a well-known safe anti-oxidant drug, has immuno-modulatory and cardioprotective properties. We therefore hypothesized that NAC could reduce the severity of pulmonary hypertension (PH) in rats exposed to monocrotaline (MCT), lowering inflammation and preserving pulmonary vascular system and right heart function. Methods Saline-treated control, MCT-exposed, MCT-exposed and NAC treated rats (day 14–28) were evaluated at day 28 following MCT for hemodynamic parameters (right ventricular systolic pressure, mean pulmonary arterial pressure and cardiac output), right ventricular hypertrophy, pulmonary vascular morphometry, lung inflammatory cells immunohistochemistry (monocyte/macrophages and dendritic cells), IL-6 expression, cardiomyocyte hypertrophy and cardiac fibrosis. Results The treatment with NAC significantly decreased pulmonary vascular remodeling, lung inflammation, and improved total pulmonary resistance (from 0.71 ± 0.05 for MCT group to 0.50 ± 0.06 for MCT + NAC group, p < 0.05). Right ventricular function was also improved with NAC treatment associated with a significant decrease in cardiomyocyte hypertrophy (625 ± 69 vs. 439 ± 21 μm2 for MCT and MCT + NAC group respectively, p < 0.001) and heart fibrosis (14.1 ± 0.8 vs. 8.8 ± 0.1% for MCT and MCT + NAC group respectively, p < 0.001). Conclusions Through its immuno-modulatory and cardioprotective properties, NAC has beneficial effect on pulmonary vascular and right heart function in experimental PH. PMID:24929652

  15. Key Role of ROS in the Process of 15-Lipoxygenase/15-Hydroxyeicosatetraenoiccid-Induced Pulmonary Vascular Remodeling in Hypoxia Pulmonary Hypertension

    PubMed Central

    Qiu, Yanli; Liu, Gaofeng; Sheng, Tingting; Yu, Xiufeng; Wang, Shuang; Zhu, Daling

    2016-01-01

    We previously reported that 15-lipoxygenase (15-LO) and its metabolite 15-hydroxyeicosatetraenoic acid (15-HETE) were up-regulated in pulmonary arterial cells from both pulmonary artery hypertension patients and hypoxic rats and that these factors mediated the progression of pulmonary hypertension (PH) by affecting the proliferation and apoptosis of pulmonary arterial (PA) cells. However, the underlying mechanisms of the remodeling induced by 15-HETE have remained unclear. As reactive oxygen species (ROS) and 15-LO are both induced by hypoxia, it is possible that ROS are involved in the events of hypoxia-induced 15-LO expression that lead to PH. We employed immunohistochemistry, tube formation assays, bromodeoxyuridine (BrdU) incorporation assays, and cell cycle analyses to explore the role of ROS in the process of 15-HETE-mediated hypoxic pulmonary hypertension (HPH). We found that exogenous 15-HETE facilitated the generation of ROS and that this effect was mainly localized to mitochondria. In particular, the mitochondrial electron transport chain and nicotinamide-adenine dinucleotide phosphate oxidase 4 (Nox4) were responsible for the significant 15-HETE-stimulated increase in ROS production. Moreover, ROS induced by 15-HETE stimulated endothelial cell (EC) migration and promoted pulmonary artery smooth muscle cell (PASMC) proliferation under hypoxia via the p38 MAPK pathway. These results indicated that 15-HETE-regulated ROS mediated hypoxia-induced pulmonary vascular remodeling (PVR) via the p38 MAPK pathway. PMID:26871724

  16. [Childhood hypertension].

    PubMed

    Takemura, Tsukasa

    2015-11-01

    For accurate diagnosis of childhood hypertension, selection of appropriate manchette size according to the child age and the circumstantial size of upper limb is essentially important. In addition, except for the emergency case of hypertension, repeated measurement of blood pressure would be desirable in several weeks interval. Recently, childhood hypertension might be closely related to the abnormality of maternal gestational period caused by the strict diet and the maternal smoking. Developmental Origins of Health and Disease(DOHaD) theory is now highlighted in the pathogenesis of adulthood hypertension. To prevent hypertension of small-for-date baby in later phase of life, maternal education for child nursing should be conducted. In children, secondary hypertension caused by renal, endocrinologic, or malignant disease is predominant rather than idiopathic hypertension. PMID:26619664

  17. Superoxide Mediates Depressive Effects Induced by Hydrogen Sulfide in Rostral Ventrolateral Medulla of Spontaneously Hypertensive Rats.

    PubMed

    Yu, Haiyun; Xu, Haiyan; Liu, Xiaoni; Zhang, Nana; He, Anqi; Yu, Jerry; Lu, Ning

    2015-01-01

    Hydrogen sulfide (H2S) plays a crucial role in the regulation of blood pressure and oxidative stress. In the present study, we tested the hypothesis that H2S exerts its cardiovascular effects by reducing oxidative stress via inhibition of NADPH oxidase activity in the rostral ventrolateral medulla (RVLM). We examined cell distributions of cystathionine-?-synthase (CBS) and effects of H2S on reactive oxygen species (ROS) and mean arterial blood pressure (MAP) in spontaneously hypertensive rats (SHRs). We found that CBS was expressed in neurons of the RVLM, and the expression was lower in SHRs than in Wistar-Kyoto rats. Microinjection of NaHS (H2S donor), S-adenosyl-l-methionine (SAM, a CBS agonist), or Apocynin (NADPH oxidase inhibitor) into the RVLM reduced the ROS level, NADPH oxidase activity, and MAP, whereas microinjection of hydroxylamine hydrochloride (HA, a CBS inhibitor) increased MAP. Furthermore, intracerebroventricular infusion of NaHS inhibited phosphorylation of p47(phox), a key step of NADPH oxidase activation. Since decreasing ROS level in the RVLM reduces MAP and heart rate and increasing H2S reduces ROS production, we conclude that H2S exerts an antihypertensive effect via suppressing ROS production. H2S, as an antioxidant, may be a potential target for cardiovascular diseases. PMID:26078823

  18. Superoxide Mediates Depressive Effects Induced by Hydrogen Sulfide in Rostral Ventrolateral Medulla of Spontaneously Hypertensive Rats

    PubMed Central

    Yu, Haiyun; Xu, Haiyan; Liu, Xiaoni; Zhang, Nana; He, Anqi; Yu, Jerry; Lu, Ning

    2015-01-01

    Hydrogen sulfide (H2S) plays a crucial role in the regulation of blood pressure and oxidative stress. In the present study, we tested the hypothesis that H2S exerts its cardiovascular effects by reducing oxidative stress via inhibition of NADPH oxidase activity in the rostral ventrolateral medulla (RVLM). We examined cell distributions of cystathionine-?-synthase (CBS) and effects of H2S on reactive oxygen species (ROS) and mean arterial blood pressure (MAP) in spontaneously hypertensive rats (SHRs). We found that CBS was expressed in neurons of the RVLM, and the expression was lower in SHRs than in Wistar-Kyoto rats. Microinjection of NaHS (H2S donor), S-adenosyl-l-methionine (SAM, a CBS agonist), or Apocynin (NADPH oxidase inhibitor) into the RVLM reduced the ROS level, NADPH oxidase activity, and MAP, whereas microinjection of hydroxylamine hydrochloride (HA, a CBS inhibitor) increased MAP. Furthermore, intracerebroventricular infusion of NaHS inhibited phosphorylation of p47phox, a key step of NADPH oxidase activation. Since decreasing ROS level in the RVLM reduces MAP and heart rate and increasing H2S reduces ROS production, we conclude that H2S exerts an antihypertensive effect via suppressing ROS production. H2S, as an antioxidant, may be a potential target for cardiovascular diseases. PMID:26078823

  19. Arrhythmogenic potential of diuretic induced hypokalaemia in patients with mild hypertension and ischaemic heart disease.

    PubMed Central

    Stewart, D E; Ikram, H; Espiner, E A; Nicholls, M G

    1985-01-01

    In view of evidence suggesting an association of mild hypokalaemia with cardiac arrhythmia, the arrhythmogenic potentials of potassium losing and potassium sparing diuretic treatments were compared in a controlled prospective crossover study of 10 patients with mild hypertension and ischaemic heart disease. Mean (SEM) plasma potassium was 4.3(0.06) mmol/l and 3.3(0.07) mmol/l after potassium sparing and potassium losing treatments respectively. Blood pressure and volume depletion as assessed by weight change, plasma renin activity, and noradrenaline concentrations did not differ significantly in the two treatment periods. The potassium losing treatment phase was associated with an increased frequency of ventricular extrasystoles, a higher Lown grading during ambulatory electrocardiographic monitoring, prolonged duration and decreased phase 0 velocity of the monophasic action potential, a prolonged ventricular effective refractory period, and increased myocardial electrical instability as assessed by programmed ventricular stimulation. It is concluded that minor changes in plasma potassium concentration are associated with increased ventricular electrical instability in patients with ischaemic heart disease. Mild hypokalaemia in such patients may predispose to life threatening arrhythmias and should be avoided. PMID:4041299

  20. Pharmacokinetic changes of DA-8159, a new erectogenic, and one of its metabolites, DA-8164 after intravenous and oral administration of DA-8159 to spontaneously hypertensive rats and DOCA-salt-induced hypertensive rats.

    PubMed

    Kim, Yu C; Shim, Hyun J; Lee, Joo H; Kim, Dong S; Kwon, Jong W; Kim, Won B; Lee, Inchul; Lee, Myung G

    2005-10-01

    The pharmacokinetics of DA-8159 and one of its metabolites, DA-8164, were compared after intravenous and oral administration of DA-8159 at a dose of 30 mg/kg to spontaneously hypertensive rats (SHRs) at 16 and 6 weeks old and their respective age-matched control normotensive Kyoto-Wistar rats (KW rats), and deoxycorticosterone acetate-salt-induced hypertensive rats (DOCA-salt rats) at 16 weeks old and their age-matched control Sprague-Dawley rats. After oral administration of DA-8159 to 16-week-old SHRs, the AUC values of both DA-8159 (157 versus 103 microg min/ml) and DA-8164 (215 versus 141 microg min/ml) were significantly greater, but the values of DA-8159 were reversed in 16-week-old DOCA-salt rats (125 versus 200 microg min/ml). However, the AUC values of both DA-8159 and DA-8164 were not significantly different between the 6-week-old SHRs and their control rats. The above AUC differences in 16-week-old SHRs may be due to neither hereditary characteristics of SHRs nor the hypertensive state itself. PMID:16035131

  1. miR-100 suppresses mTOR signaling in hypoxia-induced pulmonary hypertension in rats.

    PubMed

    Wang, Ai-ping; Li, Xiao-hui; Gong, Shao-xin; Li, Wen-qun; Hu, Chang-ping; Zhang, Zheng; Li, Yuan-Jian

    2015-10-15

    Mammalian Target of Rapamycin (mTOR) is involved in the proliferation and survival of pulmonary artery smooth muscle cells (PASMCs) in human pulmonary hypertension (PH) and animal PH models, and miRNAs are reported to play a key role in modulation of the proliferation of PASMCs. The purposes of this study are to determine the functions of miR-100 and mTOR in cardiovascular remodeling of the hypoxic PH rats and to clarify the correlation between them. We established a rat model of hypoxic PH, which showed an increase in right ventricle systolic pressure, right ventricular and pulmonary vascular remodeling, accompanied by an up-regulation of mTOR and a down-regulation of miR-100. Next, we established an in vitro model of hypoxia-induced proliferation of PASMCs. Consistent with the in vivo findings, hypoxia induced proliferation of PASMCs, accompanied by a down-regulation of miR-100 and an up-regulation of mTOR; these phenomena were reversed by miR-100 mimics or the antagonist of mTOR. Finally, the dual-luciferase reporter gene assay was utilized to reveal the direct interaction between miR-100 and the 3 '-UTR region of mTOR gene. Based on these observations, we conclude that miR-100 can modulate the proliferation of PASMCs in hypoxic PH rats through suppressing the mTOR expression. PMID:26409044

  2. Central Infusion of Angiotensin II Type 2 Receptor Agonist Compound 21 Attenuates DOCA/NaCl-Induced Hypertension in Female Rats

    PubMed Central

    Dai, Shu-Yan; Zhang, Yu-Ping; Peng, Wei; Shen, Ying; He, Jing-Jing

    2016-01-01

    The present study investigated whether central activation of angiotensin II type 2 receptor (AT2-R) attenuates deoxycorticosterone acetate (DOCA)/NaCl-induced hypertension in intact and ovariectomized (OVX) female rats and whether female sex hormone status has influence on the effects of AT2-R activation. DOCA/NaCl elicited a greater increase in blood pressure in OVX females than that in intact females. Central infusion of compound 21, a specific AT2-R agonist, abolished DOCA/NaCl pressor effect in intact females, whereas same treatment in OVX females produced an inhibitory effect. Real-time RT-PCR analysis revealed that DOCA/NaCl enhanced the mRNA expression of hypertensive components including AT1-R, ACE-1, and TNF-α in the paraventricular nucleus of hypothalamus in both intact and OVX females. However, the mRNA expressions of antihypertensive components such as AT2-R, ACE-2, and IL-10 were increased only in intact females. Central AT2-R agonist reversed the changes in the hypertensive components in all females, while this agonist further upregulated the expression of ACE2 and IL-10 in intact females, but only IL-10 in OVX females. These results indicate that brain AT2-R activation plays an inhibitory role in the development of DOCA/NaCl-induced hypertension in females. This beneficial effect of AT2-R activation involves regulation of renin-angiotensin system and proinflammatory cytokines. PMID:26783414

  3. Antihypertensive and antioxidant effects of hydroalcoholic extract from the aerial parts of Kelussia odoratissima Mozaff. in dexamethasone-induced hypertensive rats

    PubMed Central

    Safaeian, Leila; Sajjadi, Seyed Ebrahim; Javanmard, Shaghayegh Haghjoo; Gholamzadeh, Hadi

    2016-01-01

    Background: Kelussia odoratissima Mozaff. is a monotypic endemic plant of Apiaceae growing wild in Iran. The aerial parts of this plant are used for treatment of hypertension, ulcer, and inflammatory conditions in folk medicine. In this study, the effects of hydroalcoholic extract of the aerial parts of K. odoratissima were evaluated in dexamethasone (Dex)-induced hypertension in male Wistar rats. Materials and Methods: For induction of hypertension, Dex (30 μg/kg/day) was administered subcutaneously for 14 days. In a prevention study, rats received oral K. odoratissima extract (100, 200, and 400 mg/kg) from 4 days before Dex administration and during the test period (days 1–18). In a reversal study, K. odoratissima extract was administered orally from day 8 to 14. Systolic blood pressure (SBP) was evaluated using tail-cuff method. The hydrogen peroxide (H2O2) concentration and ferric-reducing antioxidant power (FRAP) were measured in plasma samples. Results: Administrations of Dex significantly induced an increase in SBP and in plasma H2O2 and a decrease in body and thymus weights, and in FRAP value (P < 0.001). K. odoratissima extract dose-dependently prevented and reversed hypertension (P < 0.001). It also prevented and reduced the plasma H2O2 concentration and prevented the body weight loss upon Dex administration at all doses (100–400 mg/kg, P < 0.001) but failed to improve FRAP value. Conclusions: These results suggest antihypertensive and antioxidant effects of K. odoratissima extract in Dex-induced hypertension. Further studies are needed to elucidate the exact mechanism of the antihypertensive effect of this herbal medicine. PMID:27014652

  4. Resistant Hypertension.

    PubMed

    Doroszko, Adrian; Janus, Agnieszka; Szahidewicz-Krupska, Ewa; Mazur, Grzegorz; Derkacz, Arkadiusz

    2016-01-01

    Resistant hypertension is a severe medical condition which is estimated to appear in 9-18% of hypertensive patients. Due to higher cardiovascular risk, this disorder requires special diagnosis and treatment. The heterogeneous etiology, risk factors and comorbidities of resistant hypertension stand in need of sophisticated evaluation to confirm the diagnosis and select the best therapeutic options, which should consider lifestyle modifications as well as pharmacological and interventional treatment. After having excluded pseudohypertension, inappropriate blood pressure measurement and control as well as the white coat effect, suspicion of resistant hypertension requires an analysis of drugs which the hypertensive patient is treated with. According to one definition - ineffective treatment with 3 or more antihypertensive drugs including diuretics makes it possible to diagnose resistant hypertension. A multidrug therapy including angiotensin - converting enzyme inhibitors, angiotensin II receptor blockers, beta blockers, diuretics, long-acting calcium channel blockers and mineralocorticoid receptor antagonists has been demonstrated to be effective in resistant hypertension treatment. Nevertheless, optional, innovative therapies, e.g. a renal denervation or baroreflex activation, may create a novel pathway of blood pressure lowering procedures. The right diagnosis of this disease needs to eliminate the secondary causes of resistant hypertension e.g. obstructive sleep apnea, atherosclerosis and renal or hormonal disorders. This paper briefly summarizes the identification of the causes of resistant hypertension and therapeutic strategies, which may contribute to the proper diagnosis and an improvement of the long term management of resistant hypertension. PMID:26935512

  5. A study on the involvement of GABA-transaminase in MCT induced pulmonary hypertension.

    PubMed

    Lingeshwar, Poorella; Kaur, Gurpreet; Singh, Neetu; Singh, Seema; Mishra, Akanksha; Shukla, Shubha; Ramakrishna, Rachumallu; Laxman, Tulsankar Sachin; Bhatta, Rabi Sankar; Siddiqui, Hefazat H; Hanif, Kashif

    2016-02-01

    Increased sympathetic nervous system (SNS) activity is associated with cardiovascular diseases but its role has not been completely explored in pulmonary hypertension (PH). Increased SNS activity is distinguished by elevated level of norepinephrine (NE) and activity of γ-Amino butyric acid Transminase (GABA-T) which degrades GABA, an inhibitory neurotransmitter within the central and peripheral nervous system. Therefore, we hypothesized that GABA-T may contribute in pathophysiology of PH by modulating level of GABA and NE. The effect of daily oral administration of GABA-T inhibitor, Vigabatrin (GVG, 50 and 75 mg/kg/day, 35 days) was studied following a single subcutaneous administration of monocrotaline (MCT, 60 mg/kg) in male SD rats. The pressure and hypertrophy of right ventricle (RV), oxidative stress, inflammation, pulmonary vascular remodelling were assessed after 35 days in MCT treated rats. The expression of GABA-T and HIF-1α was studied in lung tissue. The levels of plasma NE (by High performance liquid chromatography coupled with electrochemical detector; HPLC-ECD) and lung GABA (by liquid chromatography-mass spectrometry) were also estimated. GVG at both doses significantly attenuated increased in pressure (35.82 ± 4.80 mm Hg, p < 0.001; 28.37 ± 3.32 mm Hg, p < 0.001 respectively) and hypertrophy of RV, pulmonary vascular remodelling, oxidative stress and inflammation in lungs of MCT exposed rats. GVG also reduced the expression of GABA-T and HIF-1α in MCT treated rats. Increased NE level and decreased GABA level was also reversed by GVG in MCT exposed rats. GABA-T plays an important role in PH by modulating SNS activity and may be considered as a therapeutic target in PH. PMID:26608704

  6. Mechanisms of the antihypertensive effects of Nigella sativa oil in L-NAME-induced hypertensive rats

    PubMed Central

    Jaarin, Kamsiah; Foong, Wai Dic; Yeoh, Min Hui; Kamarul, Zaman Yusoff Nik; Qodriyah, Haji Mohd Saad; Azman, Abdullah; Zuhair, Japar Sidik Fadhlullah; Juliana, Abdul Hamid; Kamisah, Yusof

    2015-01-01

    OBJECTIVES This study was conducted to determine whether the blood pressure-lowering effect of Nigella sativa might be mediated by its effects on nitric oxide, angiotensin-converting enzyme, heme oxygenase and oxidative stress markers. METHODS: Twenty-four adult male Sprague-Dawley rats were divided equally into 4 groups. One group served as the control (group 1), whereas the other three groups (groups 2-4) were administered L-NAME (25 mg/kg, intraperitoneally). Groups 3 and 4 were given oral nicardipine daily at a dose of 3 mg/kg and Nigella sativa oil at a dose of 2.5 mg/kg for 8 weeks, respectively, concomitantly with L-NAME administration. RESULTS Nigella sativa oil prevented the increase in systolic blood pressure in the L-NAME-treated rats. The blood pressure reduction was associated with a reduction in cardiac lipid peroxidation product, NADPH oxidase, angiotensin-converting enzyme activity and plasma nitric oxide, as well as with an increase in heme oxygenase-1 activity in the heart. The effects of Nigella sativa on blood pressure, lipid peroxidation product, nicotinamide adenine dinucleotide phosphate oxidase and angiotensin-converting enzyme were similar to those of nicardipine. In contrast, L-NAME had opposite effects on lipid peroxidation, angiotensin-converting enzyme and NO. CONCLUSION: The antihypertensive effect of Nigella sativa oil appears to be mediated by a reduction in cardiac oxidative stress and angiotensin-converting enzyme activity, an increase in cardiac heme oxygenase-1 activity and a prevention of plasma nitric oxide loss. Thus, Nigella sativa oil might be beneficial for controlling hypertension. PMID:26602523

  7. Angiotensin II-induced hypertension in the rat. Effects on the plasma concentration, renal excretion, and tissue release of prostaglandins.

    PubMed Central

    Diz, D I; Baer, P G; Nasjletti, A

    1983-01-01

    We examined in rats the effects of intraperitoneal angiotensin II (AII) infusion for 12 d on urinary excretion, plasma concentration, and in vitro release of prostaglandin (PG) E2 and 6-keto-PGF1 alpha, a PGI2 metabolite. AII at 200 ng/min increased systolic blood pressure (SBP) progressively from 125 +/- 3 to 170 +/- 9 mmHg (P less than 0.01) and elevated fluid intake and urine volume. Urinary 6-keto-PGF1 alpha excretion increased from 38 +/- 6 to 55 +/- 5 and 51 +/- 7 ng/d (P less than 0.05) on days 8 and 11, respectively, of AII infusion, but urinary PGE2 excretion did not change. Relative to a control value of 129 +/- 12 pg/ml in vehicle-infused (V) rats, arterial plasma 6-keto-PGF1 alpha concentration increased by 133% (P less than 0.01) with AII infusion. Aortic rings from AII-infused rats released more 6-keto-PGF1 alpha (68 +/- 7 ng/mg) during 15-min incubation in Krebs solution than did rings from V rats (40 +/- 3 ng/mg); release of PGE2, which was less than 1% of that of 6-keto-PGF1 alpha, was also increased. Slices of inner renal medulla from AII-infused rats released more 6-keto-PGF1 alpha (14 +/- 1 ng/mg) during incubation than did slices from V rats (8 +/- 1 ng/mg, P less than 0.05), but PGE2 release was not altered. In contrast, AII infusion did not alter release of 6-keto-PGF1 alpha or PGE2 from inferior vena cava segments or from renal cortex slices. Infusion of AII at 125 ng/min also increased SBP, plasma 6-keto-PGF1 alpha concentration, and in vitro release of 6-keto-PGF1 alpha from rings of aorta and renal inner medulla slices; at 75 ng/min AII had no effect. SBP on AII infusion day 11 correlated positively with both 6-keto-PGF1 alpha plasma concentration (r = 0.54) and net aortic ring release (r = 0.70) when data from all rats were combined. We conclude that augmentation of PGI2 production is a feature of AII-induced hypertension. The enhancement of PGI2 production may be an expression of nonspecific alteration in vascular structure and metabolic functions during AII-induced hypertension, as well as the result of a specific effect of the peptide on the arachidonate-prostaglandin system. PMID:6575977

  8. Long-term exposure to high-altitude chronic hypoxia during gestation induces neonatal pulmonary hypertension at sea level

    PubMed Central

    Herrera, Emilio A.; Riquelme, Raquel A.; Ebensperger, Germn; Reyes, Roberto V.; Ulloa, Csar E.; Cabello, Gertrudis; Krause, Bernardo J.; Parer, Julian T.; Giussani, Dino A.

    2010-01-01

    We determined whether postnatal pulmonary hypertension induced by 70% of pregnancy at high altitude (HA) persists once the offspring return to sea level and investigated pulmonary vascular mechanisms operating under these circumstances. Pregnant ewes were divided into two groups: conception, pregnancy, and delivery at low altitude (580 m, LLL) and conception at low altitude, pregnancy at HA (3,600 m) from 30% of gestation until delivery, and return to lowland (LHL). Pulmonary arterial pressure (PAP) was measured in vivo. Vascular reactivity and morphometry were assessed in small pulmonary arteries (SPA). Protein expression of vascular mediators was determined. LHL lambs had higher basal PAP and a greater increment in PAP after NG-nitro-l-arginine methyl ester (20.9 1.1 vs. 13.7 0.5 mmHg; 39.9 5.0 vs. 18.3 1.3 mmHg, respectively). SPA from LHL had a greater maximal contraction to K+ (1.34 0.05 vs. 1.16 0.05 N/m), higher sensitivity to endothelin-1 and nitroprusside, and persistence of dilatation following blockade of soluble guanylate cyclase. The heart ratio of the right ventricle-to-left ventricle plus septum was higher in the LHL relative to LLL. The muscle area of SPA (29.3 2.9 vs. 21.1 1.7%) and the protein expression of endothelial nitric oxide synthase (1.7 0.1 vs. 1.1 0.2), phosphodiesterase (1.4 0.1 vs. 0.7 0.1), and Ca2+-activated K+ channel (0.76 0.16 vs. 0.30 0.01) were greater in LHL compared with LLL lambs. In contrast, LHL had decreased heme oxygenase-1 expression (0.82 0.26 vs. 2.22 0.44) and carbon monoxide production (all P < 0.05). Postnatal pulmonary hypertension induced by 70% of pregnancy at HA promotes cardiopulmonary remodeling that persists at sea level. PMID:20881096

  9. Early Macrophage Recruitment and Alternative Activation Are Critical for the Later Development of Hypoxia-induced Pulmonary Hypertension

    PubMed Central

    Vergadi, Eleni; Chang, Mun Seog; Lee, Changjin; Liang, Olin; Liu, Xianlan; Fernandez-Gonzalez, Angeles; Mitsialis, S. Alex; Kourembanas, Stella

    2011-01-01

    Background Lung inflammation precedes the development of hypoxia-induced pulmonary hypertension (HPH); however its role in the pathogenesis of HPH is poorly understood. We sought to characterize the hypoxic inflammatory response and elucidate its role in the development of HPH. We also aimed to investigate the mechanisms by which heme oxygenase-1 (HO-1), an anti-inflammatory enzyme, is protective in HPH. Methods and Results We generated bitransgenic mice that overexpress human HO-1 under doxycycline (dox) control in an inducible, lung-specific manner. Hypoxic exposure of mice in the absence of dox resulted in early transient accumulation of monocytes/macrophages in the bronchoalveolar lavage. Alveolar macrophages acquired an alternatively activated phenotype (M2) in response to hypoxia, characterized by the expression of Found in Inflammatory Zone-1, Arginase-1 and Chitinase-3-like-3. A brief, two-day pulse of dox delayed but did not prevent the peak of hypoxic inflammation, and could not protect from HPH. In contrast, a seven-day dox treatment sustained high HO-1 levels during the entire period of hypoxic inflammation, inhibited macrophage accumulation and activation, induced macrophage IL-10 expression, and prevented the development of HPH. Supernatants from hypoxic M2 macrophages promoted proliferation of pulmonary artery smooth muscle cells while treatment with carbon monoxide, a HO-1 enzymatic product, abrogated this effect. Conclusions Early recruitment and alternative activation of macrophages in hypoxic lungs is critical for the later development of HPH. HO-1 may confer protection from HPH by effectively modifing macrophage activation state in hypoxia. PMID:21518986

  10. MAP kinase kinase kinase-2 (MEKK2) regulates hypertrophic remodeling of the right ventricle in hypoxia-induced pulmonary hypertension

    PubMed Central

    Ambler, S. Kelly; Li, Min; Sullivan, Timothy M.; Henry, Lauren N.; Crossno, Joseph T.; Long, Carlin S.; Garrington, Timothy P.; Stenmark, Kurt R.

    2013-01-01

    Pulmonary hypertension (PH) results in pressure overload of the right ventricle (RV) of the heart, initiating pathological RV remodeling and ultimately leading to right heart failure. Substantial research indicates that signaling through the MAPK superfamily mediates pathological cardiac remodeling. These considerations led us to test the hypothesis that the regulatory protein MAPKKK-2 (MEKK2) contributes to RV hypertrophy in hypoxia-induced PH. Transgenic mice with global knockout of MEKK2 (MEKK2?/? mice) and age-matched wild-type (WT) mice were exposed to chronic hypobaric hypoxia (10% O2, 6 wk) and compared with animals under normoxia. Exposure to chronic hypoxia induced PH in WT and MEKK2?/? mice. In response to PH, WT mice showed RV hypertrophy, demonstrated as increased ratio of RV weight to body weight, increased RV wall thickness at diastole, and increased cardiac myocyte size compared with normoxic control animals. In contrast, each of these measures of RV hypertrophy seen in WT mice after chronic hypoxia was attenuated in MEKK2?/? mice. Furthermore, chronic hypoxia elicited altered programs of hypertrophic and inflammatory gene expression consistent with pathological RV remodeling in WT mice; MEKK2 deletion selectively inhibited inflammatory gene expression compared with WT mice. The actions of MEKK2 were mediated in part through regulation of the abundance and phosphorylation of its effector, ERK5. In conclusion, signaling by MEKK2 contributes to RV hypertrophy and altered myocardial inflammatory gene expression in response to hypoxia-induced PH. Therapies targeting MEKK2 may protect the myocardium from hypertrophy and pathological remodeling in human PH. PMID:23125215

  11. Structural and Mechanical Adaptations of Right Ventricular Free Wall Myocardium to Pulmonary-Hypertension Induced Pressure Overload

    PubMed Central

    Hill, Michael R.; Simon, Marc A.; Valdez-Jasso, Daniela; Zhang, Will; Champion, Hunter C.; Sacks, Michael S.

    2014-01-01

    Right ventricular (RV) failure in response to pulmonary hypertension (PH) is a severe disease that remains poorly understood. PH-induced pressure overload leads to changes in the RV free wall (RVFW) that eventually results in RV failure. While the development of computational models can benefit our understanding of the onset and progression of PH-induced pressure overload, detailed knowledge of the underlying structural and biomechanical events remains limited. The goal of the present study was to elucidate the structural and biomechanical adaptations of RV myocardium subjected to sustained pressure overload in a rat model. Hemodynamically confirmed severe chronic RV pressure overload was induced in Sprague-Dawley rats via pulmonary artery banding. Extensive tissue-level biaxial mechanical and histomorphological analyses were conducted to assess the remodeling response in the RV free wall. Simultaneous myofiber hypertrophy and longitudinal re-orientation of myo- and collagen fibers was observed, with both fiber types becoming more highly aligned. Transmural myo- and collagen fiber orientations were co-aligned in both the normal and diseased state. The overall tissue stiffness increased, with larger increases in longitudinal versus circumferential stiffness. Interestingly, estimated myofiber stiffness increased while the collagen fiber stiffness remained unchanged. The latter was attributed to longitudinal fiber re-orientation, which increased the degree of anisotropy. Increased mechanical coupling between the two axes was attributed to the increased fiber alignment. The increased myofiber stiffness was consistent with clinical results showing titin-associated increased sarcomeric stiffening observed in PH patients. These results further our understanding of the underlying adaptive and maladaptive remodeling mechanisms and may lead to improved techniques for prognosis, diagnosis, and treatment for PH. PMID:25164124

  12. Cardiomyocyte-Specific Overexpression of HEXIM1 Prevents Right Ventricular Hypertrophy in Hypoxia-Induced Pulmonary Hypertension in Mice

    PubMed Central

    Maruyama, Takako; Sano, Motoaki; Matsuhashi, Tomohiro; Fukuda, Keiichi; Kataoka, Masaharu; Satoh, Toru; Ojima, Hidenori; Sawai, Takashi; Morimoto, Chikao; Kuribara, Akiko; Hosono, Osamu; Tanaka, Hirotoshi

    2012-01-01

    Right ventricular hypertrophy (RVH) and right ventricular (RV) contractile dysfunction are major determinants of prognosis in pulmonary arterial hypertension (PAH) and PAH remains a severe disease. Recently, direct interruption of left ventricular hypertrophy has been suggested to decrease the risk of left-sided heart failure. Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) is a negative regulator of positive transcription elongation factor b (P-TEFb), which activates RNA polymerase II (RNAPII)-dependent transcription and whose activation is strongly associated with left ventricular hypertrophy. We hypothesized that during the progression of PAH, increased P-TEFb activity might also play a role in RVH, and that HEXIM1 might have a preventive role against such process. We revealed that, in the mouse heart, HEXIM1 is highly expressed in the early postnatal period and its expression is gradually decreased, and that prostaglandin I2, a therapeutic drug for PAH, increases HEXIM1 levels in cardiomyocytes. These results suggest that HEXIM1 might possess negative effect on cardiomyocyte growth and take part in cardiomyocyte regulation in RV. Using adenovirus-mediated gene delivery to cultured rat cardiomyocytes, we revealed that overexpression of HEXIM1 prevents endothelin-1-induced phosphorylation of RNAPII, cardiomyocyte hypertrophy, and mRNA expression of hypertrophic genes, whereas a HEXIM1 mutant lacking central basic region, which diminishes P-TEFb-suppressing activity, could not. Moreover, we created cardiomyocyte-specific HEXIM1 transgenic mice and revealed that HEXIM1 ameliorates RVH and prevents RV dilatation in hypoxia-induced PAH model. Taken together, these findings indicate that cardiomyocyte-specific overexpression of HEXIM1 inhibits progression to RVH under chronic hypoxia, most possibly via inhibition of P-TEFb-mediated enlargement of cardiomyocytes. We conclude that P-TEFb/HEXIM1-dependent transcriptional regulation may play a pathophysiological role in RVH and be a novel therapeutic target for mitigating RVH in PAH. PMID:23300697

  13. Folic Acid Promotes Recycling of Tetrahydrobiopterin and Protects Against Hypoxia-Induced Pulmonary Hypertension by Recoupling Endothelial Nitric Oxide Synthase

    PubMed Central

    Chalupsky, Karel; Kračun, Damir; Kanchev, Ivan; Bertram, Katharina

    2015-01-01

    Abstract Aims: Nitric oxide (NO) derived from endothelial NO synthase (eNOS) has been implicated in the adaptive response to hypoxia. An imbalance between 5,6,7,8-tetrahydrobiopterin (BH4) and 7,8-dihydrobiopterin (BH2) can result in eNOS uncoupling and the generation of superoxide instead of NO. Dihydrofolate reductase (DHFR) can recycle BH2 to BH4, leading to eNOS recoupling. However, the role of DHFR and eNOS recoupling in the response to hypoxia is not well understood. We hypothesized that increasing the capacity to recycle BH4 from BH2 would improve NO bioavailability as well as pulmonary vascular remodeling (PVR) and right ventricular hypertrophy (RVH) as indicators of pulmonary hypertension (PH) under hypoxic conditions. Results: In human pulmonary artery endothelial cells and murine pulmonary arteries exposed to hypoxia, eNOS was uncoupled as indicated by reduced superoxide production in the presence of the nitric oxide synthase inhibitor, L-(G)-nitro-L-arginine methyl ester (L-NAME). Concomitantly, NO levels, BH4 availability, and expression of DHFR were diminished under hypoxia. Application of folic acid (FA) restored DHFR levels, NO bioavailability, and BH4 levels under hypoxia. Importantly, FA prevented the development of hypoxia-induced PVR, right ventricular pressure increase, and RVH. Innovation: FA-induced upregulation of DHFR recouples eNOS under hypoxia by improving BH4 recycling, thus preventing hypoxia-induced PH. Conclusion: FA might serve as a novel therapeutic option combating PH. Antioxid. Redox Signal. 23, 1076–1091. PMID:26414244

  14. Monocrotaline pyrrole-induced pulmonary hypertension in fawn-hooded rats with platelet storage pool deficiency: 5-hydroxytryptamine uptake by isolated, perfused lungs.

    PubMed

    Hilliker, K S; Bell, T G; Roth, R A

    1983-12-30

    Platelets are believed to be involved in the development of monocrotaline pyrrole (MCTP)-induced pulmonary hypertension. To help identify the role of the platelet, the cardiopulmonary toxicity of MCTP was examined in fawn-hooded (FH) rats, a strain with a platelet function defect. Both Sprague-Dawley (SD) and FH rats developed right ventricular hypertrophy and increased lung weights and exhibited decreased biogenic amine removal by isolated, perfused lung preparations after MCTP treatment. The responses of the FH rats were not significantly different from those of the SD rats, suggesting that platelet uptake and release of 5-hydroxytryptamine (5HT) are not the platelet functions involved in MCTP-induced pulmonary hypertension. The FH rats had an interesting strain-related difference from SD rats; isolated lungs from FH rats removed and metabolized a greater proportion of perfused 5HT than the SD rats. PMID:6665765

  15. Angiotensin II-Induced Hypertension Is Attenuated by Reduction of Sympathetic Output in NO-Sensitive Guanylyl Cyclase 1 Knockout Mice.

    PubMed

    Broekmans, Kathrin; Stegbauer, Johannes; Potthoff, Sebastian A; Russwurm, Michael; Koesling, Doris; Mergia, Evanthia

    2016-01-01

    In the regulation of vascular tone, the dilatory nitric oxide (NO)/cGMP pathway balances vasoconstriction induced by the renin-angiotensin and sympathetic nervous systems. NO-induced cGMP formation is catalyzed by two guanylyl cyclases (GC), NO-sensitive guanylyl cyclase 1 (NO-GC1) and NO-GC2, with indistinguishable enzymatic properties. In vascular smooth muscle cells, NO-GC1 is the major isoform and is responsible for more than 90% of cGMP formation. Despite reduced vasorelaxation, NO-GC1-deficient mice are not hypertensive. Here, the role of NO-GC1 in hypertension provoked by contractile agonists angiotensin II (Ang II) and norepinephrine (NE) was evaluated in NO-GC1-deficient mice. Hypertension induced by chronic Ang II treatment did not differ between wild-type (WT) and NO-GC1 knockout mice (KO). Also, attenuation of NO-dependent aortic relaxation induced by the Ang II treatment was similar in both genotypes and was most probably attributable to an increase of phosphodiesterase 1 expression. Analysis of plasma NE content-known to be influenced by Ang II-revealed lower NE in the NO-GC1 KO under Ang II-treated- and nontreated conditions. The finding indicates reduced sympathetic output and is underlined by the lower heart rate in the NO-GC1 KO. To find out whether the lack of higher blood pressure in the NO-GC1 KO is a result of reduced sympathetic activity counterbalancing the reduced vascular relaxation, mice were challenged with chronic NE application. As the resulting blood pressure was higher in the NO-GC1 KO than in WT, we conclude that the reduced sympathetic activity in the NO-GC1 KO prevents hypertension and postulate a possible sympatho-excitatory action of NO-GC1 counteracting NO-GC1's dilatory effect in the vasculature. PMID:26559126

  16. Chronic N(G)-nitro-L-arginine methyl ester-induced hypertension : novel molecular adaptation to systolic load in absence of hypertrophy

    NASA Technical Reports Server (NTRS)

    Bartunek, J.; Weinberg, E. O.; Tajima, M.; Rohrbach, S.; Katz, S. E.; Douglas, P. S.; Lorell, B. H.; Schneider, M. (Principal Investigator)

    2000-01-01

    BACKGROUND: Chronic N(G)-nitro-L-arginine methyl ester (L-NAME), which inhibits nitric oxide synthesis, causes hypertension and would therefore be expected to induce robust cardiac hypertrophy. However, L-NAME has negative metabolic effects on protein synthesis that suppress the increase in left ventricular (LV) mass in response to sustained pressure overload. In the present study, we used L-NAME-induced hypertension to test the hypothesis that adaptation to pressure overload occurs even when hypertrophy is suppressed. METHODS AND RESULTS: Male rats received L-NAME (50 mg. kg(-1). d(-1)) or no drug for 6 weeks. Rats with L-NAME-induced hypertension had levels of systolic wall stress similar to those of rats with aortic stenosis (85+/-19 versus 92+/-16 kdyne/cm). Rats with aortic stenosis developed a nearly 2-fold increase in LV mass compared with controls. In contrast, in the L-NAME rats, no increase in LV mass (1. 00+/-0.03 versus 1.04+/-0.04 g) or hypertrophy of isolated myocytes occurred (3586+/-129 versus 3756+/-135 microm(2)) compared with controls. Nevertheless, chronic pressure overload was not accompanied by the development of heart failure. LV systolic performance was maintained by mechanisms of concentric remodeling (decrease of in vivo LV chamber dimension relative to wall thickness) and augmented myocardial calcium-dependent contractile reserve associated with preserved expression of alpha- and beta-myosin heavy chain isoforms and sarcoplasmic reticulum Ca(2+) ATPase (SERCA-2). CONCLUSIONS: When the expected compensatory hypertrophic response is suppressed during L-NAME-induced hypertension, severe chronic pressure overload is associated with a successful adaptation to maintain systolic performance; this adaptation depends on both LV remodeling and enhanced contractility in response to calcium.

  17. Mineralocorticoid hypertension

    PubMed Central

    Gupta, Vishal

    2011-01-01

    Hypertension affects about 10 25% of the population and is an important risk factor for cardiovascular and renal disease. The renin-angiotensin system is frequently implicated in the pathophysiology of hypertension, be it primary or secondary. The prevalence of primary aldosteronism increases with the severity of hypertension, from 2% in patients with grade 1 hypertension to 20% among resistant hypertensives. Mineralcorticoid hypertension includes a spectrum of disorders ranging from renin-producing pathologies (renin-secreting tumors, malignant hypertension, coarctation of aorta), aldosterone-producing pathologies (primary aldosteronism Conns syndrome, familial hyperaldosteronism 1, 2, and 3), non-aldosterone mineralocorticoid producing pathologies (apparent mineralocorticoid excess syndrome, Liddle syndrome, deoxycorticosterone-secreting tumors, ectopic adrenocorticotropic hormones (ACTH) syndrome, congenitalvadrenal hyperplasia), and drugs with mineraocorticoid activity (locorice, carbenoxole therapy) to glucocorticoid receptor resistance syndromes. Clinical presentation includes hypertension with varying severity, hypokalemia, and alkalosis. Ratio of plasma aldosterone concentraion to plasma renin activity remains the best screening tool. Bilateral adrenal venous sampling is the best diagnostic test coupled with a CT scan. Treatment is either surgical (adrenelectomy) for unilateral adrenal disease versus medical therapy for idiopathic, ambiguous, or bilateral disease. Medical therapy focuses on blood pressure control and correction of hypokalemia using a combination of anti-hypertensives (calcium channel blockers, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers) and potassium-raising therapies (mineralcorticoid receptor antagonist or potassium sparing diuretics). Direct aldosterone synthetase antagonists represent a promising future therapy. PMID:22145132

  18. SPONTANEOUSLY HYPERTENSIVE RATS ARE SUSCEPTIBLE TO AIRWAY DISEASE INDUCED BY SULFUR DIOXIDE

    EPA Science Inventory

    Rodent models of chronic pulmonary diseases induced by sulfur dioxide (SO2), elastase or tobacco smoke have limited utility because of their lack of chronicity of inflammation, and they demonstrate limited sensitivity to a given experimental manipulation. We hypothesized that dis...

  19. Induced hypertension for the treatment of cerebral ischemia after subarachnoid hemorrhage. Direct effect on cerebral blood flow

    SciTech Connect

    Muizelaar, J.P.; Becker, D.P.

    1986-04-01

    The best treatment for symptomatic cerebral ischemia from presumed vasospasm after aneurysmal subarachnoid hemorrhage remains a matter of controversy. A direct effect of any treatment modality on regional cerebral blood flow has never been documented. In a series of 43 patients operated on for ruptured anterior circulation aneurysms, five patients (11.6%) developed clinical signs of cerebral ischemia postoperatively. In four of those patients, the diagnosis of vasospasm was made with measurements of cerebral blood flow (133Xe inhalation or intravenous injection, 10-16 detectors, cerebral blood flow infinity). Treatment with induced arterial hypertension with phenylephrine was instituted. Hemodilution was instituted in one patient; the other three patients already had hematocrits in the range of 33. Within 1 hour, the cerebral blood flow measurement was repeated to document the effect of treatment. The average pretreatment hemispherical blood flow on the operated side was 18.8 mL/100 g per minute, on the contralateral side 21.0 mL/100 g per minute. With treatment these flows increased to 30.8 and 35.8 mL/100 g per minute, respectively. There was also an immediate and obvious positive clinical effect in all patients. The role of measurement of cerebral blood flow in the clinical management of vasospasm is discussed. We stress the theoretical and practical advances of measurements of cerebral blood flow over cerebral angiography, especially in comatose patients.

  20. Candidate genes in quantitative trait loci associated with absolute and relative kidney weight in rats with Inherited Stress Induced Arterial Hypertension

    PubMed Central

    2015-01-01

    Background The kidney mass is significantly increased in hypertensive ISIAH rats with Inherited Stress Induced Arterial Hypertension as compared with normotensive WAG rats. The QTL/microarray approach was carried out to determine the positional candidate genes in the QTL for absolute and relative kidney weight. Results Several known and predicted genes differentially expressed in ISIAH and WAG kidney were mapped to genetic loci associated with the absolute and relative kidney weight in 6-month old F2 hybrid (ISIAHxWAG) males. The knowledge-driven filtering of the list of candidates helped to suggest several positional candidate genes, which may be related to the structural and mass changes in hypertensive ISIAH kidney. In the current study, we showed that all loci found for absolute and relative kidney weight didn't overlap with significant or suggestive loci for arterial blood pressure level. So, the genes differentially expressed in ISIAH and WAG kidneys and located in these QTL regions associated with absolute and relative kidney weight shouldn't substantially influence the BP level in the 6 month-old ISIAH rats. However, in some cases, small effects may be suggested. Conclusions The further experimental validation of causative genes and detection of polymorphisms will provide opportunities to advance our understanding of the underlying nature of structural and mass changes in hypertensive ISIAH kidney. PMID:25707311

  1. Synergistic Antihypertensive Effect of Carthamus tinctorius L. Extract and Captopril in l-NAME-Induced Hypertensive Rats via Restoration of eNOS and AT₁R Expression.

    PubMed

    Maneesai, Putcharawipa; Prasarttong, Patoomporn; Bunbupha, Sarawoot; Kukongviriyapan, Upa; Kukongviriyapan, Veerapol; Tangsucharit, Panot; Prachaney, Parichat; Pakdeechote, Poungrat

    2016-01-01

    This study examined the effect of Carthamus tinctorius (CT) extract plus captopril treatment on blood pressure, vascular function, nitric oxide (NO) bioavailability, oxidative stress and renin-angiotensin system (RAS) in N(ω)-Nitro-l-arginine methyl ester (l-NAME)-induced hypertension. Rats were treated with l-NAME (40 mg/kg/day) for five weeks and given CT extract (75 or 150 or 300 or 500 mg/kg/day): captopril (5 mg/kg/day) or CT extract (300 mg/kg/day) plus captopril (5 mg/kg/day) for two consecutive weeks. CT extract reduced blood pressure dose-dependently, and the most effective dose was 300 mg/kg/day. l-NAME-induced hypertensive rats showed abnormalities including high blood pressure, high vascular resistance, impairment of acetylcholine-induced vasorelaxation in isolated aortic rings and mesenteric vascular beds, increased vascular superoxide production and plasma malondialdehyde levels, downregulation of eNOS, low level of plasma nitric oxide metabolites, upregulation of angiotensin II type 1 receptor and increased plasma angiotensin II. These abnormalities were alleviated by treatment with either CT extract or captopril. Combination treatment of CT extract and captopril normalized all the abnormalities found in hypertensive rats except endothelial dysfunction. These data indicate that there are synergistic antihypertensive effects of CT extract and captopril. These effects are likely mediated by their anti-oxidative properties and their inhibition of RAS. PMID:26938552

  2. Effects of vitamin C on high blood pressure induced by salt in spontaneously hypertensive rats.

    PubMed

    Nishikawa, Yoshiyuki; Tatsumi, Kaori; Matsuura, Takeshi; Yamamoto, Ayako; Nadamoto, Tomonori; Urabe, Kimiko

    2003-10-01

    By breeding and feeding salt to spontaneously hypertensive rats (SHR) continuously over a long period (until 60 wk old), rats with systolic blood pressures (SBP) of over 270 mmHg were prepared. It was studied whether or not supplying large amounts of vitamin C (200 mg/rat/d) over this period might bring any beneficial effect to blood pressure. Moreover, physico-chemical studies were performed to measure the components and enzymes in the blood and urine at 53 and 60 wk-old, and biochemical studies on vitamin C were also carried out in this experiment. Male (14 rats: 7 wk-old, 100-105 g) and female (15 rats: 7 wk-old, 95-100 g) SHR were divided into three groups and bred continuously for 53 wk. The A group rats were given salt (2.5 g/100 g of diet), the B group rats were given salt and vitamin C (500 mg/100 mL of drinking water), and the C group rats were controls. The results showed almost the same tendencies between male and female rats. The body weights of the SHR in groups A and B were slightly lower than group C. The amount of food intake in groups A and B was almost the same as group C. The amount of water intake was, in the order from highest to lowest, group A, B and C. The SBP of group A rats exhibited the highest value among the three groups. The SBP of group B rats given vitamin C simultaneously with the salt resulted in a low blood pressure level close to that of the controls (group C). Furthermore, the DBP (diastolic blood pressure) also reflected the antihypertensive effect of vitamin C as well. The heartbeat of the rats was highest in group A, and was comparable to the value in the rats receiving vitamin C simultaneously with salt. For the tests on occult blood and protein in the urine, group A rats showed strong positive reactions, whereas the group B and C rats had decreased results for both tests. The organ weights of the liver, stomach, spleen, adrenal gland and kidneys per 100 g rat body weight were not different among the three groups. The values for the bilirubin content, and the enzyme activities of ALT and AST in the blood showed to be the highest in the male rats of group A. The values from the group B rats decreased near to the normal value like the control group. Vitamin C was found to decrease the blood pressure in SHR, and also to work effectively to protect liver and kidney functions even under the condition of very high blood pressure, as high as 250 mmHg. PMID:14703303

  3. Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension

    PubMed Central

    Sawada, Hirofumi; Saito, Toshie; Nickel, Nils P.; Alastalo, Tero-Pekka; Glotzbach, Jason P.; Chan, Roshelle; Haghighat, Leila; Fuchs, Gabriele; Januszyk, Michael; Cao, Aiqin; Lai, Ying-Ju; Perez, Vinicio de Jesus; Kim, Yu-Mee; Wang, Lingli; Chen, Pin-I; Spiekerkoetter, Edda; Mitani, Yoshihide; Gurtner, Geoffrey C.; Sarnow, Peter

    2014-01-01

    Idiopathic pulmonary arterial hypertension (PAH [IPAH]) is an insidious and potentially fatal disease linked to a mutation or reduced expression of bone morphogenetic protein receptor 2 (BMPR2). Because intravascular inflammatory cells are recruited in IPAH pathogenesis, we hypothesized that reduced BMPR2 enhances production of the potent chemokine granulocyte macrophage colony-stimulating factor (GM-CSF) in response to an inflammatory perturbation. When human pulmonary artery (PA) endothelial cells deficient in BMPR2 were stimulated with tumor necrosis factor (TNF), a twofold increase in GM-CSF was observed and related to enhanced messenger RNA (mRNA) translation. The mechanism was associated with disruption of stress granule formation. Specifically, loss of BMPR2 induced prolonged phospho-p38 mitogen-activated protein kinase (MAPK) in response to TNF, and this increased GADD34PP1 phosphatase activity, dephosphorylating eukaryotic translation initiation factor (eIF2?), and derepressing GM-CSF mRNA translation. Lungs from IPAH patients versus unused donor controls revealed heightened PA expression of GM-CSF co-distributing with increased TNF and expanded populations of hematopoietic and endothelial GM-CSF receptor ? (GM-CSFR?)positive cells. Moreover, a 3-wk infusion of GM-CSF in mice increased hypoxia-induced PAH, in association with increased perivascular macrophages and muscularized distal arteries, whereas blockade of GM-CSF repressed these features. Thus, reduced BMPR2 can subvert a stress granule response, heighten GM-CSF mRNA translation, increase inflammatory cell recruitment, and exacerbate PAH. PMID:24446489

  4. Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension.

    PubMed

    Sawada, Hirofumi; Saito, Toshie; Nickel, Nils P; Alastalo, Tero-Pekka; Glotzbach, Jason P; Chan, Roshelle; Haghighat, Leila; Fuchs, Gabriele; Januszyk, Michael; Cao, Aiqin; Lai, Ying-Ju; Perez, Vinicio de Jesus; Kim, Yu-Mee; Wang, Lingli; Chen, Pin-I; Spiekerkoetter, Edda; Mitani, Yoshihide; Gurtner, Geoffrey C; Sarnow, Peter; Rabinovitch, Marlene

    2014-02-10

    Idiopathic pulmonary arterial hypertension (PAH [IPAH]) is an insidious and potentially fatal disease linked to a mutation or reduced expression of bone morphogenetic protein receptor 2 (BMPR2). Because intravascular inflammatory cells are recruited in IPAH pathogenesis, we hypothesized that reduced BMPR2 enhances production of the potent chemokine granulocyte macrophage colony-stimulating factor (GM-CSF) in response to an inflammatory perturbation. When human pulmonary artery (PA) endothelial cells deficient in BMPR2 were stimulated with tumor necrosis factor (TNF), a twofold increase in GM-CSF was observed and related to enhanced messenger RNA (mRNA) translation. The mechanism was associated with disruption of stress granule formation. Specifically, loss of BMPR2 induced prolonged phospho-p38 mitogen-activated protein kinase (MAPK) in response to TNF, and this increased GADD34-PP1 phosphatase activity, dephosphorylating eukaryotic translation initiation factor (eIF2?), and derepressing GM-CSF mRNA translation. Lungs from IPAH patients versus unused donor controls revealed heightened PA expression of GM-CSF co-distributing with increased TNF and expanded populations of hematopoietic and endothelial GM-CSF receptor ? (GM-CSFR?)-positive cells. Moreover, a 3-wk infusion of GM-CSF in mice increased hypoxia-induced PAH, in association with increased perivascular macrophages and muscularized distal arteries, whereas blockade of GM-CSF repressed these features. Thus, reduced BMPR2 can subvert a stress granule response, heighten GM-CSF mRNA translation, increase inflammatory cell recruitment, and exacerbate PAH. PMID:24446489

  5. An increase in adenosine-5-triphosphate (ATP) content in rostral ventrolateral medulla is engaged in the high fructose diet-induced hypertension

    PubMed Central

    2014-01-01

    Background The increase in fructose ingestion has been linked to overdrive of sympathetic activity and hypertension associated with the metabolic syndrome. The premotor neurons for generation of sympathetic vasomotor activity reside in the rostral ventrolateral medulla (RVLM). Activation of RVLM results in sympathoexcitation and hypertension. Neurons in the central nervous system are able to utilize fructose as a carbon source of ATP production. We examined in this study whether fructose affects ATP content in RVLM and its significance in the increase in central sympathetic outflow and hypertension induced by the high fructose diet (HFD). Results In normotensive rats fed with high fructose diet (HFD) for 12 weeks, there was a significant increase in tissue ATP content in RVLM, accompanied by the increases in the sympathetic vasomotor activity and blood pressure. These changes were blunted by intracisternal infusion of an ATP synthase inhibitor, oligomycin, to the HFD-fed animals. In the catecholaminergic-containing N2a cells, fructose dose-dependently upregulated the expressions of glucose transporter 2 and 5 (GluT2, 5) and the rate-limiting enzyme of fructolysis, ketohexokinase (KHK), leading to the increases in pyruvate and ATP production, as well as the release of the neurotransmitter, dopamine. These cellular events were significantly prevented after the gene knocking down by lentiviral transfection of small hairpin RNA against KHK. Conclusion These results suggest that increases in ATP content in RVLM may be engaged in the augmented sympathetic vasomotor activity and hypertension associated with the metabolic syndrome induced by the HFD. At cellular level, the increase in pyruvate levels via fructolysis is involved in the fructose-induced ATP production and the release of neurotransmitter. PMID:24467657

  6. Cardiac-specific overexpression of metallothionein attenuates myocardial remodeling and contractile dysfunction in l-NAME-induced experimental hypertension: Role of autophagy regulation.

    PubMed

    Yang, Lifang; Gao, Jian-Yuan; Ma, Jipeng; Xu, Xihui; Wang, Qiurong; Xiong, Lize; Yang, Jian; Ren, Jun

    2015-09-01

    Hypertension is an independent risk factor for heart disease and is responsible for the increased cardiac morbidity and mortality. Oxidative stress plays a key role in hypertensive heart diseases although the precise mechanism remains unclear. This study was designed to examine the effect of cardiac-specific overexpression of metallothionein, a cysteine-rich antioxidant, on myocardial contractile and intracellular Ca(2+) anomalies in N(G)-nitro-l-arginine methyl ester (l-NAME)-induced experimental hypertension and the mechanism involved with a focus on autophagy. Our results revealed that l-NAME treatment (14 days) led to hypertension and myocardial anomalies evidenced by interstitial fibrosis, cardiomyocyte hypertrophy, increased LV end systolic and diastolic diameters (LVESD and LVEDD) along with suppressed fractional shortening. l-NAME compromised cardiomyocyte contractile and intracellular Ca(2+) properties manifested as depressed peak shortening, maximal velocity of shortening/relengthening, electrically-stimulated rise in intracellular Ca(2+), elevated baseline and peak intracellular Ca(2+). These l-NAME-induced histological and mechanical changes were attenuated or reconciled by metallothionein. Protein levels of autophagy markers LC3B and p62 were decreased and increased, respectively. Autophagy signaling molecules AMPK, TSC2 and ULK1 were inactivated while those of mTOR and p70s6K were activated by l-NAME, the effects of which were ablated by metallothionein. Autophagy induction mimicked whereas autophagy inhibition nullified the beneficial effect of metallothionein against l-NAME. These findings suggested that metallothionein protects against l-NAME-induced myocardial anomalies possibly through restoration of autophagy. PMID:26068063

  7. PARP-Inhibitor Treatment Prevents Hypertension Induced Cardiac Remodeling by Favorable Modulation of Heat Shock Proteins, Akt-1/GSK-3? and Several PKC Isoforms

    PubMed Central

    Deres, Laszlo; Bartha, Eva; Palfi, Anita; Eros, Krisztian; Riba, Adam; Lantos, Janos; Kalai, Tamas; Hideg, Kalman; Sumegi, Balazs; Gallyas, Ferenc; Toth, Kalman; Halmosi, Robert

    2014-01-01

    Spontaneously hypertensive rat (SHR) is a suitable model for studies of the complications of hypertension. It is known that activation of poly(ADP-ribose) polymerase enzyme (PARP) plays an important role in the development of postinfarction as well as long-term hypertension induced heart failure. In this study, we examined whether PARP-inhibitor (L-2286) treatment could prevent the development of hypertensive cardiopathy in SHRs. 6-week-old SHR animals were treated with L-2286 (SHR-L group) or placebo (SHR-C group) for 24 weeks. Wistar-Kyoto rats were used as aged-matched, normotensive controls (WKY group). Echocardiography was performed, brain-derived natriuretic peptide (BNP) activity and blood pressure were determined at the end of the study. We detected the extent of fibrotic areas. The amount of heat-shock proteins (Hsps) and the phosphorylation state of Akt-1Ser473, glycogen synthase kinase (GSK)-3?Ser9, forkhead transcription factor (FKHR)Ser256, mitogen activated protein kinases (MAPKs), and protein kinase C (PKC) isoenzymes were monitored. The elevated blood pressure in SHRs was not influenced by PARP-inhibitor treatment. Systolic left ventricular function and BNP activity did not differ among the three groups. L-2286 treatment decreased the marked left ventricular (LV) hypertrophy which was developed in SHRs. Interstitial collagen deposition was also decreased by L-2286 treatment. The phosphorylation of extracellular signal-regulated kinase (ERK)1/2Thr183-Tyr185, Akt-1Ser473, GSK-3?Ser9, FKHRSer256, and PKC ?Ser729 and the level of Hsp90 were increased, while the activity of PKC ?/?IIThr638/641, ?/?410/403 were mitigated by L-2286 administration. We could detect signs of LV hypertrophy without congestive heart failure in SHR groups. This alteration was prevented by PARP inhibition. Our results suggest that PARP-inhibitor treatment has protective effect already in the early stage of hypertensive myocardial remodeling. PMID:25014216

  8. Blood Pressure Interventions Affect Acute and Four-Week Diesel Exhaust Induced Pulmonary Injury in Healthy and Hypertensive Rats

    EPA Science Inventory

    Rationale: We recently showed that inhalation exposure of normotensive Wistar Kyoto (WKY) rats to whole diesel exhaust (DE) elicits changes in cardiac gene expression that broadly mimics expression in spontaneously hypertensive (SH) rats without DE. We hypothesized that pharmacol...

  9. Erythropoietin-induced hypertensive urgency in a patient with chronic renal insufficiency: case report and review of the literature.

    PubMed

    Novak, Barbara L; Force, Rex W; Mumford, Brett T; Solbrig, Ronald M

    2003-02-01

    Hypertension is a potentially dangerous side effect of erythropoietin treatment; however, extreme elevations in blood pressure are rare. A 75-year-old woman with chronic renal insufficiency was treated with subcutaneous erythropoietin. Three weeks before she started receiving erythropoietin, her hematocrit was 27.2%; after 5 weeks of treatment, it rose to 45.7%. The patient came to the emergency department and was admitted with hypertensive urgency. During her hospital stay she was treated with nitroglycerin and nitroprusside infusions, extended-release nifedipine, a variety of beta-blockers, clonidine, and furosemide. By day 3, her blood pressure was adequately controlled. Her renal insufficiency may have progressed as a result of the hypertensive episode, which probably was related to erythropoietin administration and the resultant rapid increase in her hematocrit. Erythropoietin dosing should be titrated to increase the hematocrit gradually, and blood pressure should be monitored closely to avoid serious side effects such as hypertensive emergencies. PMID:12587817

  10. Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

    SciTech Connect

    Kang, Yu-Ming; Zhang, Dong-Mei; Yu, Xiao-Jing; Yang, Qing; Qi, Jie; Su, Qing; Suo, Yu-Ping; Yue, Li-Ying; Zhu, Guo-Qing; Qin, Da-Nian

    2014-02-01

    The reninangiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 ?g/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1? and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. - Highlights: Chronic ANG II infusion results in sympathetic hyperactivity and cardiac hypertrophy. PVN inhibition of ACE attenuates ANG II-induced hypertension and cardiac hypertrophy. PVN inhibition of ACE attenuates ANG II-induced imbalance of PVN neurotransmitters. PVN inhibition of ACE attenuates ANG II-induced imbalance of cytokines in the PVN. PVN blockade of AT1-R attenuates ANG II-induced imbalance of cytokines in the PVN.

  11. The lipoprotein lipase gene serine 447 stop variant influences hypertension-induced left ventricular hypertrophy and risk of coronary heart disease.

    PubMed

    Talmud, Philippa J; Flavell, David M; Alfakih, Khaled; Cooper, Jackie A; Balmforth, Anthony J; Sivananthan, Mohan; Montgomery, Hugh E; Hall, Alistair S; Humphries, Steve E

    2007-06-01

    LVH [LV (left ventricular) hypertrophy] is an independent risk factor for CHD (coronary heart disease). During LVH, the preferred cardiac energy substrate switches from FAs (fatty acids) to glucose. LPL (lipoprotein lipase) is the key enzyme in triacylglycerol (triglyceride) hydrolysis and supplies FAs to the heart. To investigate whether substrate utilization influences cardiac growth and CHD risk, we examined the association between the functional LPL S447X (rs328) variant and hypertension-induced LV growth and CHD risk. LPL-X447 has been shown to be more hydrolytically efficient and would therefore release more free FAs than LPL-S477. In a cohort of 190 hypertensive subjects, LPL X447 was associated with a greater LV mass index [85.2 (1.7) in S/S compared with 91.1 (3.4) in S/X+X/X; P=0.01], but no such association was seen in normotensive controls (n=60). X447 allele frequency was higher in hypertensives with than those without LVH {0.14 [95% CI (confidence interval), 0.08-0.19] compared with 0.07 (95% CI, 0.05-0.10) respectively; odds ratio, 2.52 (95% CI, 1.17-5.40), P=0.02}. The association of LPL S447X with CHD risk was then examined in a prospective study of healthy middle-aged U.K. men (n=2716). In normotensive individuals, compared with S447 homozygotes, X447 carriers were protected from CHD risk [HR (hazard ratio), 0.48 (95% CI, 0.23-1.00); P=0.05], whereas, in the hypertensives, X447 carriers had increased risk [HR, 1.54 (95% CI, 1.13-2.09) for S/S (P=0.006) and 2.30 (95% CI, 1.53-3.45) for X447+ (P<0.0001)] and had a significant interaction with hypertension in CHD risk determination (P=0.007). In conclusion, hypertensive LPL X447 carriers have increased risk of LVH and CHD, suggesting that altered FA delivery constitutes a mechanism through which LVH and CHD are associated in hypertensive subjects. PMID:17291198

  12. Group B streptococcal phospholipid causes pulmonary hypertension

    NASA Astrophysics Data System (ADS)

    Curtis, Jerri; Kim, Geumsoo; Wehr, Nancy B.; Levine, Rodney L.

    2003-04-01

    Group B Streptococcus is the most common cause of bacterial infection in the newborn. Infection in many cases causes persistent pulmonary hypertension, which impairs gas exchange in the lung. We purified the bacterial components causing pulmonary hypertension and identified them as cardiolipin and phosphatidylglycerol. Synthetic cardiolipin or phosphatidylglycerol also induced pulmonary hypertension in lambs. The recognition that bacterial phospholipids may cause pulmonary hypertension in newborns with Group B streptococcal infection opens new avenues for therapeutic intervention.

  13. A pivotal role of the vascular endothelial growth factor signaling pathway in the formation of venous hypertension-induced dural arteriovenous fistulas

    PubMed Central

    LI, QIANG; ZHANG, QI; HUANG, QING-HAI; FANG, YI-BIN; ZHANG, ZHAO-LONG; XU, YI; LIU, JIAN-MIN

    2014-01-01

    Dural arteriovenous fistulas (DAVFs) are associated with venous hypertension. Numerous studies have revealed high expression levels of vascular endothelial growth factor (VEGF) in human DAVF specimens, as well as in animal models of experimental venous hypertension. The objective of the present study was to clarify whether the VEGF signaling pathway is important in the development of DAVFs. Rats (n=216) were randomly divided into six groups. In the rats from five groups (groups A and C-E, n=45 in each group; group B, n=12), experimental venous hypertension was induced by right common carotid artery (CCA)-external jugular vein (EJV) anastomosis, superior sinus occlusion and left transver sinus occlusion, while the remaining group (group F, n=24) underwent sham surgery. The rats in group A received a VEGF recombinant adenovirus injection into the distal section of the right EJV 30 min prior to anastomosis of the CCA and EJV. An equivalent control adenovirus was injected into the right EJV of group B rats prior to anastomosis. The rats in group C received no virus prior to anastomosis and no medicine subsequent to surgery. The group D rats were lavaged with Vatalanib, a VEGF receptor (VEGFR) inhibitor, and the group E rats were lavaged with an equal quantity of saline weekly following surgery. Six rats from groups A-E and one rat from group F were sacrificed in the first, second, fourth and twelfth weeks after surgery for immunohistochemical analysis of VEGF expression and analysis of microvessel density. Cerebral angiography was performed on the remaining rats in each group on the twelfth week after surgery. The results revealed that following transfection with VEGF recombinant adenovirus, angiogenesis in the dura mater of venous hypertensive rats was increased subsequent to the increase in the VEGF expression levels of the brain and dura mater. The rate of DAVF induction by venous hypertension was significantly reduced by the VEGFR antagonist due to reduced angiogenesis in the dura mater. In conclusion, VEGF and its receptor may be important in the formation of venous hypertension-induced DAVFs. PMID:24626343

  14. The Effect of Umbilical Cord Blood Derived Mesenchymal Stem Cells in Monocrotaline-induced Pulmonary Artery Hypertension Rats.

    PubMed

    Lee, Hyeryon; Lee, Jae Chul; Kwon, Jung Hyun; Kim, Kwan Chang; Cho, Min-Sun; Yang, Yoon Sun; Oh, Wonil; Choi, Soo Jin; Seo, Eun-Seok; Lee, Sang-Joon; Wang, Tae Jun; Hong, Young Mi

    2015-05-01

    Pulmonary arterial hypertension (PAH) causes right ventricular failure due to a gradual increase in pulmonary vascular resistance. The purposes of this study were to confirm the engraftment of human umbilical cord blood-mesenchymal stem cells (hUCB-MSCs) placed in the correct place in the lung and research on changes of hemodynamics, pulmonary pathology, immunomodulation and several gene expressions in monocrotaline (MCT)-induced PAH rat models after hUCB-MSCs transfusion. The rats were grouped as follows: the control (C) group; the M group (MCT 60 mg/kg); the U group (hUCB-MSCs transfusion). They received transfusions via the external jugular vein a week after MCT injection. The mean right ventricular pressure (RVP) was significantly reduced in the U group after the 2 week. The indicators of RV hypertrophy were significantly reduced in the U group at week 4. Reduced medial wall thickness in the pulmonary arteriole was noted in the U group at week 4. Reduced number of intra-acinar muscular pulmonary arteries was observed in the U group after 2 week. Protein expressions such as endothelin (ET)-1, endothelin receptor A (ERA), endothelial nitric oxide synthase (eNOS) and matrix metalloproteinase (MMP)-2 significantly decreased at week 4. The decreased levels of ERA, eNOS and MMP-2 immunoreactivity were noted by immnohistochemical staining. After hUCB-MSCs were administered, there were the improvement of RVH and mean RVP. Reductions in several protein expressions and immunomodulation were also detected. It is suggested that hUCB-MSCs may be a promising therapeutic option for PAH. PMID:25931788

  15. Heme Oxygenase-1 and Inflammation in Experimental Right Ventricular Failure on Prolonged Overcirculation-Induced Pulmonary Hypertension

    PubMed Central

    Kerbaul, Franois; Brimioulle, Serge; Dewachter, Cline; Rondelet, Benot

    2013-01-01

    Heme oxygenase (HO)-1 is a stress response enzyme which presents with cardiovascular protective and anti-inflammatory properties. Six-month chronic overcirculation-induced pulmonary arterial hypertension (PAH) in piglets has been previously reported as a model of right ventricular (RV) failure related to the RV activation of apoptotic and inflammatory processes. We hypothesized that altered HO-1 signalling could be involved in both pulmonary vascular and RV changes. Fifteen growing piglets were assigned to a sham operation (n?=?8) or to an anastomosis of the left innominate artery to the pulmonary arterial trunk (n?=?7). Six months later, hemodynamics was evaluated after closure of the shunt. After euthanasia of the animals, pulmonary and myocardial tissue was sampled for pathobiological evaluation. Prolonged shunting was associated with a tendency to decreased pulmonary gene and protein expressions of HO-1, while pulmonary gene expressions of interleukin (IL)-33, IL-19, intercellular adhesion molecule (ICAM)-1 and -2 were increased. Pulmonary expressions of constitutive HO-2 and pro-inflammatory tumor necrosis factor (TNF)-? remained unchanged. Pulmonary vascular resistance (evaluated by pressure/flow plots) was inversely correlated to pulmonary HO-1 protein and IL-19 gene expressions, and correlated to pulmonary ICAM-1 gene expression. Pulmonary arteriolar medial thickness and PVR were inversely correlated to pulmonary IL-19 expression. RV expression of HO-1 was decreased, while RV gene expressions TNF-? and ICAM-2 were increased. There was a correlation between RV ratio of end-systolic to pulmonary arterial elastances and RV HO-1 expression. These results suggest that downregulation of HO-1 is associated to PAH and RV failure. PMID:23936023

  16. The Anti-hypertensive Drug Prazosin Induces Apoptosis in the Medullary Thyroid Carcinoma Cell Line TT

    PubMed Central

    STRACKE, ANIKA; MEIER-ALLARD, NATHALIE; ABSENGER, MARKUS; INGOLIC, ELISABETH; HAAS, HELGA SUSANNE; PFRAGNER, ROSWITHA; SADJAK, ANTON

    2015-01-01

    Background/Aim Medullary thyroid carcinoma (MTC) is a tumor associated with poor prognosis since it exhibits high resistance against conventional cancer therapy. Recent studies have shown that quinazolines exhibit a pro-apoptotic effect on malignant cells. The aim of the present study was to elucidate whether MTC cells are affected by quinazolines, in particular prazosin. Materials and Methods Proliferation, apoptosis and cell morphology of the MTC cell line TT were analyzed by WST-1 assay, caspase 3/7 activation tests and microscopy. Fibroblasts were used as control for non-malignant cells. Results Prazosin potently inhibited the growth of TT cells, induced apoptosis and caused vacuolization, as well as needle-like filopodia. Fibroblasts were affected by prazosin in the same way as MTC cells. Conclusion MTC cells are responsive to prazosin treatment similar to other malignancies. The fact that fibroblasts also respond to prazosin further highlights the importance to identify the unknown pro-apoptotic target of quinazolines. PMID:25550532

  17. Hypertension exacerbates liver injury and hepatic fibrosis induced by a choline-deficient L-amino acid-defined diet in rats.

    PubMed

    Arima, Shiho; Uto, Hirofumi; Ibusuki, Rie; Kumamoto, Ryo; Tanoue, Shirou; Mawatari, Seiichi; Oda, Kohei; Numata, Masatsugu; Fujita, Hiroshi; Oketani, Makoto; Ido, Akio; Tsubouchi, Hirohito

    2014-01-01

    The effect of hypertension on non-alcoholic fatty liver disease (NAFLD) remains unclear at the molecular level. In this study, we investigated the effects of hypertension on the degree of hepatic steatosis, liver injury and hepatic fibrosis induced by a choline-deficient L-amino acid-defined (CDAA) diet in spontaneously hypertensive rats (SHRs). Seven-week-old male SHRs were fed standard chow with high or normal salt concentrations for 7 weeks, followed by a CDAA diet containing high or normal salt for an additional 8 or 24 weeks. Hepatic steatosis was assessed using hepatic triglyceride levels and Oil red O staining. Hepatic fibrosis was evaluated using Sirius red and Azan staining. Systolic blood pressure (SBP) gradually increased with a high-salt diet and was significantly higher after 7 weeks of feeding with high-salt vs. normal-salt chow. After 8 weeks on the CDAA diet, the degree of hepatic steatosis did not differ between the high-salt and normal-salt groups; however, alanine aminotransferase and fasting blood glucose levels were significantly higher and hepatic mRNA levels for interleukin (IL)-10 and heme oxygenase (HO)-1 were significantly lower in the high-salt group compared with the normal-salt group. After 24 weeks on the CDAA diet, the high-salt group had significantly more severe hepatic fibrosis and a higher hepatic mRNA expression of ?-smooth muscle actin and lower hepatic IL-10 and HO-1 mRNA levels compared with the normal-salt group. In conclusion, our results indicate that hypertension is a potential risk factor for liver injury and hepatic fibrosis through glucose intolerance and decreased IL-10-mediated or HO-1-induced anti-inflammatory mechanisms. PMID:24190226

  18. Tranexamic Acid Diminishes Laser-Induced Melanogenesis

    PubMed Central

    Kim, Myoung Shin; Bang, Seung Hyun; Kim, Jeong-Hwan; Shin, Hong-Ju; Choi, Jee-Ho

    2015-01-01

    Background The treatment of post-inflammatory hyperpigmentation (PIH) remains challenging. Tranexamic acid, a well-known anti-fibrinolytic drug, has recently demonstrated a curative effect towards melasma and ultraviolet-induced PIH in Asian countries. However, the precise mechanism of its inhibitory effect on melanogenesis is not fully understood. Objective In order to clarify the inhibitory effect of tranexamic acid on PIH, we investigated its effects on mouse melanocytes (i.e., melan-a cells) and human melanocytes. Methods Melan-a cells and human melanocytes were cultured with fractional CO2 laser-treated keratinocyte-conditioned media. Melanin content and tyrosinase activity were evaluated in cells treated with or without tranexamic acid. Protein levels of tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2 were evaluated in melan-a cells. Signaling pathway molecules involved in melanogenesis in melanoma cells were also investigated. Results Tranexamic acid-treated melanocytes exhibited reduced melanin content and tyrosinase activity. Tranexamic acid also decreased tyrosinase, TRP-1, and TRP-2 protein levels. This inhibitory effect on melanogenesis was considered to be involved in extracellular signal-regulated kinase signaling pathways and subsequently microphthalmia-associated transcription factor degradation. Conclusion Tranexamic acid may be an attractive candidate for the treatment of PIH. PMID:26082580

  19. Exercise training-induced remodeling of paraventricular nucleus (nor)adrenergic innervation in normotensive and hypertensive rats.

    PubMed

    Higa-Taniguchi, Keila T; Silva, Fabiana C P; Silva, Helaine M V; Michelini, Lisete C; Stern, Javier E

    2007-04-01

    Activation of oxytocin (OT)ergic projections from the hypothalamic paraventricular nucleus (PVN) to the nucleus tractus solitarii contributes to cardiovascular adjustments during exercise training (EXT). Moreover, a deficit in this central OTergic pathway is associated with altered cardiovascular function in hypertension. Since PVN catecholaminergic inputs, known to be activated during EXT, modulate PVN cardiovascular-related functions, we aimed here to determine whether remodeling of PVN (nor)adrenergic innervation occurs during EXT and whether this phenomenon is affected by hypertension. Confocal immunofluorescence microscopy and tract tracing were used to quantify changes in (nor)adrenergic innervation density in PVN subnuclei and in identified dorsal vagal complex (DVC) projecting neurons (PVN-DVC) in EXT normotensive [Wistar-Kyoto rat (WKY)] and hypertensive [spontaneously hypertensive rat (SHR)] rats. In WKY, EXT increased the density of PVN dopamine beta-hydroxylase immunoreactivity (DBHir) (160%). Furthermore, the number and density of DBHir boutons overlapping PVN-DVC OTergic neurons were also increased during EXT (130%), effects that were blunted in SHR. Conversely, while DBHir in the medial parvocellular subnucleus (an area enriched in corticotropin-releasing hormone neurons) was not changed by EXT in WKY, a diminished DBHir was observed in trained SHR. Overall, these data support the concept that the PVN (nor)adrenergic innervation undergoes plastic remodeling during EXT, an effect that is differentially affected during hypertension. The functional implications of PVN (nor)adrenergic remodeling in relation to the central peptidergic control of cardiovascular function during EXT are discussed. PMID:17218443

  20. Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression

    PubMed Central

    Trudu, Matteo; Janas, Sylvie; Lanzani, Chiara; Debaix, Huguette; Schaeffer, Céline; Ikehata, Masami; Citterio, Lorena; Demaretz, Sylvie; Trevisani, Francesco; Ristagno, Giuseppe; Glaudemans, Bob; Laghmani, Kamel; Dell’Antonio, Giacomo; Loffing, Johannes; Rastaldi, Maria P.; Manunta, Paolo

    2013-01-01

    Elevated blood pressure (BP) and chronic kidney disease (CKD) are complex traits representing major global health problems1,2. Multiple genome-wide association studies (GWAS) identified common variants giving independent susceptibility for CKD and hypertension in the promoter of the UMOD gene3-9, encoding uromodulin, the major protein secreted in the normal urine. Despite compelling genetic evidence, the underlying biological mechanism is not understood. Here, we demonstrate that UMOD risk variants directly increase UMOD expression in vitro and in vivo. We modeled this effect in transgenic mice and showed that uromodulin overexpression leads to salt-sensitive hypertension and to age-dependent renal lesions that are similarly observed in elderly subjects homozygous for UMOD risk variants. We demonstrate that the link between uromodulin and hypertension is caused by activation of the renal sodium co-transporter NKCC2. This very mechanism is relevant in humans, as pharmacological inhibition of NKCC2 is more effective in lowering BP in hypertensive patients homozygous for UMOD risk variants. Our findings establish a link between the genetic susceptibility to hypertension and CKD, the control of uromodulin expression and its role in a salt-reabsorbing tubular segment of the kidney. These data point to uromodulin as a novel therapeutic target to lower BP and preserve renal function. PMID:24185693

  1. Pulmonary Hypertension

    MedlinePLUS

    Pulmonary hypertension (PH) is high blood pressure in the arteries to your lungs. It is a serious condition. If you have ... and you can develop heart failure. Symptoms of PH include Shortness of breath during routine activity, such ...

  2. Hypertension screening

    NASA Technical Reports Server (NTRS)

    Foulke, J. M.

    1975-01-01

    An attempt was made to measure the response to an announcement of hypertension screening at the Goddard Space Center, to compare the results to those of previous statistics. Education and patient awareness of the problem were stressed.

  3. Renovascular hypertension

    MedlinePLUS

    ... hypertension: Therapy. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald's Heart Disease: A Textbook ... and diagnosis. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald's Heart Disease: A Textbook ...

  4. [Hypertensive retinopathy].

    PubMed

    Genevois, Olivier; Paques, Michel

    2010-01-20

    Acute hypertensive retinopathy should be distinguished from retinal arteriolosclerosis. The presence of microvascular abnormalities in the ocular fundus increases the risk of heart and/or brain attack. At the clinical level, the current classification of chronic hypertensive retinopathy is based on the long-term risk of stroke. In research, a great number of studies are focused on the predictive value of retinal vascular diameters related to the general micro- and macrovascular disease. PMID:20222306

  5. Persistent perioperative tachycardia and hypertension diagnosed as thyroid storm induced by a hydatidiform mole: a case report.

    PubMed

    Hwang, Wonjung; Im, Daehwan; Kim, Eunsung

    2014-09-01

    Thyroid storm is a critical complication of molar pregnancy. However, early diagnosis of it is difficult because it is a rare complication and usually presents nonspecific findings. In this case report, we present a woman with molar pregnancy who had persistent tachycardia and hypertension. She was diagnosed initially with preeclampsia and sepsis as complications of molar pregnancy. During dilation and curettage under general anesthesia with sevoflurane and remifentanil, tachycardia and hypertension remained even with continuous infusion of labetalol. The patient was subsequently diagnosed with thyroid storm associated with molar pregnancy. She was restored to a clinically euthyroid state 1 day after the operation, and her thyroid function test and ?-hCG values were normal 3 months later. The anesthesiologists should bear in mind the possibility of thyroid storm in patients with molar pregnancies who show persistent tachycardia and hypertension. PMID:25302097

  6. Prenatal inflammation-induced NF-?B dyshomeostasis contributes to renin-angiotensin system over-activity resulting in prenatally programmed hypertension in offspring.

    PubMed

    Deng, Youcai; Deng, Yafei; He, Xiaoyan; Chu, Jianhong; Zhou, Jianzhi; Zhang, Qi; Guo, Wei; Huang, Pei; Guan, Xiao; Tang, Yuan; Wei, Yanling; Zhao, Shanyu; Zhang, Xingxing; Wei, Chiming; Namaka, Michael; Yi, Ping; Yu, Jianhua; Li, Xiaohui

    2016-01-01

    Studies involving the use of prenatally programmed hypertension have been shown to potentially contribute to prevention of essential hypertension (EH). Our previous research has demonstrated that prenatal inflammatory stimulation leads to offspring's aortic dysfunction and hypertension in pregnant Sprague-Dawley rats challenged with lipopolysaccharide (LPS). The present study found that prenatal LPS exposure led to NF-?B dyshomeostasis from fetus to adult, which was characterized by PI3K-Akt activation mediated degradation of I?B? protein and impaired NF-?B self-negative feedback loop mediated less newly synthesis of I?B? mRNA in thoracic aortas (gestational day 20, postnatal week 7 and 16). Prenatal or postnatal exposure of the I?B? degradation inhibitor, pyrollidine dithiocarbamate, effectively blocked NF-?B activation, endothelium dysfunction, and renin-angiotensin system (RAS) over-activity in thoracic aortas, resulting in reduced blood pressure in offspring that received prenatal exposure to LPS. Surprisingly, NF-?B dyshomeostasis and RAS over-activity were only found in thoracic aortas but not in superior mesenteric arteries. Collectively, our data demonstrate that the early life NF-?B dyshomeostasis induced by prenatal inflammatory exposure plays an essential role in the development of EH through triggering RAS over-activity. We conclude that early life NF-?B dyshomeostasis is a key predictor of EH, and thus, NF-?B inhibition represents an effective interventional strategy for EH prevention. PMID:26877256

  7. Prenatal inflammation-induced NF-κB dyshomeostasis contributes to renin-angiotensin system over-activity resulting in prenatally programmed hypertension in offspring

    PubMed Central

    Deng, Youcai; Deng, Yafei; He, Xiaoyan; Chu, Jianhong; Zhou, Jianzhi; Zhang, Qi; Guo, Wei; Huang, Pei; Guan, Xiao; Tang, Yuan; Wei, Yanling; Zhao, Shanyu; Zhang, Xingxing; Wei, Chiming; Namaka, Michael; Yi, Ping; Yu, Jianhua; Li, Xiaohui

    2016-01-01

    Studies involving the use of prenatally programmed hypertension have been shown to potentially contribute to prevention of essential hypertension (EH). Our previous research has demonstrated that prenatal inflammatory stimulation leads to offspring’s aortic dysfunction and hypertension in pregnant Sprague-Dawley rats challenged with lipopolysaccharide (LPS). The present study found that prenatal LPS exposure led to NF-κB dyshomeostasis from fetus to adult, which was characterized by PI3K-Akt activation mediated degradation of IκBα protein and impaired NF-κB self-negative feedback loop mediated less newly synthesis of IκBα mRNA in thoracic aortas (gestational day 20, postnatal week 7 and 16). Prenatal or postnatal exposure of the IκBα degradation inhibitor, pyrollidine dithiocarbamate, effectively blocked NF-κB activation, endothelium dysfunction, and renin-angiotensin system (RAS) over-activity in thoracic aortas, resulting in reduced blood pressure in offspring that received prenatal exposure to LPS. Surprisingly, NF-κB dyshomeostasis and RAS over-activity were only found in thoracic aortas but not in superior mesenteric arteries. Collectively, our data demonstrate that the early life NF-κB dyshomeostasis induced by prenatal inflammatory exposure plays an essential role in the development of EH through triggering RAS over-activity. We conclude that early life NF-κB dyshomeostasis is a key predictor of EH, and thus, NF-κB inhibition represents an effective interventional strategy for EH prevention. PMID:26877256

  8. Endocrine causes of hypertension.

    PubMed

    Gomez-Sanchez, C E; Gomez-Sanchez, E P; Yamakita, N

    1995-03-01

    Hypertension is a prominent feature of various endocrine diseases including primary aldosteronism, pheochromocytoma (considered separately in this issue), Cushing's syndrome, adrenal enzymatic deficiencies like 11 beta-hydroxylase, 17 alpha-hydroxylase deficiencies, and congenital or acquired 11 beta-hydroxysteroid dehydrogenase deficiencies. Patients with 11 beta-hydroxylase deficiency cannot convert 11-deoxycortisol or deoxycorticosterone into the active glucocorticoids cortisol and corticosterone, respectively. The increase in the powerful mineralocorticoid deoxycorticosterone, resulting from the enzymatic block, promotes sodium retention, hypertension, and hypokalemia. Females who have the deficiency also show signs of virilization due to the shunting of the precursors to the synthesis of adrenal androgens. Patients with 17 alpha-hydroxylase deficiency present with hypertension and/or hypokalemia, and male members exhibit pseudohermaphroditism with no development of male sexual characteristics. The defect is due to the lack of 17-hydroxylated steroids, which are necessary precursors in the synthesis of androgens and estrogens. The hypertension is due to the accumulation of the mineralocorticoid deoxycorticosterone. The mineralocorticoid receptor derives its specificity from the co-expression of the 11 beta-hydroxysteroid dehydrogenase, which converts the active steroids corticosterone and cortisol to the inactive 11-dehydrocorticosterone and cortisone, preventing their interaction with the receptor. Congenital absence of the 11 beta-hydroxysteroid dehydrogenase or acquired deficiency induced by consuming licorice or its derivatives result in occupancy of the mineralocorticoid receptor by cortisol and corticosterone, and production of mineralocorticoid-type hypertension. PMID:7777721

  9. Sleep and Hypertension

    PubMed Central

    Harding, Susan M.

    2010-01-01

    Ambulatory BP studies indicate that even small increases in BP, particularly nighttime BP levels, are associated with significant increases in cardiovascular morbidity and mortality. Accordingly, sleep-related diseases that induce increases in BP would be anticipated to substantially affect cardiovascular risk. Both sleep deprivation and insomnia have been linked to increases in incidence and prevalence of hypertension. Likewise, sleep disruption attributable to restless legs syndrome increases the likelihood of having hypertension. Observational studies demonstrate a strong correlation between the severity of obstructive sleep apnea (OSA) and the risk and severity of hypertension, whereas prospective studies of patients with OSA demonstrate a positive relationship between OSA and risk of incident hypertension. Intervention trials with continuous positive airway pressure (CPAP) indicate a modest, but inconsistent effect on BP in patients with severe OSA and a greater likelihood of benefit in patients with most CPAP adherence. Additional prospective studies are needed to reconcile observational studies suggesting that OSA is a strong risk factor for hypertension with the modest antihypertensive effects of CPAP observed in intervention studies. PMID:20682533

  10. Over-Expression of Copper/Zinc Superoxide Dismutase in the Median Preoptic Nucleus Attenuates Chronic Angiotensin II-Induced Hypertension in the Rat

    PubMed Central

    Collister, John P.; Bellrichard, Mitch; Drebes, Donna; Nahey, David; Tian, Jun; Zimmerman, Matthew C.

    2014-01-01

    The brain senses circulating levels of angiotensin II (AngII) via circumventricular organs, such as the subfornical organ (SFO), and is thought to adjust sympathetic nervous system output accordingly via this neuro-hormonal communication. However, the cellular signaling mechanisms involved in these communications remain to be fully understood. Previous lesion studies of either the SFO, or the downstream median preoptic nucleus (MnPO) have shown a diminution of the hypertensive effects of chronic AngII, without providing a clear explanation as to the intracellular signaling pathway(s) involved. Additional studies have reported that over-expressing copper/zinc superoxide dismutase (CuZnSOD), an intracellular superoxide (O2·−) scavenging enzyme, in the SFO attenuates chronic AngII-induced hypertension. Herein, we tested the hypothesis that overproduction of O2·− in the MnPO is an underlying mechanism in the long-term hypertensive effects of chronic AngII. Adenoviral vectors encoding human CuZnSOD (AdCuZnSOD) or control vector (AdEmpty) were injected directly into the MnPO of rats implanted with aortic telemetric transmitters for recording of arterial pressure. After a 3 day control period of saline infusion, rats were intravenously infused with AngII (10 ng/kg/min) for ten days. Rats over-expressing CuZnSOD (n = 7) in the MnPO had a blood pressure increase of only 6 ± 2 mmHg after ten days of AngII infusion while blood pressure increased 21 ± 4 mmHg in AdEmpty-infected rats (n = 9). These results support the hypothesis that production of O2·− in the MnPO contributes to the development of chronic AngII-dependent hypertension. PMID:25474089

  11. Novel mechanism of intra?renal angiotensin II-induced sodium/proton exchanger 3 expression by losartan in spontaneously hypertensive rats.

    PubMed

    Fan, Xiaoqin; Liu, Kaishan; Cui, Wei; Huang, Jiongmei; Wang, Weina; Gao, Yuan

    2014-11-01

    The present study aimed to investigate the molecular pharmacodynamic mechanisms of losartan used in the treatment of hypertension. A total of 12 spontaneously hypertensive rats (SHR) were divided randomly into an SHR group treated with saline and LOS group treated with losartan. Six Wistar?kyoto rats (WKY) were enrolled as the WKY group with saline in the study. The LOS group received 30mg/kg/day losartan by intragastric injection, while the SHR and WKY were fed the same volume of saline. The dosage was modulated according to the weekly weight. Changes in blood pressure were measured by the indirect tail cuff method. Angiotensin (Ang) II production in the plasma and renal tissue was measured by an immunoradiometric method. Na+/H+ exchanger (NHE)3 and serum and glucocorticoid?inducible kinase (SGK)1 were assessed by quantitative polymerase chain reaction (qPCR) and western blot analysis. When compared with the WKY group, the blood pressure of the SHR and LOS groups were higher prior to treatment with losartan. Following two weeks, blood pressure was reduced and the trend continued to decrease over the following six weeks. The plasma and renal tissue levels of Ang II in the SHR and LOS groups were significantly higher than those in the WKY group. NHE3 and SGK1 were increased at the mRNA and protein level in the SHR group, and losartan reduced the expression of both of them. The results suggested that in hypertensive rats, the circular and tissue renin angiotensin systems were activated, and the increased Ang II stimulated the expression of NHE3 and SGK1, which was reduced by losartan. Therefore, the effects of losartan in hypertension may be associated with the AngII?SGK1?NHE3 of intra?renal tissue. PMID:25119059

  12. Increased neuronal activity in the OVLT of Cyp1a1-Ren2 transgenic rats with inducible Ang II-dependent malignant hypertension.

    PubMed

    Issa, Alexandra T; Miyata, Kayoko; Heng, Vibol; Mitchell, Kenneth D; Derbenev, Andrei V

    2012-06-21

    The contribution of angiotensin II (Ang II) to the pathophysiology of hypertension is established based on facts that high levels of circulating Ang II increase vasoconstriction of peripheral arteries causing a rise in blood pressure (BP). In addition, circulating Ang II has various effects on the central nervous system, including the osmosensitive neurons in the organum vasculosum of the lamina terminalis (OVLT). Osmosensitive neurons in the OVLT transduce hypertonicity via the activation of the nonselective cation channel known as transient receptor potential vanilloid 1 (TRPV1), causing membrane depolarization, followed by increased action potential discharge. This effect is absent in mice lacking expression of the TRPV1 gene. Most observations related to the importance of the OVLT in cardiovascular control are mainly based on models of lesion of the entire preoptic periventricular tissue. However, it remains unclear whether neuronal activity and TRPV1 protein expression levels alter in the OVLT of Cyp1a1-Ren2 transgenic rats with inducible Ang II-dependent malignant hypertension. C-fos was used as a marker of neuronal activity. Immunostaining was used to demonstrate distribution of c-fos positive neurons in the OVLT of Cyp1a1Ren2 transgenic rats. Western blot analysis showed increased c-fos and TRPV1 total protein expression levels in the OVLT of hypertensive rats. The present findings demonstrate increased c-fos and TRPV1 expression levels in the OVLT of Cyp1a1-Ren2 transgenic rats with Ang II-dependent malignant hypertension. PMID:22579820

  13. Over-expression of copper/zinc superoxide dismutase in the median preoptic nucleus attenuates chronic angiotensin II-induced hypertension in the rat.

    PubMed

    Collister, John P; Bellrichard, Mitch; Drebes, Donna; Nahey, David; Tian, Jun; Zimmerman, Matthew C

    2014-01-01

    The brain senses circulating levels of angiotensin II (AngII) via circumventricular organs, such as the subfornical organ (SFO), and is thought to adjust sympathetic nervous system output accordingly via this neuro-hormonal communication. However, the cellular signaling mechanisms involved in these communications remain to be fully understood. Previous lesion studies of either the SFO, or the downstream median preoptic nucleus (MnPO) have shown a diminution of the hypertensive effects of chronic AngII, without providing a clear explanation as to the intracellular signaling pathway(s) involved. Additional studies have reported that over-expressing copper/zinc superoxide dismutase (CuZnSOD), an intracellular superoxide (O2·-) scavenging enzyme, in the SFO attenuates chronic AngII-induced hypertension. Herein, we tested the hypothesis that overproduction of O2·- in the MnPO is an underlying mechanism in the long-term hypertensive effects of chronic AngII. Adenoviral vectors encoding human CuZnSOD (AdCuZnSOD) or control vector (AdEmpty) were injected directly into the MnPO of rats implanted with aortic telemetric transmitters for recording of arterial pressure. After a 3 day control period of saline infusion, rats were intravenously infused with AngII (10 ng/kg/min) for ten days. Rats over-expressing CuZnSOD (n = 7) in the MnPO had a blood pressure increase of only 6 ± 2 mmHg after ten days of AngII infusion while blood pressure increased 21 ± 4 mmHg in AdEmpty-infected rats (n = 9). These results support the hypothesis that production of O2·- in the MnPO contributes to the development of chronic AngII-dependent hypertension. PMID:25474089

  14. An inhibitory effect of tumor necrosis factor-alpha antagonist to gene expression in monocrotaline-induced pulmonary hypertensive rats model

    PubMed Central

    Kwon, Jung Hyun; Kim, Kwan Chang; Cho, Min-Sun; Kim, Hae Soon; Sohn, Sejung

    2013-01-01

    Purpose Tumor necrosis factor (TNF)-? is thought to contribute to pulmonary hypertension. We aimed to investigate the effect of infliximab (TNF-? antagonist) treatment on pathologic findings and gene expression in a monocrotaline-induced pulmonary hypertension rat model. Methods Six-week-old male Sprague-Dawley rats were allocated to 3 groups: control (C), single subcutaneous injection of normal saline (0.1 mL/kg); monocrotaline (M), single subcutaneous injection of monocrotaline (60 mg/kg); and monocrotaline + infliximab (M+I), single subcutaneous injection of monocrotaline plus single subcutaneous injection of infliximab (5 mg/kg). The rats were sacrificed after 1, 5, 7, 14, or 28 days. We examined changes in pathology and gene expression levels of TNF-?, endothelin-1 (ET-1), endothelin receptor A (ERA), endothelial nitric oxide synthase (eNOS), matrix metalloproteinase (MMP)2, and tissue inhibitor of matrix metalloproteinase (TIMP). Results The increase in medial wall thickness of the pulmonary arteriole in the M+I group was significantly lower than that in the M group on day 7 after infliximab treatment (P<0.05). The number of intra-acinar muscular arteries in the M+I group was lower than that in the M group on days 14 and 28 (P<0.05). Expression levels of TNF-?, ET-1, ERA, and MMP2 were significantly lower in the M+I group than in the M group on day 5, whereas eNOS and TIMP expressions were late in the M group (day 28). Conclusion Infliximab administration induced early changes in pathological findings and expression levels of TNF-?, and MMP2 in a monocrotaline-induced pulmonary hypertension rat model. PMID:23559973

  15. Flax lignan concentrate reverses alterations in blood pressure, left ventricular functions, lipid profile and antioxidant status in DOCA-salt induced renal hypertension in rats.

    PubMed

    Sawant, Sameer H; Bodhankar, Subhash L

    2016-04-01

    Context Earlier we reported cardioprotective, antihyperlipidemic, and in vitro antioxidant activity of flax lignan concentrate (FLC) obtained from the seeds of Linum usitatissimum L. (Linaceae). Objective To investigate the effect of FLC in deoxycorticosterone acetate (DOCA)-salt induced experimental renal hypertension in rats. Materials and methods Hypertension was induced in uninephrectomized (UNTZD) male Wistar rats (230-280 g) by injecting DOCA (25 mg/kg, subcutaneously, twice weekly) and supplementing 1% NaCl in drinking water for 5 weeks. The rats were divided in six groups. Captopril (30 mg/kg, p.o.) and FLC (200, 400 and 800 mg/kg, p.o.) were administered daily to the rats of groups III-VI, respectively, for 5 weeks. Various hemodynamic and biochemical parameters were investigated as well as histology of kidney and heart were carried out. Results In this study, the FLC (400 and 800 mg/kg) significantly (p < 0.01, p < 0.001) decreased the systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure. It also significantly (p < 0.01, p < 0.001) decreased elevated end diastolic pressure (EDP), dP/dt max and dP/dt min, organs weights (kidney and heart) and activities of hepatic, renal and cardiac marker enzymes in the serum. Furthermore, FLC (400 and 800 mg/kg) significantly (p < 0.01, p < 0.001) restored altered antioxidant status, serum electrolyte level, lipid profile values, and histological abnormalities. Captopril (30 mg/kg) showed maximum antihypertensive effect but low dose of FLC (200 mg/kg) was not enough to show the antihypertensive activity. Conclusion FLC possessed antihypertensive effect via modulation of endogenous enzymes in DOCA-salt induced renal hypertension in rats. PMID:26795298

  16. The effect of hydroalcoholic extract from the leaves of Moringa peregrina (Forssk.) Fiori. on blood pressure and oxidative status in dexamethasone-induced hypertensive rats

    PubMed Central

    Safaeian, Leila; Asghari, Gholamreza; Javanmard, Shaghayegh Haghjoo; Heidarinejad, Arman

    2015-01-01

    Background: Moringa peregrina (Forssk.) Fiori. is a tropical tree growing in southeast of Iran. All parts of this plant have nutritional uses and pharmacological activities. The present study was designed to evaluate the effect of hydroalcoholic extract from the leaves of M. peregrina in dexamethasone (Dex)-induced hypertension in rats. Materials and Methods: Male Wistar rats received Dex (30 μg/kg, subcutaneously; s.c.) or saline (as vehicle, 1 ml/kg, s.c.) for 14 days. In a prevention study, the rats received M. peregrina extract (100, 200 and 400 mg/kg, orally) for 4 days, followed by Dex for 14 days. In a reversal study, the animals received M. peregrina extract orally from day 8 to 14. The systolic blood pressure (SBP) was measured using tail-cuff method. The hydrogen peroxide (H2O2) concentration and ferric reducing antioxidant power (FRAP) were assessed in plasma samples. Results: Dex significantly increased the SBP and the plasma H2O2 and decreased the plasma FRAP value (P < 0.001). M. peregrina extract at a dose of 400 mg/kg prevented (P < 0.01) but did not reverse Dex-induced hypertension in rats. It also dose-dependently reduced the plasma H2O2 concentration and improved the FRAP value upon Dex administration. Conclusions: The findings of the present study indicated the antioxidant and partially antihypertensive effects of the hydroalcoholic extract from the leaves of M. peregrina in Dex-induced hypertension. Further experiments on other fractions of the leaves and also other parts of this plant are suggested for better evaluation of its antihypertensive effect and finding its mechanisms of action. PMID:26015927

  17. Gene expression of cyclin-dependent kinase inhibitors and effect of heparin on their expression in mice with hypoxia-induced pulmonary hypertension

    SciTech Connect

    Yu Lunyin; Quinn, Deborah A.; Garg, Hari G.; Hales, Charles A. . E-mail: chales@partners.org

    2006-07-14

    The balance between cell proliferation and cell quiescence is regulated delicately by a variety of mediators, in which cyclin-dependent kinases (CDK) and CDK inhibitors (CDKI) play a very important role. Heparin which inhibits pulmonary artery smooth muscle cell (PASMC) proliferation increases the levels of two CDKIs, p21 and p27, although only p27 is important in inhibition of PASMC growth in vitro and in vivo. In the present study we investigated the expression profile of all the cell cycle regulating genes, including all seven CDKIs (p21, p27, p57, p15, p16, p18, and p19), in the lungs of mice with hypoxia-induced pulmonary hypertension. A cell cycle pathway specific gene microarray was used to profile the 96 genes involved in cell cycle regulation. We also observed the effect of heparin on gene expression. We found that (a) hypoxic exposure for two weeks significantly inhibited p27 expression and stimulated p18 activity, showing a 98% decrease in p27 and 81% increase in p18; (b) other CDKIs, p21, p57, p15, p16, and p19 were not affected significantly in response to hypoxia; (c) heparin treatment restored p27 expression, but did not influence p18; (d) ERK1/2 and p38 were mediators in heparin upregulation of p27. This study provides an expression profile of cell cycle regulating genes under hypoxia in mice with hypoxia-induced pulmonary hypertension and strengthens the previous finding that p27 is the only CDKI involved in heparin regulation of PASMC proliferation and hypoxia-induced pulmonary hypertension.

  18. Attenuation of Monocrotaline-Induced Pulmonary Hypertension by Luminal Adeno-Associated Virus Serotype 9 Gene Transfer of Prostacyclin Synthase

    PubMed Central

    Gubrij, Igor B.; Martin, Sara Rebecca; Pangle, Amanda K.; Kurten, Richard

    2014-01-01

    Abstract Idiopathic pulmonary arterial hypertension (iPAH) is associated with high morbidity and mortality. We evaluated whether luminal delivery of the human prostacyclin synthase (hPGIS) cDNA with adeno-associated virus (AAV) vectors could attenuate PAH. AAV serotype 5 (AAV5) and AAV9 vectors containing the hPGIS cDNA under the control of a cytomegalovirus-enhanced chicken β-actin (CB) promoter or vehicle (saline) were instilled into lungs of rats. Two days later, rats were injected with monocrotaline (MCT, 60 mg/kg) or saline. Biochemical, hemodynamic, and morphologic assessments were performed when the rats developed symptoms (3–4 weeks) or at 6 weeks. Luminal (airway) administration of AAV5 and AAV9CBhPGIS vectors (MCT-AAV5 and MCT-AAV9 rats) significantly increased plasma levels of 6-keto-PGF1α as compared with MCT-controls, and closely resembled levels measured in rats not treated with MCT (saline–saline). Right ventricular (RV)/left ventricular (LV)+septum (S) ratios and RV systolic pressure (RVSP) were greater in MCT-control rats than in saline–saline rats, whereas the ratios and RVSP in MCT-AAV5CBhPGIS and MCT-AAV9CBhPGIS rats were similar to saline–saline rats. Thickening of the muscular media of small pulmonary arteries of MCT-control rats was detected in histological sections, whereas the thickness of the muscular media in MCT-AAV5CBhPGIS and MCT-AAV9CBhPGIS rats was similar to saline–saline controls. In experiments with different promoters, a trend toward increased levels of PGF1α expression was detected in lung homogenates, but not plasma, of MCT-treated rats transduced with an AAV9-hPGIS vector containing a CB promoter. This correlated with significant reductions in the RV/LV+S ratio and RVSP in MCT-AAV9CBhPGIS rats that resembled levels in saline–saline rats. No changes in levels of PGF1α, RV/LV+S, or RVSP were detected in rats transduced with AAV9-hPGIS vectors containing a modified CB promoter (CB7) or a distal epithelial cell-specific promoter (CC10). Thus, AAV9CBhPGIS vectors prevented development of MCT-induced PAH and associated pulmonary vascular remodeling. PMID:24512101

  19. Ursodeoxycholic acid limits liver histologic alterations and portal hypertension induced by bile duct ligation in the rat.

    PubMed

    Poo, J L; Feldmann, G; Erlinger, S; Braillon, A; Gaudin, C; Dumont, M; Lebrec, D

    1992-05-01

    Chronic administration of ursodeoxycholic acid (UDCA) has recently been suggested as a potential treatment for cholestatic liver disease. The purpose of this study was to examine the effects of chronic oral administration of UDCA on the histological, biochemical, and hemodynamic abnormalities induced by bile duct ligation in the rat. Fifty-one rats with ligation-section of the common bile duct were randomly and blindly assigned to receive UDCA (25 mg/kg each day) or placebo by gavage for 4 weeks. At the end of the treatment period, morphometric analysis showed that in rats treated with UDCA, hepatocyte and sinusoidal volume fractions were significantly higher than in rats receiving placebo [41.9 +/- 3.2% vs. 28.1 +/- 1.8%, (mean +/- SE) and 7.4 +/- 0.1% vs. 4.3 +/- 0.3%, respectively], whereas bile duct volume fraction (reflecting bile ductular proliferation) and connective tissue fraction were significantly lower in rats treated with UDCA than in rats receiving placebo (14.2 +/- 1.5% vs. 20.0 +/- 1.0% and 35.4 +/- 2.4% vs. 47.6 +/- 1.7%, respectively). Serum aminotransferase and alkaline phosphatase activities, and total serum bile acids and individual bile acid concentrations were not significantly different between the two groups. Portal pressure (12.7 +/- 0.5 mm Hg vs. 17.1 +/- 0.5 mm Hg), portal tributary blood flow (5.7 +/- 0.4 vs. 9.3 +/- 0.4 mL.min-1.100 g-1 body weight), and cardiac index (41.1 +/- 1.8 vs. 50.6 +/- 1.4 mL.min-1.100 g-1 body weight) were significantly lower in UDCA-treated rats than in placebo-treated animals. In portal vein stenosed rats, chronic administration of UDCA had no hemodynamic effects, a finding that suggests UDCA has no direct vasoactive effect on splanchnic circulation. It is concluded that in rats with bile duct ligation UDCA limits the severity of liver disease and consequently of portal hypertension and hyperkinetic circulation. PMID:1568585

  20. Beneficial effects of a novel agonist of the adenosine A2A receptor on monocrotaline-induced pulmonary hypertension in rats

    PubMed Central

    Alencar, Allan K N; Pereira, Sharlene L; Montagnoli, Tadeu L; Maia, Rodolfo C; Kmmerle, Arthur E; Landgraf, Sharon S; Caruso-Neves, Celso; Ferraz, Emanuelle B; Tesch, Roberta; Nascimento, Jos H M; de Sant'Anna, Carlos M R; Fraga, Carlos A M; Barreiro, Eliezer J; Sudo, Roberto T; Zapata-Sudo, Gisele

    2013-01-01

    Background and Purpose Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance, right ventricular hypertrophy and increased right ventricular systolic pressure. Here, we investigated the effects of a N-acylhydrazone derivative, 3,4-dimethoxyphenyl-N-methyl-benzoylhydrazide (LASSBio-1359), on monocrotaline (MCT)-induced pulmonary hypertension in rats. Experimental Approach PAH was induced in male Wistar rats by a single i.p. injection of MCT (60 mgkg?1) and 2 weeks later, oral LASSBio-1359 (50 mgkg?1) or vehicle was given once daily for 14 days. Echocardiography was used to measure cardiac function and pulmonary artery dimensions, with histological assay of vascular collagen. Studies of binding to human recombinant adenosine receptors (A1, A2A, A3) and of docking with A2A receptors were also performed. Key Results MCT administration induced changes in vascular and ventricular structure and function, characteristic of PAH. These changes were reversed by treatment with LASSBio-1359. MCT also induced endothelial dysfunction in pulmonary artery, as measured by diminished relaxation of pre-contracted arterial rings, and this dysfunction was reversed by LASSBio-1359. In pulmonary artery rings from normal Wistar rats, LASSBio-1359 induced relaxation, which was decreased by the adenosine A2A receptor antagonist, ZM 241385. In adenosine receptor binding studies, LASSBio-1359 showed most affinity for the A2A receptor and in the docking analyses, binding modes of LASSBio-1359 and the A2A receptor agonist, CGS21680, were very similar. Conclusion and Implications In rats with MCT-induced PAH, structural and functional changes in heart and pulmonary artery were reversed by treatment with oral LASSBio-1359, most probably through the activation of adenosine A2A receptors. PMID:23530610

  1. Diagnosing hypertension

    PubMed Central

    Gelfer, Mark; Dawes, Martin; Kaczorowski, Janusz; Padwal, Raj; Cloutier, Lyne

    2015-01-01

    Abstract Objective To highlight the 2015 Canadian Hypertension Education Program (CHEP) recommendations for the diagnosis and assessment of hypertension. Quality of evidence A systematic search was performed current to August 2014 by a Cochrane Collaboration librarian using the MEDLINE and PubMed databases. The search results were critically appraised by the CHEP subcommittee on blood pressure (BP) measurement and diagnosis, and evidence-based recommendations were presented to the CHEP Central Review Committee for independent review and grading. Finally, the findings and recommendations were presented to the Recommendations Task Force for discussion, debate, approval, and voting. The main recommendations are based on level II evidence. Main message Based on the most recent evidence, CHEP has made 4 recommendations in 2 broad categories for 2015 to improve BP measurement and the way hypertension is diagnosed. A strong recommendation is made to use electronic BP measurement in the office setting to replace auscultatory BP measurement. For patients with elevated office readings, CHEP is recommending early use of out-of-office BP measurement, preferably ambulatory BP measurement, in order to identify early in the process those patients with white-coat hypertension. Conclusion Improvements in diagnostic accuracy are critical to optimizing hypertension management in Canada. The annual updates provided by CHEP ensure that practitioners have up-to-date evidence-based information to inform practice. PMID:26564654

  2. Angiotensin II-induced Hypertension Differentially Affects Estrogen and Progestin Receptors in Central Autonomic Regulatory Areas of Female Rats

    PubMed Central

    Milner, Teresa A.; Drake, Carrie T.; Lessard, Andree; Waters, Elizabeth M.; Torres-Reveron, Annelyn; Graustein, Bradley; Mitterling, Katherine; Frys, Kelly; Iadecola, Costantino

    2008-01-01

    Estrogen receptor (ER) activation in central autonomic nuclei modulates arterial blood pressure (ABP) and counteracts the deleterious effect of hypertension. We tested the hypothesis that hypertension, in turn, influences the expression and trafficking of gonadal steroid receptors in central cardiovascular circuits. Thus, we examined whether ER- and progestin receptor (PR)-immunoreactivity (ir) are altered in medullary and hypothalamic autonomic areas of cycling rats following chronic infusion of the hypertensive agent, angiotensin II (AngII). After 1 week AngII-infusion, systolic ABP was elevated from 1034 to 1728 mmHg (p<0.05; N = 8/group) and all rats were in diestrus (low estrogen). In AngII-infused rats the number of PR-immunoreactive nuclei was reduced (?72%) compared to saline-infused controls also in diestrus (p<0.05). Furthermore, the intensity of ER?-ir in nuclei (16%) and cytoplasm (21%) of cells increased selectively in the commissural nucleus of the solitary tract (cNTS; p<0.05) while neither the number nor intensity of ER?-labeled cells changed (p>0.05). Following chronic AngII-infusion, electron microscopy showed a higher cytoplasmic-to-nuclear ratio of ER?-labeling selectively in tyrosine hydroxylase (TH)-labeled neurons in the cNTS. Furthermore, AngII-infusion increased ER?-ir in the cytosol of TH- and non-TH neuronal perikarya and increased the amount of ER?-ir associated with endoplasmic reticulum only in TH-containing perikarya. The data suggest that hypertension modulates the expression and subcellular distribution of ER? and PR in central autonomic regions involved in blood pressure control. Considering that ER? counteracts the central and peripheral effects of AngII, these receptor changes may underlie adaptive responses that protect females from the deleterious effects of hypertension. PMID:18533148

  3. [Coronary endothelial dysfunction in hypertension].

    PubMed

    Antony, I; Nitenberg, A

    1997-11-01

    Intracoronary injection of acetylcholine leads to coronary vasodilatation in normal subjects and vasoconstriction in hypertensive subjects, suggesting an abnormality of endothelial function in hypertension. In order to study the response to physiological stimulation which induces endothelium-dependent vasodilatation, the effects of sympathetic stimulation (cold pressor test) and of the increase in flow velocity in the left anterior descending artery were analysed in 10 control and 26 hypertensive subjects. All had angiographically normal coronary arteries and normal lipid profiles. None of the subjects were smokers or diabetic. During the cold test (12 patients), the flow velocity increased by 47 +/- 26% (p < 0.05) in controls and by 68 +/- 48% (p < 0.01) in the hypertensives. Dilatation of the coronary arteries was observed in controls (+12.0 +/- 4.5%, p < 0.001) and constriction in the hypertensives (-10.3 +/- 8.5%, p < 0.001). Injection of papaverine in the distal left anterior descending artery (14 patients) induced proximal dilatation in controls (+17.0 +/- 10.6%, p < 0.001) and was ineffective in hypertensives (-0.4 +/- 1.5%), whereas the flow velocity increased by 521 +/- 129% and 406 +/- 120% (p < 0.001) respectively. Intracoronary injection of 2 mg of isosorbide dinitrate induced comparable dilatation in control subjects (+30.0 +/- 12.9%, p < 0.001) and in the 26 hypertensives (+22.8 +/- 6.5%, p < 0.001). In 10 hypertensive patients, intravenous injection of an angiotensin converting enzyme inhibitor, perindoprilat, immediately re-established the vasodilatory response to these two stimuli. The authors conclude that the coronary responses to physiological stimuli (sympathetic stimulation, increase in flow velocity) are altered in hypertensive subjects with angiographically normal coronary arteries with no other risk factors. Normal vasomotion may be restored by an angiotensin converting enzyme inhibitor. PMID:9515110

  4. The effect of hydro-alcoholic celery (Apiumgraveolens) leaf extract on cardiovascular parameters and lipid profile in animal model of hypertension induced by fructose

    PubMed Central

    Dianat, Mahin; Veisi, Ali; Ahangarpour, Akram; Fathi Moghaddam, Hadi

    2015-01-01

    Objectives: Hypertension is one of the most common diseases of the modern era. This study evaluates the effect of hydro-alcoholic celery leaf extract onsystolic blood pressure (SBP), heart rate (HR) and lipid profile in animals model of hypertension induced by fructose. Materials and Methods: Sprague Dawley rats were divided into five groups: 1) control group (free access to tap drinking water), 2) group receiving 200mg/kg celery leaf extract, 3) group receiving fructose 10%, and 4,5) receiving fructose and 100mg/kg or 200mg/kg of extract (n=8). In all groups, before and during the test period, SBP and HR were measured by Power lab system. Lipid profiles were determined by auto analysis. Repeated measurement and one way ANOVA were used for data analysis. P<0.05 was considered statistically significant. Results: The SBP in the fructose group significantly increased compared to control group (P<0.01). SBP, in groups receiving fructose+100mg/kg extract, fructose and receiving 200mg/kg extract, and receiving 200mg/kg of extract, compared to fructose group significantly decreased. Heart rate in any of these groups showed no significant difference. Cholesterol, triglyceride, LDL and VLDL in the fructose group significantly increased; however, these effects significantly decreased in the recipient extract groups. HDL levels in the fructose group showed no difference while in the groups receiving the extract they significantly increased. Conclusions: Celery leaf extract reduces SBP, cholesterol, triglyceride, LDL and VLDL in animal model of fructose-induced hypertension. In conclusion, celery leaf extract with its blood pressure and lipid lowering effects, can be considered as an antihypertensive agent in chronic treatment of elevated SBP. PMID:26101753

  5. Augmented Endothelial-Specific L-Arginine Transport Blunts the Contribution of the Sympathetic Nervous System to Obesity Induced Hypertension in Mice

    PubMed Central

    Rajapakse, Niwanthi W.; Karim, Florian; Evans, Roger G.

    2015-01-01

    Augmenting endothelial specific transport of the nitric oxide precursor L-arginine via cationic amino acid transporter-1 (CAT1) can prevent obesity related hypertension. We tested the hypotheses that CAT1 overexpression prevents obesity-induced hypertension by buffering the influence of the sympathetic nervous system (SNS) on the maintenance of arterial pressure and by buffering pressor responses to stress. Wild type (WT; n=13) and CAT1 overexpressing mice (CAT+; n=13) were fed a normal or a high fat diet for 20 weeks. Mice fed a high fat diet were returned to the control diet before experiments commenced. Baseline mean arterial pressure (MAP) and effects of restraint-, shaker- and almond feeding-stress and ganglionic blockade (pentolinium; 5 mg/kg; i.p.) on MAP were determined in conscious mice. Fat feeding increased body weight to a similar extent in WT and CAT+ but MAP was greater only in WT compared to appropriate controls (by 29%). The depressor response to pentolinium was 65% greater in obese WT than lean WT (P < 0.001), but was similar in obese and lean CAT+ (P = 0.65). In lean WT and CAT+, pressor responses to shaker and feeding stress, but not restraint stress, were less in the latter genotype compared to the former (P ? 0.001). Pressor responses to shaker and feeding stress were less in obese WT than lean WT (P ? 0.001), but similar in obese and lean CAT+. The increase in MAP in response to restraint stress was less in obese WT (22 2%), but greater in obese CAT+ (37 2%), when compared to respective lean WT (31 3%) and lean CAT+ controls (27 2%; P ? 0.02). We conclude that CAT1 overexpression prevents obesity-induced hypertension by reducing the influence of the SNS on the maintenance of arterial pressure but not by buffering pressor responses to stress. PMID:26186712

  6. Role of the Na+/H+ exchanger 3 in angiotensin II-induced hypertension in NHE3-deficient mice with transgenic rescue of NHE3 in small intestines

    PubMed Central

    Li, Xiao C; Shull, Gary E; Miguel-Qin, Elisa; Chen, Fang; Zhuo, Jia L

    2015-01-01

    The role of Na+/H+ exchanger 3 (NHE3) in the kidney in angiotensin II (ANG II)-induced hypertension remains unknown. The present study used global NHE3-deficient mice with transgenic rescue of the Nhe3 gene in small intestines (tgNhe3?/?) to test the hypothesis that genetic deletion of NHE3 selectively in the kidney attenuates ANG II-induced hypertension. Six groups of wild-type (tgNhe3+/+) and tgNhe3?/? mice were infused with either vehicle or ANG II (1.5mg/kg/day, i.p., 2 weeks, or 10nmol/min, i.v., 30min), treated with or without losartan (20mg/kg/day, p.o.) for 2weeks. Basal systolic blood pressure (SBP) and mean intra-arterial blood pressure (MAP) were significantly lower in tgNhe3?/? mice (P<0.01). Basal glomerular filtration rate, 24h urine excretion, urinary Na+ excretion, urinary K+ excretion, and urinary Cl? excretion were significantly lower in tgNhe3?/? mice (P<0.01). These responses were associated with significantly elevated plasma ANG II and aldosterone levels, and marked upregulation in aquaporin 1, the Na+/HCO3 cotransporter, the ?1 subunit isoform of Na+/K+-ATPase, protein kinase C?, MAP kinases ERK1/2, and glycogen synthase kinase 3 ?/? in the renal cortex of tgNhe3?/? mice (P<0.01). ANG II infusion markedly increased SBP and MAP and renal cortical transporter and signaling proteins in tgNhe3+/+, as expected, but all of these responses to ANG II were attenuated in tgNhe3?/? mice (P<0.01). These results suggest that NHE3 in the kidney is necessary for maintaining normal blood pressure and fully developing ANG II-dependent hypertension. PMID:26564064

  7. Role of STAT3 in Angiotensin II-Induced Hypertension and Cardiac Remodeling Revealed by Mice Lacking STAT3 Serine 727 Phosphorylation

    PubMed Central

    Zouein, Fouad A.; Zgheib, Carlos; Hamza, Shereen; Fuseler, John W.; Hall, John E.; Soljancic, Andrea; Lopez-Ruiz, Arnaldo; Kurdi, Mazen; Booz, George W.

    2013-01-01

    STAT3 is involved in protection of the heart provided by ischemic preconditioning. However, the role of this transcription factor in the heart in chronic stresses such as hypertension has not been defined. We assessed whether STAT3 is important in hypertension-induced cardiac remodeling using mice with reduced STAT3 activity due to a S727A mutation (SA/SA). Wild type (WT) and SA/SA mice received angiotensin (ANG) II or saline for 17 days. ANG II increased mean arterial and systolic pressure in SA/SA and WT mice, but cardiac levels of cytokines associated with heart failure were increased less in SA/SA mice. Unlike WT mice, hearts of SA/SA mice showed signs of developing systolic dysfunction as evidenced by reduction in ejection fraction and fractional shortening. In the left ventricle of both WT and SA/SA mice, ANG II induced fibrosis. However, fibrosis in SA/SA mice appeared more extensive and was associated with loss of myocytes. Cardiac hypertrophy as indexed by heart to body weight ratio and left ventricular anterior wall dimension during diastole was greater in WT mice. In WT+ANG II mice there was an increase in the mass of individual myofibrils. In contrast, cardiac myocytes of SA/SA+ANG II mice showed a loss in myofibrils and myofibrillar mass density was decreased during ANG II infusion. Our findings reveal that STAT3 transcriptional activity is important for normal cardiac myocyte myofibril morphology. Loss of STAT3 may impair cardiac function in the hypertensive heart due to defective myofibrillar structure and remodeling that may lead to heart failure. PMID:23364341

  8. Role of the Renin-Angiotensin System, Renal Sympathetic Nerve System, and Oxidative Stress in Chronic Foot Shock-Induced Hypertension in Rats

    PubMed Central

    Dong, Tao; Chen, Jing-Wei; Tian, Li-Li; Wang, Lin-Hui; Jiang, Ren-Di; Zhang, Zhe; Xu, Jian-Bing; Zhao, Xiao-Dong; Zhu, Wei; Wang, Guo-Qing; Sun, Wan-Ping; Zhang, Guo-Xing

    2015-01-01

    Objective: The renin-angiotensin system (RAS) and renal sympathetic nerve system (RSNS) are involved in the development of hypertension. The present study is designed to explore the possible roles of the RAS and the RSNS in foot shock-induced hypertension. Methods: Male Sprague-Dawley rats were divided into six groups: control, foot shock, RSNS denervation, denervation plus foot shock, Captopril (angiotensin I converting enzyme inhibitor, ACE inhibitor) plus foot shock, and Tempol (superoxide dismutase mimetic) plus foot shock. Rats received foot shock for 14 days. We measured the quantity of thiobarbituric acid reactive substances (TBARS), corticosterone, renin, and angiotensin II (Ang II) in plasma, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and renal noradrenaline content. RAS component mRNA and protein levels were quantified in the cerebral cortex and hypothalamus. Results: The two week foot shock treatment significantly increased systolic blood pressure, which was accompanied by an increase in angiotensinogen, renin, ACE1, and AT1a mRNA and protein expression in the cerebral cortex and hypothalamus, an increase of the plasma concentrations of renin, Ang II, corticosterone, and TBARS, as well as a decrease in plasma SOD and GSH-Px activities. Systolic blood pressure increase was suppressed by denervation of the RSNS or treatment with Captopril or Tempol. Interestingly, denervation or Tempol treatment both decreased main RAS components not only in the circulatory system, but also in the central nervous system. In addition, decreased antioxidant levels and increased TBARS and corticosterone levels were also partially restored by denervation or treatment with Tempol or Captopril. Conclusions: RAS, RSNS and oxidative stress reciprocally potentiate to play important roles in the development of foot shock-induced hypertension. PMID:25999788

  9. Mechanism of IFN-γ in regulating OPN/Th17 pathway during vascular collagen remodeling of hypertension induced by ANG II

    PubMed Central

    Jiang, Lei; He, Pengcheng; Liu, Yong; Chen, Jiyan; Wei, Xuebiao; Tan, Ning

    2015-01-01

    More and more researches show that hypertensive vascular remodeling is closely related to the imbalance of immune system in recent years. IFN-γ is natural protein with the function of immune regulation and has resistance effect on vascular remodeling. However, the mechanism of IFN-γ is to be defined. This paper is to explore the mechanism of IFN-γ in regulating OPN/Th17 pathway. In this research, animal models of vascular collagen remodeling were established by inducing hypertensive mice with ANG II. There was no statistical significance when the systolic blood pressures and the percentages of wall thickness/lumen diameter in both groups of WT + AngII + IFN-γ and WT + PBS were compared (P=0.219>0.05, P=0.118>0.05). The concentration of serum precollagen-type I and III and their ratio in WT + AngII + IFN-γ group were decreased after the IFN-γ being given (P<0.01). Expression of OPN within tissue in WT + Ang II group was relatively high, but lowered after treated by IFN-γ. Th17 cell ratio was decreased in WT + AngII + IFN-γ group (P<0.01). Expressions of RORα and RORγt mRNA within Th17 cell were decreased (P<0.01). The content of IL-23 in WT + AngII + IFN-γ group was increased, while IL-10 and TGF-β decreased. It has proved that IFN-γ can regulate the hypertensive vascular collagen remodeling induced by ANG II, lower the systolic pressure and reduce the pathological damage of vascular collagen remodeling and the collagen synthesis. The mechanism may that the differentiation of Th17 is inhibited by suppressing the OPN expression and regulating the secretion of inflammatory cytokines. PMID:26823760

  10. Monoclonal antibody to an endogenous bufadienolide, marinobufagenin, reverses preeclampsia-induced Na/K-ATPase inhibition and lowers blood pressure in NaCl-sensitive hypertension

    PubMed Central

    Fedorova, Olga V.; Simbirtsev, Andrey S.; Kolodkin, Nikolai I.; Kotov, Alexander Y.; Agalakova, Natalia I.; Kashkin, Vladimir A.; Tapilskaya, Natalia I.; Bzhelyansky, Anton; Reznik, Vitaly A.; Frolova, Elena V.; Nikitina, Elena R.; Budny, Georgy V.; Longo, Dan L.; Lakatta, Edward G.; Bagrov, Alexei Y.

    2008-01-01

    Background Levels of marinobufagenin (MBG), an endogenous bufadienolide Na/K-ATPase (NKA) inhibitor, increase in preeclampsia and in NaCl-sensitive hypertension. Methods We tested a 3E9 monoclonal anti-MBG antibody (mAb) for the ability to lower blood pressure (BP) in NaCl-sensitive hypertension and to reverse the preeclampsia-induced inhibition of erythrocyte NKA. Measurements of MBG were performed via immunoassay based on 4G4 anti-MBG mAb. Results In hypertensive Dahl-S rats, an intraperitoneal administration of 50 μg/kg 3E9 mAb lowered BP by 40 mmHg and activated Na/K-pump in thoracic aorta by 51%. NaCl supplementation of pregnant rats (n = 16) produced a 37 mmHg increase in BP, a 3.5-fold rise in MBG excretion, and a 25% inhibition of the Na/K-pump in the thoracic aorta, compared with pregnant rats on a normal NaCl intake. In eight pregnant hypertensive rats, 3E9 mAb reduced the BP (25 mmHg) and restored the vascular Na/K-pump. In 14 patients with preeclampsia (mean BP, 126 ± 3 mmHg; 26.9 ± 1.4 years; gestational age, 37 ± 0.8 weeks), plasma MBG was increased three-fold and erythrocyte NKA was inhibited compared with that of 12 normotensive pregnant women (mean BP, 71 W 3 mmHg)(1.5 ± 0.1 vs. 3.1 ± 0.2 μmol Pi/ml/h, respectively; P < .01). Ex-vivo 3E9 mAb restored NKA activity in erythrocytes from patients with preeclampsia. As compared with 3E9 mAb, Digibind, an affinity-purified antidigoxin antibody, was less active with respect to lowering BP in both hypertensive models and to restoration of NKA from erythrocytes from patients with preeclampsia. Conclusion Anti-MBG mAbs may be a useful tool in the studies of MBG in vitro and in vivo and may offer treatment of preeclampsia. PMID:19008721

  11. Exercise Hypertension

    PubMed Central

    Schultz, Martin G.; Sharman, James E.

    2014-01-01

    Irrespective of apparent ‘normal' resting blood pressure (BP), some individuals may experience an excessive elevation in BP with exercise (i.e. systolic BP ≥210 mm Hg in men or ≥190 mm Hg in women or diastolic BP ≥110 mm Hg in men or women), a condition termed exercise hypertension or a ‘hypertensive response to exercise' (HRE). An HRE is a relatively common condition that is identified during standard exercise stress testing; however, due to a lack of information with respect to the clinical ramifications of an HRE, little value is usually placed on such a finding. In this review, we discuss both the clinical importance and underlying physiological contributors of exercise hypertension. Indeed, an HRE is associated with an increased propensity for target organ damage and also predicts the future development of hypertension, cardiovascular events and mortality, independent of resting BP. Moreover, recent work has highlighted that some of the elevated cardiovascular risks associated with an HRE may be related to high-normal resting BP (pre-hypertension) or ambulatory ‘masked' hypertension and that an HRE may be an early warning signal of abnormal BP control that is otherwise undetected with clinic BP. Whilst an HRE may be amenable to treatment via pharmacological and lifestyle interventions, the exact physiological mechanism of an HRE remains elusive, but it is likely a manifestation of multiple factors including large artery stiffness, increased peripheral resistance, neural circulatory control and metabolic irregularity. Future research focus may be directed towards determining threshold values to denote the increased risk associated with an HRE and further resolution of the underlying physiological factors involved in the pathogenesis of an HRE. PMID:26587435

  12. Exercise Hypertension.

    PubMed

    Schultz, Martin G; Sharman, James E

    2014-05-01

    Irrespective of apparent 'normal' resting blood pressure (BP), some individuals may experience an excessive elevation in BP with exercise (i.e. systolic BP ?210 mm Hg in men or ?190 mm Hg in women or diastolic BP ?110 mm Hg in men or women), a condition termed exercise hypertension or a 'hypertensive response to exercise' (HRE). An HRE is a relatively common condition that is identified during standard exercise stress testing; however, due to a lack of information with respect to the clinical ramifications of an HRE, little value is usually placed on such a finding. In this review, we discuss both the clinical importance and underlying physiological contributors of exercise hypertension. Indeed, an HRE is associated with an increased propensity for target organ damage and also predicts the future development of hypertension, cardiovascular events and mortality, independent of resting BP. Moreover, recent work has highlighted that some of the elevated cardiovascular risks associated with an HRE may be related to high-normal resting BP (pre-hypertension) or ambulatory 'masked' hypertension and that an HRE may be an early warning signal of abnormal BP control that is otherwise undetected with clinic BP. Whilst an HRE may be amenable to treatment via pharmacological and lifestyle interventions, the exact physiological mechanism of an HRE remains elusive, but it is likely a manifestation of multiple factors including large artery stiffness, increased peripheral resistance, neural circulatory control and metabolic irregularity. Future research focus may be directed towards determining threshold values to denote the increased risk associated with an HRE and further resolution of the underlying physiological factors involved in the pathogenesis of an HRE. PMID:26587435

  13. Grape seed proanthocyanidins prevent DOCA-salt hypertension-induced renal injury and its mechanisms in rats.

    PubMed

    Lan, Chao-Zong; Ding, Ling; Su, Yi-Lin; Guo, Kun; Wang, Li; Kan, Hong-Wei; Ou, Yu-Rong; Gao, Shan

    2015-07-01

    Renal dysfunction is one of the major effects of DOCA (deoxycorticosterone acetate)-salt hypertension and there is an increasing amount of evidence that oxidative stress damages the function of the kidney. Grape seed proanthocyanidins (GSPE) have been reported to be potent anti-oxidants and free radical scavengers. The present study sought to investigate the ability of GSPE to prevent renal injury in DOCA-salt hypertensive rats and to explore the molecular mechanisms underlying its protective effects. A total of 54 Sprague Dawley (SD) rats were randomly divided into 7 groups: Sham group (n = 7), UnX-sham group (n = 8), DOCA-salt group (n = 8), GSPE150 group (150 mg kg(-1), n = 7), GSPE240 group (240 mg kg(-1), n = 8), GSPE384 group (384 mg kg(-1), n = 8) and ALM (amlodipine besylate tablets) group (5 mg kg(-1), n = 8), and treated for 4 weeks. Compared to sham group rats, renal injury was observed in DOCA-salt hypertensive group rats as the urine protein, KW/BW (kidney weight/body weight), degree of renal fibrosis, renal MDA (malondialdehyde) and Hyp (hydroxyproline) contents significantly increased (P < 0.01). Moreover, SOD (Superoxide Dismutase) activities decreased in the model group (P < 0.01). In contrast, DOCA-salt hypertensive rats treated with different dose of GSPE or ALM showed a significant improvement of renal injury with decreased urine protein, KW/BW, degree of renal fibrosis, renal total MDA and Hyp contents compared to the untreated group. In addition, SOD activities increased in the treatment group. Since the experimental modeling time was short, kidney damage occurs to a lesser extent. BUN (Blood Urea Nitrogen), Scr (Serum Creatinine) and UA (Uric Acid) contents did not appear significantly changed in all groups. Finally, the activation of JNK and p38 kinases in the kidney was suppressed in rats treated with GSPEs or ALM compared to the untreated group, suggesting that the inhibition of these kinase pathways by GSPE contributes to the improvement of renal function. Taking these results together, we conclude that the anti-hypertensive and anti-oxidative stress beneficial effects of GSPE on renal injury in rats with DOCA-salt hypertension occur via the attenuation of JNK and p38 activity. PMID:26011796

  14. Pulmonary hypertension in patients with chronic myeloproliferative disorders.

    PubMed

    Adir, Yochai; Elia, Davide; Harari, Sergio

    2015-09-01

    Pulmonary hypertension (PH) is a major complication of several haematological disorders. Chronic myeloproliferative diseases (CMPDs) associated with pulmonary hypertension have been included in group five of the clinical classification for pulmonary hypertension, corresponding to pulmonary hypertension for which the aetiology is unclear and/or multifactorial. The aim of this review is to discuss the epidemiology, pathogenic mechanism and treatment approaches of the more common forms of pulmonary hypertension in the context of CMPD's: chronic thromboembolic pulmonary hypertension, precapillary pulmonary hypertension and drug-induced PH. PMID:26324801

  15. Differential Responses to Blood Pressure and Oxidative Stress in Streptozotocin-Induced Diabetic Wistar-Kyoto Rats and Spontaneously Hypertensive Rats: Effects of Antioxidant (Honey) Treatment

    PubMed Central

    Erejuwa, Omotayo O.; Sulaiman, Siti A.; Wahab, Mohd Suhaimi Ab; Sirajudeen, Kuttulebbai N. S.; Salleh, Md Salzihan Md; Gurtu, Sunil

    2011-01-01

    Oxidative stress is implicated in the pathogenesis and/or complications of hypertension and/or diabetes mellitus. A combination of these disorders increases the risk of developing cardiovascular events. This study investigated the effects of streptozotocin (60 mg/kg; ip)-induced diabetes on blood pressure, oxidative stress and effects of honey on these parameters in the kidneys of streptozotocin-induced diabetic Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Diabetic WKY and SHR were randomized into four groups and received distilled water (0.5 mL) and honey (1.0 g/kg) orally once daily for three weeks. Control SHR had reduced malondialdehyde (MDA) and increased systolic blood pressure (SBP), catalase (CAT) activity, and total antioxidant status (TAS). SBP, activities of glutathione peroxidase (GPx) and glutathione reductase (GR) were elevated while TAS was reduced in diabetic WKY. In contrast, SBP, TAS, activities of GPx and GR were reduced in diabetic SHR. Antioxidant (honey) treatment further reduced SBP in diabetic SHR but not in diabetic WKY. It also increased TAS, GSH, reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio, activities of GPx and GR in diabetic SHR. These data suggest that differences in types, severity, and complications of diseases as well as strains may influence responses to blood pressure and oxidative stress. PMID:21673929

  16. Sequential changes in plasma renin activity and plasma catecholamines in mildly hypertensive patients during acute, furosemide-induced body-fluid loss.

    PubMed

    Cannella, G; Galva, M D; Campanini, M; Cesura, A M; De Marinis, S; Picotti, G B

    1983-01-01

    To evaluate the role of adrenergic mechanisms in the acute response of renin to furosemide, plasma renin activity (PRA) and plasma catecholamine concentrations were measured for 3 h after i.v. administration of furosemide 1 mg/kg to 8 patients with mild essential hypertension. Furosemide induced a prompt and long-lasting increase in renin, with PRA more than doubled at all times. The increase in PRA within the first 30 min paralleled the peak increases in urinary water and sodium flow rates, and significant decreases in plasma volume and central venous pressure. There was no change in plasma catecholamine concentrations. Plasma noradrenaline was increased significantly at 60 min and adrenaline at 90 min, once furosemide had induced a marked loss of body-fluid and approximately 65% decrease in central venous pressure. Both catecholamines remained elevated until the end of the study, whereas urinary water and sodium flow rates had returned to their pre-treatment values by 150 min. Mean blood pressure was essentially unchanged throughout the study, whereas heart rate increased significantly after 90 min. The findings suggest that in mildly hypertensive patients adrenergic mechanisms are not involved in the initial renin response to furosemide, but they come into play later, probably as a result of reflex sympathetic activation triggered by marked volume depletion. PMID:6354727

  17. Ellagic Acid Prevents L-NAME-Induced Hypertension via Restoration of eNOS and p47phox Expression in Rats.

    PubMed

    Berkban, Thewarid; Boonprom, Pattanapong; Bunbupha, Sarawoot; Welbat, Jariya Umka; Kukongviriyapan, Upa; Kukongviriyapan, Veerapol; Pakdeechote, Poungrat; Prachaney, Parichat

    2015-07-01

    The effect of ellagic acid on oxidative stress and hypertension induced by N?-Nitro-L-arginine methyl ester hydrochloride (L-NAME) was investigated. Male Sprague-Dawley rats were administrated with L-NAME (40 mg/kg/day) for five weeks. L-NAME induced high systolic blood pressure (SBP) and increased heart rate (HR), hindlimb vascular resistance (HVR) and oxidative stress. Concurrent treatment with ellagic acid (7.5 or 15 mg/kg) prevented these alterations. Co-treatment with ellagic acid was associated with up-regulation of endothelial nitric oxide synthase (eNOS) protein production and alleviation of oxidative stress as indicated by decreased superoxide production in the vascular tissue, reduced plasma malondialdehyde levels, reduced NADPH oxidase subunit p47phox expression and increased plasma nitrate/nitrite levels. Our results indicate that ellagic acid attenuates hypertension by reducing NADPH oxidase subunit p47phox expression, which prevents oxidative stress and restores NO bioavailability. PMID:26133972

  18. Ellagic Acid Prevents L-NAME-Induced Hypertension via Restoration of eNOS and p47phox Expression in Rats

    PubMed Central

    Berkban, Thewarid; Boonprom, Pattanapong; Bunbupha, Sarawoot; Umka Welbat, Jariya; Kukongviriyapan, Upa; Kukongviriyapan, Veerapol; Pakdeechote, Poungrat; Prachaney, Parichat

    2015-01-01

    The effect of ellagic acid on oxidative stress and hypertension induced by N?-Nitro-l-arginine methyl ester hydrochloride (L-NAME) was investigated. Male Sprague-Dawley rats were administrated with L-NAME (40 mg/kg/day) for five weeks. L-NAME induced high systolic blood pressure (SBP) and increased heart rate (HR), hindlimb vascular resistance (HVR) and oxidative stress. Concurrent treatment with ellagic acid (7.5 or 15 mg/kg) prevented these alterations. Co-treatment with ellagic acid was associated with up-regulation of endothelial nitric oxide synthase (eNOS) protein production and alleviation of oxidative stress as indicated by decreased superoxide production in the vascular tissue, reduced plasma malondialdehyde levels, reduced NADPH oxidase subunit p47phox expression and increased plasma nitrate/nitrite levels. Our results indicate that ellagic acid attenuates hypertension by reducing NADPH oxidase subunit p47phox expression, which prevents oxidative stress and restores NO bioavailability. PMID:26133972

  19. Portal hypertension induced by congenital hepatic arterioportal fistula: Report of four clinical cases and review of the literature

    PubMed Central

    Zhang, Dan-Ying; Weng, Shu-Qiang; Dong, Ling; Shen, Xi-Zhong; Qu, Xu-Dong

    2015-01-01

    Intrahepatic arterioportal fistula (IAPF) can be caused by many secondary factors. We report four cases of portal hypertension that were eventually determined to be caused by congenital hepatic arterioportal fistula. The clinical manifestations included ascites, variceal hemorrhage and hepatic encephalopathy. Computed tomography scans from all of the patients revealed the early enhancement of the portal branches in the hepatic arterial phase. All patients were diagnosed using digital subtraction angiography (DSA). DSA before embolization revealed an arteriovenous fistula with immediate filling of the portal venous radicles. All four patients were treated with interventional embolization. The four patients remained in good condition throughout follow-up and at the time of publication. IAPF is frequently misdiagnosed due to its rarity; therefore, clinicians should consider IAPF as a potential cause of non-cirrhotic portal hypertension. PMID:25717263

  20. Angiotensin converting enzyme expression is increased in small pulmonary arteries of rats with hypoxia-induced pulmonary hypertension.

    PubMed Central

    Morrell, N W; Atochina, E N; Morris, K G; Danilov, S M; Stenmark, K R

    1995-01-01

    Previous studies suggest that while lung angiotensin converting enzyme (ACE) activity is reduced during chronic hypoxia, inhibitors of ACE attenuate hypoxic pulmonary hypertension. In an attempt to explain this paradox we investigated the possibility that whole lung ACE activity may not reflect local pulmonary vascular ACE expression. The experimental approach combined in vivo hemodynamic studies in control and chronically hypoxic rats, measurement of whole lung ACE activity, and evaluation of local pulmonary vascular ACE expression by in situ hybridization and immunohistochemistry. Total lung ACE activity was reduced to 50% of control activity by 5 d of hypoxia and remained low for the duration of the study. Immunohistochemistry showed a marked reduction of ACE staining in alveolar capillary endothelium. However, an increase in ACE staining was observed in the walls of small newly muscularized pulmonary arteries at the level of alveolar ducts and walls. In situ hybridization studies showed increased signal for ACE mRNA in the same vessels. Inhibition of ACE by captopril during chronic hypoxia attenuated pulmonary hypertension and markedly reduced distal muscularization of small pulmonary arteries. In addition, we demonstrated marked longitudinal variation in ACE expression along the normal pulmonary vasculature with the highest levels found in small muscular arteries associated with terminal and respiratory bronchioles. We conclude that local ACE expression is increased in the walls of small pulmonary arteries during the development of hypoxic pulmonary hypertension, despite a generalized reduction in alveolar capillary ACE expression, and we speculate that local arteriolar ACE may play a role in the vascular remodeling associated with pulmonary hypertension. Images PMID:7560074

  1. Full-length human chromogranin-A cardioactivity: myocardial, coronary, and stimulus-induced processing evidence in normotensive and hypertensive male rat hearts.

    PubMed

    Pasqua, Teresa; Corti, Angelo; Gentile, Stefano; Pochini, Lorena; Bianco, Mimma; Metz-Boutigue, Marie-Hlne; Cerra, Maria Carmela; Tota, Bruno; Angelone, Tommaso

    2013-09-01

    Plasma chromogranin-A (CgA) concentrations correlate with severe cardiovascular diseases, whereas CgA-derived vasostatin-I and catestatin elicit cardiosuppression via an antiadrenergic/nitric oxide-cGMP mediated mechanism. Whether these phenomena are related is unknown. We here investigated whether and to what extent full-length CgA directly influences heart performance and may be subjected to stimulus-elicited intracardiac processing. Using normotensive and hypertensive rats, we evaluated the following: 1) direct myocardial and coronary effects of full-length CgA; 2) the signal-transduction pathway involved in its action mechanism; and 3) CgA intracardiac processing after ?-adrenergic [isoproterenol (Iso)]- and endothelin-1(ET-1)-dependent stimulation. The study was performed by using a Langendorff perfusion apparatus, Western blotting, affinity chromatography, and ELISA. We found that CgA (1-4 nM) dilated coronaries and induced negative inotropism and lusitropism, which disappeared at higher concentrations (10-16 nM). In spontaneously hypertensive rats (SHRs), negative inotropism and lusitropism were more potent than in young normotensive rats. We found that perfusion itself, Iso-, and endothelin-1 stimulation induced intracardiac CgA processing in low-molecular-weight fragments in young, Wistar Kyoto, and SHR rats. In young normotensive and adult hypertensive rats, CgA increased endothelial nitric oxide synthase phosphorylation and cGMP levels. Analysis of the perfusate from both Wistar rats and SHRs of untreated and treated (Iso) hearts revealed CgA absence. In conclusion, in normotensive and hypertensive rats, we evidenced the following: 1) full-length CgA directly affects myocardial and coronary function by AkT/nitric oxide synthase/nitric oxide/cGMP/protein kinase G pathway; and 2) the heart generates intracardiac CgA fragments in response to hemodynamic and excitatory challenges. For the first time at the cardiovascular level, our data provide a conceptual link between systemic and intracardiac actions of full-length CgA and its fragments, expanding the knowledge on the sympathochromaffin/CgA axis under normal and physiopathological conditions. PMID:23751870

  2. [Successful treatment of acute promyelocytic leukemia complicated with autoimmune hepatitis-induced portal hypertension with all-trans retinoic acid].

    PubMed

    Ushiki, Takashi; Nikkuni, Koji; Yoshida, Chie; Shibasaki, Yasuhiko; Ishikawa, Toru; Masuko, Masayoshi; Takai, Kazue

    2012-01-01

    A 35-year-old man admitted to the hospital for oral hemorrhage was diagnosed with acute promyelocytic leukemia (APL). Remission from APL was achieved by induction therapy with all-trans retinoic acid (ATRA); the PML/RARA fusion gene was not detected on PCR analysis. Despite complete molecular remission, severe persistent pancytopenia, massive ascites, and renal failure were observed. The liver surface appeared rough and irregular on computed tomographic images. On the basis of the liver biopsy results, we diagnosed his condition as portal hypertension due to autoimmune hepatitis. Indocyanine green test showed good residual function of the liver, and therefore, 2 courses of consolidation therapy were administered; chemotherapy was stopped because of severe pancytopenia due to portal hypertension. Instead of continuing the consolidation therapy, maintenance therapy involving 8 rounds of ATRA monotherapy (45 mg/m(2), days1∼14) was initiated. Portal hypertension did not progress further with this maintenance therapy and therefore it was continued. The patient has been in remission from APL ever since, and no relapses have occurred since the past 5 years. These results suggest that ATRA can be used for long-term therapy in such cases. PMID:22374532

  3. Hypertensive Crisis

    MedlinePLUS

    ... kidney function Aortic dissection Angina (unstable chest pain) Pulmonary edema (fluid backup in the lungs) Eclampsia If you get a blood pressure reading of 180 or higher on top or 110 or higher on the bottom, and are having any ... Hypertension Metabolic Syndrome BP vs. Heart Rate BP ...

  4. Interleukin 13 and interleukin 17Ainduced pulmonary hypertension phenotype due to inhalation of antigen and fine particles from air pollution

    PubMed Central

    Park, Sung-Hyun; Chen, Wen-Chi; Esmaeil, Nafiseh; Lucas, Benjamin; Marsh, Leigh M.; Reibman, Joan

    2014-01-01

    Abstract Pulmonary hypertension has a marked detrimental effect on quality of life and life expectancy. In a mouse model of antigen-induced pulmonary arterial remodeling, we have recently shown that coexposure to urban ambient particulate matter (PM) significantly increased the thickening of the pulmonary arteries and also resulted in significantly increased right ventricular systolic pressures. Here we interrogate the mechanism and show that combined neutralization of interleukin 13 (IL-13) and IL-17A significantly ameliorated the increase in right ventricular systolic pressure, the circumferential muscularization of pulmonary arteries, and the molecular change in the right ventricle. Surprisingly, our data revealed a protective role of IL-17A for the antigen- and PM-induced severe thickening of pulmonary arteries. This protection was due to the inhibition of the effects of IL-13, which drove this response, and the expression of metalloelastase and resistin-like molecule ?. However, the latter was redundant for the arterial thickening response. Anti-IL-13 exacerbated airway neutrophilia, which was due to a resulting excess effect of IL-17A, confirming concurrent cross inhibition of IL-13- and IL-17A-dependent responses in the lungs of animals exposed to antigen and PM. Our experiments also identified IL-13/IL-17A-independent molecular reprogramming in the lungs induced by exposure to antigen and PM, which indicates a risk for arterial remodeling and protection from arterial constriction. Our study points to IL-13- and IL-17A-coinduced inflammation as a new template for biomarkers and therapeutic targeting for the management of immune responseinduced pulmonary hypertension. PMID:25610601

  5. Mechanisms and treatment of resistant hypertension.

    TOXLINE Toxicology Bibliographic Information

    Pimenta E; Gaddam KK; Oparil S

    2008-03-01

    Resistant hypertension is defined as blood pressure (BP) that remains uncontrolled in spite of the use of >/=3 antihypertensive medications. Stricter BP goals, higher obesity rates, older age, and increased use of exogenous BP-elevating substances are related to an increasing prevalence of resistant hypertension. The evaluation of patients with resistant hypertension is focused on identifying contributing and secondary causes of hypertension, including hyperaldosteronism, obstructive sleep apnea, chronic kidney disease, renal artery stenosis, and pheochromocytoma. Hyperaldosteronism is now recognized as the most common cause of resistant hypertension, and all patients with resistant hypertension should be screened with a plasma aldosterone/renin ratio even if the serum potassium level is normal. Treatment includes removal of contributing factors, appropriate management of secondary causes, and use of effective multidrug regimens. Recent studies indicate that the addition of spironolactone to standard treatment induces significant BP reduction in most patients with resistant hypertension.

  6. Activation of KCa3.1 by SKA-31 induces arteriolar dilatation and lowers blood pressure in normo- and hypertensive connexin40-deficient mice

    PubMed Central

    Radtke, Josephine; Schmidt, Kjestine; Wulff, Heike; Khler, Ralf; Wit, Cor

    2013-01-01

    BACKGROUND AND PURPOSE The calcium-activated potassium channel KCa3.1 is expressed in the vascular endothelium where its activation causes endothelial hyperpolarization and initiates endothelium-derived hyperpolarization (EDH)-dependent dilatation. Here, we investigated whether pharmacological activation of KCa3.1 dilates skeletal muscle arterioles and whether myoendothelial gap junctions formed by connexin40 (Cx40) are required for EDH-type dilatations and pressure depressor responses in vivo. EXPERIMENTAL APPROACH We performed intravital microscopy in the cremaster muscle microcirculation and blood pressure telemetry in Cx40-deficient mice. KEY RESULTS In wild-type mice, the KCa3.1-activator SKA-31 induced pronounced concentration-dependent arteriolar EDH-type dilatations, amounting to ?40% of maximal dilatation, and enhanced the effects of ACh. These responses were absent in mice devoid of KCa3.1 channels. In contrast, SKA-31-induced dilatations were not attenuated in mice with endothelial cells deficient in Cx40 (Cx40fl/fl:Tie2-Cre). In isolated endothelial cell clusters, SKA-31 induced hyperpolarizations of similar magnitudes (by ?38 mV) in Cx40fl/fl:Tie2-Cre, ubiquitous Cx40-deficient mice (Cx40-/-) and controls (Cx40fl/fl), which were reversed by the specific KCa3.1-blocker TRAM-34. In normotensive wild-type and Cx40fl/fl:Tie2-Cre as well as in hypertensive Cx40-/- animals, i.p. injections of SKA-31 (30 and 100 mgkg?1) decreased arterial pressure by ?32 mmHg in all genotypes. The depressor response to 100 mgkg?1 SKA-31 was associated with a decrease in heart rate. CONCLUSIONS AND IMPLICATIONS We conclude that endothelial hyperpolarization evoked by pharmacological activation of KCa3.1 channels induces EDH-type arteriolar dilatations that are independent of endothelial Cx40 and Cx40-containing myoendothelial gap junctions. As SKA-31 reduced blood pressure in hypertensive Cx40-deficient mice, KCa3.1 activators may be useful drugs for severe treatment-resistant hypertension. PMID:23734697

  7. Inhibition of Nitric Oxide Synthase 1 Induces Salt-Sensitive Hypertension in Nitric Oxide Synthase 1α Knockout and Wild-Type Mice.

    PubMed

    Wang, Ximing; Chandrashekar, Kiran; Wang, Lei; Lai, En Yin; Wei, Jin; Zhang, Gensheng; Wang, Shaohui; Zhang, Jie; Juncos, Luis A; Liu, Ruisheng

    2016-04-01

    We recently showed that α, β, and γ splice variants of neuronal nitric oxide synthase (NOS1) expressed in the macula densa and NOS1β accounts for most of the NO generation. We have also demonstrated that the mice with deletion of NOS1 specifically from the macula densa developed salt-sensitive hypertension. However, the global NOS1 knockout (NOS1KO) strain is neither hypertensive nor salt sensitive. This global NOS1KO strain is actually an NOS1αKO model. Consequently, we hypothesized that inhibition of NOS1β in NOS1αKO mice induces salt-sensitive hypertension. NOS1αKO and C57BL/6 wild-type (WT) mice were implanted with telemetry transmitters and divided into 7-nitroindazole (10 mg/kg/d)-treated and nontreated groups. All of the mice were fed a normal salt (0.4% NaCl) diet for 5 days, followed by a high-salt diet (4% NaCl). NO generation by the macula densa was inhibited by >90% in WT and NOS1αKO mice treated with 7-nitroindazole. Glomerular filtration rate in conscious mice was increased by ≈40% after a high-salt diet in both NOS1αKO and WT mice. In response to acute volume expansion, glomerular filtration rate, diuretic and natriuretic response were significantly blunted in the WT and knockout mice treated with 7-nitroindazole. Mean arterial pressure had no significant changes in mice fed a high-salt diet, but increased ≈15 mm Hg similarly in NOS1αKO and WT mice treated with 7-nitroindazole. We conclude that NOS1β, but not NOS1α, plays an important role in control of sodium excretion and hemodynamics in response to either an acute or a chronic salt loading. PMID:26883268

  8. Immunization with an ApoB-100 Related Peptide Vaccine Attenuates Angiotensin-II Induced Hypertension and Renal Fibrosis in Mice

    PubMed Central

    Honjo, Tomoyuki; Chyu, Kuang-Yuh; Dimayuga, Paul C.; Lio, Wai Man; Yano, Juliana; Trinidad, Portia; Zhao, Xiaoning; Zhou, Jianchang; Cercek, Bojan; Shah, Prediman K.

    2015-01-01

    Recent studies suggest the potential involvement of CD8+ T cells in the pathogenesis of murine hypertension. We recently reported that immunization with apoB-100 related peptide, p210, modified CD8+ T cell function in angiotensin II (AngII)-infused apoE (-/-) mice. In this study, we hypothesized that p210 vaccine modulates blood pressure in AngII-infused apoE (-/-) mice. Male apoE (-/-) mice were immunized with p210 vaccine and compared to unimmunized controls. At 10 weeks of age, mice were subcutaneously implanted with an osmotic pump which released AngII for 4 weeks. At 13 weeks of age, p210 immunized mice showed significantly lower blood pressure response to AngII compared to controls. CD8+ T cells from p210 immunized mice displayed a different phenotype compared to CD8+ T cells from unimmunized controls. Serum creatinine and urine albumin to creatinine ratio were significantly decreased in p210 immunized mice suggesting that p210 vaccine had renal protective effect. At euthanasia, inflammatory genes IL-6, TNF-α, and MCP-1 in renal tissue were down-regulated by p210 vaccine. Renal fibrosis and pro-fibrotic gene expression were also significantly reduced in p210 immunized mice. To assess the role of CD8+ T cells in these beneficial effects of p210 vaccine, CD8+ T cells were depleted by CD8 depleting antibody in p210 immunized mice. p210 immunized mice with CD8+ T cell depletion developed higher blood pressure compared to mice receiving isotype control. Depletion of CD8+ T cells also increased renal fibrotic gene expression compared to controls. We conclude that immunization with p210 vaccine attenuated AngII-induced hypertension and renal fibrosis. CD8+ T cells modulated by p210 vaccine could play an important role in the anti-hypertensive, anti-fibrotic and renal-protective effect of p210 vaccine. PMID:26121471

  9. Common Secondary Causes of Resistant Hypertension and Rational for Treatment

    PubMed Central

    Faselis, Charles; Doumas, Michael; Papademetriou, Vasilios

    2011-01-01

    Resistant hypertension is defined as uncontrolled blood pressure despite the use of three antihypertensive drugs, including a diuretic, in optimal doses. Treatment resistance can be attributed to poor adherence to antihypertensive drugs, excessive salt intake, physician inertia, inappropriate or inadequate medication, and secondary hypertension. Drug-induced hypertension, obstructive sleep apnoea, primary aldosteronism, and chronic kidney disease represent the most common secondary causes of resistant hypertension. Several drugs can induce or exacerbate pre-existing hypertension, with non-steroidal anti-inflammatory drugs being the most common due to their wide use. Obstructive sleep apnoea and primary aldosteronism are frequently encountered in patients with resistant hypertension and require expert management. Hypertension is commonly found in patients with chronic kidney disease and is frequently resistant to treatment, while the management of renovascular hypertension remains controversial. A step-by-step approach of patients with resistant hypertension is proposed at the end of this review paper. PMID:21423678

  10. Effect of endurance training on seizure susceptibility, behavioral changes and neuronal damage after kainate-induced status epilepticus in spontaneously hypertensive rats.

    PubMed

    Tchekalarova, J; Shishmanova, M; Atanasova, D; Stefanova, M; Alova, L; Lazarov, N; Georgieva, K

    2015-11-01

    The therapeutic efficacy of regular physical exercises in an animal model of epilepsy and depression comorbidity has been confirmed previously. In the present study, we examined the effects of endurance training on susceptibility to kainate (KA)-induced status epilepticus (SE), behavioral changes and neuronal damage in spontaneously hypertensive rats (SHRs). Male SHRs were randomly divided into two groups. One group was exercised on a treadmill with submaximal loading for four weeks and the other group was sedentary. Immediately after the training period, SE was evoked in half of the sedentary and trained rats by KA, while the other half of the two groups received saline. Basal systolic (SP), diastolic (DP) and mean arterial pressure (MAP) of all rats were measured at the beginning and at the end of the training period. Anxiety, memory and depression-like behaviour were evaluated a month after SE. The release of 5-HT in the hippocampus was measured using a liquid scintillation method and neuronal damage was analyzed by hematoxylin and eosin staining. SP and MAP of exercised SHRs decreased in comparison with the initial values. The increased resistance of SHRs to KA-induced SE was accompanied by an elongated latent seizure-free period, improved object recognition memory and antidepressant effect after the training program. While the anticonvulsant and positive behavioral effects of endurance training were accompanied by an increase of 5-HT release in the hippocampus, it did not exert neuroprotective activity. Our results indicate that prior exercise is an effective means to attenuate KA-induced seizures and comorbid behavioral changes in a model of hypertension and epilepsy suggesting a potential influence of hippocampal 5-HT on a comorbid depression. However, this beneficial impact does not prevent the development of epilepsy and concomitant brain damage. PMID:26319691

  11. Effects of Single Drug and Combined Short-term Administration of Sildenafil, Pimobendan, and Nicorandil on Right Ventricular Function in Rats With Monocrotaline-induced Pulmonary Hypertension.

    PubMed

    Nakata, Telma M; Tanaka, Ryou; Yoshiyuki, Rieko; Fukayama, Toshiharu; Goya, Seijiro; Fukushima, Ryuji

    2015-06-01

    This study was designed to assess the progression of pulmonary arterial hypertension (PAH) and the effectiveness of therapy using recently investigated echocardiographic parameters. PAH is characterized by the progressive elevation of pulmonary artery pressure and right ventricular hypertrophy and dysfunction, which ultimately results in right-sided heart failure and death. Echocardiography results and invasive measurements of right and left ventricular systolic pressures were compared after 3-week administrations of sildenafil (S group), pimobendan (P group), nicorandil (N group), and their combinations (SP and SPN groups) in male rats with monocrotaline (MCT)-induced pulmonary hypertension (M group) and without this condition (C group). The groups that received pimobendan alone and in combinations (SP and SPN groups) showed improvement in their echocardiographic parameters of systolic function. A significant improvement of diastolic function was achieved in the SPN group. Invasive measurements showed the most significant decreases of right ventricular systolic pressure in the N and SPN groups, and the use of pimobendan resulted in a comparatively low risk of adverse hemodynamic effects (left ventricular systolic pressure). Although our results suggested the attenuation of PAH severity in all treatment groups, PAH could not be reversed. PMID:25806612

  12. Effects of Single Drug and Combined Short-term Administration of Sildenafil, Pimobendan, and Nicorandil on Right Ventricular Function in Rats With Monocrotaline-induced Pulmonary Hypertension

    PubMed Central

    Tanaka, Ryou; Yoshiyuki, Rieko; Fukayama, Toshiharu; Goya, Seijiro; Fukushima, Ryuji

    2015-01-01

    Abstract: This study was designed to assess the progression of pulmonary arterial hypertension (PAH) and the effectiveness of therapy using recently investigated echocardiographic parameters. PAH is characterized by the progressive elevation of pulmonary artery pressure and right ventricular hypertrophy and dysfunction, which ultimately results in right-sided heart failure and death. Echocardiography results and invasive measurements of right and left ventricular systolic pressures were compared after 3-week administrations of sildenafil (S group), pimobendan (P group), nicorandil (N group), and their combinations (SP and SPN groups) in male rats with monocrotaline (MCT)-induced pulmonary hypertension (M group) and without this condition (C group). The groups that received pimobendan alone and in combinations (SP and SPN groups) showed improvement in their echocardiographic parameters of systolic function. A significant improvement of diastolic function was achieved in the SPN group. Invasive measurements showed the most significant decreases of right ventricular systolic pressure in the N and SPN groups, and the use of pimobendan resulted in a comparatively low risk of adverse hemodynamic effects (left ventricular systolic pressure). Although our results suggested the attenuation of PAH severity in all treatment groups, PAH could not be reversed. PMID:25806612

  13. Comparison of. beta. -adrenergic receptors between different strains of rat with different susceptibility to hypertension: a survey of binding characteristics, responsiveness and corticosteroid induced modulation

    SciTech Connect

    Jazayeri, A.

    1987-01-01

    The objective of this research was two fold: the first objective was to measure ..beta..-adrenergic receptor characteristics (Bmax and Kd) and responsiveness (isoproterenol induced c-AMP production) between different strains of rat with different susceptibility to hypertension. The second objective of this research was to determine if ..beta..-adrenergic receptors of arterial smooth muscle cells (ASMC) can be modulated by corticosteroids. These studies were done under controlled conditions using ASMC grown in culture from the rat aorta. (/sup 3/H)-dihydroalprenolol (DHA) was used to measure ..beta..-adrenergic receptor binding characteristics (Kd and Bmax). Scatchard analysis of (/sup 3/H)-DHA binding revealed one class of binding sites with affinity in the range of 100 pM. (/sup 3/H)-DHA binding comparison between Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) revealed that the Bmax for SHR was significantly lower than WKY. However, isoproterenol stimulated c-AMP production by SHR, is significantly higher than WKY. Fischer 344 rats, showed similar Bmax, Kd, and responsiveness as WKY rats. Dahl-sensitive and Dahl-resistant rats had equal Bmax and Kd measured by (/sup 3/H)-DHA binding.

  14. Role of Endothelin in Mediating Soluble fms-like Tyrosine Kinase-1 (sFlt-1)-induced Hypertension in Pregnant Rats

    PubMed Central

    Murphy, Sydney R.; LaMarca, B. Babbette D.; Cockrell, Kathy; Granger, Joey P.

    2010-01-01

    While soluble fms-like tyrosine kinase-1 (sFlt-1), an antagonist of vascular endothelial growth factor and placental growth factor has been implicated in the pathogenesis of hypertension during preeclampsia (PE), the mechanisms whereby enhanced sFlt-1 production leads to hypertension remain unclear. Both sFlt-1 and endothelin-1 production are elevated in women with PE and in placental ischemic animal models of PE, however, the importance of endothelin-1 and sFlt-1 interactions in control of blood pressure during pregnancy is unknown. The purpose of this study was to determine the role of endothelin-1 in mediating sFlt-1-induced hypertension in pregnant rats. To achieve this goal, sFlt-1 (3.7?g/kg/day for 6 days) was infused into normal pregnant rats (NP) and pregnant rats treated with a selective endothelin type A receptor antagonist, ABT 627 (5 mg/kg/day for 6 days). Plasma concentration of sFlt-1 increased from 73534 pg/ml in NP rats to 2498645 pg/ml, (p<0.05) with infusion of sFlt-1. Arterial pressure increased from 1001 mmHg in NP rats to 1223 mmHg, (p<0.05) in sFlt-1 infused rats. Chronic increases in plasma sFlt-1 in NP rats increased preproendothelin mRNA expression in the renal cortices ? 3 fold. In addition, chronic ETA blockade completely abolished the blood pressure response to sFlt-1 in pregnant rats (1043 vs. 1001 mmHg, p<0.05), while the ETA receptor antagonist had no effect on arterial pressure in NP rats (1052 vs. 1001mm Hg). In conclusion, this study demonstrates that endothelin-1, via endothelin type A receptor activation, plays an important role in mediating the hypertension in response to excess sFlt-1 during pregnancy. PMID:20026766

  15. Low-Salt Diet and Circadian Dysfunction Synergize to Induce Angiotensin II-Dependent Hypertension in Mice.

    PubMed

    Pati, Paramita; Fulton, David J R; Bagi, Zsolt; Chen, Feng; Wang, Yusi; Kitchens, Julia; Cassis, Lisa A; Stepp, David W; Rudic, R Daniel

    2016-03-01

    Blood pressure exhibits a robust circadian rhythm in health. In hypertension, sleep apnea, and even shift work, this balanced rhythm is perturbed via elevations in night-time blood pressure, inflicting silent damage to the vasculature and body organs. Herein, we examined the influence of circadian dysfunction during experimental hypertension in mice. Using radiotelemetry to measure ambulatory blood pressure and activity, the effects of angiotensin II administration were studied in wild-type (WT) and period isoform knockout (KO) mice (Per2-KO, Per2, 3-KO, and Per1, 2, 3-KO/Per triple KO [TKO] mice). On a normal diet, administration of angiotensin II caused nondipping blood pressure and exacerbated vascular hypertrophy in the Period isoform KO mice relative to WT mice. To study the endogenous effects of angiotensin II stimulation, we then administered a low-salt diet to the mice, which does stimulate endogenous angiotensin II in addition to lowering blood pressure. A low-salt diet decreased blood pressure in wild-type mice. In contrast, Period isoform KO mice lost their circadian rhythm in blood pressure on a low-salt diet, because of an increase in resting blood pressure, which was restorable to rhythmicity by the angiotensin receptor blocker losartan. Chronic administration of low salt caused vascular hypertrophy in Period isoform KO mice, which also exhibited increased renin levels and altered angiotensin 1 receptor expression. These data suggest that circadian clock genes may act to inhibit or control renin/angiotensin signaling. Moreover, circadian disorders such as sleep apnea and shift work may alter the homeostatic responses to sodium restriction to potentially influence nocturnal hypertension. PMID:26781276

  16. [PHYSICAL EXERCISE TRAINING CAN- CELS CONSTITUTIVE NOS UNCOUPLING AND INDUCED VIOLATIONS OF CARDIAC HEMODYNAMICS IN HYPERTENSION (PART III)].

    PubMed

    Dorofeyeva, N A; Kotsuruba, A V; Kopjak, B S; Sagach, V F

    2015-01-01

    In the heart and heart mitochondria spontaneously hypertensive rats investigated the effect of physical exercise training (swimming in a moderate and excessive training mode) on the physiological indicators of cardiac hemodynamics and biochemical parameters that characterize the level of oxidative and nitrosative stress. The index of coupling Ca(2+)-dependent constitutive NO-synthases (cNOS = eNOS + nNOS) and biochemical index of dysfunction were calculated. It turned out that both modes of training is completely restored, and even exceed the reference values in untrained rats Wistar conjugate cNOS state and Ca(2+)-dependent synthesis of nitric oxide (NO). Intensity regime of exercise on the border of functionality have been ineffective for improving the functional state of the cardiovascular system and hypertension can provoke it further. Moderate physical training regime, on the contrary, improves the diastolic function of the heart due to an increase dP/dtmin, reducing end-diastolic pressure and a significant reduction in end-diastolic stiffness. Moderate exercise decreased peripheral resistance and cardiac afterload, as indicated by the decrease in end-systolic pressure and arterial stiffness, which contributed to more efficient and energy-saving of heart work. Improve physiological indicators of cardiac hemodynamics and functional state of the heart in moderate mode of training correlated with changes in both the calculated indices. Moderate mode of training is recommended as a simple physiological preconditioning method for the prevention of cardiac dysfunction, hypertension as a result of state uncoupling cNOS and the resulting excessive generation of superoxide and, conversely, inhibition of Ca(2+)-dependent synthesis of NO. PMID:26552300

  17. Disruption of the cytochrome P-450 1B1 gene exacerbates renal dysfunction and damage associated with angiotensin II-induced hypertension in female mice.

    PubMed

    Jennings, Brett L; Moore, Joseph A; Pingili, Ajeeth K; Estes, Anne M; Fang, Xiao R; Kanu, Alie; Gonzalez, Frank J; Malik, Kafait U

    2015-05-01

    Recently, we demonstrated in female mice that protection against ANG II-induced hypertension and associated cardiovascular changes depend on cytochrome P-450 (CYP)1B1. The present study was conducted to determine if Cyp1b1 gene disruption ameliorates renal dysfunction and organ damage associated with ANG II-induced hypertension in female mice. ANG II (700 ngkg(-1)min(-1)) infused by miniosmotic pumps for 2 wk in female Cyp1b1(+/+) mice did not alter water consumption, urine output, Na(+) excretion, osmolality, or protein excretion. However, in Cyp1b1(-/-) mice, ANG II infusion significantly increased (P < 0.05) water intake (5.50 0.42 ml/24 h with vehicle vs. 8.80 0.60 ml/24 h with ANG II), urine output (1.44 0.37 ml/24 h with vehicle vs. 4.30 0.37 ml/24 h with ANG II), and urinary Na(+) excretion (0.031 0.016 mmol/24 h with vehicle vs. 0.099 0.010 mmol/24 h with ANG II), decreased osmolality (2,630 79 mosM/kg with vehicle vs. 1,280 205 mosM/kg with ANG II), and caused proteinuria (2.60 0.30 mg/24 h with vehicle vs. 6.96 0.55 mg/24 h with ANG II). Infusion of ANG II caused renal fibrosis, as indicated by an accumulation of renal interstitial ?-smooth muscle actin, collagen, and transforming growth factor-? in Cyp1b1(-/-) but not Cyp1b1(+/+) mice. ANG II also increased renal production of ROS and urinary excretion of thiobarburic acid-reactive substances and reduced the activity of antioxidants and urinary excretion of nitrite/nitrate and the 17?-estradiol metabolite 2-methoxyestradiol in Cyp1b1(-/-) but not Cyp1b1(+/+) mice. These data suggest that Cyp1b1 plays a critical role in female mice in protecting against renal dysfunction and end-organ damage associated with ANG II-induced hypertension, in preventing oxidative stress, and in increasing activity of antioxidant systems, most likely via generation of 2-methoxyestradiol from 17?-estradiol. PMID:25694484

  18. Uncoupling Protein-2 Mediates DPP-4 Inhibitor-Induced Restoration of Endothelial Function in Hypertension Through Reducing Oxidative Stress

    PubMed Central

    Liu, Limei; Liu, Jian; Tian, Xiao Yu; Wong, Wing Tak; Lau, Chi Wai; Xu, Aimin; Xu, Gang; Ng, Chi Fai; Yao, Xiaoqiang; Gao, Yuansheng

    2014-01-01

    Abstract Aims: Although uncoupling protein 2 (UCP2) negatively regulates intracellular reactive oxygen species (ROS) production and protects vascular function, its participation in vascular benefits of drugs used to treat cardiometabolic diseases is largely unknown. This study investigated whether UCP2 and associated oxidative stress reduction contribute to the improvement of endothelial function by a dipeptidyl peptidase-4 inhibitor, sitagliptin, in hypertension. Results: Pharmacological inhibition of cyclooxygenase-2 (COX-2) but not COX-1 prevented endothelial dysfunction, and ROS scavengers reduced COX-2 mRNA and protein expression in spontaneously hypertensive rats (SHR) renal arteries. Angiotensin II (Ang II) evoked endothelium-dependent contractions (EDCs) in C57BL/6 and UCP2 knockout (UCP2KO) mouse aortae. Chronic sitagliptin administration attenuated EDCs in SHR arteries and Ang II-infused C57BL/6 mouse aortae and eliminated ROS overproduction in SHR arteries, which were reversed by glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin 9-39, AMP-activated protein kinase (AMPK)α inhibitor compound C, and UCP2 inhibitor genipin. By contrast, sitagliptin unaffected EDCs in Ang II-infused UCP2KO mice. Sitagliptin increased AMPKα phosphorylation, upregulated UCP2, and downregulated COX-2 expression in arteries from SHR and Ang II-infused C57BL/6 mice. Importantly, exendin 9-39, compound C, and genipin reversed the inhibitory effect of GLP-1R agonist exendin-4 on Ang II-stimulated mitochondrial ROS rises in SHR endothelial cells. Moreover, exendin-4 improved the endothelial function of renal arteries from SHR and hypertensive patients. Innovation: We elucidate for the first time that UCP2 serves as an important signal molecule in endothelial protection conferred by GLP-1-related agents. UCP2 could be a useful target in treating hypertension-related vascular events. Conclusions: UCP2 inhibits oxidative stress and downregulates COX-2 expression through GLP-1/GLP-1R/AMPKα cascade. Antioxid. Redox Signal. 21, 1571–1581. PMID:24328731

  19. Sex differences in primary hypertension

    PubMed Central

    2012-01-01

    Men have higher blood pressure than women through much of life regardless of race and ethnicity. This is a robust and highly conserved sex difference that it is also observed across species including dogs, rats, mice and chickens and it is found in induced, genetic and transgenic animal models of hypertension. Not only do the differences between the ovarian and testicular hormonal milieu contribute to this sexual dimorphism in blood pressure, the sex chromosomes also play a role in and of themselves. This review primarily focuses on epidemiological studies of blood pressure in men and women and experimental models of hypertension in both sexes. Gaps in current knowledge regarding what underlie male-female differences in blood pressure control are discussed. Elucidating the mechanisms underlying sex differences in hypertension may lead to the development of anti-hypertensives tailored to one's sex and ultimately to improved therapeutic strategies for treating this disease and preventing its devastating consequences. PMID:22417477

  20. [The renin-angiotensin-aldosterone system and the adrenergic system in normal pregnancy and hypertension induced by pregnancy].

    PubMed

    Fiévet, P; Coevoet, B; Andrejak, M; Comoy, E; Legrand, J; Lalau, J D; Gheerbrand, J D; Boulanger, J C; Fournier, A

    1982-06-01

    Plasma renin activity (PRA), plasma aldosterone (PA) and plasma catecholamines were measured in 3 groups of women with pregnancy of 20-38 weeks: group I of 16 normotensive controls, group II of 17 women with rest responding hypertension (RRH) and group III of 18 women with permanent hypertension (PH) (supine blood pressure greater than 140-90 mmHg after 8 days of rest, disappearing after delivery). Studies were realized on fasting ambulatory women on a normal salt diet. PRA (mean +/- SEM) was significantly higher in the RRH group than in the control and PH groups (15,8 +/- 2,3 ng/ml/h versus 6,7 +/- 0,5 and 8,9 +/- 0,9). PA was higher but not significantly in the RRH group (736 +/- 122 versus 533 +/- 52 and 502 +/- 103 pg/ml). Plasma epinephrine (PE) and norepinephrine (PNE) were significantly higher in the PH than in the control and RRH groups. 135 +/- 28 pg/nl versus 56 +/- 13 and 63 +/- 17 for PE and 387 +/- 91 versus 206 +/- 32 and 200 +/- 47 pg/ml). These data suggest that PH is linked with activation of the adrenergic system whereas RRH is linked with activation of the RAA system. PMID:6810837

  1. Des-aspartate angiotensin I (DAA-I) reduces endothelial dysfunction in the aorta of the spontaneously hypertensive rat through inhibition of angiotensin II-induced oxidative stress.

    PubMed

    Loh, Wei Mee; Ling, Wei Chih; Murugan, Dharmani D; Lau, Yeh Siang; Achike, Francis I; Vanhoutte, Paul M; Mustafa, Mohd Rais

    2015-08-01

    Des-aspartate angiotensin I (DAA-I), an endogenous nonapeptide, counteracts several effects of angiotensin II on vascular tone. The aim of this study was to investigate the acute protective effect of DAA-I on endothelial function in the spontaneously hypertensive rat (SHR) as well as its effect on angiotensin II-induced contractions and oxidative stress. Aortic rings were incubated with DAA-I (0.1?M) for 30min prior to the assessment of angiotensin II-induced contractions (0.1nM-10?M) in WKY and SHR aortas. Total nitrate and nitrite levels were assessed using a colorimetric method and reactive oxygen species (ROS) were measured by dihydroethidium (DHE) fluorescence and lucigenin-enhanced chemiluminescence. The effect of DAA-I was also assessed against endothelium-dependent and -independent relaxations to acetylcholine and sodium nitroprusside, respectively. Angiotensin II-induced contractions were significantly reduced by DAA-I, losartan and tempol. Incubation with ODQ (soluble guanylyl cyclase inhibitor) and removal of the endothelium prevented the reduction of angiotensin II-induced contractions by DAA-I. Total nitrate and nitrite levels were increased in DAA-I, losartan and tempol treated-SHR tissues while ROS level was reduced by DAA-I and the latter inhibitors. In addition, DAA-I significantly improved the impaired acetylcholine-induced relaxation in SHR aortas whilst sodium nitroprusside-induced endothelium-independent relaxation remained unaffected. The present findings indicate that improvement of endothelial function by DAA-I in the SHR aorta is mediated through endothelium-dependent release of nitric oxide and inhibition of angiotensin II-induced oxidative stress. PMID:25869508

  2. Effects of nebivolol in obese African Americans with hypertension (NOAAH): markers of inflammation and obesity in response to exercise-induced stress.

    PubMed

    Merchant, N; Rahman, S T; Ferdinand, K C; Haque, T; Umpierrez, G E; Khan, B V

    2011-03-01

    We sought to determine whether the antihypertensive drug nebivolol has beneficial effects on vascular markers of inflammation and oxidation in obese African-American patients with hypertension when exposed to exercise-induced stress. Forty-three obese, African-American subjects with hypertension were treated with nebivolol (5-10?mg/day) for 8 weeks. Before treatment the subjects underwent an exercise treadmill study to a level of eight metabolic equivalents. Circulating levels of soluble interleukin-6 (sIL-6), vascular cell adhesion molecule (VCAM-1), adiponectin and leptin were measured at pre-treadmill, and 1?min, 30?min, 60?min and 24?h after treadmill. After the 8-week treatment period, exercise treadmill study and the measurement of markers were repeated. Treatment with nebivolol reduced levels of sVCAM-1 at pre-exercise by 21% and at 1 and 30?min by 12.5 and 20%, respectively (P<0.005 from corresponding time point). In nebivolol-treated patients there was a reduction in sIL-6 levels by 20% and pre-exercise and at 1 and 60?min by 19.7 and 33.5%, respectively (P<0.005 from corresponding time point). Treatment with nebivolol increased levels of serum adiponectin by 28% (P=0.012) and decreased levels of leptin by 32% (P<0.005 from pre-treatment). Treatment with nebivolol improves markers of inflammation and obesity in a high-risk African-American population. Moreover, this effect is potentiated in response to exercise-induced stress. These results suggest that nebivolol differentially regulates markers of inflammation and obesity, thereby providing vascular protection. PMID:20376076

  3. Enhanced expression of epithelial sodium channels causes salt-induced hypertension in mice through inhibition of the ?2-isoform of Na+, K+-ATPase.

    PubMed

    Leenen, Frans H H; Hou, Xiaohong; Wang, Hong-Wei; Ahmad, Monir

    2015-05-01

    Knockout of the Nedd4-2 gene in mice results in overexpression of epithelial sodium channels (ENaC) on the plasma membrane in the kidney, choroid plexus and brain nuclei. These mice exhibit enhanced pressor responses to CSF [Na(+)] as well as dietary salt-induced hypertension which both can be blocked by central infusion of the ENaC blocker benzamil. Functional studies suggest that ENaC activation in the CNS results in release of endogenous ouabain (EO) and inhibition of the ?2-isoform of Na(+), K(+)-ATPase. To test this concept more specifically, we studied Nedd4-2(-/-) mice expressing the ouabain-resistant ?2R/R-isoform of Na(+), K(+)-ATPase. Intracerebroventricular (icv) infusion of Na(+)-rich aCSF (225mmol/L Na(+) at 0.4?L/min) increased MAP by 10-15mmHg in wild-type mice and by 25-30mmHg in Nedd4-2(-/-) mice, but by only ~5mmHg in ?2R/R and in ?2R/R/Nedd4-2(-/-) mice. Icv infusion of EO-binding Fab fragments also blocked the BP response in Nedd4-2(-/-) mice. In Nedd4-2(-/-) mice, 8% high-salt diet increased MAP by 25-30mmHg, but in ?2R/R/Nedd4-2(-/-) mice, it increased by only 5-10mmHg. In contrast, Nedd4-2(-/-) or ?2R/R did not affect the hypertension caused by sc infusion of Ang II. These findings substantiate the concept that enhanced ENaC activity causes salt-induced pressor responses mainly through EO inhibiting the ?2-isoform of Na(+), K(+)-ATPase in the brain. PMID:25991719

  4. Enhanced expression of epithelial sodium channels causes salt-induced hypertension in mice through inhibition of the α2-isoform of Na+, K+-ATPase

    PubMed Central

    Leenen, Frans H H; Hou, Xiaohong; Wang, Hong-Wei; Ahmad, Monir

    2015-01-01

    Knockout of the Nedd4-2 gene in mice results in overexpression of epithelial sodium channels (ENaC) on the plasma membrane in the kidney, choroid plexus and brain nuclei. These mice exhibit enhanced pressor responses to CSF [Na+] as well as dietary salt-induced hypertension which both can be blocked by central infusion of the ENaC blocker benzamil. Functional studies suggest that ENaC activation in the CNS results in release of endogenous ouabain (EO) and inhibition of the α2-isoform of Na+, K+-ATPase. To test this concept more specifically, we studied Nedd4-2−/− mice expressing the ouabain-resistant -isoform of Na+, K+-ATPase. Intracerebroventricular (icv) infusion of Na+-rich aCSF (225 mmol/L Na+ at 0.4 μL/min) increased MAP by 10–15 mmHg in wild-type mice and by 25–30 mmHg in Nedd4-2−/− mice, but by only ~5 mmHg in and in /Nedd4-2−/− mice. Icv infusion of EO-binding Fab fragments also blocked the BP response in Nedd4-2−/− mice. In Nedd4-2−/− mice, 8% high-salt diet increased MAP by 25–30 mmHg, but in /Nedd4-2−/− mice, it increased by only 5–10 mmHg. In contrast, Nedd4-2−/− or did not affect the hypertension caused by sc infusion of Ang II. These findings substantiate the concept that enhanced ENaC activity causes salt-induced pressor responses mainly through EO inhibiting the α2-isoform of Na+, K+-ATPase in the brain. PMID:25991719

  5. Hypertension (High Blood Pressure)

    MedlinePLUS

    ... I Help a Friend Who Cuts? Hypertension (High Blood Pressure) KidsHealth > For Teens > Hypertension (High Blood Pressure) ... Hypertension Treated? Can I Prevent It? What Is Blood Pressure? We all need blood pressure to live. ...

  6. What Causes Pulmonary Hypertension?

    MedlinePLUS

    ... page from the NHLBI on Twitter. What Causes Pulmonary Hypertension? Pulmonary hypertension (PH) begins with inflammation and changes in the ... that can cause them, go to "Types of Pulmonary Hypertension." Rate This Content: NEXT >> Updated: August 2, 2011 ...

  7. Types of Pulmonary Hypertension

    MedlinePLUS

    ... page from the NHLBI on Twitter. Types of Pulmonary Hypertension The World Health Organization divides pulmonary hypertension (PH) ... small blood vessels of the lungs. Group 2 Pulmonary Hypertension Group 2 includes PH with left heart disease. ...

  8. Enhanced Ca(2+)-induced Ca(2+) release from intracellular stores contributes to catecholamine hypersecretion in adrenal chromaffin cells from spontaneously hypertensive rats.

    PubMed

    Segura-Chama, Pedro; López-Bistrain, Patricia; Pérez-Armendáriz, Elia Martha; Jiménez-Pérez, Nicolás; Millán-Aldaco, Diana; Hernández-Cruz, Arturo

    2015-11-01

    Adrenal chromaffin cells (CCs) from spontaneously hypertensive rats (SHRs) secrete more catecholamine (CA) upon stimulation than CCs from normotensive Wistar Kyoto rats (WKY). Unitary CA exocytosis events, both spontaneous and stimulated, were amperometrically recorded from cultured WKY and SHR CCs. Both strains display spontaneous amperometric spikes but SHR CCs produce more spikes and of higher mean amplitude. After a brief stimulation with high K(+) or caffeine which produces voltage-gated Ca(2+) influx or intracellular Ca(2+) release, respectively, more spikes and of greater mean amplitude and unitary charge were recorded in SHR CCs. Consequently, peak cumulative charge was ~2-fold higher in SHR CCs. Ryanodine (10 μM), a specific blocker of the ryanodine receptors reduced depolarization-induced peak cumulative charge by ~10 % in WKY and ~77 % in SHR CCs, suggesting, a larger contribution of Ca(2+)-induced Ca(2+) release to CA exocytosis in SHR CCs. Accordingly, Ca(2+) imaging showed larger [Ca(2+)]i signals induced both by depolarization and caffeine in SHR CCs. Distribution amplitude histograms showed that small amperometric spikes (0-50 pA) are more frequent in WKY than in SHR CCs. Conversely, medium (50-190 pA) and large (190-290 pA) spikes are more numerous in SHR than in WKY CCs. This study reveals that the enhanced CA secretion in SHR CCs results from a combination of (1) larger depolarization-induced Ca(2+) transients, due to a greater Ca(2+)-induced intracellular Ca(2+) release, (2) more exocytosis events per time unit, and (3) a greater proportion of medium and large amperometric spikes probably due to a higher mean CA content per granule. Enhanced CA release by excessive amplification by Ca(2+) induced Ca(2+) release and larger granule catecholamine content contributes to the increased CA plasma levels and vasomotor tone in SHRs. PMID:25791627

  9. Lack of nitric oxide- and guanosine 3?:5?-cyclic monophosphate-dependent regulation of ?-thrombin-induced calcium transient in endothelial cells of spontaneously hypertensive rat hearts

    PubMed Central

    Failli, Paola; Fazzini, Alessandro; Ruocco, Carlo; Mazzetti, Luca; Cecchi, Enrica; Giovannelli, Lisa; Marra, Fabio; Milani, Stefano; Giotti, Alberto

    2000-01-01

    While the expression and/or activity of endothelial nitric oxide synthase (eNOS) has been characterized in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rat (WKY) hearts, in coronary endothelial cells (ECs) from both strains, the effect of NO on intracellular calcium concentration ([Ca2+]i) is still unknown. Coronary microvascular ECs were isolated from SHR and WKY and characterized. Immunocytochemistry and Western blot analysis showed that eNOS was similarly expressed in ECs from both strains. Measuring [Ca2+]i by imaging analysis of fura-2-loaded cells, we demonstrated that ?-thrombin (3?180?U?l?1) induced a superimposable dose-dependent calcium transient in ECs from both strains. In WKY ECs, S-nitroso-N-acetyl-DL-penicillamine (SNAP) dose-dependently (10100??M) and 0.1??M atrial natriuretic factor (ANF) reduced the maximum and the decay time of ?-thrombin-induced calcium transient. The inhibitory effects of SNAP and ANF were prevented by blocking cyclic GMP-dependent protein kinase. Non selective eNOS inhibitors prolonged the decay time of ?-thrombin-induced calcium transient, while the selective inducible NOS inhibitor 1400?W was ineffective. SNAP (100??M) and 0.1??M ANF increased cyclic GMP content up to 22.9 and 42.3 fold respectively. In SHR ECs, ?-thrombin-induced calcium transient was not modified by SNAP, ANF or eNOS inhibition. SNAP (100??M) and 0.1??M ANF increased cyclic GMP content up to 9.3 and 51 fold respectively. In WKY ECs, SNAP dose-dependently (10100??M) reduced also bradykinin-induced calcium transient, while in SHR ECs was ineffective. We concluded that in SHR ECs, the cyclic GMP-dependent regulation of calcium transient is lost. PMID:10928946

  10. Impromidine-induced changes in the permeability of the blood-brain barrier of normotensive and spontaneously hypertensive rats

    SciTech Connect

    Boertje, S.B.; Le Beau, D.; Ward, S. )

    1990-08-01

    Previous studies suggested histamine receptors mediate changes in the cerebrovascular permeability of rats. To test this, we investigated the effects of impromidine, a specific agonist at the histamine H2-receptor, on blood pressure and permeability of the blood-brain barrier (BBB). Impromidine produced dose-dependent hypotension in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Two higher doses of impromidine increased BBB permeability to 99mTc-sodium pertechnetate in WKY rats; however, two lower doses decreased permeability in SHR rats. All doses of impromidine increased cerebrovascular permeability to 131I-labeled serum albumin in both species. Doses of the drug were 100 times greater than those required to produce similar alterations using histamine.

  11. Renin-Angiotensin System Genes and Exercise Training-Induced Changes in Sodium Excretion in African American Hypertensives

    PubMed Central

    Jones, Jennifer M.; Park, Jung-Jun; Johnson, Jennifer; Vizcaino, Dave; Hand, Brian; Ferrell, Robert; Weir, Matthew; Dowling, Thomas; Obisesan, Thomas; Brown, Michael

    2008-01-01

    Objective To determine whether angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) genotypes could predict changes in urinary sodium excretion in response to short-term aerobic exercise training (AEX). Design Longitudinal intervention. Setting The study was conducted at the University of Maryland at College Park and at Baltimore, and the University of Pittsburgh General Clinical Research Center. Participants 31 (age 53 2 years) sedentary, hypertensive (146 2/88 2 mm Hg) African Americans. Intervention Aerobic exercise training (AEX) consisted of seven or eight consecutive days, 50 minutes per day, at 65% of heart rate reserve. Participants underwent a 24-hour period of ambulatory blood pressure (BP) monitoring and urine collection at baseline and 1418 hours after the last exercise session. Main Outcome Measures Angiotensiongen (AGT) M235T and ACE I/D genotype and sodium excretion and ambulatory BP. Results Average sodium excretion for the entire group independent of genotype increased after AEX (108 9 vs 143 12 mEq/day, P=.003). Sodium excretion significantly increased after exercise training in the ACE II (114 22 vs 169 39 mEq/day, P=.04), but not in the ID (100 8 vs 133 17 mEq/day, P=.12) or DD (113 18 vs 138 11 mEq/day, P=.13) genotype groups. In the II genotype group, the increase in sodium excretion was significantly and inversely correlated with decreases in 24-hour diastolic (r=?.88, P=.02) and mean (r=?.95, P=.004) BP. The AGT TT and MT+MM genotype groups similarly increased their sodium excretion by 34 16 (P=.05) and 37 17 (P=.05) mEq/day respectively. Conclusions These results suggest that African American hypertensives with the ACE II genotype may be m