Sample records for ace inhibitor enalapril

  1. Angiotensin-converting enzyme inhibitor (enalapril maleate) accelerates recovery of mouse skin from UVB-induced wrinkles

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

    Matsuura-Hachiya, Yuko; Arai, Koji Y.; Ozeki, Rieko

    Highlights: •Angiotensin converting enzyme (ACE) increases in UVB-irradiated skin. •Administration of an ACE inhibitor improved UVB-induced skin wrinkle. •ACE inhibitor improved UVB-induced epidermal hypertrophy. •ACE inhibitor improved transepidermal water loss in the UVB-irradiated skin. -- Abstract: Angiotensin-converting enzyme (ACE) activity and angiotensin II signaling regulate cell proliferation, differentiation, and tissue remodeling, as well as blood pressure, while in skin, angiotensin II signaling is involved in wound healing, inflammation, and pathological scar formation. Therefore, we hypothesized that angiotensin II is also involved in photoaging of skin. In this study, we examined the effect of enalapril maleate, an ACE inhibitor, on recoverymore » of wrinkled skin of hairless mice exposed to long-term UVB irradiation. Immunohistochemical observation revealed that expression of ACE, angiotensin II, and angiotensin II type 1 (AT1) and type 2 (AT2) receptors in the skin was increased after UVB irradiation (3 times/week at increasing intensities for 8 weeks). Administration of enalapril maleate (5 times/week for 6 weeks, starting 1 week after 10-week irradiation) accelerated recovery from UVB-induced wrinkles, epidermal hyperplasia and epidermal barrier dysfunction, as compared with the vehicle control. Our results indicate that ACE and angiotensin II activity are involved in skin photoaging, and suggest that ACE inhibitor such as enalapril maleate may have potential for improvement of photoaged skin.« less

  2. ACE Phenotyping as a Guide Toward Personalized Therapy With ACE Inhibitors.

    PubMed

    Danilov, Sergei M; Tovsky, Stan I; Schwartz, David E; Dull, Randal O

    2017-07-01

    Angiotensin-converting enzyme (ACE) inhibitors (ACEI) are widely used in the management of cardiovascular diseases but with significant interindividual variability in the patient's response. To investigate whether interindividual variability in the response to ACE inhibitors is explained by the "ACE phenotype"-for example, variability in plasma ACE concentration, activity, and conformation and/or the degree of ACE inhibition in each individual. The ACE phenotype was determined in plasma of 14 patients with hypertension treated chronically for 4 weeks with 40 mg enalapril (E) or 20 mg E + 16 mg candesartan (EC) and in 20 patients with hypertension treated acutely with a single dose (20 mg) of E with or without pretreatment with hydrochlorothiazide. The ACE phenotyping included (1) plasma ACE concentration; (2) ACE activity (with 2 substrates: Hip-His-Leu and Z-Phe-His-Leu and calculation of their ratio); (3) detection of ACE inhibitors in patient's blood (indicator of patient compliance) and the degree of ACE inhibition (ie, adherence); and (4) ACE conformation. Enalapril reduced systolic and diastolic blood pressure in most patients; however, 20% of patients were considered nonresponders. Chronic treatment results in 40% increase in serum ACE concentrations, with the exception of 1 patient. There was a trend toward better response to ACEI among patients who had a higher plasma ACE concentration. Due to the fact that "20% of patients do not respond to ACEI by blood pressure drop," the initial blood ACE level could not be a predictor of blood pressure reduction in an individual patient. However, ACE phenotyping provides important information about conformational and kinetic changes in ACE of individual patients, and this could be a reason for resistance to ACE inhibitors in some nonresponders.

  3. Interactions between ACE inhibitors and classical antiepileptic drugs in the mouse maximal electroshock seizures.

    PubMed

    Łukawski, Krzysztof; Jakubus, Tomasz; Janowska, Agnieszka; Czuczwar, Stanisław J

    2011-11-01

    This study evaluated the effect of two angiotensin-converting enzyme (ACE) inhibitors, enalapril and cilazapril, commonly used antihypertensive drugs, on the protective efficacy of the classical antiepileptics - carbamazepine (CBZ), phenytoin (PHT), valproate (VPA) and phenobarbital (PB). For this purpose, we used the maximal electroshock seizure (MES) test in mice. Additionally, adverse effects of combined treatment with ACE inhibitors and antiepileptic drugs in the passive avoidance task and chimney test were assessed. All drugs were administered intraperitoneally. Neither enalapril (10, 20 and 30 mg/kg) nor cilazapril (5, 10 and 20mg/kg) affected the threshold for electroconvulsions. Enalapril (30 mg/kg) but not cilazapril (20mg/kg), enhanced the protective action of VPA, decreasing its ED(50) value from 249.5 to 164.9 mg/kg (p<0.01). Free plasma (non-protein-bound) and total brain concentrations of VPA were not significantly influenced by enalapril. Therefore, the observed interaction could be pharmacodynamic in nature. The combinations of ACE inhibitors with other antiepileptics (CBZ, PHT, and PB) were ineffective in that their ED(50) values against MES were not significantly changed. Enalapril and cilazapril remained ineffective as regards memory retention in the passive avoidance task or motor performance in the chimney test. The current study suggests that there are no negative interactions between the studied ACE inhibitors and classical antiepileptic drugs. Enalapril was even documented to enhance the anticonvulsant activity of VPA. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. ADVERSE PREGNANCY OUTCOMES ASSOCIATED WITH MATERNAL ENALAPRIL ANTIHYPERTENSIVE TREATMENT

    EPA Science Inventory

    Enalapril, one of several antihypertensive drugs that act as angiotensin-converting enzyme (ACE) inhibitors, is often used for treatment of hypertension in women of reproductive age. Adverse birth outcomes following the use of ACE inhibitors, including enalapril, during pregnanc...

  5. Angiotensin-converting enzyme inhibitor (enalapril maleate) accelerates recovery of mouse skin from UVB-induced wrinkles.

    PubMed

    Matsuura-Hachiya, Yuko; Arai, Koji Y; Ozeki, Rieko; Kikuta, Ayako; Nishiyama, Toshio

    2013-12-06

    Angiotensin-converting enzyme (ACE) activity and angiotensin II signaling regulate cell proliferation, differentiation, and tissue remodeling, as well as blood pressure, while in skin, angiotensin II signaling is involved in wound healing, inflammation, and pathological scar formation. Therefore, we hypothesized that angiotensin II is also involved in photoaging of skin. In this study, we examined the effect of enalapril maleate, an ACE inhibitor, on recovery of wrinkled skin of hairless mice exposed to long-term UVB irradiation. Immunohistochemical observation revealed that expression of ACE, angiotensin II, and angiotensin II type 1 (AT1) and type 2 (AT2) receptors in the skin was increased after UVB irradiation (3 times/week at increasing intensities for 8 weeks). Administration of enalapril maleate (5 times/week for 6 weeks, starting 1 week after 10-week irradiation) accelerated recovery from UVB-induced wrinkles, epidermal hyperplasia and epidermal barrier dysfunction, as compared with the vehicle control. Our results indicate that ACE and angiotensin II activity are involved in skin photoaging, and suggest that ACE inhibitor such as enalapril maleate may have potential for improvement of photoaged skin. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Comparison of captopril and enalapril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with ACE inhibitors in high dieted methionine mice.

    PubMed

    Liu, Yu-Hui; Liu, Li-Ying; Wu, Jin-Xiang; Chen, Shuang-Xiu; Sun, Yin-Xue

    2006-01-01

    To examine the role of sulfhydryl (-SH) group in improvement of endothelial dysfunction with angiotensin-converting enzyme (ACE) inhibitors in experimental high dose of methionine dieted rats. We compared the effects of Captopril (an ACE inhibitor with -SH group), enalapril (an ACE-inhibitor without -SH group), N-acetylcysteine (only -SH group not ACE inhibitor) on endothelial dysfunction injured by methionine-induced hyperhomocysteinemia (HHcy) in rats. Male Sprague-Dawley rats were divided randomly into seven groups: control group, L-methionine group, low dose Captopril (15 mg/kg), middle dose Captopril (30 mg/kg), high dose Captopril (45 mg/kg), enalapril (20 mg/kg), N-acetylcysteine (200 mg/kg); control group were intragastric gavaged by water and others groups were intragastric gavaged by L-methionine and drugs in water one time every day. Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation of aortic rings were examined. Paraoxonase1 (PON1) and ACE activity, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) in serum were analyzed. It was found that a single intragastric gavage by L-methionine resulted in inhibition of endothelium-dependent relaxation, markedly increased the serum level of malondialdehyde and decreased the activity of PON1 and SOD, similarly decreased the level of NO in the serum; but had no effects on endothelium-independent relaxation and angiotensin-converting enzyme activity compared with the control group. Given the treatment with three doses of Captopril (15 approximately 45 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, and eliminated the increased level of malondialdehyde, the decreased level of NO, activity of PON1 and SOD in serum by single intragastric gavaged L-methionine. However, there were some significant differences among Captopril (30 mg/kg or 45 mg/kg), enalapril (20 mg/kg), and N

  7. Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure.

    PubMed

    McMurray, John J V; Krum, Henry; Abraham, William T; Dickstein, Kenneth; Køber, Lars V; Desai, Akshay S; Solomon, Scott D; Greenlaw, Nicola; Ali, M Atif; Chiang, Yanntong; Shao, Qing; Tarnesby, Georgia; Massie, Barry M

    2016-04-21

    Among patients with chronic heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is unknown. We compared the ACE inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction. After a single-blind run-in period, we assigned patients, in a double-blind fashion, to one of three groups: 2336 patients were assigned to receive enalapril at a dose of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once daily, and 2340 to receive both treatments (combination therapy). The primary composite outcome was death from cardiovascular causes or hospitalization for heart failure. After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval [CI], 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P=0.005), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P=0.009) and an elevated potassium level (17.1% vs. 12.5%, P<0.001). In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapril. (Funded by Novartis; ATMOSPHERE ClinicalTrials.gov number, NCT00853658.).

  8. Differential recognition of ACE inhibitors in Xenopus laevis oocytes expressing rat PEPT1 and PEPT2.

    PubMed

    Zhu, T; Chen, X Z; Steel, A; Hediger, M A; Smith, D E

    2000-05-01

    To examine the mechanism of inhibition of glycylsarcosine (GlySar) transport by quinapril and enalapril, and whether or not angiotensin converting enzyme (ACE) inhibitors are transported by PEPT2 as well as by PEPT1. Xenopus laevis oocytes were cRNA-injected with rat PEPT1 or PEPT2 and the transport kinetics of radiolabeled GlySar were studied in the absence and presence of quinapril and enalapril. The two-microelectrode voltage-clamp technique was also performed to probe the electrogenic uptake of captopril, quinapril and enalapril. Kinetic analyses demonstrated that quinapril inhibited the uptake of GlySar in a noncompetitive manner in Xenopus oocytes injected with PEPT1 or PEPT2 (Ki = 0.8 or 0.4 mM, respectively). In contrast, a competitive interaction was observed between GlySar and enalapril (Ki = 10.8 mM for PEPT1 or 4.3 mM for PEPT2). Most significantly, captopril and enalapril, but not quinapril, induced inwardly-directed currents in both PEPT1- and PEPT2-expressed oocytes. These results are unique in providing direct evidence for the substrate recognition and transport of some ACE inhibitors by the high- and low-affinity oligopeptide transporters. Our findings point to differences between PEPT1 and PEPT2 in their affinity to, rather than in their specificity for, ACE inhibitors.

  9. Enalapril and diltiazem co-administration and respiratory side effects of enalapril.

    PubMed

    Franová, S; Nosál'ová, G; Antosová, M; Nosál', S

    2005-01-01

    A persistent, chronic dry cough is the most common adverse effect of angiotensin converting enzyme (ACE) inhibitors therapy. The mechanism of this respiratory adverse effect is related to the inhibition of ACE and the accumulation of bradykinin, substance P, prostanoids and other inflammatory neuropeptides in the airways. The aim of this study was to follow the relationship between 15-day administration of enalapril and the defense reflexes (cough and bronchoconstriction) of the airways in experimental animals, as well as the possibility of their pharmacological restriction with simultaneous diltiazem administration. Cough reflex was investigated by the method of mechanical irritation of laryngopharyngeal and tracheobronchial area in non-anesthetized cats. The reactivity of tracheal smooth muscles of the airways to bronchoconstrictor mediators (histamine 10 nM - 1 mM, acetylcholine 10 nM - 1 mM and KCl 1 mM - 100 mM) was evaluated by an in vitro method in guinea pigs. Enalapril 5 mg/kg/day and diltiazem 30 mg/kg/day were administered perorally for 15 days. The results showed that long-lasting administration of enalapril resulted in a significant increase of measured cough parameters and increased reactivity of tracheal smooth muscle to histamine and KCl. Simultaneous administration of enalapril together with diltiazem significantly decreased the enalapril induced cough, and decreased enalapril induced hyperreactivity of tracheal smooth muscles to KCl. The results showed a partially protective effect of diltiazem and enalapril co-administration on the respiratory adverse effects induced by enalapril therapy.

  10. Enalapril enhances the anticonvulsant activity of lamotrigine in the test of maximal electroshock.

    PubMed

    Łukawski, Krzysztof; Jakubus, Tomasz; Janowska, Agnieszka; Raszewski, Grzegorz; Czuczwar, Stanisław J

    2013-01-01

    The aim of this study was to find out whether angiotensin-converting enzyme (ACE) inhibitors, enalapril and cilazapril, affect the anticonvulsant action of some second-generation antiepileptics, lamotrigine (LTG), topiramate (TPM) and oxcarbazepine (OXC). The effects of ACE inhibitors on antiepileptic drugs were examined in the mouse model of maximal electroshock. Enalapril (30 mg/kg ip) potentiated the anticonvulsant action of LTG, decreasing its ED50 value from 5.3 to 3.6 mg/kg (p < 0.01). The anticonvulsant activity of TPM or OXC was not modified by enalapril. Cilazapril did not affect the protective activity of the studied antiepileptics. The interaction between enalapril and LTG could be pharmacodynamic in nature because enalapril did not change plasma and total brain concentrations of LTG. This study shows that there are no negative interactions between the studied antiepileptic drugs and enalapril or cilazapril. Enalapril even enhanced the anticonvulsant activity of LTG in the MES test in mice that is thought to be a predictive model of human generalized tonic-clonic seizures.

  11. ENALAPRIL: PHARMACOKINETIC/DYNAMIC INFERENCES FOR COMPARATIVE DEVELOPMENTAL TOXICITY

    EPA Science Inventory

    Enalapril is an antihypertensive drug of the class of angiotensin-converting enzyme inhibitors (ACEI) used in pregnancy for treatment of pre-existing or pregnancy-induced hypertension. The use of ACE inhibitors (drugs that act directly on the renin-angiotensin system) during the ...

  12. Impact of angiotensin-converting enzyme gene polymorphism on neurohormonal responses to high- versus low-dose enalapril in advanced heart failure.

    PubMed

    Tang, W H Wilson; Vagelos, Randall H; Yee, Yin-Gail; Fowler, Michael B

    2004-11-01

    The impact of angiotensin-converting enzyme (ACE) gene polymorphism on neurohormonal dose response to ACE inhibitor therapy is unclear. ACE Insertion (I) or Deletion (D) genotype was determined in 74 patients with chronic heart failure who were randomly assigned to receive either high-dose or low-dose enalapril over a period of 6 months. Monthly pre-enalapril and post-enalapril neurohormone levels (serum ACE activity (sACE), plasma angiotensin II (A-II), plasma renin activity (PRA), and serum aldosterone (ALDO) were compared between genotype subgroups and between patients who received high- or low-dose enalapril within each genotype subgroup. At baseline, predose/postdose sACE and postdose PRA were significantly higher in the DD genotype. At 6-month follow-up, postdose sACE was reduced in a dose-dependent fashion in all three genotypes (P < .05). However, predose and postdose ALDO and A-II levels did not differ between each genotype subgroup at baseline or by enalapril dose within each genotype subgroup. ALDO escape and A-II reactivation were not affected by ACE genotype or enalapril dosage. Predose sACE were consistently higher in the DD genotype when compared with ID or II subgroups. Despite a dose-dependent suppression of sACE, there were no observed statistically significant differences in ALDO and A-II suppression or escape with escalating doses of enalapril within each subgroup.

  13. Hydronephrosis alters cardiac ACE2 and Mas receptor expression in mice.

    PubMed

    Zhang, Yanling; Ma, Lulu; Wu, Junyan; Chen, Tingting

    2015-06-01

    Hydronephrosis is characterized by substantial loss of tubules and affects renin secretion in the kidney. However, whether alterations of angiotensin-converting enzyme (ACE), ACE2 and Mas receptor in the heart are observed in hydronephrosis is unknown. Thus, we assessed these components in hydronephrotic mice treated with AT1 receptor blockade and ACE inhibitor. Hydronephrosis was induced by left ureteral ligation in Balb/C mice except sham-operated animals. The levels of cardiac ACE, ACE2 and Mas receptor were measured after treatment of losartan or enalapril. Hydronephrosis led to an increase of ACE level and a decrease of ACE2 and Mas receptor in the heart. Losartan decreased cardiac ACE level, but ACE2 and Mas receptor levels significantly increased in hydronephrotic mice (p < 0.01). Enalapril increased ACE2 levels (p < 0.01), but did not affect Mas receptor in the heart. Plasma renin activity (PRA) and Ang II decreased in hydronephrotic mice, but significantly increased after treatment with losartan or enalapril. Hydronephrosis increased cardiac ACE and suppressed ACE2 and Mas receptor levels. AT1 blockade caused sustained activation of cardiac ACE2 and Mas receptor, but ACE inhibitor had the limitation of such activation of Mas receptor in hydronephrotic animals. © The Author(s) 2015.

  14. Association of insertion/deletion polymorphism of angiotensin-converting enzyme gene among Malay male hypertensive subjects in response to ACE inhibitors.

    PubMed

    Heidari, Farzad; Vasudevan, Ramachandran; Mohd Ali, Siti Zubaidah; Ismail, Patimah; Etemad, Ali; Pishva, Seyyed Reza; Othman, Fauziah; Abu Bakar, Suhaili

    2015-12-01

    Several studies show that the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with hypertension in various populations. The present study sought to determine the association of the I/D gene polymorphism among Malay male essential hypertensive subjects in response to ACE inhibitors (enalapril and lisinopril). A total of 72 patients with newly diagnosed hypertension and 72 healthy subjects were recruited in this study. Blood pressure was recorded from 0 to 24 weeks of treatment with enalapril or lisinopril. Genotyping of the I/D polymorphism was carried out using a standard PCR method. Statistically significant association of the D allele of the ACE gene was observed between the case and control subjects (p < 0.01). There was a decrease in blood pressure in the patients carrying the DD genotype (SBP=18.5±8.1 mmHg, DBP=15.29±7.1 mmHg) rather than the ID (SBP=4.1±3.3 mmHg, DBP=9.1±3.5 mmHg) and II genotypes (SBP= 3.0±0.2 mmHg, DBP 0.11±6.1 mmHg) of the ACE gene. Patients carrying the DD genotype had higher blood pressure-lowering response when treated with ACE inhibitors enalapril or lisinopril than those carrying ID and II genotypes, suggesting that the D allele may be a possible genetic marker for essential hypertension among Malay male subjects. © The Author(s) 2014.

  15. Enalapril protects against myocardial ischemia/reperfusion injury in a swine model of cardiac arrest and resuscitation

    PubMed Central

    Wang, Guoxing; Zhang, Qian; Yuan, Wei; Wu, Junyuan; Li, Chunsheng

    2016-01-01

    There is strong evidence to suggest that angiotensin-converting enzyme inhibitors (ACEIs) protect against local myocardial ischemia/reperfusion (I/R) injury. This study was designed to explore whether ACEIs exert cardioprotective effects in a swine model of cardiac arrest (CA) and resuscitation. Male pigs were randomly assigned to three groups: sham-operated group, saline treatment group and enalapril treatment group. Thirty minutes after drug infusion, the animals in the saline and enalapril groups were subjected to ventricular fibrillation (8 min) followed by cardiopulmonary resuscitation (up to 30 min). Cardiac function was monitored, and myocardial tissue and blood were collected for analysis. Enalapril pre-treatment did not improve cardiac function or the 6-h survival rate after CA and resuscitation; however, this intervention ameliorated myocardial ultrastructural damage, reduced the level of plasma cardiac troponin I and decreased myocardial apoptosis. Plasma angiotensin (Ang) II and Ang-(1–7) levels were enhanced in the model of CA and resuscitation. Enalapril reduced the plasma Ang II level at 4 and 6 h after the return of spontaneous circulation whereas enalapril did not affect the plasma Ang-(1–7) level. Enalapril pre-treatment decreased the myocardial mRNA and protein expression of angiotensin-converting enzyme (ACE). Enalapril treatment also reduced the myocardial ACE/ACE2 ratio, both at the mRNA and the protein level. Enalapril pre-treatment did not affect the upregulation of ACE2, Ang II type 1 receptor (AT1R) and MAS after CA and resuscitation. Taken together, these findings suggest that enalapril protects against ischemic injury through the attenuation of the ACE/Ang II/AT1R axis after CA and resuscitation in pigs. These results suggest the potential therapeutic value of ACEIs in patients with CA. PMID:27633002

  16. Physiological disposition and metabolism of enalapril maleate in laboratory animals

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

    Tocco, D.J.; deLuna, F.A.; Duncan, A.E.

    N-(1-(S)-carboxy-3-phenylpropyl)-L-alanyl-L-proline (MK-422), is a potent angiotensin I-converting enzyme (ACE) inhibitor, but as a diacid is poorly absorbed in laboratory animals. Enalapril maleate, the monoethyl ester of MK-422, proved to be significantly better absorbed in both rats and dogs. Peak levels of radioactivity in plasma occurred in 30 min in rats and 2 hr in dogs after a single dose of /sup 14/C-enalapril maleate (1 mg/kg, po). Rats excreted 26% of the dose in the urine and 72% in the feces in 72 hr; dogs excreted 40% of the dose in the urine and 36% in the feces. After the intravenousmore » dose, the presence of radioactivity in the feces of both species suggested that some biliary excretion had occurred. Absorption was estimated to be 34% in the rat and 61% in the dog. The major metabolite of enalapril maleate in dogs, accounting for 86% of the urine radioactivity, was identified as MK-422 by GC/MS. A procedure was developed for the quantitation of MK-422 and enalapril in plasma and urine by their inhibition of purified ACE. The assays showed that enalapril was absorbed intact in dogs and converted to MK-422 after absorption.« less

  17. Renin-angiotensin system phenotyping as a guidance toward personalized medicine for ACE inhibitors: can the response to ACE inhibition be predicted on the basis of plasma renin or ACE?

    PubMed

    Schilders, Joyce E M; Wu, Haiyan; Boomsma, Frans; van den Meiracker, Anton H; Danser, A H Jan

    2014-08-01

    Not all hypertensive patients respond well to ACE inhibition. Here we determined whether renin-angiotensin system (RAS) phenotyping, i.e., the measurement of renin or ACE, can predict the individual response to RAS blockade, either chronically (enalapril vs. enalapril + candesartan) or acutely (enalapril ± hydrochlorothiazide, HCT). Chronic enalapril + candesartan induced larger renin rises, but did not lower blood pressure (BP) more than enalapril. Similar observations were made for enalapril + HCT vs. enalapril when given acutely. Baseline renin predicted the peak changes in BP chronically, but not acutely. Baseline ACE levels had no predictive value. Yet, after acute drug intake, the degree of ACE inhibition, like Δrenin, did correlate with ΔBP. Only the relationship with Δrenin remained significant after chronic RAS blockade. Thus, a high degree of ACE inhibition and a steep renin rise associate with larger acute responses to enalapril. However, variation was large, ranging >50 mm Hg for a given degree of ACE inhibition or Δrenin. The same was true for the relationships between Δrenin and ΔBP, and between baseline renin and the maximum reduction in BP in the chronic study. Our data do not support that RAS phenotyping will help to predict the individual BP response to RAS blockade. Notably, these conclusions were reached in a carefully characterized, homogenous population, and when taking into account the known fluctuations in renin that relate to gender, age, ethnicity, salt intake and diuretic treatment, it seems unlikely that a cut-off renin level can be defined that has predictive value.

  18. Investigation of interaction studies of cefpirome with ACE-inhibitors in various buffers

    NASA Astrophysics Data System (ADS)

    Nawaz, Muhammad; Arayne, Muhammad Saeed; Sultana, Najma; Abbas, Hira Fatima

    2015-02-01

    This work describes a RP-HPLC method for the determination and interaction studies of cefpirome with ACE-inhibitors (captopril, enalapril and lisinopril) in various buffers. The separation and interaction of cefpirome with ACE-inhibitors was achieved on a Purospher Star, C18 (5 μm, 250 × 4.6 mm) column. Mobile phase consisted of methanol: water (80:20, v/v, pH 3.3); however, for the separation of lisinopril, it was modified to methanol-water (40:60, v/v, pH 3.3) and pumped at a flow rate of 1 mL min-1. In all cases, UV detection was performed at 225 nm. Interactions were carried out in physiological pH i.e., pH 1 (simulated gastric juice), 4 (simulated full stomach), 7.4 (blood pH) and 9 (simulated GI), drug contents were analyzed by reverse phase high performance liquid chromatography. Method was found linear in the concentration range of 1.0-50.0 μg mL-1 with correlation coefficient (r2) of 0.999. Precision (RSD%) was less than 2.0%, indicating good precision of the method and accuracy was 98.0-100.0%. Furthermore, cefpirome-ACE-inhibitors' complexes were also synthesized and results were elucidated on the basis of FT-IR, and 1H NMR. The interaction results show that these interactions are pH dependent and for the co-administration of cefpirome and ACE-inhibitors, a proper interval should be given.

  19. Relative lipophilicities and structural-pharmacological considerations of various angiotensin-converting enzyme (ACE) inhibitors.

    PubMed

    Ranadive, S A; Chen, A X; Serajuddin, A T

    1992-11-01

    Lipophilicities of seven structurally diverse angiotensin-converting enzyme (ACE) inhibitors, viz., captopril, zofenoprilat, enalaprilat, ramiprilat, lisinopril, fosinoprilat, and ceronapril (SQ29852), were compared by determining their octanol-water distribution coefficients (D) under physiological pH conditions. The distribution co-efficients of zofenopril, enalapril, ramipril and fosinopril, which are the prodrug forms of zofenoprilat, enalaprilat, ramiprilat, and fosinoprilat, respectively, were also determined. Attempts were made to correlate lipophilicities with the reported data for oral absorption, protein binding, ACE inhibitory activity, propensity for biliary excretion, and penetration across the blood-brain barrier for these therapeutic entities. Better absorption of prodrugs compared to their respective active forms is in agreement with their greater lipophilicities. Captopril, lisinopril, and ceronapril are orally well absorbed despite their low lipophilicities, suggesting involvement of other factors such as a carrier-mediated transport process. Of all the compounds studied, the two most lipophilic ACE inhibitors, fosinoprilat and zofenoprilat, exhibit a rank-order correlation with respect to biliary excretion. This may explain the dual routes of elimination (renal and hepatic) observed with fosinoprilat in humans. The more lipophilic compounds also exhibit higher protein binding. Both the lipophilicity and a carrier-mediated process may be involved in penetration of some of these drugs into brain. For structurally similar compounds, in vitro ACE inhibitory activity increased with the increase in lipophilicity. However, no clear correlation between lipophilicity and ACE inhibitory activity emerged when different types of inhibitors are compared, possibly because their interactions with enzymes are primarily ionic in nature.

  20. Angioedema in heart failure patients treated with sacubitril/valsartan (LCZ696) or enalapril in the PARADIGM-HF study.

    PubMed

    Shi, Victor; Senni, Michele; Streefkerk, Hendrik; Modgill, Vikas; Zhou, Wenchun; Kaplan, Allen

    2018-08-01

    PARADIGM-HF demonstrated significant clinical benefits for sacubitril/valsartan (LCZ696, an angiotensin receptor neprilysin inhibitor) versus the angiotensin-converting enzyme inhibitor (ACEI) enalapril in patients with heart failure with reduced ejection fraction. As inhibition of ACE, and co-inhibition of ACE and neprilysin, may increase the risk of angioedema, this was an adverse event of special interest. Following sequential enalapril and sacubitril/valsartan run-ins, patients were randomized to twice-daily sacubitril/valsartan 200 mg or enalapril 10 mg. The study design incorporated two wash-out periods (~36 h each) to minimize any potential risk of angioedema due to overlapping ACE and neprilysin inhibition. Suspected cases of angioedema were reported to, and blindly adjudicated by, an independent angioedema adjudication committee (AAC). Of the 10,513 patients entering the enalapril run-in, 9419 entered the sacubitril/valsartan run-in and 8432 received double-blind treatment. Overall, 148 suspected angioedema events occurring in 144 patients were reported to AAC, with one event reported during screening period. Of the remaining 147 events, 54 were confirmed as angioedema by AAC. A confirmed event was experienced by 15 (0.14%) and 10 (0.11%) patients, during the enalapril and sacubitril/valsartan run-ins, respectively, and by 10 (0.24%) and 19 (0.45%) patients in the corresponding randomized arms during the double-blind phase. The frequency of confirmed angioedema was higher in black patients. Most events were mild. Only five patients required hospitalization and none required mechanical airway support. The number of confirmed angioedema events in PARADIGM-HF was low and there was no-marked excess risk of angioedema with sacubitril/valsartan versus enalapril. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  1. [ACE inhibitors and the kidney].

    PubMed

    Hörl, W H

    1996-01-01

    Treatment with ACE inhibitors results in kidney protection due to reduction of systemic blood pressure, intraglomerular pressure, an antiproliferative effect, reduction of proteinuria and a lipid-lowering effect in proteinuric patients (secondary due to reduction of protein excretion). Elderly patients with diabetes melitus, coronary heart disease or peripheral vascular occlusion are at risk for deterioration of kidney function due to a high frequency of renal artery stenosis in these patients. In patients with renal insufficiency dose reduction of ACE inhibitors is necessary (exception: fosinopril) but more important is the risk for development of hyperkalemia. Patients at risk for renal artery stenosis and patients pretreated with diuretics should receive a low ACE inhibitor dosage initially ("start low - go slow"). For compliance reasons once daily ACE inhibitor dosage is recommended.

  2. Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited.

    PubMed

    Knütter, Ilka; Wollesky, Claudia; Kottra, Gabor; Hahn, Martin G; Fischer, Wiebke; Zebisch, Katja; Neubert, Reinhard H H; Daniel, Hannelore; Brandsch, Matthias

    2008-11-01

    Angiotensin-converting enzyme (ACE) inhibitors are often regarded as substrates for the H+/peptide transporters (PEPT)1 and PEPT2. Even though the conclusions drawn from published data are quite inconsistent, in most review articles PEPT1 is claimed to mediate the intestinal absorption of ACE inhibitors and thus to determine their oral availability. We systematically investigated the interaction of a series of ACE inhibitors with PEPT1 and PEPT2. First, we studied the effect of 14 ACE inhibitors including new drugs on the uptake of the dipeptide [14C]glycylsarcosine into human intestinal Caco-2 cells constitutively expressing PEPT1 and rat renal SKPT cells expressing PEPT2. In a second approach, the interaction of ACE inhibitors with heterologously expressed human PEPT1 and PEPT2 was determined. In both assay systems, zofenopril and fosinopril were found to have very high affinity for binding to peptide transporters. Medium to low affinity for transporter interaction was found for benazepril, quinapril, trandolapril, spirapril, cilazapril, ramipril, moexipril, quinaprilat, and perindopril. For enalapril, lisinopril, and captopril, very weak affinity or lack of interaction was found. Transport currents of PEPT1 and PEPT2 expressed in Xenopus laevis oocytes were recorded by the two-electrode voltage-clamp technique. Statistically significant, but very low currents were only observed for lisinopril, enalapril, quinapril, and benazepril at PEPT1 and for spirapril at PEPT2. For the other ACE inhibitors, electrogenic transport activity was extremely low or not measurable at all. The present results suggest that peptide transporters do not control intestinal absorption and renal reabsorption of ACE inhibitors.

  3. Enalapril and captopril enhance glutathione-dependent antioxidant defenses in mouse tissues.

    PubMed

    de Cavanagh, E M; Inserra, F; Ferder, L; Fraga, C G

    2000-03-01

    The effect of enalapril and captopril on total glutathione content (GSSG + GSH) and selenium-dependent glutathione peroxidase (Se-GPx) and glutathione reductase (GSSG-Rd) activities was investigated in mouse tissues. CF-1 mice (4-mo-old females) received water containing enalapril (20 mg/l) or captopril (50 mg/l) for 11 wk. Enalapril increased GSSG + GSH content (P < 0.05) in erythrocytes (147%), brain (112%), and lung (67%), and captopril increased GSSG + GSH content in erythrocytes (190%) and brain (132%). Enalapril enhanced Se-GPx activity in kidney cortex (42%) and kidney medulla (23%) and captopril in kidney cortex (30%). GSSG-Rd activity was enhanced by enalapril in erythrocytes (21%), brain (21%), liver (18%), and kidney cortex (53%) and by captopril in erythrocytes (25%), brain (19%), and liver (34%). In vitro erythrocyte oxidant stress was evaluated by thiobarbituric acid-reactive substances (TBARS) production (control 365 +/- 11, enalapril 221 +/- 26, captopril 206 +/- 17 nmol TBARS x g Hb(-1) x h(-1); both P < 0.05 vs. control) and phenylhydrazine-induced methemoglobin (MetHb) formation (control 66.5 +/- 3.5, enalapril 52.9 +/- 0.4, captopril: 56.4 +/- 2.9 micromol MetHb/g Hb; both P < 0.05 vs. control). Both angiotensin-converting enzyme inhibitor treatments were associated with increased nitric oxide production, as assessed by plasma NO-(3) + NO-(2) level determination (control 9.22 +/- 0.64, enalapril 13.7 +/- 1.9, captopril 17.3 +/- 3.0 micromol NO-(3) + NO-(2)/l plasma; both P < 0.05 vs. control). These findings support our previous reports on the enalapril- and captopril-induced enhancement of endogenous antioxidant defenses and include new data on glutathione-dependent defenses, thus furthering current knowledge on the association of ACE inhibition and antioxidants.

  4. Similar clinical benefits from below-target and target dose enalapril in patients with heart failure in the SOLVD Treatment trial.

    PubMed

    Lam, Phillip H; Dooley, Daniel J; Fonarow, Gregg C; Butler, Javed; Bhatt, Deepak L; Filippatos, Gerasimos S; Deedwania, Prakash; Forman, Daniel E; White, Michel; Fletcher, Ross D; Arundel, Cherinne; Blackman, Marc R; Adamopoulos, Chris; Kanonidis, Ioannis E; Aban, Inmaculada B; Patel, Kanan; Aronow, Wilbert S; Allman, Richard M; Anker, Stefan D; Pitt, Bertram; Ahmed, Ali

    2018-02-01

    To examine associations of below-target and target dose of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, with outcomes in patients with heart failure and reduced ejection fraction (HFrEF) in the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial. Two thousand five hundred and sixty-nine patients with HFrEF (ejection fraction ≤35%) were randomized to below-target (5-10 mg/day) dose placebo (n = 1284) or enalapril (n = 1285). One month post-randomization, blind up-titration to target (20 mg/day) dose was attempted for both study drugs in 2458 patients. Among the 1444 patients who achieved dose up-titration (placebo, n = 748; enalapril, n = 696; mean dose for both groups, 20.0 mg/day), target dose enalapril (vs. target dose placebo) was associated with a 9% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality [adjusted hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.60-0.81; P < 0.001] during 4 years of follow-up. Among the 1014 patients who could not achieve target dose (placebo, n = 486; enalapril, n = 528; mean dose for both groups, 8.8 mg/day), below-target dose enalapril (vs. below-target dose placebo) was associated with a 12% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 0.68; 95% CI 0.57-0.81; P < 0.001). Among the 1224 patients receiving enalapril, target (vs. below-target) dose had no association with the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 1.04; 95% CI 0.87-1.23; P = 0.695). In patients with HFrEF, the clinical benefits of ACE inhibitors appear to be similar at both below-target and target doses. © 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.

  5. ACE inhibitors and potassium foods--nurses' knowledge.

    PubMed

    Bertrand, Brenda; Livingston-Bowen, Carrie; Duffrin, Christopher; Mann, Amanda

    2014-01-01

    According to Joint Commission standards, patients should be educated about drug-nutrient interactions. Because nurses are well-suited to educating patients, this paper aims to assess their knowledge of ACE inhibitor drugs, nutrient interactions and high- and low-potassium foods. Licensed nurses from a teaching hospital in the US south eastern Atlantic region completed a self-administered questionnaire (n = 83). Means, standard deviations and 95 percent confidence intervals were calculated for continuous data and frequency and percentage distribution for discrete data. Student's t-test was used to evaluate responses by ACE inhibitor patient load and nursing education. Mean nurse knowledge of ACE inhibitors and potassium was 62 +/- 16 percent and identifying high- and low-potassium foods was 32 +/- 23 percent. Most identified five from 12 high-potassium foods and did not know the designation of six, one from 14 low-potassium foods and did not know the designation of 11. Knowledge scores and identifying high- and low-potassium foods were similar regardless of ACE inhibitor patient load and nursing education. ACE inhibitors are the fourth most commonly used drug class in the USA. Nurses are well positioned to recognize potential drug-nutrient interactions owing to changing or adding a drug, dose delivery method, dietary change or a patient's physical or clinical status that may indicate nutrient deficiency. The findings suggest that the nurses surveyed were proficient in identifying ACE inhibitors pharmacology, but that most were unable to identify foods that increase drug-nutrient interaction risk, and thus this is an area in which additional training might be beneficial. Case menus were used to portray real-life scenarios in which healthcare practitioners can provide patient education about ACE inhibitor drug and dietary potassium interactions.

  6. Unraveling the Pivotal Role of Bradykinin in ACE Inhibitor Activity.

    PubMed

    Taddei, Stefano; Bortolotto, L

    2016-10-01

    Historically, the first described effect of an angiotensin converting enzyme (ACE) inhibitor was an increased activity of bradykinin, one of the substrates of ACE. However, in the subsequent years, molecular models describing the mechanism of action of ACE inhibitors in decreasing blood pressure and cardiovascular risk have focused mostly on the renin-angiotensin system. Nonetheless, over the last 20 years, the importance of bradykinin in regulating vasodilation, natriuresis, oxidative stress, fibrinolysis, inflammation, and apoptosis has become clearer. The affinity of ACE appears to be higher for bradykinin than for angiotensin I, thereby suggesting that ACE inhibitors may be more effective inhibitors of bradykinin degradation than of angiotensin II production. Data describing the effect of ACE inhibition on bradykinin signaling support the hypothesis that the most cardioprotective benefits attributed to ACE inhibition may be due to increased bradykinin signaling rather than to decreased angiotensin II signaling, especially when high dosages of ACE inhibitors are considered. In particular, modulation of bradykinin in the endothelium appears to be a major target of ACE inhibition. These new mechanistic concepts may lead to further development of strategies enhancing the bradykinin signaling.

  7. Use of ACE inhibitors in Fontan: Rational or irrational?

    PubMed

    Wilson, Thomas G; Iyengar, Ajay J; Winlaw, David S; Weintraub, Robert G; Wheaton, Gavin R; Gentles, Thomas L; Ayer, Julian; Grigg, Leeanne E; Justo, Robert N; Radford, Dorothy J; Bullock, Andrew; Celermajer, David S; Dalziel, Kim; Schilling, Chris; d'Udekem, Yves

    2016-05-01

    Despite a lack of evidence supporting the use of angiotensin-converting enzyme (ACE) inhibitors in patients with a Fontan circulation, their use is frequent. We decided to identify the rationale for ACE inhibitor therapy in patients within the Australia and New Zealand Fontan Registry. All patients in the Registry taking an ACE inhibitor at last follow up were identified, and a review of medical records was undertaken to determine the rationale for treatment initiation and reasons for treatment continuation or dose increase. In 2015, 36% of the surviving patients in the Registry (462/1268) were taking an ACE inhibitor. Indications for initiation of therapy were ventricular systolic or diastolic dysfunction (29%), atrioventricular valve regurgitation (19%), preservation of normal ventricular function (7%), prolonged effusions at Fontan (6%), hypertension (6%), other (6%) and unknown (2%). No indication was stated in the remaining patients (25%). Those with hypoplastic left heart syndrome were more likely to be on an ACE inhibitor than those with an alternative primary morphology (70% vs 32%; p<0.001). Only 36% of the patients treated with an ACE inhibitor at last follow up (166/462) had an indication that would generally justify treatment in a two-ventricle circulation. It is likely that the use of ACE inhibitors in patients with a Fontan circulation is excessive within our region. The coordination of prospective, multicentre studies and initiatives such as the Australia and New Zealand Fontan Registry will facilitate further investigations to guide treatment decisions in the growing Fontan population. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  8. Losartan and enalapril decrease viral absorption and interleukin 1 beta production by macrophages in an experimental dengue virus infection.

    PubMed

    Hernández-Fonseca, Juan Pablo; Durán, Anyelo; Valero, Nereida; Mosquera, Jesús

    2015-11-01

    The role of angiotensin II (Ang II) in dengue virus infection remains unknown. The aim of this study was to determine the effect of losartan, an antagonist of the angiotensin II type 1 receptor (AT1 receptor), and enalapril, an inhibitor of angiotensin I-converting enzyme (ACE), on viral antigen expression and IL-1β production in peritoneal macrophages infected with dengue virus type 2. Mice treated with losartan or enalapril and untreated controls were infected intraperitoneally with the virus, and macrophages were analyzed. Infection resulted in increased IL-1β production and a high percentage of cells expressing viral antigen, and this was decreased by treatment with anti-Ang II drugs, suggesting a role for Ang II in dengue virus infection.

  9. Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema.

    PubMed

    Brown, Nancy J; Byiers, Stuart; Carr, David; Maldonado, Mario; Warner, Barbara Ann

    2009-09-01

    Dipeptidyl peptidase-IV (DPP-IV) inhibitors decrease degradation of the incretins. DPP-IV inhibitors also decrease degradation of peptides, such as substance P, that may be involved in the pathogenesis of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. This study tested the hypothesis that DPP-IV inhibition affects risk of clinical angioedema, by comparing the incidence of angioedema in patients treated with the DPP-IV inhibitor vildagliptin versus those treated with comparator in Phase III randomized clinical trials. Prospectively defined angioedema-related events were adjudicated in a blinded fashion by an internal medicine adjudication committee and expert reviewer. Concurrent ACE inhibitor or angiotensin receptor blocker exposure was ascertained from case report forms. Study drug exposure was ascertained from unblinded data from phase III studies. Odds ratios and 95% confidence intervals comparing angioedema risk in vildagliptin-treated and comparator-treated patients were calculated for the overall population and for patients taking ACE inhibitors or angiotensin receptor blockers, using both an analysis of pooled data and a meta-analysis (Peto method). Overall, there was no association between vildagliptin use and angioedema. Among individuals taking an ACE inhibitor, however, vildagliptin use was associated with an increased risk of angioedema (14 confirmed cases among 2754 vildagliptin users versus 1 case among 1819 comparator users: odds ratio 4.57 [95% confidence interval 1.57 to 13.28]) in the meta-analysis. Vildagliptin use may be associated with increased risk of angioedema among patients taking ACE inhibitors, although absolute risk is small. Physicians confronted with angioedema in a patient taking an ACE inhibitor and DPP-IV inhibitor should consider this possible drug-drug interaction.

  10. The influence of angiotensin-converting enzyme inhibitors on the aorta elastin metabolism in diet-induced hypercholesterolaemia in rabbits.

    PubMed

    Wojakowski, W; Gminski, J; Siemianowicz, K; Goss, M; Machalski, M

    2001-03-01

    Aortic elastin turnover is significantly accelerated in atherosclerosis, partly because of activation of the renin-angiotensin-aldosterone system caused by hypercholesterolaemia. We postulated that angiotensin-converting enzyme inhibitors (ACE-I) prevent the aortic elastin loss in experimental hypercholesterolaemia. Two doses of ACE-I (captopril, enalapril and quinapril) were used: a dose equivalent to that applied to human subjects and a dose 10 times higher. We found that the increase in serum and aortic elastolytic activity in cholesterol-fed rabbits was prevented by high-dose captopril. The elastin content in aorta homogenates from cholesterol-fed rabbits was significantly decreased. The higher dose of captopril, but no other ACE-I, prevented this decrease in aortic elastin content. In cholesterol-fed rabbits the elastin-bound calcium content was significantly elevated. The higher doses of captopril and enalapril lowered the elastin-bound calcium content. In serum and aortic homogenates of cholesterol-fed rabbits, ACE activity was elevated by 15% and 77%, respectively. Both doses of captopril, enalapril and quinapril prevented this cholesterol-induced increase in serum and aortic ACE activity. We conclude that: 1) administration of captopril at doses 10 times higher than those used in humans prevents hypercholesterolaemia increased aortic elastin loss. 2) higher doses of captopril and enalapril prevent the hypercholesterolaemia-induced increase in aortic elastin-bound calcium.

  11. Enalapril treatment discloses an early role of angiotensin II in inflammation- and oxidative stress-related muscle damage in dystrophic mdx mice☆

    PubMed Central

    Cozzoli, Anna; Nico, Beatrice; Sblendorio, Valeriana Teresa; Capogrosso, Roberta Francesca; Dinardo, Maria Maddalena; Longo, Vito; Gagliardi, Sara; Montagnani, Monica; De Luca, Annamaria

    2011-01-01

    Inhibitors of angiotensin converting enzymes (ACE) are clinically used to control cardiomyopathy in patients of Duchenne muscular dystrophy. Various evidences suggest potential usefulness of long-term treatment with ACE inhibitors to reduce advanced fibrosis of dystrophic muscle in the mdx mouse model. However, angiotensin II is known to exert pro-inflammatory and pro-oxidative actions that might contribute to early events of dystrophic muscle degeneration. The present study has been aimed at evaluating the effects of an early treatment with enalapril on the pathology signs of exercised mdx mouse model. The effects of 1 and 5 mg/kg enalapril i.p. for 4–8 weeks have been compared with those of 1 mg/kg α-methyl-prednisolone (PDN), as positive control. Enalapril caused a dose-dependent increase in fore limb strength, the highest dose leading to a recovery score similar to that observed with PDN. A dose-dependent reduction of superoxide anion production was observed by dihydroethidium staining in tibialis anterior muscle of enalapril-treated mice, approaching the effect observed with PND. In parallel, a significant reduction of the activated form of the pro-inflammatory Nuclear Factor-kB has been observed in gastrocnemious muscle. Histologically, 5 mg/kg enalapril reduced the area of muscle necrosis in both gastrocnemious muscle and diaphragm, without significant effect on non-muscle area. In parallel no significant changes have been observed in both muscle TGF-β1 and myonuclei positive to phosphorylated Smad2/3. Myofiber functional indices were also monitored by microelectrodes recordings. A dose-dependent recovery of macroscopic chloride conductance has been observed upon enalapril treatment in EDL muscle, with minor effects being exerted in diaphragm. However a modest effect, if any, was found on mechanical threshold, a functional index of calcium homeostasis. No recovery was observed in creatine kinase and lactate dehydrogenase. Finally the results suggest

  12. ACE-Inhibition Benefit on Lung Function in Heart Failure is Modulated by ACE Insertion/Deletion Polymorphism.

    PubMed

    Contini, Mauro; Compagnino, Elisa; Cattadori, Gaia; Magrì, Damiano; Camera, Marina; Apostolo, Anna; Farina, Stefania; Palermo, Pietro; Gertow, Karl; Tremoli, Elena; Fiorentini, Cesare; Agostoni, Piergiuseppe

    2016-04-01

    The benefit of angiotensin converting enzyme (ACE) inhibition in chronic heart failure (HF) is partially due to its effects on pulmonary function and particularly on lung diffusion, the latter being counteracted by acetylsalicylic acid (ASA). Tissue ACE activity is largely determined by an insertion/deletion (I/D) polymorphism resulting in three possible genotypes (DD, ID and II). It is not clear if ACE inhibitor therapy could exert different effects in these genotypes. The aim of the study was to understand whether I/D polymorphism interferes with ACE inhibitor's protection of the lungs in HF during acute fluid overload. 100 HF patients (left ventricular ejection fraction ≤40 %) in stable clinical conditions, treated with enalapril but without ASA performed pulmonary function tests including lung diffusion (DLco) and its subcomponents, membrane diffusion (Dm) and capillary volume (Vcap), and a cardiopulmonary exercise test before and immediately after rapid infusion of 500 cc saline. ACE I/D genotype prevalence was: DD = 28, ID =55 and II = 17 cases. No significant differences in major pulmonary function and exercise parameters were observed before saline infusion among ACE genotypes. After fluid challenge, DD patients presented a higher DLco and Dm reduction than ID and II (DLco -2.3 ± 1.3 vs. -0.8 ± 1.9 and -0.6 ± 1 mL/mmHg/min, p < 0.0001 and p < 0.01; Dm -7 ± 5 vs. -3.2 ± 7.4 and -1.3 ± 5 mL/mmHg/min, p < 0.05, respectively) and a higher increase in VE/VCO2 slope than II (1.8 ± 1.9 vs. -0.8 ± 2.3, p = 0.01). ACE DD genotype is associated with higher vulnerability of the alveolar-capillary membrane to acute fluid overload in HF patients treated with ACE inhibitors.

  13. A review of the preclinical cardiovascular pharmacology of cilazapril, a new angiotensin converting enzyme inhibitor

    PubMed Central

    Waterfall, J. F.

    1989-01-01

    1 Cilazapril is the monoethyl ester prodrug form of the di-acid cilazaprilat, a new angiotensin converting enzyme (ACE) inhibitor. Cilazaprilat has an IC50 of 1.9 nM as an inhibitor of rabbit lung ACE in vitro making it one of the most potent ACE inhibitors currently available. Studies on a wide range of other enzymes show that the inhibition is highly specific. 2 An oral dose of 0.1 mg kg-1 cilazapril evoked the same maximum degree of plasma ACE inhibition (∼76%) in the rat as 0.25 mg kg-1 enalapril. Cilazapril (0.25 mg kg-1 p.o.) inhibited plasma ACE by > 95%. The rate of recovery of ACE activity was slower with cilazapril (5-6% h-1) than with enalapril (10% h-1). 3 In anaesthetised rats cilazaprilat was equipotent with ramiprilat and slightly more potent (1.5×) than enalaprilat as an inhibitor of the angiotensin I pressor response. 4 Following oral administration to conscious rats and intravenous administration to anaesthetised dogs, cilazapril was 2-4.5× more potent than enalapril as an ACE inhibitor. 5 In cats cilazapril (0.1 and 0.3 mg kg-1 p.o.) dose dependently decreased plasma ACE activity and the angiotensin pressor response. Peak effects occurred at 2 h after dosing and plasma ACE inhibition was maintained at ≥ 50% for up to 18 h. Mean arterial pressure was also decreased dose dependently with a peak effect at 3-4 h. 6 Daily oral dosing of cilazapril (30 mg kg-1 p.o.) to spontaneously hypertensive rats evoked a progressive and prolonged (24 h) antihypertensive response with a maximum decrease in systolic blood pressure of 110 mm Hg. 7 Cilazapril (10 mg kg-1 p.o. twice daily for 3.5 days) progressively decreased blood pressure in volume depleted renal hypertensive dogs. The maximum fall in systolic pressure was 39 ± 6 mm Hg. 8 Haemodynamic studies in open chest anaesthetised dogs showed that the hypotensive response to intravenous cilazapril was accompanied by a reduction in total peripheral resistance. Small decreases in cardiac output and

  14. Angiotensin converting enzyme inhibitors potentiate the bronchoconstriction induced by substance P in the guinea-pig.

    PubMed Central

    Subissi, A.; Guelfi, M.; Criscuoli, M.

    1990-01-01

    1. The effects of intravenous captopril and enalaprilic acid on the increase in pulmonary inflation pressure induced by different bronchoconstrictor agents were evaluated in the anaesthetized guinea-pig. 2. Captopril and enalaprilic acid (1.6-200 micrograms kg-1) enhanced dose-dependently the bronchoconstriction (BC) induced by substance P. The threshold effective dose was 1.6 micrograms kg-1 and maximal potentiation over the control response was more than 400% for both agents. Enalaprilic acid was also assayed for serum and lung angiotensin converting enzyme (ACE) inhibition in anaesthetized guinea-pigs. This drug produced a dose-dependent inhibition of ACE in both tissues, with ED50 s of 7.6 and 9.4 micrograms kg-1, respectively: this inhibitory activity was positively correlated to substance P potentiation. 3. Captopril (8-1000 micrograms kg-1) enhanced dose-dependently the BC induced by capsaicin. The threshold effective dose was 40 micrograms kg-1 and maximal potentiation about 90%. 4. Captopril (200-1000 micrograms kg-1) did not affect BC induced by bradykinin. However, this response was markedly enhanced (about 200%) by captopril 200 micrograms kg-1 in propranolol-pretreated animals. 5. Captopril and enalaprilic acid (200-1000 micrograms kg-1) slightly (20-40%) but significantly enhanced the BC induced by 5-hydroxytryptamine. However, this response was potentiated to the same extent by a dose of prazosin, which produced a degree of hypotension similar to that observed after administration of the ACE inhibitors. 6. In conclusion, ACE inhibitors potentiate the BC induced by substance P and, to a minor extent, that induced by capsaicin in the anaesthetized guinea-pig.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1697196

  15. Effect of SQ29,852, a new angiotensin converting enzyme (ACE) inhibitor with a phosphonic acid group, on the activity of angiotensin converting enzyme from human kidney.

    PubMed

    Hiwada, K; Inoue, Y; Kokubu, T

    1990-01-01

    1. An in vitro experiment was carried out to compare the inhibitory effect of SQ29,852 on human renal angiotensin converting enzyme (ACE) with those of captopril, enalapril and enalaprilat. 2. SQ29,852 strongly inhibited human renal ACE; its IC50 value was 1.5 x 10(-8) M. In terms of the IC50, SQ29,852's efficacy was about 1/10 of that of captopril and 1/28 of that of enalaprilat, but it was about 14 times more potent than enalapril. 3. SQ29,852 showed no inhibitory effects on cathepsin D, urinary kallikrein, renal renin, pepsin, trypsin and chymotrypsin. Its ACE-specificity was higher than that of captopril. 4. ACE inhibition by SQ29,852 was shown to be competitive, as revealed by Lineweaver-Burk plots. The affinity of SQ29,852 to ACE was shown to be high by a Ki value of 1.2 x 10(-8) M.

  16. Enalapril and losartan restored blood pressure and vascular reactivity in intrauterine undernourished rats.

    PubMed

    Ceravolo, Graziela S; Franco, Maria C P; Carneiro-Ramos, Marcela S; Barreto-Chaves, Maria L M; Tostes, Rita C A; Nigro, Dorothy; Fortes, Zuleica B; Carvalho, Maria Helena C

    2007-01-30

    Epidemiological studies suggest that intrauterine undernutrition plays an important role in the development of arterial hypertension and endothelial dysfunction in adulthood. We have evaluated the effect of the Renin Angiotensin System inhibition on the blood pressure and the mesenteric arteriolar reactivity of the intrauterine undernourished rats. Wistar rats were fed either normal or 50% of the normal intake diets, during the whole gestational period. In this study only the male offspring was used. At 16 weeks of age, the rats were used for the study of blood pressure, microvascular reactivity studied in vivo-in situ to Angiotensin II (Ang II), Bradykinin (Bk) and Acetylcholine (Ach) before and after either losartan (10 mg/kg/15 days) or enalapril (15 mg/kg/21 days) treatment. We also evaluated the mesenteric and plasmatic Angiotensin Converting Enzyme (ACE), renal function, lipid plasmatic content, and insulin and glucose metabolism. Intrauterine undernutrition induced hypertension and increased response of mesenteric arterioles to Ang II and decreased vasodilation to Bk and Ach. The treatments with losartan or enalapril normalized the blood pressure levels and significantly improved the arteriolar responses to Bk, Ach and reduced the response to Ang II. No differences have been detected to ACE activity, renal function, lipid content and insulin and glucose metabolism. This study shows for the first time that Renin Angiotensin System inhibitors can normalize the cardiovascular alterations induced by intrauterine undernutrition.

  17. Renin-Angiotensin-Aldosterone Signaling Inhibitors-Losartan, Enalapril, and Cardosten-Prevent Infarction-induced Heart Failure Development in Rats.

    PubMed

    Kiss, Krisztina; Fekete, Veronika; Pálóczi, János; Sárközy, Márta; Murlasits, Zsolt; Pipis, Judit; Kheyfets, Irina A; Dugina, Julia L; Sergeeva, Svetlana A; Epstein, Oleg I; Csonka, Csaba; Csont, Tamás; Ferdinandy, Péter; Bencsik, Péter

    2016-01-01

    The activation of the renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of congestive heart failure, which is the reason that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin 2 receptor blockers (ARBs) have become established therapies for heart failure. However, it is still not known whether preventive treatment with losartan or enalapril can reduce symptoms of infarction-induced heart failure. Ultra-low dose (ULD) drug therapy is thought to exert specific activity, with a lower chance of side effects. OBJECTIVES • The research team had hypothesized that preventive treatment with inhibitors of RAAS signaling-losartan, enalapril, and a preparation of a ULD antibody (ie, cardosten), which target the angiotensin type 1 (AT1) receptor-might alleviate pathological hypertrophy and/or functional decline in infarction-induced heart failure. The research team treated male Wistar rats orally for 30 d with 20 mg/kg of losartan, 10 mg/kg enalapril, 5 or 7.5 mL/kg of cardosten, or a control solution, started 1 d prior to permanent coronary occlusion. A sham-operated group functioned as a second control group. The study was conducted at the Department of Biochemistry of the Faculty of Medicine at the University of Szeged in Szeged, Hungary, in cooperation with the Pharmahungary Group, also in Szeged, Hungary, and with OOO "NPF" Materia Medica Holding Ltd in Moscow, Russia. To determine cardiac functional parameters in vivo, the research team inserted a catheter into the left ventricle of the rats and measured the parameters of ventricular pressure, and cardiac output was determined by thermodilution. Morphological parameters were measured after heart isolation in transverse sections by a digital caliper. A total of 30 d after permanent coronary ligation, both losartan and enalapril, significantly decreased mean arterial blood pressure (MABP), attenuated the development of the left-ventricular anterior-wall and septum

  18. Enalapril and Hydrochlorothiazide

    MedlinePlus

    ... in a class of medications called angiotensin-converting enzyme (ACE) inhibitors. It works by decreasing certain chemicals ... in Vaseretic); hydrochlorothiazide (HCTZ, Microzide, Oretic); angiotensin-converting enzyme (ACE) inhibitors such as benazepril (Lotensin, in Lotrel), ...

  19. A prospective study of frequency and characteristics of cough during ACE inhibitor treatment.

    PubMed

    Sato, Atsuhisa; Fukuda, Seiichi

    2015-01-01

    Angiotensin converting enzyme (ACE) inhibitors are reportedly effective, and positively indicated in patients with chronic heart failure with decreased contractility, after myocardial infarction, after cerebrovascular disorders, and in those with chronic kidney disease. However, the biggest challenge to continuous use of ACE inhibitors is the adverse reaction of cough. Accordingly, in the present study, we investigated the present state and characteristics of ACE inhibitor-induced cough in patients with essential hypertension currently being treated with an ACE inhibitor for an average of 18 months, who could be regularly checked for cough. Subjects in this study were 176 patients overall (mean age 67 ± 11 years old), 90 men and 86 women. The adverse reaction of cough was observed in 20% of patients, and more frequently in women than in men. However, in 26 of the patients with cough, the cough either resolved naturally or completely disappeared while the treatment continued, after which patients could continue taking the medication. Specifically, ACE inhibitor treatment was eventually discontinued due to cough in 5.1% of patients. Cough occurred less frequently with concomitant calcium antagonists or diuretics than with ACE inhibitor monotherapy. Cough as an adverse reaction occurred at a low frequency when medication was taken at bedtime. We considered a number of measures to counteract cough, then in addition to starting the ACE inhibitor treatment as early as possible, it is important to devise ways for the ACE inhibitor treatment to be continued for as long as possible, through the adept use of these measures.

  20. Leptin regulates ACE activity in mice.

    PubMed

    Hilzendeger, Aline Mourao; Morais, Rafael Leite; Todiras, Mihail; Plehm, Ralph; da Costa Goncalves, Andrey; Qadri, Fatimunnisa; Araujo, Ronaldo Carvalho; Gross, Volkmar; Nakaie, Clovis Ryuichi; Casarini, Dulce Elena; Carmona, Adriana Karaoglanovic; Bader, Michael; Pesquero, João Bosco

    2010-09-01

    Leptin is a hormone related to metabolism. It also influences blood pressure, but the mechanisms triggered in this process are not yet elucidated. Angiotensin-I converting enzyme (ACE) regulates cardiovascular functions and recently has been associated with metabolism control and obesity. Here, we used ob/ob mice, a model lacking leptin, to answer the question whether ACE and leptin could interact to influence blood pressure, thereby linking the renin-angiotensin system and obesity. These mice are obese and diabetic but have normal 24 h mean arterial pressure. Our results show that plasma and lung ACE activities as well as ACE mRNA expression were significantly decreased in ob/ob mice. In agreement with these findings, the hypotensive effect produced by enalapril administration was attenuated in the obese mice. Plasma renin, angiotensinogen, angiotensin I, bradykinin, and angiotensin 1-7 were increased, whereas plasma angiotensin II concentration was unchanged in obese mice. Chronic infusion of leptin increased renin activity and angiotensin II concentration in both groups and increased ACE activity in ob/ob mice. Acute leptin infusion restored ACE activity in leptin-deficient mice. Moreover, the effect of an ACE inhibitor on blood pressure was not changed in ob/+ mice during leptin treatment but increased four times in obese mice. In summary, our findings show that the renin-angiotensin system is altered in ob/ob mice, with markedly reduced ACE activity, which suggests a possible connection between the renin-angiotensin system and leptin. These results point to an important interplay between the angiotensinergic and the leptinergic systems, which may play a role in the pathogenesis of obesity, hypertension, and metabolic syndrome.

  1. Are ACE Inhibitors and Beta-blockers Dangerous in Patients at Risk for Anaphylaxis?

    PubMed

    Coop, Christopher A; Schapira, Rebecca S; Freeman, Theodore M

    The objective of this article is to review the available studies regarding angiotensin converting enzyme (ACE) inhibitors and beta-blockers and their effect on patients at risk for anaphylaxis. A literature search was conducted in PUBMED to identify peer-reviewed articles using the following keywords: anaphylaxis, ACE inhibitor, beta-blocker, food allergy, radiocontrast media, venom allergy, skin testing, and immunotherapy. Some studies show an increased risk of anaphylaxis in patients who are taking ACE inhibitors and beta-blockers, whereas others studies do not show an increased risk. For venom immunotherapy, there are more data supporting the concomitant use of beta-blockers and ACE inhibitors in the build-up and maintenance phases. Most of the medical literature is limited to case reports and retrospective data. Prospective controlled trials are needed on this important topic. For those patients at risk of anaphylaxis who lack cardiovascular disease, it is recommended to avoid beta-blockers and possibly ACE inhibitors. However, for those patients with cardiovascular disease, beta-blockers and ACE inhibitors have been shown to increase life expectancy. Consideration should be given for the concomitant use of these medications while patients are receiving venom immunotherapy. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.

  2. Angiotensin-converting enzyme inhibitor associated cough: deceptive information from the Physicians' Desk Reference.

    PubMed

    Bangalore, Sripal; Kumar, Sunil; Messerli, Franz H

    2010-11-01

    Dry cough is a common, annoying adverse effect of all angiotensin-converting enzyme (ACE) inhibitors. The present study was designed to compare the rate of coughs reported in the literature with reported rates in the Physicians' Desk Reference (PDR)/drug label. We searched MEDLINE/EMBASE/CENTRAL for articles published from 1990 to the present about randomized clinical trials (RCTs) of ACE inhibitors with a sample size of at least 100 patients in the ACE inhibitors arm with follow-up for at least 3 months and reporting the incidence or withdrawal rates due to cough. Baseline characteristics, cohort enrolled, metrics used to assess cough, incidence, and withdrawal rates due to cough were abstracted. One hundred twenty-five studies that satisfied our inclusion criteria enrolled 198,130 patients. The pooled weighted incidence of cough for enalapril was 11.48% (95% confidence interval [CI], 9.54% to 13.41%), which was ninefold greater compared to the reported rate in the PDR/drug label (1.3%). The pooled weighted withdrawal rate due to cough for enalapril was 2.57% (95% CI, 2.40-2.74), which was 31-fold greater compared to the reported rate in the PDR/drug label (0.1%). The incidence of cough has increased progressively over the last 2 decades with accumulating data, but it has been reported consistently several-fold less in the PDR compared to the RCTs. The results were similar for most other ACE inhibitors. The incidence of ACE inhibitor-associated cough and the withdrawal rate (the more objective metric) due to cough is significantly greater in the literature than reported in the PDR/drug label and is likely to be even greater in the real world when compared with the data from RCTs. There exists a gap between the data available from the literature and that which is presented to the consumers (prescribing physicians and patients). Copyright © 2010 Elsevier Inc. All rights reserved.

  3. Binding of ACE-inhibitors to in vitro and patient-derived amyloid-β fibril models.

    PubMed

    Bhavaraju, Manikanthan; Phillips, Malachi; Bowman, Deborah; Aceves-Hernandez, Juan M; Hansmann, Ulrich H E

    2016-01-07

    Currently, no drugs exist that can prevent or reverse Alzheimer's disease, a neurodegenerative disease associated with the presence, in the brain, of plaques that are composed of β-amyloid (Aβ) peptides. Recent studies suggest that angiotensin-converting enzyme (ACE) inhibitors, a set of drugs used to treat hypertension, may inhibit amyloid formation in vitro. In the present study, we investigate through computer simulations the binding of ACE inhibitors to patient-derived Aβ fibrils and contrast it with that of ACE inhibitors binding to in vitro generated fibrils. The binding affinities of the ACE inhibitors are compared with that of Congo red, a dye that is used to identify amyloid structures and that is known to be a weak inhibitor of Aβ aggregation. We find that ACE inhibitors have a lower binding affinity to the patient-derived fibrils than to in vitro generated ones. For patient-derived fibrils, their binding affinities are even lower than that of Congo red. Our observations raise doubts on the hypothesis that these drugs inhibit fibril formation in Alzheimer patients by interacting directly with the amyloids.

  4. ACE Inhibitor and ARB utilization and expenditures in the Medicaid fee-for-service program from 1991 to 2008.

    PubMed

    Bian, Boyang; Kelton, Christina M L; Guo, Jeff J; Wigle, Patricia R

    2010-01-01

    Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are widely prescribed for the treatment of hypertension and heart failure, as well as for kidney disease prevention in patients with diabetes mellitus and the management of patients after myocardial infarction. To (a) describe ACE inhibitor and ARB utilization and spending in the Medicaid fee-for-service program from 1991 through 2008, and (b) estimate the potential cost savings for the collective Medicaid programs from a higher ratio of generic ACE inhibitor utilization. A retrospective, descriptive analysis was performed using the National Summary Files from the Medicaid State Drug Utilization Data, which are composed of pharmacy claims that are subject to federally mandated rebates from pharmaceutical manufacturers. For the years 1991-2008, quarterly claim counts and expenditures were calculated by summing data for individual ACE inhibitors and ARBs. Quarterly per-claim expenditure as a proxy for drug price was computed for all brand and generic drugs. Market shares were calculated based on the number of pharmacy claims and Medicaid expenditures. In the Medicaid fee-for-service program, ACE inhibitors accounted for 100% of the claims in the combined market for ACE inhibitors and ARBs in 1991, 80.6% in 2000, and 64.7% in 2008. The Medicaid expenditure per ACE inhibitor claim dropped from $37.24 in 1991 to $24.03 in 2008 when generics accounted for 92.5% of ACE inhibitor claims; after adjusting for inflation for the period from 1991 to 2008, the real price drop was 59.2%. Brand ACE inhibitors accounted for only 7.5% of the claims in 2008 for all ACE inhibitors but 32.1% of spending; excluding the effects of manufacturer rebates, Medicaid spending would have been reduced by $28.7 million (9%) in 2008 if all ACE inhibitor claims were generic. The average price per ACE inhibitor claim in 2008 was $24.03 ($17.64 per generic claim vs. $103.45 per brand claim) versus $81.98 per ARB

  5. The influence of angiotensin converting enzyme inhibitors on lipid peroxidation in sera and aorta of rabbits in diet-induced hypercholesterolemia.

    PubMed

    Wojakowski, W; Gminski, J; Siemianowicz, K; Goss, M; Machalski, M

    2000-11-01

    In hypercholesterolemia increased lipid and lipoprotein peroxidation occurs. The renin-angiotensin system plays an important role in atherogenesis. Angiotensin II induces smooth muscle cells proliferation and stimulates oxidation of LDL particles and foam cell accumulation. Inhibition of ang II production leads to decrease in lipid peroxide production. The aim of this study was to assess the lipid peroxidation expressed as concentration of thiobarbituric acid reactive species (TBARS) in sera and aorta homogenates after administration of two doses of angiotensin-converting enzyme (ACE) inhibitors (captopril, enalapril and quinapril) in diet-induced hypercholesterolemia in rabbits. Sixty-four New Zealand rabbits were used. Animals were fed with standard fodder, special diet (1% cholesterol content) or special diet + tested ACEI. Two doses of ACE inhibitors were used: i), equivalent to applied to humans, ii), dose 10 times higher. The animals were divided into 8 groups: control, standard fodder; B, special diet; C1, C2, special diet + captopril in doses 2.5 and 25 mg/kg/24 h, respectively; E1, E2, special diet + enalapril in doses 0.75 and 7.5 mg/kg/24 h, respectively; Q1 and Q2, special diet + quinapril in doses 0.75 and 7.5 mg/kg per day, respectively. In cholesterol-fed rabbits and in groups receiving lower doses of tested ACE inhibitors, the serum TBARS concentration at 6 months was significantly higher in comparison to the control. The higher doses of enalapril, quinapril and captopril, prevented the cholesterol-induced rise in TBARS concentration. Lower dose of captopril attenuated the rise in TBARS concentration, it was significantly lower in comparison to group B, but higher than in the control group. In animals from groups B, E1, C1, Q1 TBARS concentration in aortae was significantly higher as compared to control group. Both doses of captopril and higher doses of enalapril and quinapril inhibited the rise of lipid peroxides concentration induced by

  6. Benazepril and Hydrochlorothiazide

    MedlinePlus

    ... in a class of medications called angiotensin-converting enzyme (ACE) inhibitors. It works by decreasing certain chemicals ... benazepril (Lotensin); hydrochlorothiazide (HCTZ, Microzide, Oretic); angiotensin-converting enzyme (ACE) inhibitors such as captopril (Capoten), enalapril (Vasotec, ...

  7. Our ACE in the HOLE: Justifying the Use of Angiotensin-converting Enzyme Inhibitors as Adjuvants to Standard Chemotherapy.

    PubMed

    Radin, Daniel P; Krebs, Austin; Maqsudlu, Arman; Patel, Parth

    2018-01-01

    Angiotensin-I-converting enzyme (ACE) inhibitors have been very effective in treating cardiac hypertension since their clinical inception over four decades ago. Since then, it has been established that angiotensin II, the product of ACE, has oncogenic and pro-proliferative qualities, which begs the question as to whether ACE inhibitors may have oncolytic characteristics. In fact, scattered reports suggest that ACE inhibitors are oncolytic and oncopreventive, but the available literature has yet to be thoroughly examined. In the present review, we examine the available literature and determine that ACE inhibitors would have great utility in the prevention and treatment of cancer. At the same time, they would augment the efficacy of chemo- and radiotherapy as well as mitigating damage to healthy tissue by standard chemotherapeutic regimens. We review some of the mounting clinical evidence and show that ACE inhibitors have oncolytic activity in multiple types of cancer and discuss the ability of ACE inhibitors to prevent cardiotoxicity of multiple chemotherapies. Our analysis demonstrates that the actions of ACE inhibitors converge on vascular endolthelial growth factor to reduce its levels in tumors and prevent construction of blood vessels to masses, leaving them nutrient-depleted and subsequently hindering their growth. Given that ACE inhibitors are approved by the Federal Drug Administration and the therapeutic dose for hypertension treatment also slows the growth of multiple cancers types, ACE inhibitors are in a perfect position to be repurposed as oncolytic agents, that would widely increase their utility in the clinic. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  8. Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Enalapril.

    PubMed

    Verbeeck, Roger K; Kanfer, Isadore; Löbenberg, Raimar; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Langguth, Peter; Polli, James E; Parr, Alan; Shah, Vinod P; Mehta, Mehul; Dressman, Jennifer B

    2017-08-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the marketing authorization of immediate-release, solid oral dosage forms containing enalapril maleate are reviewed. Enalapril, a prodrug, is hydrolyzed by carboxylesterases to the active angiotensin-converting enzyme inhibitor enalaprilat. Enalapril as the maleate salt is shown to be highly soluble, but only 60%-70% of an orally administered dose of enalapril is absorbed from the gastrointestinal tract into the enterocytes. Consequently, enalapril maleate is a Biopharmaceutics Classification System class III substance. Because in situ conversion of the maleate salt to the sodium salt is sometimes used in production of the finished drug product, not every enalapril maleate-labeled finished product actually contains the maleate salt. Enalapril is not considered to have a narrow therapeutic index. With this background, a biowaiver-based approval procedure for new generic products or after major revisions to existing products is deemed acceptable, provided the in vitro dissolution of both test and reference preparation is very rapid (at least 85% within 15 min at pH 1.2, 4.5, and 6.8). Additionally, the test and reference product must contain the identical active drug ingredient. Copyright © 2017 American Pharmacists Association®. All rights reserved.

  9. The effect of angiotensin-converting enzyme inhibitors of left atrial pressure in dogs with mitral valve regurgitation.

    PubMed

    Ishikawa, T; Tanaka, R; Suzuki, S; Miyaishi, Y; Akagi, H; Iino, Y; Fukushima, R; Yamane, Y

    2010-01-01

    Despite many epidemiological reports concerning the efficacy of angiotensin-converting enzyme (ACE) inhibitors in dogs with mitral regurgitation (MR), the hemodynamic effects of ACE inhibitor administration have not been fully evaluated. To document left atrial pressure (LAP) in dogs with MR administered ACE inhibitors, in order to obtain interesting information about daily LAP changes with administration of ACE inhibitors. Five healthy Beagle dogs weighing 9.8 to 14.2 kg (2 males and 3 females; aged 2 years). Experimental, crossover, and interventional study. Chordae tendineae rupture was induced, and a radiotelemetry transmitter catheter was inserted into the left atrium. LAP was recorded for 72 consecutive hours during which each of 3 ACE inhibitors--nalapril (0.5 mg/kg/d), temocapril (0.1 mg/kg/d), and alacepril (3.0 mg/kg/d)--were administered in a crossover study. Averaged diurnal LAP was significantly, but slightly reduced by alacepril (P = .03, 19.03 +/- 3.01-18.24 +/- 3.07 mmHg). The nightly drops in LAP caused by alacepril and enalapril were significantly higher than the daily drops (P = .03, -0.98 +/- 0.19 to -0.07 +/- 0.25 mmHg, and P = .03, -0.54 +/- 0.21-0.02 +/- 0.17 mmHg, respectively), despite the fact that the oral administrations were given in the morning. Systolic blood pressure (122.7 +/- 14.4-117.4 +/- 13.1 mmHg, P = .04) and systemic vascular resistance (5800 +/- 2685-5144 +/- 2077 dyne x s/cm5, P = .03) were decreased by ACE inhibitors. ACE inhibitors decrease LAP minimally, despite reductions in left ventricular afterload. ACE inhibitors should not be used to decrease LAP.

  10. A Detailed Physiologically Based Model to Simulate the Pharmacokinetics and Hormonal Pharmacodynamics of Enalapril on the Circulating Endocrine Renin-Angiotensin-Aldosterone System

    PubMed Central

    Claassen, Karina; Willmann, Stefan; Eissing, Thomas; Preusser, Tobias; Block, Michael

    2013-01-01

    The renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathogenesis of cardiovascular disorders including hypertension and is one of the most important targets for drugs. A whole body physiologically based pharmacokinetic (wb PBPK) model integrating this hormone circulation system and its inhibition can be used to explore the influence of drugs that interfere with this system, and thus to improve the understanding of interactions between drugs and the target system. In this study, we describe the development of a mechanistic RAAS model and exemplify drug action by a simulation of enalapril administration. Enalapril and its metabolite enalaprilat are potent inhibitors of the angiotensin-converting-enzyme (ACE). To this end, a coupled dynamic parent-metabolite PBPK model was developed and linked with the RAAS model that consists of seven coupled PBPK models for aldosterone, ACE, angiotensin 1, angiotensin 2, angiotensin 2 receptor type 1, renin, and prorenin. The results indicate that the model represents the interactions in the RAAS in response to the pharmacokinetics (PK) and pharmacodynamics (PD) of enalapril and enalaprilat in an accurate manner. The full set of RAAS-hormone profiles and interactions are consistently described at pre- and post-administration steady state as well as during their dynamic transition and show a good agreement with literature data. The model allows a simultaneous representation of the parent-metabolite conversion to the active form as well as the effect of the drug on the hormone levels, offering a detailed mechanistic insight into the hormone cascade and its inhibition. This model constitutes a first major step to establish a PBPK-PD-model including the PK and the mode of action (MoA) of a drug acting on a dynamic RAAS that can be further used to link to clinical endpoints such as blood pressure. PMID:23404365

  11. Keeping pace with ACE: are ACE inhibitors and angiotensin II type 1 receptor antagonists potential doping agents?

    PubMed

    Wang, Pei; Fedoruk, Matthew N; Rupert, Jim L

    2008-01-01

    In the decade since the angiotensin-converting enzyme (ACE) gene was first proposed to be a 'human gene for physical performance', there have been numerous studies examining the effects of ACE genotype on physical performance phenotypes such as aerobic capacity, muscle function, trainability, and athletic status. While the results are variable and sometimes inconsistent, and corroborating phenotypic data limited, carriers of the ACE 'insertion' allele (the presence of an alu repeat element in intron 16 of the gene) have been reported to have higher maximum oxygen uptake (VO2max), greater response to training, and increased muscle efficiency when compared with individuals carrying the 'deletion' allele (absence of the alu repeat). Furthermore, the insertion allele has been reported to be over-represented in elite athletes from a variety of populations representing a number of endurance sports. The mechanism by which the ACE insertion genotype could potentiate physical performance is unknown. The presence of the ACE insertion allele has been associated with lower ACE activity (ACEplasma) in number of studies, suggesting that individuals with an innate tendency to have lower ACE levels respond better to training and are at an advantage in endurance sporting events. This could be due to lower levels of angiotensin II (the vasoconstrictor converted to active form by ACE), higher levels of bradykinin (a vasodilator degraded by ACE) or some combination of the two phenotypes. Observations that individuals carrying the ACE insertion allele (and presumably lower ACEplasma) have an enhanced response to training or are over-represented amongst elite athletes raises the intriguing question: would individuals with artificially lowered ACEplasma have similar training or performance potential? As there are a number of drugs (i.e. ACE inhibitors and angiotensin II type 1 receptor antagonists [angiotensin receptor blockers--ARBs]) that have the ability to either reduce ACEplasma

  12. RAS blockade with ARB and ACE inhibitors: current perspective on rationale and patient selection.

    PubMed

    Werner, Christian; Baumhäkel, Magnus; Teo, Koon K; Schmieder, Roland; Mann, Johannes; Unger, Thomas; Yusuf, Salim; Böhm, Michael

    2008-07-01

    Cardiovascular disease represents a continuum that starts with risk factors such as hypertension and progresses to atherosclerosis, target organ damage, and ultimately to myocardial infarction, heart failure, stroke or death. Renin-angiotensin system (RAS) blockade with angiotensin converting enzyme (ACE) inhibitors or angiotensin AT(1)-receptor blockers (ARBs) has turned out to be beneficial at all stages of this continuum. Both classes of agent can prevent or reverse endothelial dysfunction and atherosclerosis, thereby reducing the risk of cardiovascular events. Such a reduction has been shown mainly for ACE inhibitors in patients with coronary artery disease, but recent studies revealed that ARBs are not inferior in this respect. However, no such data are currently available on the combination of these drugs. Both ACE inhibitors and ARBs have been shown to reduce target organ damage in organs such as the kidney, brain and heart, and to decrease cardiovascular mortality and morbidity in patients with congestive heart failure. Experimental data point to an influence of ACE inhibitors and ARBs on the number and function of endothelial progenitor cells revealing additional mechanisms of action of these drugs. The VALIANT trial has shown equivalent effects of ARB valsartan and the ACE-inhibitor captopril in patients post myocardial infarction, but the dual RAS-blockade, compared to monotherapy, did not further reduce events. In secondary prevention, the most-recently published ONTARGET study provides evidence that on top of a better tolerability AT(1)-receptors antagonists are equal to ACE inhibitors in the prevention of clinical endpoints like cardiovascular mortality and morbidity, myocardial infarction and stroke. The combined RAS blockade, however, achieved no further benefits in vascular high-risk patients and was associated with more adverse events. In chronic heart failure, ValHeFT and CHARM-ADDED have shown that combined RAS inhibition with ACE inhibitor and

  13. Does the use of ACE inhibitors or angiotensin receptor blockers affect bone loss in older men?

    PubMed Central

    Leung, J.; Zhang, Y. F.; Bauer, D.; Ensrud, K. E.; Barrett-Connor, E.; Leung, P. C.

    2013-01-01

    Summary In a prospective cohort study of 5,995 older American men (MrOS), users of angiotensin-converting enzyme (ACE) inhibitors had a small but significant increase in bone loss at the hip over 4 years after adjustment for confounders. Use of angiotensin II AT1 receptor blockers (ARB) was not significantly associated with bone loss. Introduction Experimental evidence suggests that angiotensin II promotes bone loss by its effects on osteoblasts. It is therefore plausible that ACE inhibitor and ARB may reduce rates of bone loss. The objective of this study is to examine the independent effects of ACE inhibitor and ARB on bone loss in older men. Methods Out of 5,995 American men (87.2%) aged ≥65 years, 5,229 were followed up for an average of 4.6 years in a prospective six-center cohort study—The Osteoporotic Fractures in Men Study (MrOS). Bone mineral densities (BMD) at total hip, femoral neck, and trochanter were measured by Hologic densitometer (QDR 4500) at baseline and year 4. Results Out of 3,494 eligible subjects with complete data, 1,166 and 433 subjects reported use of ACE inhibitors and ARBs, respectively. When compared with nonusers, continuous use of ACE inhibitors was associated with a small (0.004 g/cm2) but significant increase in the average rate of BMD loss at total hip and trochanter over 4 years after adjustment for confounders. Use of ARB was not significantly associated with bone loss. Conclusion Use of ACE inhibitors but not ARB may marginally increase bone loss in older men. PMID:22080379

  14. ARB users exhibit a lower fracture incidence than ACE inhibitor users among older hypertensive men

    PubMed Central

    Kwok, Timothy; Leung, Jason; Barrett-Connor, Elizabeth

    2017-01-01

    Abstract Introduction angiotensin II, a major effector protein of the renin angiotensin system (RAS), induces bone loss under certain conditions. Drugs that block the RAS may therefore reduce bone loss and fracture incidence. The fracture incidence in older hypertensive men with long-term use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) were compared with the incidence in users of calcium channel blockers (CCBs) and non-users. Methods a total of 5,994 US men aged 65 years or older who had bone mineral density measured at baseline in the Osteoporotic Fractures in Men Study (MrOS) were followed for fracture incidence for an average of 6.8 years. Men with follow-up dual-energy X-ray absorptiometry bone mineral density data and who reported hypertension at any visit, or use of antihypertensive medications at any visit among those with non-missing mediation data were included in the study (N = 2,573). Results six hundred and nineteen men had taken ACE inhibitors, while 182 took ARBs for at least 4 years. Using Cox regression for the incidence of non-vertebral fractures, we found that long-term users of ACE inhibitors and ARBs each had a significantly lower fracture incidence than non-users. The hazard ratio of non-vertebral fractures was three times lower in ARB users than ACE inhibitor users (Hazard ratio (95% confidence interval): 0.194 (0.079–0.474) versus 0.620 (0.453–0.850), P = 0.0168). There was a trend of greater fracture risk reduction with longer duration of ARB use, but not for ACE inhibitor use. Conclusions in older hypertensive men, ARBs use was associated with lower incidence of non-vertebral fracture than ACE inhibitors or CCBs. PMID:28181652

  15. ARB users exhibit a lower fracture incidence than ACE inhibitor users among older hypertensive men.

    PubMed

    Kwok, Timothy; Leung, Jason; Barrett-Connor, Elizabeth

    2017-01-10

    Angiotensin II, a major effector protein of the renin angiotensin system (RAS), induces bone loss under certain conditions. Drugs that block the RAS may therefore reduce bone loss and fracture incidence. The fracture incidence in older hypertensive men with long-term use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) were compared with the incidence in users of calcium channel blockers (CCBs) and non-users. A total of 5,994 US men aged 65 years or older who had bone mineral density measured at baseline in the Osteoporotic Fractures in Men Study (MrOS) were followed for fracture incidence for an average of 6.8 years. Men with follow-up dual-energy X-ray absorptiometry bone mineral density data and who reported hypertension at any visit, or use of antihypertensive medications at any visit among those with non-missing mediation data were included in the study (N = 2,573). Six hundred and nineteen men had taken ACE inhibitors, while 182 took ARBs for at least 4 years. Using Cox regression for the incidence of non-vertebral fractures, we found that long-term users of ACE inhibitors and ARBs each had a significantly lower fracture incidence than non-users. The hazard ratio of non-vertebral fractures was three times lower in ARB users than ACE inhibitor users (Hazard ratio (95% confidence interval): 0.194 (0.079–0.474) versus 0.620 (0.453–0.850), P = 0.0168). There was a trend of greater fracture risk reduction with longer duration of ARB use, but not for ACE inhibitor use. In older hypertensive men, ARBs use was associated with lower incidence of non-vertebral fracture than ACE inhibitors or CCBs.

  16. Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans.

    PubMed

    Marney, Annis; Kunchakarra, Siri; Byrne, Loretta; Brown, Nancy J

    2010-10-01

    Dipeptidyl peptidase-IV inhibitors improve glucose homeostasis in type 2 diabetics by inhibiting degradation of the incretin hormones. Dipeptidyl peptidase-IV inhibition also prevents the breakdown of the vasoconstrictor neuropeptide Y and, when angiotensin-converting enzyme (ACE) is inhibited, substance P. This study tested the hypothesis that dipeptidyl peptidase-IV inhibition would enhance the blood pressure response to acute ACE inhibition. Subjects with the metabolic syndrome were treated with 0 mg of enalapril (n=9), 5 mg of enalapril (n=8), or 10 mg enalapril (n=7) after treatment with sitagliptin (100 mg/day for 5 days and matching placebo for 5 days) in a randomized, cross-over fashion. Sitagliptin decreased serum dipeptidyl peptidase-IV activity (13.08±1.45 versus 30.28±1.76 nmol/mL/min during placebo; P≤0.001) and fasting blood glucose. Enalapril decreased ACE activity in a dose-dependent manner (P<0.001). Sitagliptin lowered blood pressure during enalapril (0 mg; P=0.02) and augmented the hypotensive response to 5 mg of enalapril (P=0.05). In contrast, sitagliptin attenuated the hypotensive response to 10 mg of enalapril (P=0.02). During sitagliptin, but not during placebo, 10 mg of enalapril significantly increased heart rate and plasma norepinephrine concentrations. There was no effect of 0 or 5 mg of enalapril on heart rate or norepinephrine after treatment with either sitagliptin or placebo. Sitagliptin enhanced the dose-dependent effect of enalapril on renal blood flow. In summary, sitagliptin lowers blood pressure during placebo or submaximal ACE inhibition; sitagliptin activates the sympathetic nervous system to diminish hypotension when ACE is maximally inhibited. This study provides the first evidence for an interactive hemodynamic effect of dipeptidyl peptidase-IV and ACE inhibition in humans.

  17. Pharmacokinetic evaluation of lisinopril-tryptophan, a novel C-domain ACE inhibitor.

    PubMed

    Denti, Paolo; Sharp, Sarah-Kate; Kröger, Wendy L; Schwager, Sylva L; Mahajan, Aman; Njoroge, Mathew; Gibhard, Liezl; Smit, Ian; Chibale, Kelly; Wiesner, Lubbe; Sturrock, Edward D; Davies, Neil H

    2014-06-02

    Angiotensin-converting enzyme (ACE, EC 3.4.15.1) is a metallopeptidase comprised of two homologous catalytic domains (N- and C-domains). The C-domain cleaves the vasoactive angiotensin II precursor, angiotensin I, more efficiently than the N-domain. Thus, C-domain-selective ACE inhibitors have been designed to investigate the pharmacological effects of blocking the C-terminal catalytic site of the enzyme and improve the side effect profile of current ACE inhibitors. Lisinopril-tryptophan (LisW-S), an analogue of the ACE inhibitor lisinopril, is highly selective for the C-domain. In this study, we have analysed the ex vivo domain selectivity and pharmacokinetic profile of LisW-S. The IC50 value of LisW-S was 38.5 nM in rat plasma using the fluorogenic substrate Abz-FRKP(Dnp)P-OH. For the pharmacokinetics analysis of LisW-S, a sensitive and selective LC-MS/MS method was developed and validated to determine the concentration of LisW-S in rat plasma. LisW-S was administered to Wistar rats at a dose of 1 mg/kg bodyweight intravenously, 5 mg/kg bodyweight orally. The Cmax obtained following oral administration of the drug was 0.082 μM and LisW-S had an apparent terminal elimination half-life of around 3.1 h. The pharmacokinetic data indicate that the oral bioavailability of LisW-S was approximately 5.4%. These data provide a basis for better understanding the absorption mechanism of LisW-S and evaluating its clinical application. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Antioxidant Effect of Captopril and Enalapril on Reactive Oxygen Species-Induced Endothelial Dysfunction in the Rabbit Abdominal Aorta

    PubMed Central

    Kim, Ji Hoon; Kim, Young Hak; Chung, Won-Sang; Suh, Jung Kook; Kim, Sung Jin

    2013-01-01

    Background Reactive oxygen species (ROS) are known to be related to cardiovascular diseases. Many studies have demonstrated that angiotensin-converting enzyme inhibitors have beneficial effects against ROS. We investigated the antioxidant effect of captopril and enalapril in nitric oxide mediated vascular endothelium-dependent relaxations. Materials and Methods Isolated rabbit abdominal aorta ring segments were exposed to ROS by electrolysis of the organ bath medium (Krebs-Henseleit solution) after pretreatment with various concentrations (range, 10-5 to 3×10-4 M) of captopril and enalapril. Before and after electrolysis, the endothelial function was measured by preconstricting the vessels with norepinephrine (10-6 M) followed by the cumulative addition of acetylcholine (range, 3×10-8 to 10-6 M). The relevance of the superoxide anion and hydrogen peroxide scavenging effect of captopril and enalapril was investigated using additional pretreatments of diethyldithiocarbamate (DETCA, 0.5 mM), an inhibitor of Cu/Zn superoxide dismutase, and 3-amino-1,2,4-triazole (3AT, 50 mM), an inhibitor of catalase. Results Both captopril and enalapril preserved vascular endothelium-dependent relaxation after exposure to ROS in a dose-dependent manner (p<0.0001). Pretreatment with DETCA attenuated the antioxidant effect of captopril and enalapril (p<0.0001), but pretreatment with 3AT did not have an effect. Conclusion Both captopril and enalapril protect endothelium against ROS in a dose-dependent fashion in isolated rabbit abdominal aortas. This protective effect is related to superoxide anion scavenging. PMID:23422724

  19. Angiotensin-neprilysin inhibition versus enalapril in heart failure.

    PubMed

    McMurray, John J V; Packer, Milton; Desai, Akshay S; Gong, Jianjian; Lefkowitz, Martin P; Rizkala, Adel R; Rouleau, Jean L; Shi, Victor C; Solomon, Scott D; Swedberg, Karl; Zile, Michael R

    2014-09-11

    We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF Clinical

  20. ACE inhibitors and the risk of acute pancreatitis-a population-based case-control study.

    PubMed

    Kuoppala, Jaana; Enlund, Hannes; Pulkkinen, Jukka; Kastarinen, Helena; Jyrkkä, Johanna; Happonen, Pertti; Paajanen, Hannu

    2017-07-01

    The aim of this study was to examine the association between angiotensin converting enzyme (ACE) inhibitor use and the risk of acute pancreatitis. Information on all 4966 cases hospitalized in 2008-2010 for acute pancreatitis was retrieved from the Finnish national registers on hospital discharges and prescriptions. A total of 24 788 age and sex-matched population-based controls were randomly selected using density sampling. ACE inhibitor use between 1 January 2003 and the index date were determined by the date of hospitalization for acute pancreatitis among the cases. The incidence rate ratios of acute pancreatitis not diagnosed as biliary or alcohol-induced were modeled by conditional logistic regression and adjusted for comorbidities. A total of 1276 (26%) cases and 3946 (16%) controls had been exposed to ACE inhibitors. The use of ACE inhibitors was associated with an increased incidence rate of acute pancreatitis (odds ratio [OR] 1.76, 95% confidence interval [CI] 1.59-1.95). The increase was slightly higher among current new users (OR 1.86, 95%CI 1.65-2.09) and somewhat lower among current prevalent (OR 1.54, 95%CI 1.35-1.75) and former users (OR 1.51, 95%CI 1.31-1.74). Angiotensin converting enzyme inhibitor use seems to be associated with a moderately increased risk of acute pancreatitis. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  1. Incidence, Predictors, and Outcomes Associated With Hypotensive Episodes Among Heart Failure Patients Receiving Sacubitril/Valsartan or Enalapril: The PARADIGM-HF Trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure).

    PubMed

    Vardeny, Orly; Claggett, Brian; Kachadourian, Jessica; Pearson, Scott M; Desai, Akshay S; Packer, Milton; Rouleau, Jean; Zile, Michael R; Swedberg, Karl; Lefkowitz, Martin; Shi, Victor; McMurray, John J V; Solomon, Scott D

    2018-04-01

    In PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure), heart failure treatment with sacubitril/valsartan reduced the primary composite outcome of cardiovascular death or heart failure hospitalization compared with enalapril but resulted in more symptomatic hypotension. Concern on hypotension may be limiting use of sacubitril/valsartan in appropriate patients. We characterized patients in PARADIGM-HF by whether they reported hypotension during study run-in periods (enalapril, followed by sacubitril/valsartan) and after randomization and assessed whether hypotension modified the efficacy of sacubitril/valsartan. Of the 10 513 patients entering the enalapril run-in, 136 (1.3%) experienced hypotension and 93 (68%) were unable to continue to the next phase; of 9419 patients entering the sacubitril/valsartan run-in period, 228 (2.4%) patients experienced hypotension and 51% were unable to successfully complete the run-in. After randomization, 388 (9.2%) participants had 501 hypotensive events with enalapril, and 588 (14.0%) participants had 803 hypotensive events with sacubitril/valsartan ( P <0.001). There was no difference between randomized treatment groups in the number of participants who discontinued therapy because of hypotension. Individuals with a hypotensive event in either group were older, had lower blood pressure at randomization, and were more likely to have an implantable cardioverter defibrillator. Participants with hypotensive events during run-in who were ultimately randomized derived similar efficacy from sacubitril/valsartan compared with enalapril as those without hypotensive events ( P interaction>0.90). Hypotension was more common with sacubitril/valsartan relative to enalapril in PARADIGM-HF but did not differentially affect permanent discontinuations. Patients with hypotension during run-in derived

  2. Angiotensin-converting enzyme inhibition and angiotensin AT1 receptor blockade downregulate angiotensin-converting enzyme expression and attenuate renal injury in streptozotocin-induced diabetic rats.

    PubMed

    Motawi, Tarek K; El-Maraghy, Shohda A; Senousy, Mahmoud A

    2013-07-01

    Angiotensin-converting enzyme (ACE) is upregulated in the diabetic kidney and contributes to renal injury. This study investigates the possible beneficial effects of the ACE inhibitor (ACEI), enalapril and the AT1 receptor blocker (ARB), valsartan, on renal ACE expression, renal structure, and function in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were allocated into four groups: control, STZ-diabetic rats, and STZ-diabetic rats treated with either enalapril (10 mg/kg/day) or valsartan (50 mg/kg/day) for 8 weeks. Enalapril and valsartan reduced renal ACE mRNA and protein expression, Na(+) /K(+) -ATPase activity, oxidative stress, and serum transforming growth factor-β1 levels compared to the diabetic group. Both treatments normalized renal nitrate/nitrite levels and ameliorated the observed histopathological changes. In conclusion, ACE downregulation by ACEI and ARB indicates that angiotensin II upregulates ACE through AT1 receptor. Prevention of diabetes-induced changes in ACE expression and Na(+) /K(+) -ATPase activity could be a new explanation of the renoprotective effects of ACEIs and ARBs. © 2013 Wiley Periodicals, Inc.

  3. Prognostic importance of early worsening renal function after initiation of angiotensin-converting enzyme inhibitor therapy in patients with cardiac dysfunction.

    PubMed

    Testani, Jeffrey M; Kimmel, Stephen E; Dries, Daniel L; Coca, Steven G

    2011-11-01

    Worsening renal function (WRF) in the setting of heart failure has been associated with increased mortality. However, it is unclear if this decreased survival is a direct result of the reduction in glomerular filtration rate (GFR) or if the mechanism underlying the deterioration in GFR is driving prognosis. Given that WRF in the setting of angiotensin-converting enzyme inhibitor (ACE-I) initiation is likely mechanistically distinct from spontaneously occurring WRF, we investigated the relative early WRF-associated mortality rates in subjects randomized to ACE-I or placebo. Subjects in the Studies Of Left Ventricular Dysfunction (SOLVD) limited data set (n=6337) were studied. The interaction between early WRF (decrease in estimated GFR ≥20% at 14 days), randomization to enalapril, and mortality was the primary end point. In the overall population, early WRF was associated with increased mortality (adjusted hazard ratio [HR], 1.2; 95% CI, 1.0-1.4; P=0.037). When analysis was restricted to the placebo group, this association strengthened (adjusted HR, 1.4; 95% CI, 1.1-1.8; P=0.004). However, in the enalapril group, early WRF had no adverse prognostic significance (adjusted HR, 1.0; 95% CI, 0.8-1.3; P=1.0; P=0.09 for the interaction). In patients who continued to receive study drug despite early WRF, a survival advantage remained with enalapril therapy (adjusted HR, 0.66; 95% CI, 0.5-0.9; P=0.018). These data support the notion that the mechanism underlying WRF is important in determining its prognostic significance. Specifically, early WRF in the setting of ACE-I initiation appears to represent a benign event that is not associated with a loss of benefit from continued ACE-I therapy.

  4. Prognostic Importance of Early Worsening Renal Function Following Initiation of Angiotensin Converting Enzyme Inhibitor Therapy in Patients with Cardiac Dysfunction

    PubMed Central

    Testani, Jeffrey M.; Kimmel, Stephen E.; Dries, Daniel L.; Coca, Steven G.

    2011-01-01

    Background Worsening renal function (WRF) in the setting of heart failure has been associated with increased mortality. However, it is unclear if this decreased survival is a direct result of the reduction in glomerular filtration rate (GFR) or if the mechanism underlying the deterioration in GFR is driving prognosis. Given that WRF in the setting of angiotensin converting enzyme inhibitor (ACE-I) initiation is likely mechanistically distinct from spontaneously occurring WRF, we sought to investigate the relative early WRF associated mortality rates in subjects randomized to ACE-I or placebo. Methods and Results Subjects in the Studies Of Left Ventricular Dysfunction limited data set were studied (6,377 patients). The interaction between early WRF (decrease in estimated GFR ≥20% at 14 days), randomization to enalapril, and mortality was the primary endpoint. In the overall population, early WRF was associated with increased mortality (adjusted HR=1.2, 95% CI 1.0–1.4, p=0.037). When analysis was restricted to the placebo group, this association strengthened (adjusted HR=1.4, 95% CI 1.1–1.8, p=0.004). However, in the enalapril group, early WRF had no adverse prognostic significance (adjusted HR=1.0, 95% CI 0.8–1.3, p=1.0, p interaction=0.09). In patients that continued study drug despite early WRF, a survival advantage remained with enalapril therapy (adjusted HR=0.66, 95% CI 0.5–0.9, p=0.018). Conclusions These data support the notion that the mechanism underlying WRF is important in determining its prognostic significance. Specifically, early WRF in the setting of ACE-I initiation appears to represent a benign event which is not associated with a loss of benefit from continued ACE-I therapy. PMID:21903907

  5. Angiotensin-Converting Enzyme Inhibition as an Adjunct to Pulmonary Rehabilitation in Chronic Obstructive Pulmonary Disease

    PubMed Central

    Curtis, Katrina J.; Meyrick, Victoria M.; Mehta, Bhavin; Haji, Gulam S.; Li, Kawah; Montgomery, Hugh; Man, William D.-C.; Polkey, Michael I.

    2016-01-01

    Rationale: Epidemiological studies in older individuals have found an association between the use of angiotensin-converting enzyme (ACE) inhibition (ACE-I) therapy and preserved locomotor muscle mass, strength, and walking speed. ACE-I therapy might therefore have a role in the context of pulmonary rehabilitation (PR). Objectives: To investigate the hypothesis that enalapril, an ACE inhibitor, would augment the improvement in exercise capacity seen during PR. Methods: We performed a double-blind, placebo-controlled, parallel-group randomized controlled trial. Patients with chronic obstructive pulmonary disease, who had at least moderate airflow obstruction and were taking part in PR, were randomized to either 10 weeks of therapy with an ACE inhibitor (10 mg enalapril) or placebo. Measurements and Main Results: The primary outcome measurement was the change in peak power (assessed using cycle ergometry) from baseline. Eighty patients were enrolled, 78 were randomized (age 67 ± 8 years; FEV1 48 ± 21% predicted), and 65 completed the trial (34 on placebo, 31 on the ACE inhibitor). The ACE inhibitor–treated group demonstrated a significant reduction in systolic blood pressure (Δ, −16 mm Hg; 95% confidence interval [CI], −22 to −11) and serum ACE activity (Δ, −18 IU/L; 95% CI, −23 to −12) versus placebo (between-group differences, P < 0.0001). Peak power increased significantly more in the placebo group (placebo Δ, +9 W; 95% CI, 5 to 13 vs. ACE-I Δ, +1 W; 95% CI, −2 to 4; between-group difference, 8 W; 95% CI, 3 to 13; P = 0.001). There was no significant between-group difference in quadriceps strength or health-related quality of life. Conclusions: Use of the ACE inhibitor enalapril, together with a program of PR, in patients without an established indication for ACE-I, reduced the peak work rate response to exercise training in patients with chronic obstructive pulmonary disease. PMID:27248440

  6. Fatal hyperkalemia related to combined therapy with a COX-2 inhibitor, ACE inhibitor and potassium rich diet.

    PubMed

    Hay, Emile; Derazon, Hashmonai; Bukish, Natalia; Katz, Leonid; Kruglyakov, Igor; Armoni, Michael

    2002-05-01

    We describe the case of a 77-year old mildly hypertensive woman with no underlying renal disease who was admitted to the Emergency Department (ED) in a comatose state with fever. The patient had been on low dose enalapril and a potassium rich diet. Five days before admission, rofecoxib, a new selective COX-2 inhibitor nonsteroidal anti-inflammatory drug (NSAID), was added for leg pain. She was found to have severe hyperkalemia and died 90 min after her arrival. We cannot absolutely determine whether the COX-2 inhibitor was the dominant contributor to the development of hyperkalemia or the combination itself, with an intercurrent infection and some degree of dehydration. Physicians should be aware of this possible complication and only prescribe NSAIDs, including the new COX-2 drugs, to the elderly under close monitoring of kidney function and electrolyte tests.

  7. Proton-coupled oligopeptide transport by rat renal cortical brush border membrane vesicles: a functional analysis using ACE inhibitors to determine the isoform of the transporter.

    PubMed

    Temple, C S; Boyd, C A

    1998-08-14

    We demonstrate that the angiotensin-converting enzyme inhibitors enalapril and captopril inhibit the transport of D-Phe-L-Gln into PepT1-expressing Xenopus oocytes and into rat renal cortical brush border membrane vesicles (BBMV). The kinetics of inhibition are competitive. Enalapril and captopril are not substrates for PepT2 (Boll et al., Proc. Natl. Acad. Sci. 93 (1996) 284-289). Therefore we conclude that in rat renal cortical BBMV this neutral dipeptide is transported via PepT1.

  8. Pharmacodynamic effects of C-domain-specific ACE inhibitors on the renin-angiotensin system in myocardial infarcted rats.

    PubMed

    Sharp, Sarah; Poglitsch, Marko; Zilla, Peter; Davies, Neil H; Sturrock, Edward D

    2015-12-01

    The renin-angiotensin system (RAS) is a dynamic network that plays a critical role in blood pressure regulation and fluid and electrolyte homeostasis. Modulators of the RAS, such as angiotensin-converting enzyme (ACE) inhibitors, are widely used to treat hypertension, heart failure and myocardial infarction. The effect of ACE inhibitors (lisinopril and C-domain-selective LisW-S) on the constituent peptides of the RAS following myocardial infarction was examined in rats. Ten angiotensin peptides were analysed using a sensitive LC-MS/MS-based assay to examine both the circulating and equilibrium levels of these peptides. Administration of lisinopril or LisW-S caused a significant decrease in Ang 1-8/Ang 1-10 ratios as determined by circulating and equilibrium peptide level analysis. Furthermore, Ang 1-7 levels were elevated by both ACE inhibitors, but only lisinopril decreased the Ang 1-5/Ang 1-7 ratio. This indicates LisW-S C-domain specificity as Ang 1-5 is generated by hydrolysis of Ang 1-7 by the N-domain. Further corroboration of LisW-S C-domain specificity is that only lisinopril increased the circulating levels of the N-domain ACE substrate Ac-SDKP. LisW-S is able to effectively block ACE in vivo by C-domain-selective inhibition. The LC-MS/MS-based assay allows the evaluation of the pharmacologic impact of RAS inhibitors in different pathophysiological conditions. © The Author(s) 2015.

  9. Azilsartan compared to ACE inhibitors in anti-hypertensive therapy: one-year outcomes of the observational EARLY registry.

    PubMed

    Gitt, Anselm K; Bramlage, Peter; Potthoff, Sebastian A; Baumgart, Peter; Mahfoud, Felix; Buhck, Hartmut; Ehmen, Martina; Ouarrak, Taoufik; Senges, Jochen; Schmieder, Roland E

    2016-03-08

    Azilsartan medoxomil (AZL-M), has been demonstrated to be more effective than the other sartans currently in use; however, there is insufficient information available comparing it with ACE-inhibitors. Therefore, we aimed to compare the efficacy, safety, and tolerability of AZL-M with that of ACE-inhibitors in a real life clinical setting. The EARLY registry is a prospective, observational, national, multicentre registry with a follow-up period of 12 months. There were two principal objectives: 1) documentation of the achievement of target BP values set according to recent national and international guidelines, and 2) description of the safety profile of AZL-M. A total of 3 849 patients with essential arterial hypertension were recruited from primary care offices in Germany. Patients who initiated monotherapy at baseline comprising either AZL-M or an ACE-inhibitor were included at a ratio of seven to three. Results demonstrated that a blood pressure target of <140/90 mmHg was achieved by a significantly greater proportion of patients in the AZL-M group (61.1 %) compared with the ACE-inhibitor group (56.4 %; p < 0.05; OR, 1.21; 95 % CI, 1.03-1.42), with this finding maintained after adjusting for differences in baseline characteristics. AZL-M appeared to have an equivalent safety profile to the ACE-inhibitors, with a similar incidence of adverse events in the two patient groups (p = 0.73). These data add to the results of previous randomized controlled clinical trials suggesting that, compared with other agents that target the renin-angiotensin system, AZL-M provides statistically significant albeit small improvements in blood pressure control.

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

    PubMed

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

    2006-12-01

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

  11. Conformational Changes of Blood ACE in Chronic Uremia

    PubMed Central

    Petrov, Maxim N.; Shilo, Valery Y.; Tarasov, Alexandr V.; Schwartz, David E.; Garcia, Joe G. N.; Kost, Olga A.; Danilov, Sergei M.

    2012-01-01

    Background The pattern of binding of monoclonal antibodies (mAbs) to 16 epitopes on human angiotensin I-converting enzyme (ACE) comprise a conformational ACE fingerprint and is a sensitive marker of subtle protein conformational changes. Hypothesis Toxic substances in the blood of patients with uremia due to End Stage Renal Disease (ESRD) can induce local conformational changes in the ACE protein globule and alter the efficacy of ACE inhibitors. Methodology/Principal Findings The recognition of ACE by 16 mAbs to the epitopes on the N and C domains of ACE was estimated using an immune-capture enzymatic plate precipitation assay. The precipitation pattern of blood ACE by a set of mAbs was substantially influenced by the presence of ACE inhibitors with the most dramatic local conformational change noted in the N-domain region recognized by mAb 1G12. The “short” ACE inhibitor enalaprilat (tripeptide analog) and “long” inhibitor teprotide (nonapeptide) produced strikingly different mAb 1G12 binding with enalaprilat strongly increasing mAb 1G12 binding and teprotide decreasing binding. Reduction in S-S bonds via glutathione and dithiothreitol treatment increased 1G12 binding to blood ACE in a manner comparable to enalaprilat. Some patients with uremia due to ESRD exhibited significantly increased mAb 1G12 binding to blood ACE and increased ACE activity towards angiotensin I accompanied by reduced ACE inhibition by inhibitory mAbs and ACE inhibitors. Conclusions/Significance The estimation of relative mAb 1G12 binding to blood ACE detects a subpopulation of ESRD patients with conformationally changed ACE, which activity is less suppressible by ACE inhibitors. This parameter may potentially serve as a biomarker for those patients who may need higher concentrations of ACE inhibitors upon anti-hypertensive therapy. PMID:23166630

  12. Effects of ACE Inhibitors on Insulin Resistance and Lipid Profile in Children with Metabolic Syndrome

    PubMed Central

    Çelebi Bitkin, Eda; Boyraz, Mehmet; Taşkın, Necati; Akçay, Arzu; Ulucan, Korkut; Akyol, Mehmet Bedir; Akçay, Teoman

    2013-01-01

    Objective: The aim of this study was to evaluate the effects of using ACE inhibitors on insulin resistance, glucose metabolism, body fat composition, and lipid profile in children over 10 years of age with obesity-associated metabolic syndrome (MS). Methods: A total of 53 children with MS, who had been followed for at least one year were included in the study. The sample was divided into two groups: Group 1-30 obese children (13 female, 17 male) who were not using an ACE inhibitor and Group 2-23 obese children (13 female, 10 male) who were using an ACE inhibitor. Anthropometric and laboratory dataobtained at baseline and at the 3rd, 6th, and 12th months of follow-up were compared in the two groups. Results: Comparison of the data in the two groups at 3rd, 6th, and 12th months revealed no statistically significant differences in terms of weight standard deviation score (SDS), body mass index SDS, weight for height percentile, body fat percentage, and very low-density lipoprotein (VLDL)values. However, there were statistically significant differences in mean glucose and insulin levels, homeostasis model assessment for insulin resistance, LDL and high-density lipoprotein values, and highly significant differences in mean triglyceride values. Conclusions: The positive effects of ACE inhibitor drugs, particularly on hypertriglyceridemia and insulin resistance, might bring them forth as first-line drugs in the treatment of obese and hypertensive children. Randomized, controlled, double-blind, and long-term studies are needed for a definitive conclusion. Conflict of interest:None declared. PMID:24072084

  13. Sacubitril/Valsartan: A Review in Chronic Heart Failure with Reduced Ejection Fraction.

    PubMed

    McCormack, Paul L

    2016-03-01

    Sacubitril/valsartan (Entresto™; LCZ696) is an orally administered supramolecular sodium salt complex of the neprilysin inhibitor prodrug sacubitril and the angiotensin receptor blocker (ARB) valsartan, which was recently approved in the US and the EU for the treatment of chronic heart failure (NYHA class II-IV) with reduced ejection fraction (HFrEF). In the large, randomized, double-blind, PARADIGM-HF trial, sacubitril/valsartan reduced the incidence of death from cardiovascular causes or first hospitalization for worsening heart failure (composite primary endpoint) significantly more than the angiotensin converting enzyme (ACE) inhibitor enalapril. Sacubitril/valsartan was also superior to enalapril in reducing death from any cause and in limiting the progression of heart failure. Sacubitril/valsartan was generally well tolerated, with no increase in life-threatening adverse events. Symptomatic hypotension was significantly more common with sacubitril/valsartan than with enalapril; the incidence of angio-oedema was low. Therefore, sacubitril/valsartan is a more effective replacement for an ACE inhibitor or an ARB in the treatment of HFrEF, and is likely to influence the basic approach to treatment.

  14. [Tranexamic acid as first-line emergency treatment for episodes of bradykinin-mediated angioedema induced by ACE inhibitors].

    PubMed

    Beauchêne, C; Martins-Héricher, J; Denis, D; Martin, L; Maillard, H

    2018-05-04

    Episodes of acquired bradykinin-mediated angioedema due to angiotensin-converting enzyme (ACE) inhibitors may result in fatal outcomes. There is no consensus regarding emergency pharmacological management of these episodes. Treatment options include icatibant and C1INH concentrate. Tranexamic acid is administered for moderate episodes. Its efficacy in the treatment of ACE inhibitor-induced episodes of angioedema is not established. The aim of this retrospective study is to assess the benefits of emergency tranexamic acid administration in the management of ACE inhibitor-induced episodes of angioedema. Retrospective analysis of the medical files of patients who consulted between 2010 and 2016 in two French tertiary care hospitals for a bradykinic angioedema attributed to an ACE treatment. All of them had received tranexamic acid as a first line treatment. Thirty three patients who had experienced severe episode of angioedema were included. Twenty seven patients showed significant improvement when treated with tranexamic acid alone. The six remaining patients were treated with icatibant (5/33) or C1INH concentrate (1/33), due to partial improvement after tranexamic acid therapy. None of the patients were intubated, no fatalities were recorded and no side effects were reported. Tranexamic acid is an easily accessible and affordable therapy that may provide effective treatment for ACE inhibitor-induced episodes of angioedema. It may help while waiting for a more specific treatment (icatibant and C1INH concentrate) that is at times unavailable in emergency departments. Copyright © 2018 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  15. Effect of combination therapy consisting of enalapril, α-lipoic acid, and menhaden oil on diabetic neuropathy in a high fat/low dose streptozotocin treated rat.

    PubMed

    Davidson, Eric P; Holmes, Amey; Coppey, Lawrence J; Yorek, Mark A

    2015-10-15

    We have previously demonstrated that treating diabetic rats with enalapril, an angiotensin converting enzyme (ACE) inhibitor, α-lipoic acid, an antioxidant, or menhaden oil, a natural source of omega-3 fatty acids can partially improve diabetic peripheral neuropathy. In this study we sought to determine the efficacy of combining these three treatments on vascular and neural complications in a high fat fed low dose streptozotocin treated rat, a model of type 2 diabetes. Rats were fed a high fat diet for 8 weeks followed by a 30 mg/kg dose of streptozotocin. Eight weeks after the onset of hyperglycemia diabetic rats were treated with a combination of enalapril, α-lipoic acid and menhaden oil. Diabetic rats not receiving treatment were continued on the high fat diet. Glucose clearance was impaired in diabetic rats and significantly improved with treatment. Diabetes caused steatosis, elevated serum lipid levels, slowing of motor and sensory nerve conduction, thermal hypoalgesia, reduction in intraepidermal nerve fiber profiles, decrease in cornea sub-basal nerve fiber length and corneal sensitivity and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles of the sciatic nerve. Treating diabetic rats with the combination of enalapril, α-lipoic acid and menhaden oil reversed all these deficits to near control levels except for motor nerve conduction velocity which was also significantly improved compared to diabetic rats but remained significantly decreased compared to control rats. These studies suggest that a combination therapeutic approach may be most effective for treating vascular and neural complications of type 2 diabetes. Published by Elsevier B.V.

  16. EARLY Treatment with azilsartan compared to ACE-inhibitors in anti-hypertensive therapy--rationale and design of the EARLY hypertension registry.

    PubMed

    Gitt, Anselm K; Baumgart, Peter; Bramlage, Peter; Mahfoud, Felix; Potthoff, Sebastian A; Senges, Jochen; Schneider, Steffen; Buhck, Hartmut; Schmieder, Roland E

    2013-07-02

    Arterial hypertension is highly prevalent but poorly controlled. Blood pressure (BP) reduction substantially reduces cardiovascular morbidity and mortality. Recent randomized, double-blind clinical trials demonstrated that azilsartan medoxomil (AZM) is more effective in reducing BP than the ubiquitary ACE inhibitor ramipril. Therefore, we aimed to test whether these can be verified under clinical practice conditions. The "Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy" (EARLY) registry is a prospective, observational, national, multicenter registry with a follow-up of up to 12 months. It will include up to 5000 patients on AZM or ACE-inhibitor monotherapy in a ratio of 7 to 3. A subgroup of patients will undergo 24-hour BP monitoring. EARLY has two co-primary objectives: 1) Description of the safety profile of azilsartan and 2) achievement of BP targets based on recent national and international guidelines for patients treated with azilsartan in comparison to those treated with ACE-inhibitors. The most important secondary endpoints are the determination of persistence with treatment and the documentation of cardiovascular and renal events. Recruitment commenced in January 2012 and will be completed by February 2013. The data obtained will supplement previous results from randomized controlled trials to document the potential value of utilizing azilsartan medoxomil in comparison to ACE-inhibitor treatment for target BP achievement in clinical practice.

  17. Evaluation of protein C and protein S levels in patients with diabetes mellitus receiving therapy with statins and ACE inhibitors or angiotensin II receptor blockers.

    PubMed

    Aktaş, Şerife; Uçak, Sema; Kurt, Fatma; Taşdemir, Mehmet; Kutlu, Orkide; Eker, Pınar

    2018-01-01

    To evaluate protein C, protein S level in patients with diabetes mellitus receiving statin and ACE inhibitor/ARB therapy. 95 patients were included in the study and divided into four groups depending on the use of statin and ACE inhibitor/ARB therapy. Group 1 comprised of patients receiving statin therapy (n = 15), Group 2 comprised of patients receiving ACE inhibitor/ARB therapy (n = 31), Group 3 comprised of patients receiving statin and ACE inhibitor/ARB therapy (n = 23), and Group 4 comprised of patients who did not receive either statin or ACE inhibitor/ARB therapy (n = 26). These four groups were compared with respect to protein C, protein S, fibrinogen, D-dimer, INR, and aPTT levels. There were statistically significant differences with respect to protein C levels. Group 1 and group 2 had higher protein C levels compared with group 4. (p < .01). Similarly, Group 3 had higher protein C levels compared with group 4. (p < .01). There was no significant difference between the groups with respect to protein S, INR, aPTT, and D-dimer levels. Diabetic patients receiving statin or ACE inhibitor/ARB therapy had higher protein C levels. Use of statin and ACE inhibitor/ARB therapy in diabetic patients decrease hypercoagulability and therefore could reduce the occurrence of cardiovascular events. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. 21 CFR 520.804 - Enalapril tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Enalapril tablets. 520.804 Section 520.804 Food... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.804 Enalapril tablets. (a) Specifications. Each tablet contains either 1.0, 2.5, 5.0, 10.0, or 20.0 milligrams of enalapril maleate. (b...

  19. Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study.

    PubMed

    Ouwerkerk, W; Voors, A A; Anker, S D; Cleland, J G; Dickstein, K; Filippatos, G; van der Harst, P; Hillege, H L; Lang, C C; Ter Maaten, J M; Ng, L L; Ponikowski, P; Samani, N J; van Veldhuisen, D J; Zannad, F; Metra, M; Zwinderman, A H

    2017-06-21

    Despite clear guidelines recommendations, most patients with heart failure and reduced ejection-fraction (HFrEF) do not attain guideline-recommended target doses. We aimed to investigate characteristics and for treatment-indication-bias corrected clinical outcome of patients with HFrEF that did not reach recommended treatment doses of ACE-inhibitors/Angiotensin receptor blockers (ARBs) and/or beta-blockers. BIOSTAT-CHF was specifically designed to study uptitration of ACE-inhibitors/ARBs and/or beta-blockers in 2516 heart failure patients from 69 centres in 11 European countries who were selected if they were suboptimally treated while initiation or uptitration was anticipated and encouraged. Patients who died during the uptitration period (n = 151) and patients with a LVEF > 40% (n = 242) were excluded. Median follow up was 21 months. We studied 2100 HFrEF patients (76% male; mean age 68 ±12), of which 22% achieved the recommended treatment dose for ACE-inhibitor/ARB and 12% of beta-blocker. There were marked differences between European countries. Reaching <50% of the recommended ACE-inhibitor/ARB and beta-blocker dose was associated with an increased risk of death and/or heart failure hospitalization. Patients reaching 50-99% of the recommended ACE-inhibitor/ARB and/or beta-blocker dose had comparable risk of death and/or heart failure hospitalization to those reaching ≥100%. Patients not reaching recommended dose because of symptoms, side effects and non-cardiac organ dysfunction had the highest mortality rate (for ACE-inhibitor/ARB: HR 1.72; 95% CI 1.43-2.01; for beta-blocker: HR 1.70; 95% CI 1.36-2.05). Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For

  20. Rapid screening and identification of ACE inhibitors in snake venoms using at-line nanofractionation LC-MS.

    PubMed

    Mladic, Marija; de Waal, Tessa; Burggraaff, Lindsey; Slagboom, Julien; Somsen, Govert W; Niessen, Wilfried M A; Manjunatha Kini, R; Kool, Jeroen

    2017-10-01

    This study presents an analytical method for the screening of snake venoms for inhibitors of the angiotensin-converting enzyme (ACE) and a strategy for their rapid identification. The method is based on an at-line nanofractionation approach, which combines liquid chromatography (LC), mass spectrometry (MS), and pharmacology in one platform. After initial LC separation of a crude venom, a post-column flow split is introduced enabling parallel MS identification and high-resolution fractionation onto 384-well plates. The plates are subsequently freeze-dried and used in a fluorescence-based ACE activity assay to determine the ability of the nanofractions to inhibit ACE activity. Once the bioactive wells are identified, the parallel MS data reveals the masses corresponding to the activities found. Narrowing down of possible bioactive candidates is provided by comparison of bioactivity profiles after reversed-phase liquid chromatography (RPLC) and after hydrophilic interaction chromatography (HILIC) of a crude venom. Additional nanoLC-MS/MS analysis is performed on the content of the bioactive nanofractions to determine peptide sequences. The method described was optimized, evaluated, and successfully applied for screening of 30 snake venoms for the presence of ACE inhibitors. As a result, two new bioactive peptides were identified: pELWPRPHVPP in Crotalus viridis viridis venom with IC 50  = 1.1 μM and pEWPPWPPRPPIPP in Cerastes cerastes cerastes venom with IC 50  = 3.5 μM. The identified peptides possess a high sequence similarity to other bradykinin-potentiating peptides (BPPs), which are known ACE inhibitors found in snake venoms.

  1. ACE inhibitor and angiotensin II type 1 receptor antagonist therapies in elderly patients with diabetes mellitus: are they underutilized?

    PubMed

    Pappoe, Lamioko Shika; Winkelmayer, Wolfgang C

    2010-02-01

    Diabetes mellitus is highly prevalent in older adults in the industrialized world. These patients are at high risk of complications from diabetes, including diabetic kidney disease. ACE inhibitors and their newer cousins, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), are powerful medications for the prevention of progression of diabetic renal disease. Unfortunately, among the elderly, these medications have been underutilized. The reasons for this include physician concerns regarding patient age and limited life expectancy and potential complications of ACE inhibitor or ARB use, specifically an increase in creatinine levels and hyperkalaemia. As discussed in this article, there have been several studies that show that the effects of inhibition of the renin-angiotensin system can be beneficial for the treatment of cardiovascular disease and renal disease among elderly patients with diabetes and that the potential risks mentioned above are no greater in this group than in the general population. For these reasons, several professional societies recommend that elderly patients with diabetes and hypertension (systolic blood pressure >or=140 mmHg or diastolic blood pressure >or=90 mmHg) be treated with an ACE inhibitor or ARB (as is recommended for younger diabetics). Use of ACE inhibitors or ARBs is also recommended for those with cardiovascular disease or those who are at risk of cardiovascular disease. Furthermore, in the management of diabetic kidney disease in elderly patients, treatment with ACE inhibitors or ARBs is also recommended to reduce the risk or slow the progression of nephropathy. Renal function and potassium levels should be monitored within the first 12 weeks of initiation of these medications, with each dose increase, and on a yearly basis thereafter. This article summarizes the current guidelines on the use of ACE inhibitors and ARBs in older adults with diabetes, reviews the evidence for their use in the elderly

  2. EARLY Treatment with azilsartan compared to ACE-inhibitors in anti-hypertensive therapy – rationale and design of the EARLY hypertension registry

    PubMed Central

    2013-01-01

    Background Arterial hypertension is highly prevalent but poorly controlled. Blood pressure (BP) reduction substantially reduces cardiovascular morbidity and mortality. Recent randomized, double-blind clinical trials demonstrated that azilsartan medoxomil (AZM) is more effective in reducing BP than the ubiquitary ACE inhibitor ramipril. Therefore, we aimed to test whether these can be verified under clinical practice conditions. Methods/Design The “Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy” (EARLY) registry is a prospective, observational, national, multicenter registry with a follow-up of up to 12 months. It will include up to 5000 patients on AZM or ACE-inhibitor monotherapy in a ratio of 7 to 3. A subgroup of patients will undergo 24-hour BP monitoring. EARLY has two co-primary objectives: 1) Description of the safety profile of azilsartan and 2) achievement of BP targets based on recent national and international guidelines for patients treated with azilsartan in comparison to those treated with ACE-inhibitors. The most important secondary endpoints are the determination of persistence with treatment and the documentation of cardiovascular and renal events. Recruitment commenced in January 2012 and will be completed by February 2013. Conclusions The data obtained will supplement previous results from randomized controlled trials to document the potential value of utilizing azilsartan medoxomil in comparison to ACE-inhibitor treatment for target BP achievement in clinical practice. PMID:23819631

  3. The association between ACE inhibitors and the complex regional pain syndrome: Suggestions for a neuro-inflammatory pathogenesis of CRPS.

    PubMed

    de Mos, M; Huygen, F J P M; Stricker, B H Ch; Dieleman, J P; Sturkenboom, M C J M

    2009-04-01

    Antihypertensive drugs interact with mediators that are also involved in complex regional pain syndrome (CRPS), such a neuropeptides, adrenergic receptors, and vascular tone modulators. Therefore, we aimed to study the association between the use of antihypertensive drugs and CRPS onset. We conducted a population-based case-control study in the Integrated Primary Care Information (IPCI) database in the Netherlands. Cases were identified from electronic records (1996-2005) and included if they were confirmed during an expert visit (using IASP criteria), or if they had been diagnosed by a medical specialist. Up to four controls per cases were selected, matched on gender, age, calendar time, and injury. Exposure to angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, beta-blockers, calcium channel blockers, and diuretics was assessed from the automated prescription records. Data were analyzed using multivariate conditional logistic regression. A total of 186 cases were matched to 697 controls (102 confirmed during an expert visit plus 84 with a specialist diagnosis). Current use of ACE inhibitors was associated with an increased risk of CRPS (OR(adjusted): 2.7, 95% CI: 1.1-6.8). The association was stronger if ACE inhibitors were used for a longer time period (OR(adjusted): 3.0, 95% CI: 1.1-8.1) and in higher dosages (OR(adjusted): 4.3, 95% CI: 1.4-13.7). None of the other antihypertensive drug classes was significantly associated with CRPS. We conclude that ACE inhibitor use is associated with CRPS onset and hypothesize that ACE inhibitors influence the neuro-inflammatory mechanisms that underlie CRPS by their interaction with the catabolism of substance P and bradykinin.

  4. ACE phenotyping in human heart.

    PubMed

    Tikhomirova, Victoria E; Kost, Olga A; Kryukova, Olga V; Golukhova, Elena Z; Bulaeva, Naida I; Zholbaeva, Aigerim Z; Bokeria, Leo A; Garcia, Joe G N; Danilov, Sergei M

    2017-01-01

    Angiotensin-converting enzyme (ACE), which metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling, is expressed as a type-1 membrane glycoprotein on the surface of different cells, including endothelial cells of the heart. We hypothesized that the local conformation and, therefore, the properties of heart ACE could differ from lung ACE due to different microenvironment in these organs. We performed ACE phenotyping (ACE levels, conformation and kinetic characteristics) in the human heart and compared it with that in the lung. ACE activity in heart tissues was 10-15 lower than that in lung. Various ACE effectors, LMW endogenous ACE inhibitors and HMW ACE-binding partners, were shown to be present in both heart and lung tissues. "Conformational fingerprint" of heart ACE (i.e., the pattern of 17 mAbs binding to different epitopes on the ACE surface) significantly differed from that of lung ACE, which reflects differences in the local conformations of these ACEs, likely controlled by different ACE glycosylation in these organs. Substrate specificity and pH-optima of the heart and lung ACEs also differed. Moreover, even within heart the apparent ACE activities, the local ACE conformations, and the content of ACE inhibitors differ in atria and ventricles. Significant differences in the local conformations and kinetic properties of heart and lung ACEs demonstrate tissue specificity of ACE and provide a structural base for the development of mAbs able to distinguish heart and lung ACEs as a potential blood test for predicting atrial fibrillation risk.

  5. ACE phenotyping in human heart

    PubMed Central

    Tikhomirova, Victoria E.; Kost, Olga A.; Kryukova, Olga V.; Golukhova, Elena Z.; Bulaeva, Naida I.; Zholbaeva, Aigerim Z.; Bokeria, Leo A.; Garcia, Joe G. N.

    2017-01-01

    Aims Angiotensin-converting enzyme (ACE), which metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling, is expressed as a type-1 membrane glycoprotein on the surface of different cells, including endothelial cells of the heart. We hypothesized that the local conformation and, therefore, the properties of heart ACE could differ from lung ACE due to different microenvironment in these organs. Methods and results We performed ACE phenotyping (ACE levels, conformation and kinetic characteristics) in the human heart and compared it with that in the lung. ACE activity in heart tissues was 10–15 lower than that in lung. Various ACE effectors, LMW endogenous ACE inhibitors and HMW ACE-binding partners, were shown to be present in both heart and lung tissues. “Conformational fingerprint” of heart ACE (i.e., the pattern of 17 mAbs binding to different epitopes on the ACE surface) significantly differed from that of lung ACE, which reflects differences in the local conformations of these ACEs, likely controlled by different ACE glycosylation in these organs. Substrate specificity and pH-optima of the heart and lung ACEs also differed. Moreover, even within heart the apparent ACE activities, the local ACE conformations, and the content of ACE inhibitors differ in atria and ventricles. Conclusions Significant differences in the local conformations and kinetic properties of heart and lung ACEs demonstrate tissue specificity of ACE and provide a structural base for the development of mAbs able to distinguish heart and lung ACEs as a potential blood test for predicting atrial fibrillation risk. PMID:28771512

  6. Associations between ACE-Inhibitors, Angiotensin Receptor Blockers, and Lean Body Mass in Community Dwelling Older Women.

    PubMed

    Bea, Jennifer W; Wassertheil-Smoller, Sylvia; Wertheim, Betsy C; Klimentidis, Yann; Chen, Zhao; Zaslavsky, Oleg; Manini, Todd M; Womack, Catherine R; Kroenke, Candyce H; LaCroix, Andrea Z; Thomson, Cynthia A

    2018-01-01

    Studies suggest that ACE-inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) may preserve skeletal muscle with aging. We evaluated longitudinal differences in lean body mass (LBM) among women diagnosed with hypertension and classified as ACE-I/ARB users and nonusers among Women's Health Initiative participants that received dual energy X-ray absorptiometry scans to estimate body composition ( n =10,635) at baseline and at years 3 and 6 of follow-up. Of those, 2642 were treated for hypertension at baseline. Multivariate linear regression models, adjusted for relevant demographics, behaviors, and medications, assessed ACE-I/ARB use/nonuse and LBM associations at baseline, as well as change in LBM over 3 and 6 years. Although BMI did not differ by ACE-I/ARB use, LBM (%) was significantly higher in ACE-I/ARB users versus nonusers at baseline (52.2% versus 51.3%, resp., p =0.001). There was no association between ACE-I/ARB usage and change in LBM over time. Reasons for higher LBM with ACE-I/ARB use cross sectionally, but not longitundinally, are unclear and may reflect a threshold effect of these medications on LBM that is attenuated over time. Nevertheless, ACE-I/ARB use does not appear to negatively impact LBM in the long term.

  7. Enalapril/amlodipine combination in cyclosporine-treated renal transplant recipients: a prospective randomized trial.

    PubMed

    Halimi, Jean-Michel; Giraudeau, Bruno; Buchler, Matthias; Al-Najjar, Azmi; Etienne, Isabelle; Laouad, Inass; Bruyère, Franck; Lebranchu, Yvon

    2007-01-01

    Most hypertensive renal transplant recipients require two or more antihypertensive medications to achieve blood pressure control. However, which medications must be combined is still a matter of debate. A prospective randomized open-label blinded evaluation trial comparing the six-month effects of the amlodipine-enalapril combination (n = 32) vs. enalapril alone (n = 33) and vs. amlodipine alone (n = 34) on arterial pressure, renal function, albuminuria and tolerability. At six months, diastolic arterial pressure was more adequately controlled (i.e., <90 mmHg) in the combination group than in the amlodipine and enalapril groups (100% vs. 82.4% and 84.8%, respectively, p = 0.038). The same trend was observed for systolic arterial pressure (65.6% vs. 58.8% and 51.5%, NS). The six-month change in albuminuria was similar in the combination group and in the enalapril group (-64.7% vs. -59.5%); however, patients in the combination group exhibited a greater reduction in albuminuria than in the amlodipine group (-64.7% vs. -29.0%, p = 0.002). As compared with baseline values, serum creatinine and potassium remained unchanged in the combination group, whereas they increased by 9 +/- 12 micromol/L (p = 0.01) and by 0.2 +/- 0.4 mmol/L (p < 0.01), respectively, in the enalapril group. The cyclosporine trough levels remained unchanged in the combination group, but increased in the amlodipine group. Angiotensin-converting enzyme inhibitor (ACEI)-calcium-channel blocker (CCB) combination controls arterial pressure more adequately than ACEI alone or CCB alone, reduces albuminuria and may prevent the ACEI-induced initial rise in serum creatinine.

  8. [High doses of aspirin reduce natriuresis in hypertensive patients treated with enalapril].

    PubMed

    Di Gennaro, Federico P; Cingolani, Oscar H; Abbate, Alejandro F; Toblli, Jorge E; Vilches, Antonio

    2004-01-01

    Angiotensin converting enzyme inhibitors have been shown to be useful in the treatment of essential hypertension while anti-platelet agents improve the overall cardiovascular risk profile in this population. Our aim was to assess the interaction of two different aspirin (ASA) doses--81 and 325 mg/day--with the antihypertensive effect of enalapril as well as their impact upon the urinary sodium excretion (Na(u)). A total of 22 patients between 35 and 65 years of age were included in a prospective double blind trial with a partial cross-over design. We excluded patients with secondary hypertension and recent use of anti-inflammatory drugs. Patients were placed on enalapril and a low sodium diet--<6 g of NaCl/day--and, sequentially, on two different doses of aspirin separated by a 10 day wash out period. Blood pressure (BP) was measured at weekly visits. Systolic, diastolic and mean BP levels decreased significantly in enalapril-treated patients (p<0.01) and no difference was detected between the two AAS dosages although a non-statistically significant difference towards better BP control was observed when 81 mg of ASA was used. Na(u) was higher at baseline when compared with the two periods under ASA (p<0.01) and Na(u) was higher with 81 mg than with 325 mg. These results suggest that in essential hypertensive individuals treated with enalapril and two ASA doses, low doses of ASA are associated with better blood pressure control and higher natriuresis.

  9. Effects of Small Molecule Calcium-Activated Chloride Channel Inhibitors on Structure and Function of Accessory Cholera Enterotoxin (Ace) of Vibrio cholerae

    PubMed Central

    Chatterjee, Tanaya; Sheikh, Irshad Ali; Chakravarty, Devlina; Chakrabarti, Pinak; Sarkar, Paramita; Saha, Tultul; Chakrabarti, Manoj K.; Hoque, Kazi Mirajul

    2015-01-01

    Cholera pathogenesis occurs due to synergistic pro-secretory effects of several toxins, such as cholera toxin (CTX) and Accessory cholera enterotoxin (Ace) secreted by Vibrio cholerae strains. Ace activates chloride channels stimulating chloride/bicarbonate transport that augments fluid secretion resulting in diarrhea. These channels have been targeted for drug development. However, lesser attention has been paid to the interaction of chloride channel modulators with bacterial toxins. Here we report the modulation of the structure/function of recombinant Ace by small molecule calcium-activated chloride channel (CaCC) inhibitors, namely CaCCinh-A01, digallic acid (DGA) and tannic acid. Biophysical studies indicate that the unfolding (induced by urea) free energy increases upon binding CaCCinh-A01 and DGA, compared to native Ace, whereas binding of tannic acid destabilizes the protein. Far-UV CD experiments revealed that the α-helical content of Ace-CaCCinh-A01 and Ace-DGA complexes increased relative to Ace. In contrast, binding to tannic acid had the opposite effect, indicating the loss of protein secondary structure. The modulation of Ace structure induced by CaCC inhibitors was also analyzed using docking and molecular dynamics (MD) simulation. Functional studies, performed using mouse ileal loops and Ussing chamber experiments, corroborate biophysical data, all pointing to the fact that tannic acid destabilizes Ace, inhibiting its function, whereas DGA stabilizes the toxin with enhanced fluid accumulation in mouse ileal loop. The efficacy of tannic acid in mouse model suggests that the targeted modulation of Ace structure may be of therapeutic benefit for gastrointestinal disorders. PMID:26540279

  10. Synthesis and evaluation of novel triazoles and mannich bases functionalized 1,4-dihydropyridine as angiotensin converting enzyme (ACE) inhibitors.

    PubMed

    Kumbhare, Ravindra M; Kosurkar, Umesh B; Bagul, Pankaj K; Kanwal, Abhinav; Appalanaidu, K; Dadmal, Tulshiram L; Banerjee, Sanjay Kumar

    2014-11-01

    A series of novel diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate embedded triazole and mannich bases were synthesized, and evaluated for their angiotensin converting enzyme (ACE) inhibitory activity. Screening of above synthesized compounds for ACE inhibition showed that triazoles functionalized compounds have better ACE inhibitory activity compared to that of mannich bases analogues. Among all triazoles we found 6 h, 6 i and 6 j to have good ACE inhibition activity with IC50 values 0.713 μM, 0.409 μM and 0.653 μM, respectively. Among mannich bases series compounds, only 7c resulted as most active ACE inhibitor with IC50 value of 0.928 μM. Copyright © 2014. Published by Elsevier Ltd.

  11. 21 CFR 520.804 - Enalapril tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Enalapril tablets. 520.804 Section 520.804 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.804 Enalapril tablets. (a...

  12. 21 CFR 520.804 - Enalapril tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Enalapril tablets. 520.804 Section 520.804 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.804 Enalapril tablets. (a...

  13. Difference in blood pressure response to ACE-Inhibitor monotherapy between black and white adults with arterial hypertension: a meta-analysis of 13 clinical trials.

    PubMed

    Peck, Robert N; Smart, Luke R; Beier, Rita; Liwa, Anthony C; Grosskurth, Heiner; Fitzgerald, Daniel W; Schmidt, Bernhard M W

    2013-09-26

    Among African-Americans adults, arterial hypertension is both more prevalent and associated with more complications than among white adults. Hypertension is also epidemic among black adults in sub-Saharan Africa. The treatment of hypertension among black adults may be complicated by lesser response to certain classes of anti-hypertensive agents. We systematically searched literature for clinical trials of ACE-inhibitors among hypertensive adults comparing blood pressure response between whites and blacks. Meta-analysis was performed to determine the difference in systolic and diastolic blood pressure response. Further analysis including meta-regressions, funnel plots, and one-study-removed analyses were performed to investigate possible sources of heterogeneity or bias. In a meta-analysis of 13 trials providing 17 different patient groups for evaluation, black race was associated with a lesser reduction in systolic (mean difference: 4.6 mmHg (95% CI 3.5-5.7)) and diastolic (mean difference: 2.8 mmHg (95% CI 2.2-3.5)) blood pressure response to ACE-inhibitors, with little heterogeneity. Meta-regression revealed only ACE-inhibitor dosage as a significant source of heterogeneity. There was little evidence of publication bias. Black race is consistently associated with a clinically significant lesser reduction in both systolic and diastolic blood pressure to ACE-inhibitor therapy in clinical trials in the USA and Europe. In black adults requiring monotherapy for uncomplicated hypertension, drugs other than ACE-inhibitors may be preferred, though the proven benefits of ACE-inhibitors in some sub-groups and the large overlap of response between blacks and whites must be remembered. These data are particularly important for interpretation of clinical drug trials for hypertensive black adults in sub-Saharan Africa and for the development of treatment recommendations in this population.

  14. Refill Adherence in Relation to Substitution and the Use of Multiple Medications: A Nationwide Population Based Study on New ACE-Inhibitor Users

    PubMed Central

    Jönsson, Anna K.; Lesén, Eva; Mårdby, Ann-Charlotte; Sundell, Karolina Andersson

    2016-01-01

    Objective Generic substitution has contributed to economic savings but switching products may affect patient adherence, particularly among those using multiple medications. The aim was to analyse if use of multiple medications influenced the association between switching products and refill adherence to angiotensin-converting-enzyme (ACE) inhibitors in Sweden. Study Design and Setting New users of ACE-inhibitors, starting between 1 July 2006 and 30 June 2007, were identified in the Swedish Prescribed Drug Register. Refill adherence was assessed using the continuous measure of medication acquisition (CMA) and analysed with linear regression and analysis of covariance. Results The study population included 42735 individuals whereof 51.2% were exposed to switching ACE-inhibitor and 39.6% used multiple medications. Refill adherence was higher among those exposed to switching products than those not, but did not vary depending on the use of multiple medications or among those not. Refill adherence varied with age, educational level, household income, country of birth, previous hospitalisation and previous cardiovascular diagnosis. Conclusion The results indicate a positive association between refill adherence and switching products, mainly due to generic substitution, among new users of ACE-inhibitors in Sweden. This association was independent of use of multiple medications. PMID:27192203

  15. Angiotensin converting enzyme immobilized on magnetic beads as a tool for ligand fishing.

    PubMed

    de Almeida, Fernando G; Vanzolini, Kenia L; Cass, Quezia B

    2017-01-05

    Angiotensin converting enzyme (ACE) presents an important role in blood pressure regulation, since that converts angiotensin I to the vasoconstrictor angiotensin II. Some commercially available ACE inhibitors are captopril, lisinopril and enalapril; due to their side effects, naturally occurring inhibitors have been prospected. In order to endorse this research field we have developed a new tool for ACE ligand screening. To this end, ACE was extracted from bovine lung, purified and chemically immobilized in modified ferrite magnetic beads (ACE-MBs). The ACE-MBs have shown a Michaelian kinetic behavior towards hippuryl-histidyl-leucine. Moreover, as proof of concept, the ACE-MBs was inhibited by lisinopril with a half maximal inhibitory concentration (IC 50 ) of 10nM. At the fishing assay, ACE-MBs were able not only to fish out the reference inhibitor, but also one peptide from a pool of tryptic digested BSA. In conclusion, ACE-MBs emerge as new straightforward tool for ACE kinetics determination, inhibition and binder screening. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. A Study to Assess the Therapeutic Effect of Enalapril on Olanzapine Induced Metabolic Syndrome in Wistar Rats.

    PubMed

    Arivazhahan, Avinash; Bairy, Laxminarayana Kurady; Nayak, Veena; Kunder, Sushil Kiran

    2017-02-01

    Metabolic Syndrome (MS) is a complex of risk factors for the development of cardiovascular complications and Type 2 Diabetes Mellitus (DM). Pharmacological management of the condition is complex, as multiple drug groups have to be used, as the syndrome itself is multi faceted. Angiotensin Converting Enzyme Inhibitors (ACEIs) are chiefly used to manage the hypertensive component of the syndrome. However, recent studies have shown that these drugs may have a role in the non hypertensive aspects of the syndrome as well. To evaluate the therapeutic effect of enalapril on total body weight, random blood glucose and serum lipid profile in a rodent model of olanzapine induced MS. Three different dosages (1 mg/kg/day, 10 mg/kg/day and 20 mg/kg/day) of oral enalapril were administered (for three weeks) in albino wistar rats, which received prior intra peritoneal olanzapine (for three weeks), and compared against control (normal saline) and standard (olanzapine only and enalapril only) groups. Parameters like total body weight, random blood glucose and serum lipid profile were measured at baseline, at three weeks and at six weeks. Enalapril at 20 mg/kg/day was found to be effective in reversing the weight gain, hyperglycaemia and hypercholesterolaemia, without any changes in triglycerides, High Density Lipoprotein (HDL) and Low Density Lipoprotein (LDL). 10 mg/kg/day of enalapril prevented any further rise in body weight, blood glucose, total cholesterol and serum triglycerides, after olanzapine was stopped. 1 mg/kg/day of enalapril was ineffective. High dose of enalapril may be considered as a component of therapeutic regimens to combat weight gain, hyperglycaemia and dyslipidaemia seen in MS, in addition to its antihypertensive utility. Further rodent and clinical studies may be required to ascertain the same.

  17. Cardiovascular risk reduction by reversing endothelial dysfunction:ARBs, ACE inhibitors, or both? Expectations from The ONTARGET Trial Programme

    PubMed Central

    Ruilope, Luis Miguel; Redón, Josep; Schmieder, Roland

    2007-01-01

    Endothelial dysfunction is the initial pathophysiological step in a progression of vascular damage that leads to overt cardiovascular and chronic kidney disease. Angiotensin II, the primary agent of the renin–angiotensin system (RAS), has a central role in endothelial dysfunction. Therefore, RAS blockade with an angiotensin receptor blocker (ARB) and/or angiotensin-converting enzyme (ACE) inhibitor provides a rational approach to reverse endothelial dysfunction, reduce microalbuminuria, and, thus, improves cardiovascular and renal prognosis. ARBs and ACE inhibitors act at different points in the RAS pathway and recent evidence suggests that there are differences regarding their effects on endothelial dysfunction. In addition to blood pressure lowering, studies have shown that ARBs reduce target-organ damage, including improvements in endothelial dysfunction, arterial stiffness, the progression of renal dysfunction in patients with type 2 diabetes, proteinuria, and left ventricular hypertrophy. The ONgoing Telmisartan Alone in combination with Ramipril Global Endpoint Trial (ONTARGET) Programme is expected to provide the ultimate evidence of whether improved endothelial function translates into reduced cardiovascular and renal events in high-risk patients, and to assess possible differential outcomes with telmisartan, the ACE inhibitor ramipril, or a combination of both (dual RAS blockade). Completion of ONTARGET is expected in 2008. PMID:17583170

  18. Occurrence and fate of ACE-inhibitor peptides in cheeses and in their digestates following in vitro static gastrointestinal digestion.

    PubMed

    Stuknytė, Milda; Cattaneo, Stefano; Masotti, Fabio; De Noni, Ivano

    2015-02-01

    The occurrence of the casein-derived angiotensin converting enzyme-inhibitor (ACE-I) peptides VPP, IPP, RYLGY, RYLG, AYFYPEL, AYFYPE, LHLPLP and HLPLP were investigated in 12 different cheese samples by Ultra Performance Liquid Chromatography/High-Resolution Mass Spectrometry. The total amount of ACE-I peptides was in the range 0.87-331mgkg(-1). VPP and IPP largely prevailed in almost all cheeses. Following in vitro static gastrointestinal digestion of Cheddar, Gorgonzola, Maasdam and Grana Padano cheeses, type and amount of ACE-I peptides changed, and only VPP, IPP, HLPLP and LHLPLP were detected in the intestinal digestates. The results evidenced that the degree of proteolysis itself cannot be regarded as a promoting or hindering factor for ACE-I peptide release during cheese digestion. Moreover, the data indicated that the ACE-I potential of cheeses cannot be inferred based on the type and amount of ACE-I peptides present in undigested samples. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Improvement of enalapril maleate chemical stability by high shear melting granulation.

    PubMed

    de Oliveira, Ana Paula Montandon; Cunha, Talita Amorim; Serpa, Raphael Caixeta; Taveira, Stephânia Fleury; Lima, Eliana Martins; Almeida Diniz, Danielle Guimarães; de Freitas, Luis Alexandre Pedro; Marreto, Ricardo Neves

    2014-09-18

    Abstract Enalapril maleate is a widely used drug, which is chemically unstable when mixed with excipients resulting in enalaprilat and diketopiperazine as the main degradation products. The preparation of enalapril sodium salt has been used to improve drug stability in solid dosage forms; however, product rejection is observed when the chemical reaction for obtaining the sodium salt is not completely finished before packaging. In this study, granules were prepared by melting granulation using stearic acid or glyceryl monostearate, with a view to developing more stable enalapril maleate solid dosage forms. The granules were prepared in a laboratory-scale high shear mixer and compressed in a rotary machine. Size distribution, flow properties, in vitro drug release and enalapril maleate chemical stability were evaluated and compared with data obtained from tablets prepared without hydrophobic binders. All formulations showed good physical properties and immediate drug release. The greatest improvement in the enalapril maleate stability was observed in formulations containing stearic acid. This study showed that hot melting granulation could be successfully used to prepare enalapril maleate granules which could substitute the in situ formation of enalapril sodium salt, since they provided better enalapril stability in solid dosage forms.

  20. The effects of sacubitril/valsartan on coronary outcomes in PARADIGM-HF.

    PubMed

    Mogensen, Ulrik M; Køber, Lars; Kristensen, Søren L; Jhund, Pardeep S; Gong, Jianjian; Lefkowitz, Martin P; Rizkala, Adel R; Rouleau, Jean L; Shi, Victor C; Swedberg, Karl; Zile, Michael R; Solomon, Scott D; Packer, Milton; McMurray, John J V

    2017-06-01

    Angiotensin converting enzyme inhibitors (ACE-I), are beneficial both in heart failure with reduced ejection fraction (HF-REF) and after myocardial infarction (MI). We examined the effects of the angiotensin-receptor neprilysin inhibitor sacubitril/valsartan, compared with the ACE-I enalapril, on coronary outcomes in PARADIGM-HF. We examined the effect of sacubitril/valsartan compared with enalapril on the following outcomes: i) the primary composite endpoint of cardiovascular (CV) death or HF hospitalization, ii) a pre-defined broader composite including, in addition, MI, stroke, and resuscitated sudden death, and iii) a post hoc coronary composite of CV-death, non-fatal MI, angina hospitalization or coronary revascularization. At baseline, of 8399 patients, 3634 (43.3%) had a prior MI and 4796 (57.1%) had a history of any coronary artery disease. Among all patients, compared with enalapril, sacubitril/valsartan reduced the risk of the primary outcome (HR 0.80 [0.73-0.87], P<.001), the broader composite (HR 0.83 [0.76-0.90], P<.001) and the coronary composite (HR 0.83 [0.75-0.92], P<.001). Although each of the components of the coronary composite occurred less frequently in the sacubitril/valsartan group, compared with the enalapril group, only CV death was reduced significantly. Compared with enalapril, sacubitril/valsartan reduced the risk of both the primary endpoint and a coronary composite outcome in PARADIGM-HF. Additional studies on the effect of sacubitril/valsartan on atherothrombotic outcomes in high-risk patients are merited. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. The angiotensin converting enzyme (ACE) inhibitor, captopril disrupts the motility activation of sperm from the silkworm, Bombyx mori.

    PubMed

    Nagaoka, Sumiharu; Kawasaki, Saori; Kawasaki, Hideki; Kamei, Kaeko

    2017-11-01

    Angiotensin I-converting enzyme (also known as peptidyl dicarboxypeptidase A, ACE, and EC 3.4.15.1), which is found in a wide range of organisms, cleaves C-terminal dipeptides from relatively short oligopeptides. Mammalian ACE plays an important role in the regulation of blood pressure. However, the precise physiological functions of insect ACE homologs have not been understood. As part of our effort to elucidate new physiological roles of insect ACE, we herein report a soluble ACE protein in male reproductive secretions from the silkmoth, Bombyx mori. Seminal vesicle sperm are quiescent in vitro, but vigorous motility is activated by treatment with either a glandula (g.) prostatica homogenate or trypsin in vitro. When seminal vesicle sperm were pre-incubated with captopril, a strong and specific inhibitor of mammalian ACE, and then stimulated to initiate motility by the addition of the g. prostatica homogenate or trypsin, the overall level of acquired motility was reduced in an inhibitor-concentration-dependent manner. In the course of this project, we detected ACE-related carboxypeptidase activity that was inhibited by captopril in both the vesicular (v.) seminalis of the noncopulative male reproductive tract and in the spermatophore that forms in the female bursa copulatrix at the time of mating, just as in an earlier report on the tomato moth, Lacanobia oleracea, which belongs to a different lepidopteran species (Ekbote et al., 2003a). Two distinct genes encoding ACE-like proteins were identified by analysis of B. mori cDNA, and were named BmAcer and BmAcer2, respectively [the former was previously reported by Quan et al. (2001) and the latter was first isolated in this paper]. RT-qPCR and Western blot analyses indicated that the BmAcer2 was predominantly produced in v. seminalis and transferred to the spermatophore during copulation, while the BmAcer was not detected in the adult male reproductive organs. A recombinant protein of BmAcer2 (devoid of a signal

  2. nNOS expression in the brain of rats after burn and the effect of the ACE inhibitor captopril.

    PubMed

    Demiralay, Ebru; Saglam, Ibrahim Yaman; Ozdamar, Emine Nur; Sehirli, Ahmet Ozer; Sener, Goksel; Saglam, Esra

    2013-08-01

    To investigate the role of endogenous neuronal nitric oxide synthase (nNOS) on brain injury after burn and the effects of the captopril. Wistar albino rats (200-250 g) were exposed on the dorsal surface to 90°C (burn) or 25°C (sham) water for 10 s. The ACE group was treated with intraperitoneal 10 mg/kg captopril immediately after burn and this treatment was repeated twice daily. At the end of the 24 h brain samples were taken. nNOS was studied in brain areas by immunohistochemistry. There was no difference between the cerebellar and hypothalamic areas the nNOS expression of all groups. nNOS expression increased in the frontal cortex, striatum and midbrain in the burn group compared to the control group. In the frontal cortex, nNOS expression significantly decreased after ACE inhibitor treatment (p<0.05). The striatal nNOS of the ACE group significantly increased when compared to the control group (p=0.001). In the midbrain of the animals, nNOS decreased in the ACE group. Hippocampal nNOS expression did not change after burn and significantly increased after ACE inhibitor therapy (p<0.05). Our data showed that the pathophysiological events following burn appear to be related to an acute inflammatory reaction which is associated with nNOS in the frontal cortex, striatum and midbrain, and captopril treatment abrogates the nNOS response in the frontal cortex and midbrain. Copyright © 2012 Elsevier Ltd and ISBI. All rights reserved.

  3. Life threatening angioedema in a patient on ACE inhibitor (ACEI) confined to the upper airway

    PubMed Central

    Tharayil, Abdulgafoor Muslim; Chanda, Arshad Hussain; Shiekh, Hakim Ahmad; Elkhatib, Mohamed Saad; Nayeemuddin, Mohammed; Alshamandy, Abdelhafiz Ali Ahmed

    2014-01-01

    Introduction: ACE inhibitors accounts for 8% of all cases of angioneurotic edema and the overall incidence is 0.1 to 0.7% of patients on ACE inhibitors. It is a leading cause (20-40%) of emergency room visits in the US with angioedema. We report a case of angioedema caused by ACE inhibitors confined to the upper airway after four years on treatment with Lisinopril which persisted for three weeks and required endotracheal intubation and subsequent tracheostomy due to delayed resolution. This case is one of the rare cases presented as upper airway edema which persisted for a long time. Presentation: A 60-year-old Sudanese male patient with osteoarthritis in both knees underwent bilateral total knee replacement under single-shot epidural anesthesia. He had significant past medical history of type II diabetes, bipolar affective disorder and hypertension managed with Lisinopril for the past four years. Postoperatively after 10 hours the patient desaturated and developed airway obstruction requiring intubation. Laryngoscopy revealed an edematous tongue and upper airway and vocal cords were not visualized. In view of this clinical picture a provisional diagnosis of angioedema secondary to Lisinopril was made and it was discontinued. CT scan of the neck and soft tissues revealed severe airway edema with snugly fitting endotracheal tube with no peritubal air. A repeat CT neck on the tenth postoperative day showed no signs of resolution and an elective tracheostomy was performed on the eleventh postoperative day. C1 inhibitor protein and C4 levels were assayed to exclude hereditary angioedema and were found to be within normal range. Decannulation of tracheostomy was done after airway edema resolved on the twenty-fourth postoperative day as confirmed by CT scan. Subsequently he was transferred to the ward and discharged home. Conclusion: ACEI induced angioedema is a well-recognized condition. Early diagnosis based on a high index of suspicion, immediate withdrawal of the

  4. Design of the heart failure endpoint evaluation of AII-antagonist losartan (HEAAL) study in patients intolerant to ACE-inhibitor.

    PubMed

    Konstam, Marvin A; Poole-Wilson, Philip A; Dickstein, Kenneth; Drexler, Helmut; Justice, Steven J; Komajda, Michel; Malbecq, William; Martinez, Felipe A; Neaton, James D; Riegger, Gunter A J; Guptha, Soneil

    2008-09-01

    In patients with heart failure and reduced left ventricular ejection fraction, angiotensin receptor blockers have been found to reduce mortality and morbidity and to prevent or reverse left ventricular remodelling, compared to optimized background treatment. In light of these data, The Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL) study was developed to determine whether losartan 150 mg is superior to losartan 50 mg (antihypertensive dose) in reducing morbidity and mortality among patients with symptomatic heart failure who are intolerant of angiotensin-converting enzyme (ACE)-inhibitors. To compare the effect of high and moderate doses of losartan on the primary endpoint of all-cause mortality and hospitalisation due to heart failure in patients (n = 3834) with symptomatic heart failure and an ejection fraction < or = 40% who are intolerant of ACE-inhibitor treatment. This paper presents the rationale, trial design, and baseline characteristics of the study population. The study, which completed recruitment on 31 March 2005, is event-driven and is estimated to accrue the target of 1710 adjudicated primary events during the latter half of 2008. The results of HEAAL should facilitate selection of an optimal dosing regimen for losartan in patients with symptomatic heart failure who are intolerant of ACE-inhibitors.

  5. A novel design of combining the angiotensin converting enzyme (ACE) inhibitor captopril with the angiotensin receptor blocker (ARB) losartan using homo coupling via PEG diacid linker.

    PubMed

    Hashemzadeh, Mehrnoosh; Park, Shery; Ju, Hee; Movahed, Mohammad R

    2013-12-01

    Cardiovascular disease is the leading cause of death in American adults. Furthermore, the incidence of congestive heart failure is on the rise as a major cause of hospitalization and mortality in this population. Angiotensin Converting Enzyme (ACE) inhibitors prevent the production of angiotensin II, which has been shown to reduce mortality in patients with congestive heart failure. Angiotensin II receptor blockers (ARB) were developed as a direct inhibitor of angiotensin II. ARBs have been shown to be effective in the treatment of patients with systolic heart failure but do not cause chronic coughing which is a common side effect of ACE inhibitors. In theory, a compound that has the combined effect of an ACE inhibitor and an ARB should be more effective in treating heart failure patients than either agents alone. Therefore, the purpose of this manuscript is to design and discuss the benefits of a new molecule, which combines captopril, an ACE inhibitor, with losartan, an ARB. In this experiment Captopril and Losartan were modified and synthesized separately and combined by homo or mono coupling. This was achieved by taking advantage of PEG (Polyethylene glycol) as a linker. It is expected that this molecule will have the combined modes of action of both ACEs and ARBs. Benefits from combination therapy include; increased efficacy, reduced adverse effects, convenience, compliance, and prolonged duration. Consequently, this combined molecule is expected to block the production of angiotensin II more efficiently and effectively. Although captopril and losartan work in the same system by blocking the effect of angiotensin II they have different action sites and mechanisms some patents are also discussed. Losartan blocks the AT1 receptor which is expressed on the cell surface, while captopril inhibits ACE, preventing production of angiotensin II, which is present in both the plasma and on the cell surface, especially on endothelial and smooth muscle cells.

  6. Inhibition of angiotensin-converting enzyme increases oestradiol production in ewes submitted to oestrous synchronization protocol.

    PubMed

    Costa, A s; Junior, A S; Viana, G E N; Muratori, M C S; Reis, A M; Costa, A P R

    2014-10-01

    This study aimed at evaluating the effects of angiotensin-converting enzyme inhibitor (enalapril) and angiotensin II antagonist (valsartan) on the oestradiol and progesterone production in ewes submitted to oestrous synchronization protocol. The animals were weighed and randomly divided into three groups (n = 7). A pre-experiment conducted to verify the effectiveness and toxicity of enalapril (0.5 mg/kg LW) and valsartan (2.2 mg/kg LW) showed that, in the doses used, these drugs were effective in reducing blood pressure without producing toxic effects. In the experiment, all animals were subjected to oestrous synchronization protocol during 12 days. On D10, D11 and D12, animals received saline, enalapril or valsartan (same doses of the pre-experiment), according to the group randomly divided. The hormonal analysis showed an increase in oestradiol on the last day of the protocol (D12) in animals that received enalapril (p < 0.05), but not in other groups, without changing the concentration of progesterone in any of the treatments. It is concluded that valsartan and enalapril are safe and effective subcutaneously for use in sheep and that the angiotensin-converting enzyme (ACE) inhibition with enalapril leads to an increase in oestradiol production near ovulation without changing the concentration of progesterone. This shows that ACE inhibition may be a useful tool in reproductive biotechnologies involving induction and synchronization of oestrus and ovulation in sheep. © 2014 Blackwell Verlag GmbH.

  7. New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) I: Endogenous Angiotensin Converting Enzyme (ACE) Inhibition

    PubMed Central

    Fagyas, Miklós; Úri, Katalin; Siket, Ivetta M.; Daragó, Andrea; Boczán, Judit; Bányai, Emese; Édes, István; Papp, Zoltán; Tóth, Attila

    2014-01-01

    Angiotensin-converting enzyme (ACE) inhibitors represent the fifth most often prescribed drugs. ACE inhibitors decrease 5-year mortality by approximately one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors, which endogenous inhibitory effects are much less characterized than that for the clinically administered ACE inhibitors. Here we aimed to investigate this endogenous ACE inhibition in human sera. It was hypothesized that ACE activity is masked by an endogenous inhibitor, which dissociates from the ACE when its concentration decreases upon dilution. ACE activity was measured by FAPGG hydrolysis first. The specific (dilution corrected) enzyme activities significantly increased by dilution of human serum samples (23.2±0.7 U/L at 4-fold dilution, 51.4±0.3 U/L at 32-fold dilution, n = 3, p = 0.001), suggesting the presence of an endogenous inhibitor. In accordance, specific enzyme activities did not changed by dilution when purified renal ACE was used, where no endogenous inhibitor was present (655±145 U/L, 605±42 U/L, n = 3, p = 0.715, respectively). FAPGG conversion strongly correlated with angiotensin I conversion suggesting that this feature is not related to the artificial substrate. Serum samples were ultra-filtered to separate ACE (MW: 180 kDa) and the hypothesized inhibitor. Filtering through 50 kDa filters was without effect, while filtering through 100 kDa filters eliminated the inhibiting factor (ACE activity after <100 kDa filtering: 56.4±2.4 U/L, n = 4, control: 26.4±0.7 U/L, n = 4, p<0.001). Lineweaver-Burk plot indicated non-competitive inhibition of ACE by this endogenous factor. The endogenous inhibitor had higher potency on the C-terminal active site than N-terminal active site of ACE. Finally, this endogenous ACE inhibition was also present in mouse, donkey, goat, bovine sera besides men (increasing of specific ACE activity

  8. Penile histomorphometrical evaluation in hypertensive rats treated with sildenafil or enalapril alone or in combination: a comparison with normotensive and untreated hypertensive rats.

    PubMed

    Felix-Patrício, Bruno; Medeiros, Jorge L; De Souza, Diogo B; Costa, Waldemar S; Sampaio, Francisco J B

    2015-01-01

    Erectile dysfunction (ED) is frequently associated to hypertension and antihypertensive drugs; however, the penile morphological aspects on these situations are poorly known. Evaluate the penile morphology of untreated hypertensive rats and rats treated with enalapril or sildenafil alone or in combination to verify the hypothesis that morphological alterations promoted by hypertension on corpus cavernosum could be ameliorated by the use of angiotensin-converting enzyme inhibitors and/or phosphodiesterase type 5 inhibitors. Fifty male rats were assigned into five groups: normotensive rats, untreated spontaneously hypertensive rats (SHRs), and SHR treated with enalapril or sildenafil alone or in combination. Blood pressure was measured weekly. At the conclusion of the study, the rats were euthanized, and their penises were collected for histomorphometrical analysis. The cross-sectional areas of the penis, tunica albuginea, and corpus cavernosum were measured. The density of the corpus cavernosum structures was quantified. Both groups of SHR rats treated with enalapril became normotensive. Untreated SHR showed no difference in penile and cavernosal cross-sectional area compared with normotensive rats; however, those rats treated with enalapril or sildenafil alone demonstrated an increase in these parameters. Rats receiving combination therapy showed no cross-sectional area differences compared with normotensive rats. Cavernosal connective tissue density was increased, while the sinusoidal spaces were diminished in untreated SHR. All treatments were effective in maintaining connective tissue density in comparison with normotensive animals. Cavernosal smooth muscle density was similar in all groups, with the exception of the combination therapy group, which demonstrated a reduction in smooth muscle. Hypertension promoted structural alterations in the corpus cavernosum that may be related to ED. Enalapril- and sildenafil-treated animals had preservation of normal corpus

  9. Angiotensin-I-Converting Enzyme (ACE)-Inhibitory Peptides from Plants

    PubMed Central

    Daskaya-Dikmen, Ceren; Yucetepe, Aysun; Karbancioglu-Guler, Funda; Daskaya, Hayrettin; Ozcelik, Beraat

    2017-01-01

    Hypertension is an important factor in cardiovascular diseases. Angiotensin-I-converting enzyme (ACE) inhibitors like synthetic drugs are widely used to control hypertension. ACE-inhibitory peptides from food origins could be a good alternative to synthetic drugs. A number of plant-based peptides have been investigated for their potential ACE inhibitor activities by using in vitro and in vivo assays. These plant-based peptides can be obtained by solvent extraction, enzymatic hydrolysis with or without novel food processing methods, and fermentation. ACE-inhibitory activities of peptides can be affected by their structural characteristics such as chain length, composition and sequence. ACE-inhibitory peptides should have gastrointestinal stability and reach the cardiovascular system to show their bioactivity. This paper reviews the current literature on plant-derived ACE-inhibitory peptides including their sources, production and structure, as well as their activity by in vitro and in vivo studies and their bioavailability. PMID:28333109

  10. Cost-effectiveness Analysis of Sacubitril/Valsartan vs Enalapril in Patients With Heart Failure and Reduced Ejection Fraction.

    PubMed

    Gaziano, Thomas A; Fonarow, Gregg C; Claggett, Brian; Chan, Wing W; Deschaseaux-Voinet, Celine; Turner, Stuart J; Rouleau, Jean L; Zile, Michael R; McMurray, John J V; Solomon, Scott D

    2016-09-01

    The angiotensin receptor neprilysin inhibitor sacubitril/valsartan was associated with a reduction in cardiovascular mortality, all-cause mortality, and hospitalizations compared with enalapril. Sacubitril/valsartan has been approved for use in heart failure (HF) with reduced ejection fraction in the United States and cost has been suggested as 1 factor that will influence the use of this agent. To estimate the cost-effectiveness of sacubitril/valsartan vs enalapril in the United States. Data from US adults (mean [SD] age, 63.8 [11.5] years) with HF with reduced ejection fraction and characteristics similar to those in the PARADIGM-HF trial were used as inputs for a 2-state Markov model simulated HF. Risks of all-cause mortality and hospitalization from HF or other reasons were estimated with a 30-year time horizon. Quality of life was based on trial EQ-5D scores. Hospital costs combined Medicare and private insurance reimbursement rates; medication costs included the wholesale acquisition cost for sacubitril/valsartan and enalapril. A discount rate of 3% was used. Sensitivity analyses were performed on key inputs including: hospital costs, mortality benefit, hazard ratio for hospitalization reduction, drug costs, and quality-of-life estimates. Hospitalizations, quality-adjusted life-years (QALYs), costs, and incremental costs per QALY gained. The 2-state Markov model of US adult patients (mean age, 63.8 years) calculated that there would be 220 fewer hospital admissions per 1000 patients with HF treated with sacubitril/valsartan vs enalapril over 30 years. The incremental costs and QALYs gained with sacubitril/valsartan treatment were estimated at $35 512 and 0.78, respectively, compared with enalapril, equating to an incremental cost-effectiveness ratio (ICER) of $45 017 per QALY for the base-case. Sensitivity analyses demonstrated ICERs ranging from $35 357 to $75 301 per QALY. For eligible patients with HF with reduced ejection fraction, the Markov

  11. Comparative effectiveness of enalapril, lisinopril, and ramipril in the treatment of patients with chronic heart failure: a propensity score-matched cohort study.

    PubMed

    Fröhlich, Hanna; Henning, Felix; Täger, Tobias; Schellberg, Dieter; Grundtvig, Morten; Goode, Kevin; Corletto, Anna; Kazmi, Syed; Hole, Torstein; Katus, Hugo A; Atar, Dan; Cleland, John G F; Agewall, Stefan; Frankenstein, Lutz; Clark, Andrew L

    2018-04-01

    Angiotensin-converting enzyme inhibitors (ACEIs) are recommended as first-line therapy in patients with heart failure with reduced ejection fraction (HFrEF). The comparative effectiveness of different ACEIs is not known. A total of 4723 outpatients with stable HFrEF prescribed enalapril, lisinopril, or ramipril were identified from three registries in Norway, England, and Germany. In three separate matching procedures, patients were individually matched with respect to both dose equivalents and their respective propensity scores for ACEI treatment. During a follow-up of 21 939 patient-years, 360 (49.5%), 337 (52.4%), and 1119 (33.4%) patients died among those prescribed enalapril, lisinopril, and ramipril, respectively. In univariable analysis of the general sample, enalapril and lisinopril were both associated with higher mortality when compared with ramipril treatment [hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.30-1.65, P < 0.001 and HR 1.38, 95% CI 1.22-1.56, P < 0.001, respectively). Patients prescribed enalapril or lisinopril had similar mortality (HR 1.06, 95% CI 0.92-1.24, P = 0.41). However, there was no significant association between ACEI choice and all-cause mortality in any of the matched samples (HR 1.07, 95% CI 0.91-1.25, P = 0.40; HR 1.12, 95% CI 0.96-1.32, P = 0.16; and HR 1.10, 95% CI 0.93-1.31, P = 0.25 for enalapril vs. ramipril, lisinopril vs. ramipril, and enalapril vs. lisinopril, respectively). Results were confirmed in subgroup analyses with respect to age, sex, left ventricular ejection fraction, New York Class Association functional class, cause of HFrEF, rhythm, and systolic blood pressure. Our results suggest that enalapril, lisinopril, and ramipril are equally effective in the treatment of patients with HFrEF when given at equivalent doses.

  12. The Pharmacogenetic Footprint of ACE Inhibition: A Population-Based Metabolomics Study.

    PubMed

    Altmaier, Elisabeth; Menni, Cristina; Heier, Margit; Meisinger, Christa; Thorand, Barbara; Quell, Jan; Kobl, Michael; Römisch-Margl, Werner; Valdes, Ana M; Mangino, Massimo; Waldenberger, Melanie; Strauch, Konstantin; Illig, Thomas; Adamski, Jerzy; Spector, Tim; Gieger, Christian; Suhre, Karsten; Kastenmüller, Gabi

    2016-01-01

    Angiotensin-I-converting enzyme (ACE) inhibitors are an important class of antihypertensives whose action on the human organism is still not fully understood. Although it is known that ACE especially cleaves COOH-terminal dipeptides from active polypeptides, the whole range of substrates and products is still unknown. When analyzing the action of ACE inhibitors, effects of genetic variation on metabolism need to be considered since genetic variance in the ACE gene locus was found to be associated with ACE-concentration in blood as well as with changes in the metabolic profiles of a general population. To investigate the interactions between genetic variance at the ACE-locus and the influence of ACE-therapy on the metabolic status we analyzed 517 metabolites in 1,361 participants from the KORA F4 study. We replicated our results in 1,964 individuals from TwinsUK. We observed differences in the concentration of five dipeptides and three ratios of di- and oligopeptides between ACE inhibitor users and non-users that were genotype dependent. Such changes in the concentration affected major homozygotes, and to a lesser extent heterozygotes, while minor homozygotes showed no or only small changes in the metabolite status. Two of these resulting dipeptides, namely aspartylphenylalanine and phenylalanylserine, showed significant associations with blood pressure which qualifies them-and perhaps also the other dipeptides-as readouts of ACE-activity. Since so far ACE activity measurement is substrate specific due to the usage of only one oligopeptide, taking several dipeptides as potential products of ACE into account may provide a broader picture of the ACE activity.

  13. ACE phenotyping in Gaucher disease.

    PubMed

    Danilov, Sergei M; Tikhomirova, Victoria E; Metzger, Roman; Naperova, Irina A; Bukina, Tatiana M; Goker-Alpan, Ozlem; Tayebi, Nahid; Gayfullin, Nurshat M; Schwartz, David E; Samokhodskaya, Larisa M; Kost, Olga A; Sidransky, Ellen

    2018-04-01

    Gaucher disease is characterized by the activation of splenic and hepatic macrophages, accompanied by dramatically increased levels of angiotensin-converting enzyme (ACE). To evaluate the source of the elevated blood ACE, we performed complete ACE phenotyping using blood, spleen and liver samples from patients with Gaucher disease and controls. ACE phenotyping included 1) immunohistochemical staining for ACE; 2) measuring ACE activity with two substrates (HHL and ZPHL); 3) calculating the ratio of the rates of substrate hydrolysis (ZPHL/HHL ratio); 4) assessing the conformational fingerprint of ACE by evaluating the pattern of binding of monoclonal antibodies to 16 different ACE epitopes. We show that in patients with Gaucher disease, the dramatically increased levels of ACE originate from activated splenic and/or hepatic macrophages (Gaucher cells), and that both its conformational fingerprint and kinetic characteristics (ZPHL/HHL ratio) differ from controls and from patients with sarcoid granulomas. Furthermore, normal spleen was found to produce high levels of endogenous ACE inhibitors and a novel, tightly-bound 10-30 kDa ACE effector which is deficient in Gaucher spleen. The conformation of ACE is tissue-specific. In Gaucher disease, ACE produced by activated splenic macrophages differs from that in hepatic macrophages, as well as from macrophages and dendritic cells in sarcoid granulomas. The observed differences are likely due to altered ACE glycosylation or sialylation in these diseased organs. The conformational differences in ACE may serve as a specific biomarker for Gaucher disease. Copyright © 2018 Elsevier Inc. All rights reserved.

  14. Angiotensin Receptor Blocker Losartan Inhibits Spontaneous Motility of Isolated Human Ureter.

    PubMed

    Jankovic, Slobodan M; Stojadinovic, Dobrivoje; Stojadinovic, Miroslav; Jankovic, Snezana V; Djuric, Janko M; Stojic, Isidora; Kostic, Marina

    2016-12-01

    Ureteral motility is essential for elimination of intraluminal stones, and it may be adversely affected by cardiovascular drugs that a patient is taking chronically. The aim of our study was to test whether ACE inhibitors and an angiotensin receptor blocker may influence spontaneous contractions of isolated human ureter. Both phasic and tonic contractions of the isolated ureteral segments taken from 10 patients were measured as changes of the longitudinal tension or pressure recordings. Captopril, enalapril and losartan were separately added to the organ baths cumulatively. While enalapril (2.7 × 10 -7 -3.9 × 10 -4  M) and captopril (6.1 × 10 -7 -2.7 × 10 -3  M) did not affect either spontaneous activity or tone of isolated ureteral segments, losartan (2.9 × 10 -7 -4.2 × 10 -4  M) caused concentration-dependent inhibition of spontaneous contractions of the segments (50 % effective concentration (EC 50 ) = 13.46 ± 1.80 × 10 -6  M; F = 10.72, r = 0.79, p < 0.001). Due to differences in molecular mechanism of action, angiotensin receptor blocker losartan does and ACE inhibitors captopril and enalapril do not inhibit spontaneous contractions of isolated human ureter.

  15. The effect of enalapril and verapamil on the left ventricular hypertrophy and the left ventricular cardiomyocyte numerical density in rats submitted to nitric oxide inhibition

    PubMed Central

    Pereira, Leila Maria Meirelles; Mandarim-de-Lacerda, Carlos Alberto

    2001-01-01

    Forty male Wistar rats were separated into four groups of ten rats each (control and other three groups that have received nitric oxide (NO) synthesis inhibitor L-NAME) but the last two groups have concomitantly received antihypertensive drugs (Enalapril and Verapamil). After 40 days of experimentation, the heart and the ventricles were measured. The optical disector was used for the calculation of numerical density of the cardiomyocytes (Nv[c]). The left ventricular myocytes number (N[c]) was calculated as the product of Nv[c] and the left ventricular myocardium volume (LVMV) that was determined by using the Scherle's method. In the L-NAME group the blood pressure (BP) had a significant weekly increment. In the enalapril and the verapamil groups, BP increased in the first two weeks, but decreased in the following weeks. The LVMV increased in the L-NAME rats and decreased in the enalapril and verapamil animals. The Nv[c] and N[c] decreased in the L-NAME rats but the verapamil and enalapril treatments maintained the Nv[c] close to the control group. In conclusion, the left ventricular hypertrophy and the significant decrease of the left ventricular cardiomyocyte number caused by the NO synthesis inhibition are efficiently prevented with the use of enalapril and verapamil. PMID:11454102

  16. Propionyl-L-carnitine limits chronic ventricular dilation after myocardial infarction in rats.

    PubMed

    Micheletti, R; Di Paola, E D; Schiavone, A; English, E; Benatti, P; Capasso, J M; Anversa, P; Bianchi, G

    1993-04-01

    To determine whether propionyl-L-carnitine (PLC) administration ameliorates ventricular remodeling after myocardial infarction, we performed coronary occlusion in rats and examined the long-term effects of the drug 19-24 wk after surgery. In view of the well-established role of angiotensin-converting enzyme (ACE) inhibitors in the reduction of ventricular dilation after infarction, the therapeutic impact of oral PLC (60 mg/kg) was compared with that of enalapril (1 mg/kg). Infarct size measured planimetrically was found to be comparable in untreated, PLC-treated, and enalapril-treated rats, averaging 40-46% of the left ventricular free wall. Heart weight was increased 14, 16, and 11% with no treatment, with PLC, and with enalapril, respectively. The relationship between left ventricular filling pressure and chamber volume demonstrated that PLC and enalapril significantly prevented the expansion in cavitary size after infarction. These protective influences were observed throughout the range of filling pressures measured, from 0 to 30 mmHg. At a uniform reference point of filling pressure of 4 mmHg, untreated infarcted hearts showed an expansion in ventricular volume of 2.17-fold (P < 0.0001). Corresponding increases in this parameter after PLC and enalapril were 36 and 43%, respectively, both not statistically significant. Moreover, PLC was capable of reducing the alterations in myocardial compliance associated with myocardial infarction. In conclusion, PLC reduces the magnitude of decompensated eccentric hypertrophy produced by myocardial infarction in a manner similar to that found with ACE inhibition.

  17. Flexible and precise dosing of enalapril maleate for all paediatric age groups utilizing orodispersible minitablets.

    PubMed

    Thabet, Yasmin; Walsh, Jennifer; Breitkreutz, Joerg

    2018-04-25

    Enalapril is an off-patent angiotensin-converting enzyme inhibitor for which no paediatric age-appropriate formulation is commercially available in Europe, and enalapril maleate (EM) orodispersible minitablets (ODMTs) have previously been formulated within the LENA (labelling enalapril from neonates to adolescents) project. In this study, a dilution method has been developed by dispersing the lowest dose strength ODMTs to enable flexible and precise EM dosing during the dose titration phase of the therapy. Furthermore, the physicochemical stability of the ODMTs has been investigated in child-friendly beverages and the administration of ODMTs via nasogastric tubes (NGT) of different sizes and materials has been evaluated. The results for the ODMT dilution procedure reveal that dispersion within an oral syringe is preferred over dispersion in a separate container, leading to flexible and precise dosing down to 0.025 mg EM. Although ODMTs were stable in the beverages over the investigated time period, dispersion in tap water only is recommended due to prolonged disintegration times within the other beverages. Dispersed ODMTs can be administered through NGTs of CH5. Almost no adsoprtion of EM on silicone, polyurethane or polyvinyl chloride could be observed. The ODMT concept together with the investigated dispersion method enables the safe administration of EM for all paediatric subpopulations from new-borns to adolescents. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. Safety of Enalapril in Infants Admitted to the Neonatal Intensive Care Unit.

    PubMed

    Ku, Lawrence C; Zimmerman, Kanecia; Benjamin, Daniel K; Clark, Reese H; Hornik, Christoph P; Smith, P Brian

    2017-01-01

    Enalapril is used to treat hypertension and congestive heart failure in infants. However, enalapril is not labeled for neonates, and safety data in infants are sparse. To evaluate the safety of enalapril in young infants, we conducted a retrospective cohort study of infants who were exposed to enalapril in the first 120 days of life and were cared for in 348 neonatal intensive care units from 1997 to 2012. We determined the proportion of exposed infants who developed adverse events, including death, hypotension requiring pressors, hyperkalemia, and elevated serum creatinine. Using multivariable logistic regression, we examined risk factors for adverse events, including postnatal age at first exposure, exposure duration, gestational age group, small for gestational age status, race, sex, 5-min Apgar score, and inborn status. Of a cohort of 887,910 infants, 662 infants (0.07%) were exposed to enalapril. Among exposed infants, 142 infants (21%) suffered an adverse event. The most common adverse event was hyperkalemia (13%), followed by elevated serum creatinine (5%), hypotension (4%), and death (0.5%). Significant risk factors for adverse events included postnatal age <30 days at first exposure and longer exposure duration. This study is the largest to date examining the safety of enalapril in young term and preterm infants without significant structural cardiac disease.

  19. Extrapolation of enalapril efficacy from adults to children using pharmacokinetic/pharmacodynamic modelling.

    PubMed

    Kechagia, Irene-Ariadne; Kalantzi, Lida; Dokoumetzidis, Aristides

    2015-11-01

    To extrapolate enalapril efficacy to children 0-6 years old, a pharmacokinetic/pharmacodynamic (PKPD) model was built using literature data, with blood pressure as the PD endpoint. A PK model of enalapril was developed from literature paediatric data up to 16 years old. A PD model of enalapril was fitted to adult literature response vs time data with various doses. The final PKPD model was validated with literature paediatric efficacy observations (diastolic blood pressure (DBP) drop after 2 weeks of treatment) in children of age 6 years and higher. The model was used to predict enalapril efficacy for ages 0-6 years. A two-compartment PK model was chosen with weight, reflecting indirectly age as a covariate on clearance and central volume. An indirect link PD model was chosen to describe drug effect. External validation of the model's capability to predict efficacy in children was successful. Enalapril efficacy was extrapolated to ages 1-11 months and 1-6 years finding the mean DBP drop 11.2 and 11.79 mmHg, respectively. Mathematical modelling was used to extrapolate enalapril efficacy to young children to support a paediatric investigation plan targeting a paediatric-use marketing authorization application. © 2015 Royal Pharmaceutical Society.

  20. Angioedema Spotlight: A Closer Examination of Sacubitril/Valsartan Safety Results.

    PubMed

    Owens, Ryan E; Oliphant, Carrie S

    2017-01-01

    Incorporation of neprilysin inhibition into heart failure pharmacotherapy regimens has recently been recommended by U.S. guidelines, based on results from the PARADIGM-HF trial comparing sacubitril/valsartan to enalapril. While most of the discussion has focused on efficacy, a closer examination of the safety results, particularly the incidence of angioedema during the run-in and double-blind periods, is also warranted. Although no major safety concerns were identified, an angioedema risk comparable to enalapril was found, primarily in the black population. Therefore, despite combination with an angiotensin receptor blocker, which historically has a lower incidence of angioedema, the addition of neprilysin inhibition yields an angioedema risk profile comparable to angiotensin converting enzyme (ACE) inhibitors. Clinicians should recognize this safety risk when prescribing sacubitril/valsartan and remain vigilant in counseling patients regarding the signs and symptoms of angioedema. As recommended by the guidelines, avoiding sacubitril/valsartan use concurrently or within 36 hours of the last dose of an ACE inhibitor or in patients with a history of angioedema is also crucial to minimize angioedema risk and prevent patient harm. © Copyright 2017 by the American Board of Family Medicine.

  1. ACE insertion/deletion (I/D) polymorphism and diabetic nephropathy.

    PubMed

    Rahimi, Zohreh

    2012-10-01

    Angiotensin converting enzyme (ACE) gene encodes ACE, a key component of renin angiotensin system (RAS), plays an important role in blood pressure homeostasis by generating the vasoconstrictor peptide angiotensin II. Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. The presence of ACE insertion/deletion (I/D) polymorphism affects the plasma level of ACE. ACE DD genotype is associated with the highest systemic and renal ACE levels compared with the lowest ACE activity in carriers of II genotype. In this review focus has been performed on the study of ACE I/D polymorphism in various populations and its influence on the risk of onset and progression of diabetic nephropathy. Also, association between ACE I/D polymorphism and response to ACE inhibitor and angiotensin II receptor antagonists will be reviewed. Further, synergistic effect of this polymorphism and variants of some genes on the risk of development of diabetic nephropathy will be discussed.

  2. Secoisolariciresinol Diglucoside (SDG) Isolated from Flaxseed, an Alternative to ACE Inhibitors in the Treatment of Hypertension

    PubMed Central

    Prasad, Kailash

    2013-01-01

    Secoisolariciresionol diglucoside (SDG) is a plant lignan isolated from flaxseed and is phytoestrogen. SDG is a potent and long-acting hypotensive agent. Plant phytoestrogens have inhibitory effects on angiotensin-converting enzyme (ACE). The hypotensive effects of SDG, a phytoestrogen, may be mediated through inhibition of ACE. The objective of this study was to investigate if SDG-induced hypotension is mediated through inhibition of ACE. The Sprague Dawley male rats were anesthetized and trachea was cannulated. The right jugular vein was cannulated to administer the drug and the carotid artery was cannulated to record arterial pressures using PIOEZ-1 miniature model transducer (Becton, Dickinson and Company, Franklin Lakes, NJ) and Beckman dynograph (Beckman Instruments, Inc., Schiller Park, IL). The effects of angiotensin I (0.2 µg/kg, intravenously [IV]) in the absence and presence of SDG (10 mg/kg, IV), and SDG alone on systolic, diastolic, and mean arterial pressures were measured before and after 15, 30, and 60 minutes of drug administration. SDG decreased the systolic, diastolic, and mean arterial pressure by 37, 47, and 43%, respectively, at 15 minutes and 18.8, 21.2, and 20.3%, respectively, at 60 minutes. Angiotensin I increased the arterial pressure. SDG decreased angiotensin I-induced rise in the systolic, diastolic, and mean arterial pressures by 60, 58, and 51%, respectively, at 15 minutes and 48, 46, and 30%, respectively, at 60 minutes. The data suggest that SDG reduced the angiotensin I-induced rise in the arterial pressures and hence SDG is a potent ACE inhibitor. PMID:24436618

  3. Secoisolariciresinol Diglucoside (SDG) Isolated from Flaxseed, an Alternative to ACE Inhibitors in the Treatment of Hypertension.

    PubMed

    Prasad, Kailash

    2013-12-01

    Secoisolariciresionol diglucoside (SDG) is a plant lignan isolated from flaxseed and is phytoestrogen. SDG is a potent and long-acting hypotensive agent. Plant phytoestrogens have inhibitory effects on angiotensin-converting enzyme (ACE). The hypotensive effects of SDG, a phytoestrogen, may be mediated through inhibition of ACE. The objective of this study was to investigate if SDG-induced hypotension is mediated through inhibition of ACE. The Sprague Dawley male rats were anesthetized and trachea was cannulated. The right jugular vein was cannulated to administer the drug and the carotid artery was cannulated to record arterial pressures using PIOEZ-1 miniature model transducer (Becton, Dickinson and Company, Franklin Lakes, NJ) and Beckman dynograph (Beckman Instruments, Inc., Schiller Park, IL). The effects of angiotensin I (0.2 µg/kg, intravenously [IV]) in the absence and presence of SDG (10 mg/kg, IV), and SDG alone on systolic, diastolic, and mean arterial pressures were measured before and after 15, 30, and 60 minutes of drug administration. SDG decreased the systolic, diastolic, and mean arterial pressure by 37, 47, and 43%, respectively, at 15 minutes and 18.8, 21.2, and 20.3%, respectively, at 60 minutes. Angiotensin I increased the arterial pressure. SDG decreased angiotensin I-induced rise in the systolic, diastolic, and mean arterial pressures by 60, 58, and 51%, respectively, at 15 minutes and 48, 46, and 30%, respectively, at 60 minutes. The data suggest that SDG reduced the angiotensin I-induced rise in the arterial pressures and hence SDG is a potent ACE inhibitor.

  4. Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial

    PubMed Central

    Seferovic, Jelena P; Claggett, Brian; Seidelmann, Sara B; Seely, Ellen W; Packer, Milton; Zile, Michael R; Rouleau, Jean L; Swedberg, Karl; Lefkowitz, Martin; Shi, Victor C; Desai, Akshay S; McMurray, John J V; Solomon, Scott D

    2017-01-01

    Summary Background Diabetes is an independent risk factor for heart failure progression. Sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, improves morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), compared with the angiotensin-converting enzyme inhibitor enalapril, and improves peripheral insulin sensitivity in obese hypertensive patients. We aimed to investigate the effect of sacubitril/valsartan versus enalapril on HbA1c and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF. Methods In a post-hoc analysis of the PARADIGM-HF trial, we included 3778 patients with known diabetes or an HbA1c≥6·5% at screening out of 8399 patients with HFrEF who were randomly assigned to treatment with sacubitril/valsartan or enalapril. Of these patients, most (98%) had type 2 diabetes. We assessed changes in HbA1c, triglycerides, HDL cholesterol and BMI in a mixed effects longitudinal analysis model. Times to initiation of oral antihyperglycaemic drugs or insulin in subjects previously not treated with these agents were compared between treatment groups. Findings There were no significant differences in HbA1c concentrations between randomised groups at screening. During the first year of follow-up, HbA1c concentrations decreased by 0·16% (SD 1·40) in the enalapril group and 0·26% (SD 1·25) in the sacubitril/valsartan group (between-group reduction 0·13%, 95% CI 0·05–0·22, p=0·0023). HbA1c concentrations were persistently lower in the sacubitril/valsartan group than in the enalapril group over the 3-year follow-up (between-group reduction 0·14%, 95% CI 0·06–0·23, p=0·0055). New use of insulin was 29% lower in patients receiving sacubitril/valsartan (114 [7%] patients) compared with patients receiving enalapril (153 [10%]; hazard ratio 0·71, 95% CI 0·56–0·90, p=0·0052). Similarly, fewer patients were started on oral

  5. Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial.

    PubMed

    Seferovic, Jelena P; Claggett, Brian; Seidelmann, Sara B; Seely, Ellen W; Packer, Milton; Zile, Michael R; Rouleau, Jean L; Swedberg, Karl; Lefkowitz, Martin; Shi, Victor C; Desai, Akshay S; McMurray, John J V; Solomon, Scott D

    2017-05-01

    Diabetes is an independent risk factor for heart failure progression. Sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, improves morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), compared with the angiotensin-converting enzyme inhibitor enalapril, and improves peripheral insulin sensitivity in obese hypertensive patients. We aimed to investigate the effect of sacubitril/valsartan versus enalapril on HbA 1c and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF. In a post-hoc analysis of the PARADIGM-HF trial, we included 3778 patients with known diabetes or an HbA 1c ≥6·5% at screening out of 8399 patients with HFrEF who were randomly assigned to treatment with sacubitril/valsartan or enalapril. Of these patients, most (98%) had type 2 diabetes. We assessed changes in HbA 1c , triglycerides, HDL cholesterol and BMI in a mixed effects longitudinal analysis model. Time to initiation of oral antihyperglycaemic drugs or insulin in subjects previously not treated with these agents were compared between treatment groups. There were no significant differences in HbA 1c concentrations between randomised groups at screening. During the first year of follow-up, HbA 1c concentrations decreased by 0·16% (SD 1·40) in the enalapril group and 0·26% (SD 1·25) in the sacubitril/valsartan group (between-group reduction 0·13%, 95% CI 0·05-0·22, p=0·0023). HbA 1c concentrations were persistently lower in the sacubitril/valsartan group than in the enalapril group over the 3-year follow-up (between-group reduction 0·14%, 95% CI 0·06-0·23, p=0·0055). New use of insulin was 29% lower in patients receiving sacubitril/valsartan (114 [7%] patients) compared with patients receiving enalapril (153 [10%]; hazard ratio 0·71, 95% CI 0·56-0·90, p=0·0052). Similarly, fewer patients were started on oral antihyperglycaemic therapy (0·77, 0·58-1·02

  6. Hypertensive bipolar: chronic lithium toxicity in patients taking ACE inhibitor.

    PubMed

    Masiran, Ruziana; Abdul Aziz, Mohammad Firdaus

    2017-08-28

    A patient with bipolar I disorder has been treated with lithium and haloperidol for the last 20 years and received an ACE inhibitor for his hypertension since 9 years ago. Despite regular clinic follow-ups and blood monitoring, he recently developed tremors and delirium. On hospital admission, serum level of lithium was far above toxic level. Mental state examination revealed an anxious and disorientated man with irrelevant speech. Immediate discontinuation of lithium resulted in slow reduction of serum lithium levels and gradual resolution of tremor but his delirium persisted for 2 weeks. His condition took a turn for the worse when he developed acute renal failure and arm abscess. We discussed about lithium toxicity and the vulnerability factors which have induced delirium and renal failure in this patient. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  7. Simultaneous quantitative and qualitative analysis of aliskiren, enalapril and its active metabolite enalaprilat in undiluted human urine utilizing LC-ESI-MS/MS.

    PubMed

    Burckhardt, Bjoern B; Tins, Jutta; Laeer, Stephanie

    2014-12-01

    The benefit-risk ratio of combined blocking by the direct renin inhibitor aliskiren and an angiotensin-converting enzyme inhibitor (e.g. enalapril) on the renin-angiotensin-aldosterone system is discussed. No method was available for simultaneous determination of both drugs in urine. A novel sensitive method for simultaneous quantification in undiluted human urine was developed which enables systematic pharmacokinetic investigations, especially in poorly investigated populations like children. Matrix effects were clearly reduced by applying solid-phase extraction followed by a chromatographic separation on Xselect(TM) C18 CSH columns. Mobile phase consisted of methanol and water, both acidified with formic acid. Under gradient conditions and a flow rate of 0.4 mL/min the column effluent was monitored by tandem mass spectrometry with electrospray ionization. Calibration curves were constructed in the range of 9.4-9600 ng/mL regarding aliskiren, 11.6-12000 ng/mL for enalapril and 8.8-9000 ng/mL for enalaprilat. All curves were analyzed utilizing 1/x(2) -weighted quadratic squared regression. Intra-run and inter-run precision were 3.2-5.8% and 6.1-10.3% for aliskiren, 2.4-6.1% and 3.9-7.9% for enalapril as well as 3.1-9.4% and 4.7-12.7% regarding enalaprilat. Selectivity, accuracy and stability results comply with current international bioanalysis guidelines. The fully validated method was successfully applied to a pharmacokinetic investigation in healthy volunteers. Copyright © 2014 John Wiley & Sons, Ltd.

  8. Comparative study of enalapril vs. losartan on residual renal function preservation in automated peritoneal dialysis. A randomized controlled study.

    PubMed

    Reyes-Marín, Fernando Arturo; Calzada, Claudia; Ballesteros, Araceli; Amato, Dante

    2012-01-01

    Residual renal function (RRF) is an important determinant of mortality and morbidity in patients receiving peritoneal dialysis (PD). Recent studies have shown a positive effect of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) on RRF in PD patients. To compare enalapril and losartan for RRF preservation in automated peritoneal dialysis (APD) patients. An open label randomized controlled trial (RCT) with a 12 month follow-up period was conducted to compare the effect of enalapril vs. losartan on RRF preservation in 60 APD patients. Measurements were done at the start of the study (baseline), 3, 6, 9, and 12 months. A historical control group (HCG) without treatment was included to assess the natural history of RRF loss. RRF in the enalapril group dropped from 3.65 +/- 1.6 (baseline) to 2.36 +/- 0.38 mL/min/1.73 m2 (12 months). In the losartan group RRF was reduced from 4.1+/- 2.01 (baseline) to 2.54 +/- 0.47 mL/min/ 1.73 m2 (12 months). There were not significant differences between the two groups regarding RRF at 12 months. In the HCG, RRF declined from 3.68 +/- 0.48 to 1.4 +/- 0.29 mL/min/ 1.73 m2 (12 months). RRF in the HCG was significantly lower than RRF in the two treated groups at 12 months (P < 0.05). There was not significant difference on RRF preservation between enalapril and losartan groups. Comparing these results to those of the HCG suggests that the treatment with any of the drugs is useful in preserving RRF.

  9. ACE-inhibitors versus angiotensin receptor blockers for prevention of events in cardiovascular patients without heart failure - A network meta-analysis.

    PubMed

    Ricci, Fabrizio; Di Castelnuovo, Augusto; Savarese, Gianluigi; Perrone Filardi, Pasquale; De Caterina, Raffaele

    2016-08-15

    Angiotensin receptor blockers (ARBs) are a valuable option to reduce cardiovascular (CV) mortality and morbidity in cardiac patients in whom ACE-inhibitors (ACE-Is) cannot be used. However, clinical outcome data from direct comparisons between ACE-Is and ARBs are scarce, and some data have recently suggested superiority of ACE-Is over ARBs. We performed a Bayesian network-meta-analysis, with data from both direct and indirect comparisons, from 27 randomized controlled trials (RCTs), including a total population of 125,330 patients, to assess the effects of ACE-Is and ARBs on the composite endpoint of CV death, myocardial infarction (MI) and stroke, and on all-cause death, new-onset heart failure (HF) and new-onset diabetes mellitus (DM) in high CV risk patients without HF. Using placebo as a common comparator, we found no significant differences between ACE-Is and ARBs in preventing the composite endpoint of CV death, MI and stroke (RR: 0.92; 95% CI 0.78-1.08). When components of the composite outcome were analysed separately, ACEi and ARBs were associated with a similar risk of CV death (RR: 0.92; 95% CI 0.73-1.10), MI (RR: 0.91; 95% CI 0.78-1.07) and stroke (RR: 0.97; 95% CI 0.79-1.19), as well as a similar incident risk of all-cause death (RR: 0.94; 95% CI 0.85-1.05), new-onset HF (RR: 0.92; 95% CI 0.77-1.15) and new-onset DM (RR: 99; 95% CI 0.81-1.21). With the limitations of indirect comparisons, we found that in patients at high CV risk without HF, ARBs were similar to ACE-Is in preventing the composite endpoint of CV death, MI and stroke. Compared with ARBs, we found no evidence of statistical superiority for ACE-Is, as a class, in preventing incident risk of all-cause death, CV death, MI, stroke, new-onset DM and new-onset HF. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. Enalapril and ASS inhibit tumor growth in a transgenic mouse model of islet cell tumors.

    PubMed

    Fendrich, V; Lopez, C L; Manoharan, J; Maschuw, K; Wichmann, S; Baier, A; Holler, J P; Ramaswamy, A; Bartsch, D K; Waldmann, J

    2014-10-01

    Accumulating evidence suggests a role for angiotensin-converting enzymes involving the angiotensin II-receptor 1 (AT1-R) and the cyclooxygenase pathway in carcinogenesis. The effects of ASS and enalapril were assessed in vitro and in a transgenic mouse model of pancreatic neuroendocrine neoplasms (pNENs). The effects of enalapril and ASS on proliferation and expression of the AGTR1A and its target gene vascular endothelial growth factor (Vegfa) were assessed in the neuroendocrine cell line BON1. Rip1-Tag2 mice were treated daily with either 0.6 mg/kg bodyweight of enalapril i.p., 20 mg/kg bodyweight of ASS i.p., or a vehicle in a prevention (weeks 5-12) and a survival group (week 5 till death). Tumor surface, weight of pancreatic glands, immunostaining for AT1-R and nuclear factor kappa beta (NFKB), and mice survival were analyzed. In addition, sections from human specimens of 20 insulinomas, ten gastrinomas, and 12 non-functional pNENs were evaluated for AT1-R and NFKB (NFKB1) expression and grouped according to the current WHO classification. Proliferation was significantly inhibited by enalapril and ASS in BON1 cells, with the combination being the most effective. Treatment with enalapril and ASS led to significant downregulation of known target genes Vegf and Rela at RNA level. Tumor growth was significantly inhibited by enalapril and ASS in the prevention group displayed by a reduction of tumor size (84%/67%) and number (30%/45%). Furthermore, daily treatment with enalapril and ASS prolonged the overall median survival compared with vehicle-treated Rip1-Tag2 (107 days) mice by 9 and 17 days (P=0.016 and P=0.013). The AT1-R and the inflammatory transcription factor NFKB were abolished completely upon enalapril and ASS treatment. AT1-R and NFKB expressions were observed in 80% of human pNENs. Enalapril and ASS may provide an approach for chemoprevention and treatment of pNENs. © 2014 Society for Endocrinology.

  11. Angiotensin-Converting Enzyme Inhibitor Use and Major Cardiovascular Outcomes in Type 2 Diabetes Mellitus Treated With the Dipeptidyl Peptidase 4 Inhibitor Alogliptin.

    PubMed

    White, William B; Wilson, Craig A; Bakris, George L; Bergenstal, Richard M; Cannon, Christopher P; Cushman, William C; Heller, Simon K; Mehta, Cyrus R; Nissen, Steven E; Zannad, Faiez; Kupfer, Stuart

    2016-09-01

    Activation of the sympathetic nervous system when there is dipeptidyl peptidase 4 inhibition in the presence of high-dose angiotensin-converting enzyme (ACE) inhibition has led to concerns of potential increases in cardiovascular events when the 2 classes of drugs are coadministered. We evaluated cardiovascular outcomes from the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care) trial according to ACE inhibitor use. Patients with type 2 diabetes mellitus and a recent acute coronary syndrome were randomly assigned to receive the dipeptidyl peptidase 4 inhibitor alogliptin or placebo added to existing antihyperglycemic and cardiovascular prophylactic therapies. Risks of adjudicated cardiovascular death, nonfatal myocardial infarction and stroke, and hospitalized heart failure were analyzed using a Cox proportional hazards model in patients according to ACE inhibitor use and dose. There were 3323 (62%) EXAMINE patients treated with an ACE inhibitor (1681 on alogliptin and 1642 on placebo). The composite rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were comparable for alogliptin and placebo with ACE inhibitor (11.4% versus 11.8%; hazard ratio, 0.97; 95% confidence interval, 0.79-1.19; P=0.76) and without ACE inhibitor use (11.2% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.73-1.21; P=0.62). Composite rates for cardiovascular death and heart failure in patients on ACE inhibitor occurred in 6.8% of patients on alogliptin versus 7.2% on placebo (hazard ratio, 0.93; 95% confidence interval, 0.72-1.2; P=0.57). There were no differences for these end points nor for blood pressure or heart rate in patients on higher doses of ACE inhibitor. Cardiovascular outcomes were similar for alogliptin and placebo in patients with type 2 diabetes mellitus and coronary disease treated with ACE inhibitors. © 2016 American Heart Association, Inc.

  12. Efficacy and Safety of Complete RAAS Blockade with ALISKIREN in Patients with Refractory Proteinuria Who were already on Combined ACE Inhibitor, ARB, and Aldosterone Antagonist.

    PubMed

    Panattil, Prabitha; Sreelatha, M

    2016-09-01

    Proteinuria is always associated with intrinsic kidney disese and is a strong predictor of later development of End Stage Renal Disease (ESRD). As Renin Angiotensin Aldosterone System (RAAS) has a role in mediating proteinuria, inhibitors of this system are renoprotective and patients with refractory proteinuria are put on a combination of these agents. The routinely employed triple blockade of RAAS with Angiotensin Converting Enzyme (ACE) inhibitor, ARB and Aldosterone antagonist has many limitations. Addition of Aliskiren to this combination suppresses the RAAS at the earliest stage and can offset many of these limitations. This study was conducted to assess the safety and efficacy of complete RAAS blockade by the addition of Aliskiren in those patients with refractory proteinuria who were already on triple blockade with ACE inhibitor, ARB and Aldosterone antagonist. This study was conducted in Nephrology Department, Calicut Medical College. A total of 36 patients with refractory proteinuria who were already on ACE inhibitor, ARB and Aldosterone antagonist were divided in to two groups A and B. Group A received Aliskiren in addition to the above combination whereas group B continued the same treatment for 12 weeks. Efficacy of the treatment was assessed by recording 24hr urine protein and safety by S.Creatinine, S.Potassium every 2 weeks of the treatment period. Statistical analysis of the lab values was done using SPSS software. Unpaired t-test, Paired t-test and Chi-square test were done for data analysis. Statistical analysis revealed that addition of Aliskiren to the combination therapy with ACE inhibitor+ ARB+ Aldosterone antagonist offers no advantage. But mean reduction in proteinuria was more with Group A than Group B. There is no statistically significant change in S.Creatinine and S.Potassium at the end of treatment. As proteinuria is a strong risk factor for progression to ESRD, even a mild decrease in proteinuria by treatment is renoprotective. Hence

  13. Lysozyme and bilirubin bind to ACE and regulate its conformation and shedding.

    PubMed

    Danilov, Sergei M; Lünsdorf, Heinrich; Akinbi, Henry T; Nesterovitch, Andrew B; Epshtein, Yuliya; Letsiou, Eleftheria; Kryukova, Olga V; Piegeler, Tobias; Golukhova, Elena Z; Schwartz, David E; Dull, Randal O; Minshall, Richard D; Kost, Olga A; Garcia, Joe G N

    2016-10-13

    Angiotensin I-converting enzyme (ACE) hydrolyzes numerous peptides and is a critical participant in blood pressure regulation and vascular remodeling. Elevated tissue ACE levels are associated with increased risk for cardiovascular and respiratory disorders. Blood ACE concentrations are determined by proteolytic cleavage of ACE from the endothelial cell surface, a process that remains incompletely understood. In this study, we identified a novel ACE gene mutation (Arg532Trp substitution in the N domain of somatic ACE) that increases blood ACE activity 7-fold and interrogated the mechanism by which this mutation significantly increases blood ACE levels. We hypothesized that this ACE mutation disrupts the binding site for blood components which may stabilize ACE conformation and diminish ACE shedding. We identified the ACE-binding protein in the blood as lysozyme and also a Low Molecular Weight (LMW) ACE effector, bilirubin, which act in concert to regulate ACE conformation and thereby influence ACE shedding. These results provide mechanistic insight into the elevated blood level of ACE observed in patients on ACE inhibitor therapy and elevated blood lysozyme and ACE levels in sarcoidosis patients.

  14. Lysozyme and bilirubin bind to ACE and regulate its conformation and shedding

    PubMed Central

    Danilov, Sergei M.; Lünsdorf, Heinrich; Akinbi, Henry T.; Nesterovitch, Andrew B.; Epshtein, Yuliya; Letsiou, Eleftheria; Kryukova, Olga V.; Piegeler, Tobias; Golukhova, Elena Z.; Schwartz, David E.; Dull, Randal O.; Minshall, Richard D.; Kost, Olga A.; Garcia, Joe G. N.

    2016-01-01

    Angiotensin I-converting enzyme (ACE) hydrolyzes numerous peptides and is a critical participant in blood pressure regulation and vascular remodeling. Elevated tissue ACE levels are associated with increased risk for cardiovascular and respiratory disorders. Blood ACE concentrations are determined by proteolytic cleavage of ACE from the endothelial cell surface, a process that remains incompletely understood. In this study, we identified a novel ACE gene mutation (Arg532Trp substitution in the N domain of somatic ACE) that increases blood ACE activity 7-fold and interrogated the mechanism by which this mutation significantly increases blood ACE levels. We hypothesized that this ACE mutation disrupts the binding site for blood components which may stabilize ACE conformation and diminish ACE shedding. We identified the ACE-binding protein in the blood as lysozyme and also a Low Molecular Weight (LMW) ACE effector, bilirubin, which act in concert to regulate ACE conformation and thereby influence ACE shedding. These results provide mechanistic insight into the elevated blood level of ACE observed in patients on ACE inhibitor therapy and elevated blood lysozyme and ACE levels in sarcoidosis patients. PMID:27734897

  15. [Effect of enalapril on nitric oxide synthesis, oxidative metabolism, and vascular tone in aging rats].

    PubMed

    Sahach, V F; Baziliuk, O V; Stepanenko, L H; Korkach, Iu P; Kotsiuruba, A V

    2007-01-01

    Endothelium-dependent and endothelium-independent reactions of relaxations of vascular smooth muscle (VSM) were examined in the aorta preparations of the two groups (6-8 and 21-22 month). The studies also two NO synthase (NOS) isoform activity--inducible (iNOS) and constitutive (cNOS), activity of arginase and nitrate reductase and the content of high-molecular nitrosothiols (HMNT) and low-molecular nitrosothiols (LMNT) and stable metabolites of NO (NO(-)2, NO(-)3). Aging rats demonstrated only endothelium-dependent responses of VSM to acethylcholine lowering. This endothelial dysfunction depend on high activity of arginase, iNOS and salvage (by nitrate reductase) NO synthesis, both reactive oxigen species (ROS) (by xanthine oxidase) and peroxynitrite generation, as well as low activity of constitutive (eNOS, nNOS) NO synthesis. Angiotensin-converting enzyme inhibitor (enalapril) administration (20 mg/kg, 30 or 55 days) up regalate constitutive NO synthesis by arginase, iNOS, nitrate reductase activity and ROS and peroxynitrite generation inhibition thus restore endothelium-dependent relaxations of VSM in aging rats. The result obtained suggest a new roles for the renin-angiotensin system in vascular tone regulation. Thus enalapril might serve as a novel tool to prevent aging-associated endothelial dysfunction.

  16. Crystal structures of sampatrilat and sampatrilat-Asp in complex with human ACE - a molecular basis for domain selectivity.

    PubMed

    Cozier, Gyles E; Schwager, Sylva L; Sharma, Rajni K; Chibale, Kelly; Sturrock, Edward D; Acharya, K Ravi

    2018-04-01

    Angiotensin-1-converting enzyme (ACE) is a zinc metallopeptidase that consists of two homologous catalytic domains (known as nACE and cACE) with different substrate specificities. Based on kinetic studies it was previously reported that sampatrilat, a tight-binding inhibitor of ACE, K i = 13.8 nm and 171.9 nm for cACE and nACE respectively [Sharma et al., Journal of Chemical Information and Modeling (2016), 56, 2486-2494], was 12.4-fold more selective for cACE. In addition, samAsp, in which an aspartate group replaces the sampatrilat lysine, was found to be a nonspecific and lower micromolar affinity inhibitor. Here, we report a detailed three-dimensional structural analysis of sampatrilat and samAsp binding to ACE using high-resolution crystal structures elucidated by X-ray crystallography, which provides a molecular basis for differences in inhibitor affinity and selectivity for nACE and cACE. The structures show that the specificity of sampatrilat can be explained by increased hydrophobic interactions and a H-bond from Glu403 of cACE with the lysine side chain of sampatrilat that are not observed in nACE. In addition, the structures clearly show a significantly greater number of hydrophilic and hydrophobic interactions with sampatrilat compared to samAsp in both cACE and nACE consistent with the difference in affinities. Our findings provide new experimental insights into ligand binding at the active site pockets that are important for the design of highly specific domain selective inhibitors of ACE. The atomic coordinates and structure factors for N- and C-domains of ACE bound to sampatrilat and sampatrilat-Asp complexes (6F9V, 6F9R, 6F9T and 6F9U respectively) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/). © 2018 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

  17. The Renin-Angiotensin Pathway in PTSD: ACE inhibitor and ARB medications are associated with fewer traumatic stress symptoms

    PubMed Central

    Khoury, Nayla; Marvar, Paul J.; Gillespie, Charles F.; Wingo, Aliza; Schwartz, Ann; Bradley, Bekh; Kramer, Michael; Ressler, Kerry J

    2014-01-01

    Objective PTSD is a debilitating stress-related illness associated with trauma exposure. The peripheral and central mechanisms mediating stress response in PTSD are incompletely understood. Recent data suggest that the renin-angiotensin pathway, essential to cardiovascular regulation, is also involved in mediating stress and anxiety. In this study, the authors examined the relationship between active treatment with blood pressure medication, including angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs), and PTSD symptom severity within a highly traumatized civilian medical population. Method Cross-sectional, observational data was analyzed from a larger study, recruiting patients from Grady Memorial Hospital's outpatient population from 2006 to November 2010. Multi-variable linear regression models were fit to statistically evaluate the independent association of being prescribed an ACE-I or ARB with PTSD symptoms, using a sub-set of patients for whom medical information was available (n=505). PTSD diagnosis was assessed using the modified PTSD Symptom Scale (PSS) based on DSM-IV criteria with PTSD symptoms based on PSS and Clinician Administered PTSD Scale (CAPS). Results A significant association was determined between presence of ACE-I / ARB medication and decreased PTSD symptoms (mean PSS score 11.4 vs 14.9 for individuals prescribed vs not prescribed ACE-I/ARBs, respectively (p = 0.014)). After adjustment for covariates, ACE-I/ARB treatment remained significantly associated with decreased PTSD symptoms (p = 0.044). Notably, other blood pressure medications, including beta-blockers, calcium channel blockers, and diuretics, were not significantly associated with reduced PTSD symptoms. Conclusions These data provide the first clinical evidence supporting a role for the reninangiotensin system in the regulation of stress response in patients diagnosed with PTSD. Further studies should examine whether available medications

  18. Randomized trial of perindopril, enalapril, losartan and telmisartan in overweight or obese patients with hypertension.

    PubMed

    Nedogoda, Sergey V; Ledyaeva, Alla A; Chumachok, Elena V; Tsoma, Vera V; Mazina, Galina; Salasyuk, Alla S; Barykina, Irina N

    2013-08-01

    Obesity exacerbates hypertension and stimulates the renin-angiotensin-aldosterone system (RAAS). Full-dose RAAS inhibition could be a therapeutic option in overweight or obese patients with hypertension. This study compared four RAAS inhibitors at full therapeutic doses to determine their effect on blood pressure (BP) and cardiovascular risk factors in these patients. We conducted a 24-week, single-blind, randomized, parallel-group study in 120 overweight or obese patients (body mass index ≥27 kg/m(2)) with hypertension, aged 18-60 years. The primary endpoint was the change in mean 24-h systolic BP and diastolic BP from baseline to study end. Central BP, arterial stiffness, and metabolic and cardiac indices were also investigated. Patients were randomly allocated to perindopril 10 mg/day, enalapril 20 mg/day, losartan 100 mg/day or telmisartan 80 mg/day. Nonpharmacological interventions were also recommended. Reductions in mean 24-h systolic BP (and diastolic BP) were all significant (p < 0.05 versus baseline) for perindopril, enalapril, losartan and telmisartan: systolic BP -22, -11, -12 and -15 mmHg, respectively; (and diastolic BP -13, -6, -13 and -12 mmHg, respectively). Aortic elasticity improved with perindopril and telmisartan. Perindopril was associated with the greatest reductions in central aortic BP and leptin levels [30 % versus 2 %, 7 % and 14 % with enalapril, losartan and telmisartan, respectively (all p < 0.05 versus perindopril)]. Reductions in other BP, echocardiographic, metabolic and anthropometric parameters occurred with all treatments. Full-dose RAAS inhibition, particularly with perindopril, effectively reduces BP, improves arterial structure and regulates cardiovascular risk factors in overweight or obese patients with hypertension.

  19. ACE-2/Ang1-7/Mas cascade mediates ACE inhibitor, captopril, protective effects in estrogen-deficient osteoporotic rats.

    PubMed

    Abuohashish, Hatem M; Ahmed, Mohammed M; Sabry, Dina; Khattab, Mahmoud M; Al-Rejaie, Salim S

    2017-08-01

    The local role of the renin angiotensin system (RAS) was documented recently beside its conventional systemic functions. Studies showed that the effector angiotensin II (AngII) alters bone health, while inhibition of the angiotensin converting enzyme (ACE-1) preserved these effects. The newly identified Ang1-7 exerts numerous beneficial effects opposing the AngII. Thus, the current study examines the role of Ang1-7 in mediating the osteo-preservative effects of ACEI (captopril) through the G-protein coupled Mas receptor using an ovariectomized (OVX) rat model of osteoporosis. 8 weeks after the surgical procedures, captopril was administered orally (40mgkg -1 d -1 ), while the specific Mas receptor blocker (A-779) was delivered at infusion rate of 400ngkg -1 min -1 for 6 weeks. Bone metabolic markers were measured in serum and urine. Minerals concentrations were quantified in serum, urine and femoral bones by inductive coupled plasma mass spectroscopy (ICP-MS). Trabecular and cortical morphometry was analyzed in the right distal femurs using micro-CT. Finally, the expressions of RAS peptides, enzymes and receptors along with the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) were determined femurs heads. OVX animals markedly showed altered bone metabolism and mineralization along with disturbed bone micro-structure. Captopril significantly restored the metabolic bone bio-markers and corrected Ca 2+ and P values in urine and bones of estrogen deficient rats. Moreover, the trabecular and cortical morphometric features were repaired by captopril in OVX groups. Captopril also improved the expressions of ACE-2, Ang1-7, Mas and OPG, while abolished OVX-induced up-regulation of ACE-1, AngII, Ang type 1 receptor (AT1R) and RANKL. Inhibition of Ang1-7 cascade by A-779 significantly eradicated captopril protective effects on bone metabolism, mineralization and micro-structure. A-779 also restored OVX effects on RANKL expression and ACE-1/AngII/AT1R

  20. New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) II: Albumin Suppresses Angiotensin Converting Enzyme (ACE) Activity in Human

    PubMed Central

    Fagyas, Miklós; Úri, Katalin; Siket, Ivetta M.; Fülöp, Gábor Á.; Csató, Viktória; Daragó, Andrea; Boczán, Judit; Bányai, Emese; Szentkirályi, István Elek; Maros, Tamás Miklós; Szerafin, Tamás; Édes, István; Papp, Zoltán; Tóth, Attila

    2014-01-01

    About 8% of the adult population is taking angiotensin-converting enzyme (ACE) inhibitors to treat cardiovascular disease including hypertension, myocardial infarction and heart failure. These drugs decrease mortality by up to one-fifth in these patients. We and others have reported previously that endogenous inhibitory substances suppress serum ACE activity, in vivo, similarly to the ACE inhibitor drugs. Here we have made an effort to identify this endogenous ACE inhibitor substance. ACE was crosslinked with interacting proteins in human sera. The crosslinked products were immunoprecipitated and subjected to Western blot. One of the crosslinked products was recognized by both anti-ACE and anti-HSA (human serum albumin) antibodies. Direct ACE-HSA interaction was confirmed by binding assays using purified ACE and HSA. HSA inhibited human purified (circulating) and human recombinant ACE with potencies (IC50) of 5.7±0.7 and 9.5±1.1 mg/mL, respectively. Effects of HSA on the tissue bound native ACE were tested on human saphenous vein samples. Angiotensin I evoked vasoconstriction was inhibited by HSA in this vascular tissue (maximal force with HSA: 6.14±1.34 mN, without HSA: 13.54±2.63 mN), while HSA was without effects on angiotensin II mediated constrictions (maximal force with HSA: 18.73±2.17 mN, without HSA: 19.22±3.50 mN). The main finding of this study is that HSA was identified as a potent physiological inhibitor of the ACE. The enzymatic activity of ACE appears to be almost completely suppressed by HSA when it is present in its physiological concentration. These data suggest that angiotensin I conversion is limited by low physiological ACE activities, in vivo. PMID:24691203

  1. ACE I/D genotype-related increase in ACE plasma activity is a better predictor for schizophrenia diagnosis than the genotype alone.

    PubMed

    Gadelha, Ary; Yonamine, Camila M; Ota, Vanessa K; Oliveira, Vitor; Sato, João Ricardo; Belangero, Sintia I; Bressan, Rodrigo A; Hayashi, Mirian A F

    2015-05-01

    Angiotensin-I converting enzyme (ACE) is a key component of the renin-angiotensin system (RAS). Although the several contradictory data, ACE has been associated with schizophrenia (SCZ) pathophysiology. Here the ACE activity of SCZ patients and healthy controls (HCs), and its possible correlations with the ACE polymorphism genotype and symptomatic dimensions, was investigated. ACE activity of 86 SCZ patients and 100 HCs paired by age, gender and educational level was measured, using the FRET peptide substrate and the specific inhibitor lisinopril. The ACE insertion/deletion (I/D) genotypes were assessed by the restriction fragment length polymorphism (RFLP) technique. Significantly higher ACE activity was observed in SCZ patients compared to HCs (t=-5.09; p<0.001). The area under the receiver operating characteristic (ROC) curve was 0.701. Mean ACE activity levels were higher for the D-allele carriers (F=5.570; p=0.005), but no significant difference was found among SCZ patients and HCs for genotypes frequencies (Chi-squared=2.08; df=2; p=0.35). Interestingly, we found that the difference between the measured ACE activity for each SCZ patient and the expected average mean value for each respective genotype group (for control subjects) was a better predictor of SCZ than the ACE dichotomized values (high/low) or ACE I/D. Our results suggest that higher levels of ACE activity are associated with SCZ with stronger impact when the genetic background of each individual is considered. This may explain the heterogeneity of the results on ACE previously reported. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Enalapril versus losartan for adults with chronic kidney disease: a systematic review and meta-analysis.

    PubMed

    He, Yuan-Mei; Feng, Li; Huo, Dong-Mei; Yang, Zhen-Hua; Liao, Yun-Hua

    2013-09-01

    Both enalapril and losartan are effective and widely used in patients with chronic kidney disease (CKD). This review aimed to evaluate the benefits of enalapril and losartan in adults with CKD. PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov were searched, without language limitations, for randomized controlled trials (RCT), in which enalapril and losartan were compared in adults with CKD. Standard methods, consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, were used. Reviewer Manager software, ver. 5.2, was used for meta-analysis. Of 318 citations retrieved, 17 RCT (14 parallel-group and three cross-over) met our inclusion criteria. The pooled analysis for parallel RCT showed that the effects of enalapril and losartan on blood pressure, renal function and serum uric acid (UA) were similar. Meta-analysis indicated that patients taking enalapril had a higher risk of dry cough (risk ratio, 2.88; 95% CI, 1.11-7.48; P=0.03). Sensitivity analysis showed good robustness of these findings. Enalapril has similar effects to losartan on systemic blood pressure, renal function and serum UA in patients with CKD, but carries a higher risk of dry cough. Larger trials are required to evaluate the effects of these medications on clinical outcomes. © 2013 The Authors. Nephrology © 2013 Asian Pacific Society of Nephrology.

  3. [ACE Inhibitors and ARB in Chronic Kidney Disease: What Has to Be Considered].

    PubMed

    Zeier, Martin

    2018-06-01

    Proteinuric kidney disease, especially in the early and middle stages of renal insufficiency, may be favorably affected by ACE-I/ARB. The progression of renal insufficiency is thereby slowed down and dialysis obligation occurs later or can even be avoided. This effect is independent of the underlying glomerular kidney disease. In the advanced stage of renal insufficiency, the benefit of ACE-I/ARB cannot yet be conclusively assessed. The interruption of ACE-I/ARB therapy may possibly contribute to a certain recovery of renal function and delay the onset of dialysis a little. However, studies are still pending and the benefits of ACE-I/ARB for the heart and blood vessels, especially at this stage of renal insufficiency, should not be overlooked.Patients with proteinuria benefit from ACE-I/ARB not only in terms of renal stabilization. A cardio-protective effect by reduction of proteinuria and a delay of progression is proven. On the other hand, the protective effect of ACE-I/ARB that can be detected directly on the heart and blood vessels should not be disregarded. Thus, even if chronic renal insufficiency no longer benefits directly from ACE-I/ARB therapy, cardiac protection may still be of great importance to the chronic kidney patient. © Georg Thieme Verlag KG Stuttgart · New York.

  4. Physical training associated with Enalapril but not to Losartan, results in better cardiovascular autonomic effects.

    PubMed

    Maida, Karina Delgado; Gastaldi, Ada Clarice; de Paula Facioli, Tabata; de Araújo, João Eduardo; de Souza, Hugo Celso Dutra

    2017-03-01

    We investigated the cardiovascular autonomic effects of physical training associated with Enalapril or Losartan pharmacological treatments in spontaneously hypertensive rats (SHR). SHRs, 18weeks of age (N=48) was assigned to either sedentary (N=24) and trained (N=24; aerobic training by swimming for 10wk). Each group was subdivided in 3 subgroups (N=8) vehicle (control); Enalapril (10mg·kg -1 ·d -1 ); and Losartan (5mg·kg -1 ·d -1 ). All animals received a 10-week treatment in drinking water. In the last week of the treatments, the animals had their femoral artery and vein cannulated for blood pressure recording and drug injection, respectively. The autonomic assessment was performed by means of different approaches: double cardiac autonomic block with atropine and propranolol, spectral analysis of heart rate variability (HRV) and systolic arterial pressure (SAPV) and assessment of baroreflex sensitivity (BRS). The groups treated with Enalapril, sedentary and trained, showed more significant decrease in blood pressure when compared to the other groups. Autonomic evaluation showed that the sedentary group treated with Enalapril or Losartan had similar results, characterized by decreased effect of sympathetic tone and/or increased effect of cardiac vagal tone associated with improved BRS. Isolated physical training attenuated only the effect of sympathetic tone. The association of physical training with Enalapril showed the best results, characterized by the predominance of vagal tone in cardiac autonomic balance, increased HRV, reduced SAPV and increased BRS. Enalapril and Losartan promoted similar beneficial cardiovascular autonomic effects in sedentary animals, while only the association of physical training with Enalapril potentiated these effects. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Pollen count and presentation of angiotensin-converting enzyme inhibitor-associated angioedema.

    PubMed

    Straka, Brittany; Nian, Hui; Sloan, Chantel; Byrd, James Brian; Woodard-Grice, Alencia; Yu, Chang; Stone, Elizabeth; Steven, Gary; Hartert, Tina; Teo, Koon K; Pare, Guillaume; McCarty, Catherine A; Brown, Nancy J

    2013-01-01

    The incidence of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema is increased in patients with seasonal allergies. We tested the hypothesis that patients with ACE inhibitor-associated angioedema present during months when pollen counts are increased. Cohort analysis examined the month of presentation of ACE inhibitor-associated angioedema and pollen counts in the ambulatory and hospital setting. Patients with ACE inhibitor-associated angioedema were ascertained through (1) an observational study of patients presenting to Vanderbilt University Medical Center, (2) patients presenting to the Marshfield Clinic and participating in the Marshfield Clinic Personalized Medicine Research Project, and (3) patients enrolled in The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). Measurements include date of presentation of ACE inhibitor-associated angioedema, population exposure to ACE inhibitor by date, and local pollen counts by date. At Vanderbilt, the rate of angioedema was significantly associated with tree pollen months (P = .01 from χ(2) test). When separate analyses were conducted in patients with a history of seasonal allergies and patients without, the rate of ACE inhibitor-associated angioedema was increased during tree pollen months only in patients with a history of seasonal allergies (P = .002). In Marshfield, the rate of angioedema was significantly associated with ragweed pollen months (P = .025). In ONTARGET, a positive trend was observed between the ACE inhibitor-associated angioedema rate and grass season, although it was not statistically significant (P = .057). Patients with ACE inhibitor-associated angioedema are more likely to present with this adverse drug event during months when pollen counts are increased. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  6. Angiotensin Converting Enzyme (ACE) Inhibitor Extends Caenorhabditis elegans Life Span

    PubMed Central

    Kumar, Sandeep; Dietrich, Nicholas; Kornfeld, Kerry

    2016-01-01

    Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabdtitis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new

  7. Beneficial effects of enalapril on chlorhexidine digluconate-induced liver peritoneal fibrosis in rats.

    PubMed

    Lee, Chung-Jen; Subeq, Yi-Maun; Lee, Ru-Ping; Ke, Chen-Yen; Lin, Nien-Tsung; Hsu, Bang-Gee

    2011-08-31

    Peritoneal fibrosis (PF) is a recognized complication of long-term peritoneal dialysis (PD) and can lead to ultrafiltration failure. The present study was designed to investigate the protective effects of enalapril on chlorhexidine digluconate-induced liver PF by decreasing transforming growth factor-β1 (TGF-β1) production in rats. PF was induced in Sprague-Dawley rats by daily administration of 0.5 ml 0.1% chlorhexidine digluconate in normal saline via PD tube for one week. Rats received daily intravenous injections of low dose enalapril (1 mg/kg), or high dose enalapril (2.5 mg/kg), for one week. After 7 days, conventional 4.25% Dianeal (30 ml) was administered via a PD catheter with a dwell time of 4 h and assessment of peritoneal function. At the end of dialysis, the rats were sacrificed and liver peritoneum was harvested for microscopic examination and immunohistochemistry. There was no significant difference in mean arterial pressure and heart rate between groups. After 4 h of PD, the D₄/P₄(urea) level was reduced, the D₄/D₀ glucose level, serum and the dialysate TGF-β1 level was increased, the liver peritoneum was markedly thicker, and the expression of TGF-β1, alpha-smooth muscle actin (α-SMA), fibronectin, collagen and vascular endothelial growth factor (VEGF) were elevated in the PF group compared with the vehicle group. High dose of enalapril decreased the serum and dialysate TGF-β1 levels, decreased the thickness of the liver peritoneum, and decreased the expression of TGF-β1, α-SMA, fibronectin, collagen and VEGF-positive cells in the liver peritoneum. Low dose of enalapril did not protect against chlorhexidine digluconate-induced PF in the rat. Enalapril protected against chlorhexidine digluconate-induced PF in rats by decreasing TGF-β1 production.

  8. Comparison of nephron-protective effects of enalapril and GLP analogues (exenatide) in diabetic nephropathy.

    PubMed

    Çavusoglu, T; Erbas, O; Karadeniz, T; Akdemir, O; Acikgoz, E; Karadeniz, M; Tuglu, M I; Ates, U

    2014-06-01

    One of the major concerns is a nephropathy in diabetes, which applies many different kinds of medicines. However, required level of the treatment of renal disease has not been achieved. To investigate and compare the effect of the enalapril and the exenatide on diabetic nephropathy in rats developed diabetes by streptozosin. 32 male Sprague Dawley rats were divided into 4 groups: (1) Control, (2) Diabetic (DM), (3) DM+ Enalapril, and (4) DM+ exenatide groups. Then, the animals were euthanized and their blood samples were collected by cardiac puncture for blood glucose; blood urea nitrogen (BUN), creatinin, and nephrectomy were performed for histopathologic examination, and urine samples were taken on stick for proteinuria. Administration of the enalapril or the exenatide in diabetic rats resulted in a significant reduction both fibronectin, induced nitric oxide synthase (i-NOS) expression in glomerular area and urine protein levels. It was shown that both of enalapril and exenatide protected the renal glomerulus more than diabetic group in the nephropathy histopathologically. The beneficial effects of enalapril and exenatide which reduces fibronectin, i-NOS expression and urine protein levels or increases recovery of glomerules, might be used for preventing the harmful effects of diabetic nephropathy. © Georg Thieme Verlag KG Stuttgart · New York.

  9. Stability of extemporaneous enalapril maleate suspensions for pediatric use prepared from commercially available tablets.

    PubMed

    Sosnowska, Katarzyna; Winnicka, Katarzyna; Czajkowska-Kośnik, Anna

    2009-01-01

    In this paper, the stability of enalapril maleate in oral formulations prepared from commercially available tablets was investigated. Extemporaneously compounded, 0.1 mg/mL and 1.0 mg/mL, oral suspensions of enalapril maleate in sugar-containing and sugar-free vehicles were stored in the absence of light at 4 degrees and 25 degrees C for 30 days. Enalapril maleate stability was quantified after 7, 14, 21, and 30 days using HPLC method. Viscosities and pH of prepared suspensions were measured on each study day and no appreciable changes from the initial pH and initial viscosities occurred in any of the samples both at 25 degrees and 4 degrees C. It was shown that all the formulations retain minimum 98% of the initial enalapril maleate concentration after 30 days of storage at 25 degrees and 4 degrees C and they may provide an option in situations where the marketed suspension is unavailable.

  10. 21 CFR 520.804 - Enalapril tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    .... The safety of enalapril for use in breeding dogs has not been established. Use in pregnant bitches is...) Sponsor. See 050604 in § 510.600(c) of this chapter. (c) Conditions of use—(1) Dogs—(i) Amount. 0.5 to 1.0... dogs. (iii) Limitations. Use 0.5 milligram per kilogram once daily. In the absence of adequate clinical...

  11. 21 CFR 520.804 - Enalapril tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    .... The safety of enalapril for use in breeding dogs has not been established. Use in pregnant bitches is...) Sponsor. See 050604 in § 510.600(c) of this chapter. (c) Conditions of use—(1) Dogs—(i) Amount. 0.5 to 1.0... dogs. (iii) Limitations. Use 0.5 milligram per kilogram once daily. In the absence of adequate clinical...

  12. Potentiation of Paclitaxel-Induced Pain Syndrome in Mice by Angiotensin I Converting Enzyme Inhibition and Involvement of Kinins.

    PubMed

    Brusco, Indiara; Silva, Cássia Regina; Trevisan, Gabriela; de Campos Velho Gewehr, Camila; Rigo, Flávia Karine; La Rocca Tamiozzo, Lidia; Rossato, Mateus Fortes; Tonello, Raquel; Dalmolin, Gerusa Duarte; de Almeida Cabrini, Daniela; Gomez, Marcus Vinícius; Ferreira, Juliano; Oliveira, Sara Marchesan

    2017-12-01

    Paclitaxel is a chemotherapeutic agent used to treat solid tumours. However, it causes an acute and neuropathic pain syndrome that limits its use. Among the mechanisms involved in neuropathic pain caused by paclitaxel is activation of kinin receptors. Angiotensin converting enzyme (ACE) inhibitors can enhance kinin receptor signalling. The goal of this study was to evaluate the role of kinins on paclitaxel-associated acute pain syndromes (P-APS) and the effect of ACE inhibition on P-APS and paclitaxel-associated chronic peripheral neuropathy (P-CPN) in mice. Herein, we show that paclitaxel caused mechanical allodynia and spontaneous nociceptive behaviour that was reduced by antagonists of kinin receptors B 1 (DALBk and SSR240612) and B 2 (Hoe140 and FR173657). Moreover, enalapril (an ACE inhibitor) enhanced the mechanical allodynia induced by a low dose of paclitaxel. Likewise, paclitaxel injection inhibited ACE activity and increased the expressions of B 1 and B 2 receptors and bradykinin-related peptides levels in peripheral tissue. Together, our data support the involvement of kinin receptors in the P-APS and suggest kinin receptor antagonists to treat this syndrome. Because hypertension is the most frequent comorbidity affecting cancer patients, treatment of hypertension with ACE inhibitors in patients undergoing paclitaxel chemotherapy should be reviewed, since this could enhance the P-APS and P-CPN.

  13. Effect of protease inhibitors on angiotensin-converting enzyme activity in human T-lymphocytes.

    PubMed

    Petrov, V; Fagard, R; Lijnen, P

    2000-05-01

    The purpose of these investigations was to determine whether the aminopeptidase B and leucine aminopeptidase inhibitor bestatin, the chymase inhibitor chymostatin, the calpain inhibitor E-64, and the neutral serine protease inhibitor leupeptin affect the angiotensin converting enzyme (ACE) activity in T-lymphocytes. ACE activity in homogenates of T-lymphocytes or in intact T-lymphocytes in suspension was measured by determining fluorimetrically histidyl-leucine, formed from the conversion of hippuryl-histidyl-leucine, coupled with ophtaldialdehyde. The effect of various concentrations (10(-9) to 10(-3) mol/L) of the angiotensin-converting enzyme inhibitors lisinopril and captopril and of the various protease inhibitors on ACE activity was studied. Lisinopril and captopril reduced the ACE activity in homogenates of T-lymphocytes in a concentration-dependent manner. Lisinopril exhibited a more pronounced inhibition of ACE in T-lymphocytes than did captopril. Chymostatin and E-64 had no effect on the ACE activity in T-lymphocytes, whereas leupeptin inhibited its activity in a dose-dependent fashion. Bestatin, on the contrary, increased the ACE activity in homogenates of T-lymphocytes as well as in intact T-lymphocytes in proportion to the concentration. Our data showed that the ACE activity in T-lymphocytes was stimulated by bestatin and inhibited by leupeptin, whereas chymostatin and E-64 did not affect the ACE activity in T-lymphocytes.

  14. New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) III: Endogenous Inhibition of Angiotensin Converting Enzyme (ACE) Provides Protection against Cardiovascular Diseases

    PubMed Central

    Fagyas, Miklós; Úri, Katalin; Siket, Ivetta M.; Daragó, Andrea; Boczán, Judit; Bányai, Emese; Édes, István; Papp, Zoltán; Tóth, Attila

    2014-01-01

    ACE inhibitor drugs decrease mortality by up to one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors. Here we investigated the clinical significance of this potential endogenous ACE inhibition. ACE concentration and activity was measured in patient's serum samples (n = 151). ACE concentration was found to be in a wide range (47–288 ng/mL). ACE activity decreased with the increasing concentration of the serum albumin (HSA): ACE activity was 56±1 U/L in the presence of 2.4±0.3 mg/mL HSA, compared to 39±1 U/L in the presence of 12±1 mg/mL HSA (values are mean±SEM). Effects of the differences in ACE concentration were suppressed in human sera: patients with ACE DD genotype exhibited a 64% higher serum ACE concentration (range, 74–288 ng/mL, median, 155.2 ng/mL, n = 52) compared to patients with II genotype (range, 47–194 ng/mL, median, 94.5 ng/mL, n = 28) while the difference in ACE activities was only 32% (range, 27.3–59.8 U/L, median, 43.11 U/L, and range 15.6–55.4 U/L, median, 32.74 U/L, respectively) in the presence of 12±1 mg/mL HSA. No correlations were found between serum ACE concentration (or genotype) and cardiovascular diseases, in accordance with the proposed suppressed physiological ACE activities by HSA (concentration in the sera of these patients: 48.5±0.5 mg/mL) or other endogenous inhibitors. Main implications are that (1) physiological ACE activity can be stabilized at a low level by endogenous ACE inhibitors, such as HSA; (2) angiotensin II elimination may have a significant role in angiotensin II related pathologies. PMID:24690767

  15. [The influence of angiotensin-converting enzyme inhibitors on collagen content of the aorta wall in experimental hypercholesterolemia].

    PubMed

    Wojakowski, W; Gmiński, J; Stajszczyk, M; Goss, M; Siemianowicz, K; Machalski, M

    1999-01-01

    In atherosclerosis numerous qualitative and quantitative changes in connective tissue metabolism parameters in serum and aorta occur. In atherosclerosis there is an enhanced activity of local renin-angiotensin systems. It leads to overexpression of ANG II, both in serum and arterial wall. ANG II stimulates SMC to over-synthesize the collagens type I and III. Hyper-cholesterolemia is a form of metabolic injury which can both induce phenotypic change of SMC and activate RA system in arterial wall. ACEI lower the accumulation of collagens type I and III, and enhance elastin content in arterial wall in experimental hypertension. The aim of this study was to assess the influence of captopril, enalapril and quinapril on connective tissue metabolism of the aorta in experimental hyper-cholesterolemia. 64 male New Zealand rabbits were used. Animals were fed with standard fodder, special diet (1% cholesterol content) or special diet + tested ACEI. Two doses of ACE inhibitors were used: 1st--equivalent to doses applied to human subjects (in mg/kg of body weight), 2nd--dose 10 times higher. The animals were divided into 8 equal groups: K--standard fodder, B--special diet, C1, C2--special diet + captopril in doses 2.5 and 25 mg/kg/24 hours, respectively, E1, E2--special diet + enalapril in doses 0.75 and 7.5 mg/kg/24 hours, respectively, Q1 i Q2--special diet + quinapril in doses 0.75 and 7.5 mg/kg per day, respectively. The experiment lasted for 6 months. After 24 weeks the animals were sacrificed and aortae were excised for collagens assay. The statistical analysis was performed using ANOVA, followed by LSD test; p < 0.05 was considered statistically significant. The aorta collagens content of cholesterol-fed rabbits significantly increased. The tested ACEI (captopril, enalapril in both doses and quinapril in lower dose) had a preventive effect against the increase of aorta collagen content.

  16. Renin-angiotensin-aldosterone system inhibition: overview of the therapeutic use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and direct renin inhibitors.

    PubMed

    Mercier, Kelly; Smith, Holly; Biederman, Jason

    2014-12-01

    Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy in hypertensive diabetic patients with macroalbuminuria, microalbuminuria, or normoalbuminuria has been repeatedly shown to improve cardiovascular mortality and reduce the decline in glomerular filtration rate. Renin-angiotensin-aldosterone system (RAAS) blockade in normotensive diabetic patients with normoalbuminuria or microalbuminuria cannot be advocated at present. Dual RAAS inhibition with ACE inhibitors plus ARBs or ACE inhibitors plus direct renin inhibitors has failed to improve cardiovascular or renal outcomes but has predisposed patients to serious adverse events. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. ACE as a Mechanosensor to Shear Stress Influences the Control of Its Own Regulation via Phosphorylation of Cytoplasmic Ser1270

    PubMed Central

    Barauna, Valerio Garrone; Campos, Luciene Cristina Gastalho; Miyakawa, Ayumi Aurea; Krieger, Jose Eduardo

    2011-01-01

    Objectives We tested whether angiotensin converting enzyme (ACE) and phosphorylation of Ser1270 are involved in shear-stress (SS)-induced downregulation of the enzyme. Methods and Results Western blotting analysis showed that SS (18 h, 15 dyn/cm2) decreases ACE expression and phosphorylation as well as p-JNK inhibition in human primary endothelial cells (EC). CHO cells expressing wild-type ACE (wt-ACE) also displayed SS-induced decrease in ACE and p-JNK. Moreover, SS decreased ACE promoter activity in wt-ACE, but had no effect in wild type CHO or CHO expressing ACE without either the extra- or the intracellular domains, and decreased less in CHO expressing a mutated ACE at Ser1270 compared to wt-ACE (13 vs. 40%, respectively). The JNK inhibitor (SP600125, 18 h), in absence of SS, also decreased ACE promoter activity in wt-ACE. Finally, SS-induced inhibition of ACE expression and phosphorylation in EC was counteracted by simultaneous exposure to an ACE inhibitor. Conclusions ACE displays a key role on its own downregulation in response to SS. This response requires both the extra- and the intracellular domains and ACE Ser1270, consistent with the idea that the extracellular domain behaves as a mechanosensor while the cytoplasmic domain elicits the downstream intracellular signaling by phosphorylation on Ser1270. PMID:21901117

  18. The Effects of Angiotensin Converting Enzyme Inhibitors (ACE-I) on Human N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) Levels: A Systematic Review and Meta-Analysis.

    PubMed

    Mnguni, Ayanda Trevor; Engel, Mark E; Borkum, Megan S; Mayosi, Bongani M

    2015-01-01

    Tuberculous pericardial effusion is a pro-fibrotic condition that is complicated by constrictive pericarditis in 4% to 8% of cases. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a ubiquitous tetrapeptide with anti-fibrotic properties that is low in tuberculous pericardial effusion, thus providing a potential mechanism for the heightened fibrotic state. Angiotensin-converting enzyme inhibitors (ACE-I), which increase Ac-SDKP levels with anti-fibrotic effects in animal models, are candidate drugs for preventing constrictive pericarditis if they can be shown to have similar effects on Ac-SDKP and fibrosis in human tissues. To systematically review the effects of ACE-Is on Ac-SDKP levels in human tissues. We searched five electronic databases (1996 to 2014) and conference abstracts with no language restrictions. Two reviewers independently selected studies, extracted data and assessed methodological quality. The protocol was registered in PROSPERO. Four studies with a total of 206 participants met the inclusion criteria. Three studies (106 participants) assessed the change in plasma levels of Ac-SDKP following ACE-I administration in healthy humans. The administration of an ACE-I was associated with an increase in Ac-SDKP levels (mean difference (MD) 5.07 pmol/ml (95% confidence intervals (CI) 0.64 pmol/ml to 9.51 pmol/ml)). Two studies with 100 participants further assessed the change in Ac-SDKP level in humans with renal failure using ACE-I. The administration of an ACE-I was associated with a significant increase in Ac-SDKP levels (MD 8.94 pmol/ml; 95% CI 2.55 to 15.33; I2 = 44%). ACE-I increased Ac-SDKP levels in human plasma. These findings provide the rationale for testing the impact of ACE-I on Ac-SDKP levels and fibrosis in tuberculous pericarditis.

  19. Angiotensin Converting Enzyme Inhibitors and the Reduced Risk of Alzheimer’s Disease in the Absence of Apolipoprotein E4 Allele

    PubMed Central

    Qiu, Wei Qiao; Mwamburi, Mkaya; Besser, Lilah M.; Zhu, Haihao; Li, Huajie; Wallack, Max; Phillips, Leslie; Qiao, Liyan; Budson, Andrew E.; Stern, Robert; Kowall, Neil

    2014-01-01

    Our cross-sectional study showed that the interaction between apolipoprotein E4 (ApoE4) and angiotensin converting enzyme (ACE) inhibitors was associated with Alzheimer’s disease (AD). The aim of this longitudinal study was to differentiate whether ACE inhibitors accelerate or reduce the risk of AD in the context of ApoE alleles. Using the longitudinal data from the National Alzheimer’s Coordinating Center (NACC) with ApoE genotyping and documentation of ACE inhibitors use, we found that in the absence of ApoE4, subjects who had been taking central ACE inhibitor use (χ2 test: 21% versus 27%, p = 0.0002) or peripheral ACE inhibitor use (χ2 test: 13% versus 27%, p < 0.0001) had lower incidence of AD compared with those who had not been taking an ACE inhibitor. In contrast, in the presence of ApoE4, there was no such association between ACE inhibitor use and the risk of AD. After adjusting for the confounders, central ACE inhibitor use (OR = 0.68, 95% CI = 0.55, 0.83, p = 0.0002) or peripheral ACE inhibitor use (OR = 0.33, 95% CI = 0.33, 0.68, p < 0.0001) still remained inversely associated with a risk of developing AD in ApoE4 non-carriers. In conclusion, ACE inhibitors, especially peripherally acting ones, were associated with a reduced risk of AD in the absence of ApoE4, but had no such effect in those carrying the ApoE4 allele. A double-blind clinical trial should be considered to determine the effect of ACE inhibitors on prevention of AD in the context of ApoE genotype. PMID:23948883

  20. A clinical pharmacological assessment of doxazosin and enalapril in combination.

    PubMed

    Bainbridge, A D; Meredith, P A; Elliott, H L

    1993-12-01

    This study in 12 normotensive males investigated potential pharmacokinetic and pharmacodynamic interaction mechanisms resulting from the combination of enalapril and doxazosin. Blood pressure reductions were consistently greater with the combination but there was no evidence of a significant pharmacodynamic interaction (as determined by heart rate changes, renal function tests or by pressor responsiveness indices) and there was no evidence of a pharmacokinetic interaction with either drug. Responsiveness to each drug i.e. blood pressure reduction per unit drug concentration was not significantly altered in the combination regimen. In conclusion, these results suggest that the combination of enalapril and doxazosin produces a usefully additive hypotensive effect but there was no evidence of synergism i.e an effect which was more than additive.

  1. Potentiation of the actions of bradykinin by angiotensin I-converting enzyme inhibitors. The role of expressed human bradykinin B2 receptors and angiotensin I-converting enzyme in CHO cells.

    PubMed

    Minshall, R D; Tan, F; Nakamura, F; Rabito, S F; Becker, R P; Marcic, B; Erdös, E G

    1997-11-01

    Part of the beneficial effects of angiotensin I-converting enzyme (ACE) inhibitors are due to augmenting the actions of bradykinin (BK). We studied this effect of enalaprilat on the binding of [3H]BK to Chinese hamster ovary (CHO) cells stably transfected to express the human BK B2 receptor alone (CHO-3B) or in combination with ACE (CHO-15AB). In CHO-15AB cells, enalaprilat (1 mumol/L) increased the total number of low-affinity [3H]BK binding sites on the cells at 37 degrees C, but not at 4 degrees C, from 18.4 +/- 4.3 to 40.3 +/- 11.9 fmol/10(6) cells (P < .05; Kd, 2.3 +/- 0.8 and 5.9 +/- 1.3 nmol/L; n = 4). Enalaprilat preserved a portion of the receptors in high-affinity conformation (Kd, 0.17 +/- 0.08 nmol/L; 8.1 +/- 0.9 fmol/10(6) cells). Enalaprilat decreased the IC50 of [Hyp3-Tyr(Me)8]BK, the BK analogue more resistant to ACE, from 3.2 +/- 0.8 to 0.41 +/- 0.16 nmol/L (P < .05, n = 3). The biphasic displacement curve of the binding of [3H]BK also suggested the presence of high-affinity BK binding sites. Enalaprilat (5 nmol to 1 mumol/L) potentiated the release of [3H]arachidonic acid and the liberation of inositol 1,4,5-trisphosphate (IP3) induced by BK and [Hyp3-Tyr(Me)8]BK. Moreover, enalaprilat (1 mumol/L) completely and immediately restored the response of the B2 receptor, desensitized by the agonist (1 mumol/L [Hyp3-Tyr(Me)8]BK); this effect was blocked by the antagonist, HOE 140. Finally, enalaprilat, but not the prodrug enalapril, decreased internalization of the receptor from 70 +/- 9% to 45 +/- 9% (P < .05, n = 7). In CHO-3B cells, enalaprilat was ineffective. ACE inhibitors in the presence of both the B2 receptor and ACE enhance BK binding, protect high-affinity receptors, block receptor desensitization, and decrease internalization, thereby potentiating BK beyond blocking its hydrolysis.

  2. The use of nitrates, calcium channel blockers and ACE inhibitors in primary care in the Northern Region: a pharmacoepidemiological study.

    PubMed Central

    Roberts, S J; Bateman, D N

    1994-01-01

    1. Prescribing rates for cardiovascular drugs have substantial local variation. The objectives of this study were to determine the prescribing prevalence of nitrates, calcium channel blockers and angiotensin-converting enzyme inhibitors in general practice, to examine the indications recorded for these prescriptions, and to identify which therapeutic areas contribute to the variation in prescribing. 2. Anonymised patient-specific prescription data were taken from computerised records in 41 VAMP research practices in the Northern Region (total population 330,749). All patients who received any prescription for calcium channel blockers, nitrates or angiotensin-converting enzyme (ACE) inhibitors during a 12 month period were included. Prescribing rates were determined in terms of patients per 1,000 population within age, sex and diagnostic groups. 3. Overall, 4.3% of the study population were prescribed one or more of the drugs. There was virtually no prescribing for patients under the age of 35 years, but thereafter the prevalences rose steeply to peak at ages 65-74 years for calcium channel blockers (91 per 1,000 population) and ACE inhibitors (34 per 1,000), and at ages 75-84 years for nitrates (100 per 1,000). Prescribing prevalence amongst the over 85's was less than half the peak rate for each drug group. Rates for men and women were comparable, except for nitrates where men had higher rates. 4. Recorded indication rates for patients with ischaemic heart disease and treated with any of these drugs reached 112 per 1,000 population in the 75-84 age group, and were higher in men than women, at all ages. Hypertension indication rates were substantially higher in women over 65; across the genders the peak rate was 88 per 1,000 for those aged 65-74 years.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7888286

  3. ACE inhibitors could be therapeutic for antisocial personality disorder.

    PubMed

    Hobgood, Donna K

    2013-11-01

    Antisocial personality traits are an important topic for research. The societal cost of these behaviors encourages efforts at a better understanding of central nervous system causes. Catecholamine genes are being studied to facilitate this understanding, and some tentative findings are being reached about several of these genes. It seems that many genes play a role to produce antisocial behaviors so complexity of elucidating each gene is obvious. One conclusion that could be drawn from the current research findings is that DA2 like receptors (DRD2, DRD3, DRD4) with alleles that decrease neurotransmission are facilitatory of antisocial behaviors. DA2 like receptors cause neuronal firing to inhibit many peripheral functions through adenylyl cyclase inhibition. When these receptors are less active by genetically decreased density, lower affinity, or by low dopamine levels as final common pathways then inhibition is released and a state of disinhibition can be said to describe this state. Peripheral metabolism is increased and behavioral activation is noted. Renin is disinhibited in this setting thus allowing sympathetic nervous system activation. The fight or flight behaviors thus produced, in the extreme, would be the setting of antisocial behavior. Research validates this hypothesis. Understanding this final common pathway toward antisocial behavior should lead to better treatment for individuals with this pattern of behavior before they have caused harm to themselves and others. ACE inhibitors are well tolerated drugs used in the treatment of hypertension and heart failure and would also treat antisocial behavior disorders. Copyright © 2013 The Author. Published by Elsevier Ltd.. All rights reserved.

  4. Somatic ACE regulates self-renewal of mouse spermatogonial stem cells via the MAPK signaling pathway.

    PubMed

    Gao, Tingting; Zhao, Xin; Liu, Chenchen; Shao, Binbin; Zhang, Xi; Li, Kai; Cai, Jinyang; Wang, Su; Huang, Xiaoyan

    2018-05-24

    Spermatogonial stem cell (SSC) self-renewal is an indispensable part of spermatogenesis. Angiotensin I-converting enzyme (ACE) is a zinc dipeptidyl carboxypeptidase that plays a critical role in regulation of the renin-angiotensin system. Here, we used RT-PCR and Western blot analysis to confirm that somatic ACE (sACE) but not testicular ACE (tACE) is highly expressed in mouse testis before postpartum day 7 and in cultured SSCs. Our results revealed that sACE is located on the membrane of SSCs. Treating cultured SSCs with the ACE competitive inhibitor captopril was found to inhibit sACE activity, and significantly reduced the proliferation rate of SSCs. Microarray analysis identified 651 genes with significant differential expression. KEGG pathway analysis showed that these differentially expressed genes are mainly involved in the mitogen-activated protein kinase (MAPK) signaling pathway and cell cycle. sACE was found to play an important role in SSC self-renewal via the regulation of MAPK-dependent cell proliferation.

  5. Effects of orally administered enalapril on blood pressure and hemodynamic response to vasopressors during isoflurane anesthesia in healthy dogs.

    PubMed

    Coleman, Amanda E; Shepard, Molly K; Schmiedt, Chad W; Hofmeister, Erik H; Brown, Scott A

    2016-09-01

    To examine whether preanesthetic administration of enalapril, compared with placebo, results in a greater decline in blood pressure (BP) or decreased responsiveness of BP to isotonic fluids or vasopressors in healthy dogs during isoflurane anesthesia. Randomized, experimental, placebo-controlled, blinded, crossover study. Twelve healthy, female, purpose-bred beagles. Dogs underwent the following week-long treatment protocols, each preceded by a 1 week washout period: oral placebo twice daily (PLA); oral enalapril, 0.5 mg kg(-1) twice daily, with the 15th dose withheld on the day of anesthesia (ENA-W), and oral enalapril, 0.5 mg kg(-1) twice daily, with the 15th dose administered 90 minutes prior to anesthetic induction (ENA). On day 8 of each treatment period, dogs were anesthetized in random order utilizing a standard protocol. Following stabilization at an end-tidal isoflurane concentration (Fe'Iso) of 1.3%, invasively measured systolic (SAP), diastolic (DAP) and mean (MAP) arterial blood pressure were continuously recorded via telemetry. Hypotension (SAP < 85 mmHg) was treated with the following sequential interventions: lactated Ringer's solution (LRS) bolus (10 mL kg(-1) ); repeated LRS bolus; dopamine (7 μg kg(-1)  min(-1) ); and dopamine (10 μg kg(-1)  min(-1) ) first without and then with vasopressin (1 mU kg(-1)  hour(-1) ). Compared with the PLA but not the ENA-W group, the ENA group had significantly lower average SAP, DAP and MAP at an Fe'Iso of 1.3%, spent more minutes in hypotension, and required a greater number of interventions to correct moderate-to-severe mean arterial hypotension. In healthy dogs, enalapril administered 90 minutes prior to isoflurane anesthesia increases the degree of intra-anesthetic hypotension and the number of interventions required to correct moderate-to-severe hypotension. Dogs receiving angiotensin-converting enzyme inhibitors on the day of anesthesia may exhibit clinically significant intra

  6. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitor-Based Treatment on Cardiovascular Outcomes in Hypertensive Blacks versus Whites

    PubMed Central

    Ogedegbe, Gbenga; Shah, Nirav R.; Phillips, Christopher; Goldfeld, Keith; Roy, Jason; Guo, Yu; Gyamfi, Joyce; Torgersen, Christopher; Capponi, Louis; Bangalore, Sripal

    2015-01-01

    BACKGROUND Clinical trial evidence suggests poorer outcomes in blacks compared to whites when treated with angiotensin-converting enzyme (ACE) inhibitor-based regimen, but this has not been evaluated in clinical practice. OBJECTIVES We evaluated the comparative effectiveness of an ACE inhibitor-based regimen on a composite outcome of all-cause mortality, stroke, and acute myocardial infarction (AMI) in hypertensive blacks compared to whites. METHODS We conducted a retrospective cohort study of 434,646 patients in a municipal health care system. Four exposure groups (Black-ACE, Black-NoACE, White-ACE, White-NoACE) were created based on race and treatment exposure (ACE or NoACE). Risk of the composite outcome and its components was compared across treatment groups and race using weighted Cox proportional hazard models. RESULTS Our analysis included 59,316 new users of ACE inhibitors, 47% of whom were black. Baseline characteristics were comparable for all groups after inverse probability weighting adjustment. For the composite outcome, the race treatment interaction was significant (p = 0.04); ACE use in blacks was associated with poorer cardiovascular outcomes (ACE vs. NoACE: 8.69% vs. 7.74%; p = 0.05) but not in whites (6.40% vs. 6.74%; p = 0.37). Similarly, the Black-ACE group had higher rates of AMI (0.46% vs. 0.26%; p = 0.04), stroke (2.43% vs. 1.93%; p = 0.05) and chronic heart failure (3.75% vs. 2.25%; p < 0.0001) than the Black-NoACE group. However, the Black-ACE group was no more likely to develop adverse effects than the White-ACE group. CONCLUSIONS ACE inhibitor-based therapy was associated with poorer cardiovascular outcomes in hypertensive blacks but not in whites. These findings confirm clinical trial evidence that hypertensive blacks have poorer outcomes than whites when treated with an ACE inhibitor-based regimen. PMID:26361152

  7. Angiotensin Converting Enzyme Inhibitors and Alzheimer Disease in the Presence of the Apolipoprotein E4 Allele

    PubMed Central

    Qiu, Wendy Wei Qiao; Lai, Angela; Mon, Timothy; Mwamburi, Mkaya; Taylor, Warren; Rosenzweig, James; Kowall, Neil; Stern, Robert; Zhu, Haihao; Steffens, David C.

    2013-01-01

    Objective The effect of angiotensin converting enzyme (ACE) inhibitors on Alzheimer disease (AD) remains unclear, with conflicting results reported. We studied the interaction of the Apolipoprotein E (ApoE) genotype and ACE inhibitors on AD. Methods This was a cross-sectional study of homebound elderly with an AD diagnosis and documentation of medications taken. ApoE genotype was determined. Results A total of 355 subjects with status on ApoE alleles and cognitive diagnoses were studied. The average age (mean ± SD) of this population was 73.3 ± 8.3 years old, and 73% were female. Cross-sectionally, there was no difference in the number of AD cases between ApoE4 carriers and ApoE4 non-carriers or between ACE inhibitor users and non-users in the homebound elderly. ApoE4 carriers treated with ACE inhibitors, however, had more diagnoses of AD compared with those who did not have the treatment (28% versus 6%, p = 0.01) or ApoE4 non-carriers treated with an ACE inhibitor (28% versus 10%, p = 0.03). ACE inhibitor use was associated with AD diagnosis only in the presence of an E4 allele. Using multivariate logistic regression analysis, we found that in diagnosed AD cases there was a significant interaction between ApoE4 and ACE inhibitor use (odds ratio: 20.85; 95% confidence interval: 3.08–140.95; p = 0.002) after adjusting for age, sex, ethnicity, and education. Conclusion The effects of ACE inhibitors on AD may be different depending on ApoE genotype. A prospective study is needed to determine whether ACE inhibitor use accelerates or poorly delays AD development in ApoE4 carriers compared with ApoE4 non-carriers. PMID:23567418

  8. Angiotensin converting enzyme inhibitors and Alzheimer disease in the presence of the apolipoprotein E4 allele.

    PubMed

    Qiu, Wendy Wei Qiao; Lai, Angela; Mon, Timothy; Mwamburi, Mkaya; Taylor, Warren; Rosenzweig, James; Kowall, Neil; Stern, Robert; Zhu, Haihao; Steffens, David C

    2014-02-01

    The effect of angiotensin converting enzyme (ACE) inhibitors on Alzheimer disease (AD) remains unclear, with conflicting results reported. We studied the interaction of the Apolipoprotein E (ApoE) genotype and ACE inhibitors on AD. This was a cross-sectional study of homebound elderly with an AD diagnosis and documentation of medications taken. ApoE genotype was determined. A total of 355 subjects with status on ApoE alleles and cognitive diagnoses were studied. The average age (mean ± SD) of this population was 73.3 ± 8.3 years old, and 73% were female. Cross-sectionally, there was no difference in the number of AD cases between ApoE4 carriers and ApoE4 non-carriers or between ACE inhibitor users and non-users in the homebound elderly. ApoE4 carriers treated with ACE inhibitors, however, had more diagnoses of AD compared with those who did not have the treatment (28% versus 6%, p = 0.01) or ApoE4 non-carriers treated with an ACE inhibitor (28% versus 10%, p = 0.03). ACE inhibitor use was associated with AD diagnosis only in the presence of an E4 allele. Using multivariate logistic regression analysis, we found that in diagnosed AD cases there was a significant interaction between ApoE4 and ACE inhibitor use (odds ratio: 20.85; 95% confidence interval: 3.08-140.95; p = 0.002) after adjusting for age, sex, ethnicity, and education. The effects of ACE inhibitors on AD may be different depending on ApoE genotype. A prospective study is needed to determine whether ACE inhibitor use accelerates or poorly delays AD development in ApoE4 carriers compared with ApoE4 non-carriers. Copyright © 2014. Published by Elsevier Inc.

  9. Comparison of the transplacental transfer of enalapril, captopril and losartan in sheep.

    PubMed Central

    Stevenson, K M; Gibson, K J; Lumbers, E R

    1995-01-01

    1. The transplacental transfers of three drugs (enalapril, captopril and losartan) which block the renin angiotensin system and have different lipophilicities were studied in chronically catheterized foetal sheep (125-139 days gestation). 2. The ability of the foeto-placental unit to convert enalapril to enalaprilat was studied in two chronically catheterized foetuses. Enalapril (3 mg kg-1, 7.9 mumol kg-1) given i.v. to the foetuses abolished the foetal pressor response to 5 micrograms angiotensin I (AI) in one foetus and attenuated the pressor response in the other. 3. Enalapril (100 mg, 5.7 mumol kg-1) given i.v. to the ewe (n = 5) abolished the maternal pressor response to 2.5 micrograms AI (n = 1) and attenuated the maternal pressor response to 5 micrograms AI (n = 5, P < 0.001). The foetal pressor response to 5 micrograms AI (n = 2) and 10 micrograms AI (n = 3) did not change. The maternal and foetal pressor responses to angiotensin II (AII; n = 5) did not change. 4. Foetal pressor responses to 5 micrograms AI (n = 1) and 10 micrograms AI (n = 2) were attenuated within 11 min of their mothers (n = 3) being given i.v. captopril (15 mg, 1.5 mumol kg-1). Foetal pressor responses to 5 micrograms AII (n = 1) and to 10 micrograms AII (n = 2) did not change. 5. Losartan (100 mg, kg-1, 21.7 mumol kg-1) given i.v. to the foetus (n = 9) attenuated the foetal pressor response to 5 micrograms AII (P < 0.001) but the maternal pressor response to 5 micrograms AII did not change.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7606354

  10. High-resolution crystal structures of Drosophila melanogaster angiotensin-converting enzyme in complex with novel inhibitors and antihypertensive drugs.

    PubMed

    Akif, Mohd; Georgiadis, Dimitris; Mahajan, Aman; Dive, Vincent; Sturrock, Edward D; Isaac, R Elwyn; Acharya, K Ravi

    2010-07-16

    Angiotensin I-converting enzyme (ACE), one of the central components of the renin-angiotensin system, is a key therapeutic target for the treatment of hypertension and cardiovascular disorders. Human somatic ACE (sACE) has two homologous domains (N and C). The N- and C-domain catalytic sites have different activities toward various substrates. Moreover, some of the undesirable side effects of the currently available and widely used ACE inhibitors may arise from their targeting both domains leading to defects in other pathways. In addition, structural studies have shown that although both these domains have much in common at the inhibitor binding site, there are significant differences and these are greater at the peptide binding sites than regions distal to the active site. As a model system, we have used an ACE homologue from Drosophila melanogaster (AnCE, a single domain protein with ACE activity) to study ACE inhibitor binding. In an extensive study, we present high-resolution structures for native AnCE and in complex with six known antihypertensive drugs, a novel C-domain sACE specific inhibitor, lisW-S, and two sACE domain-specific phosphinic peptidyl inhibitors, RXPA380 and RXP407 (i.e., nine structures). These structures show detailed binding features of the inhibitors and highlight subtle changes in the orientation of side chains at different binding pockets in the active site in comparison with the active site of N- and C-domains of sACE. This study provides information about the structure-activity relationships that could be utilized for designing new inhibitors with improved domain selectivity for sACE. 2010 Elsevier Ltd. All rights reserved.

  11. ACE

    NASA Technical Reports Server (NTRS)

    Lumia, R.

    1999-01-01

    This document describes the progress made during the fourth year of the Center for Autonomous Control Engineering (ACE). We currently support 30 graduate students, 52 undergraduate students, 9 faculty members, and 4 staff members. Progress will be divided into two categories. The first category explores progress for ACE in general. The second describes the results of each specific project supported within ACE.

  12. Meta-analysis of genome wide association studies (GWAS) on the intolerance of Angiotensin converting enzyme inhibitors

    PubMed Central

    Mahmoudpour, Seyed Hamidreza; Veluchamy, Abirami; Siddiqui, Moneeza Kalhan; Asselbergs, Folkert W.; Souverein, Patrick C.; de Keyser, Catherine E.; Hofman, Albert; Lang, Chim C.; Doney, Alexander SF.; Stricker, Bruno H.; de Boer, Anthonius; Maitland-van der Zee, Anke-Hilse; Palmer, Colin NA.

    2016-01-01

    Objectives To identify SNPs associated with switching from an ACE-inhibitor to an angiotensin receptor blocker (ARB). Methods Two cohorts of patients starting ACE-inhibitors were identified within the Rotterdam Study in the Netherlands and the GoDARTS study in Scotland. Cases were intolerant subjects who switched from an ACE-inhibitor to an ARB, controls were subjects who used ACE-inhibitors continuously for at least 2 years and did not switch. GWAS using an additive model was run in these sets and results were meta-analysed using GWAMA. Results 972 cases out of 5 161 ACE-inhibitor starters were identified. 8 SNPs within 4 genes reached the GWAS significance level (P<5×10-8) in the meta-analysis (RBFOX3, GABRG2, SH2B1 and MBOAT1). The strongest associated SNP was located in an intron of RBFOX3, which contains a RNA binding protein (rs2061538: MAF=0.16, OR=1.52[95%CI: 1.32-1.76], p=6.2x10-9). Conclusions These results indicate that genetic variation in abovementioned genes may increase the risk of ACE-inhibitors induced adverse reactions. PMID:28030426

  13. Comparison of zofenopril and lisinopril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with ACE-inhibitors in experimental heart failure

    PubMed Central

    Buikema, H; Monnink, S H J; Tio, R A; Crijns, H J G M; de Zeeuw, D; van Gilst, W H

    2000-01-01

    We evaluated the role of SH-groups in improvement of endothelial dysfunction with ACE-inhibitors in experimental heart failure. To this end, we compared the vasoprotective effect of chronic treatment with zofenopril (plus SH-group) versus lisinopril (no SH-group), or N-acetylcysteine (only SH-group) in myocardial infarcted (MI) heart failure rats.After 11 weeks of treatment, aortas were obtained and studied as ring preparations for endothelium-dependent and -independent dilatation in continuous presence of indomethacin to avoid interference of vasoactive prostanoids, and the selective presence of the NOS-inhibitor L-NMMA to determine NO-contribution.Total dilatation after receptor-dependent stimulation with acetylcholine (ACh) was attenuated (−49%, P<0.05) in untreated MI (n=11), compared to control rats with no-MI (n=8). This was in part due to impaired NO-contribution in MI (−50%, P<0.05 versus no-MI). At the same time the capacity for generation of biologically active NO after receptor-independent stimulation with A23187 remained intact.Chronic treatment with n-acetylcysteine (n=8) selectively restored NO-contribution in total dilatation to ACh. In contrast, both ACE-inhibitors fully normalized total dilatation to ACh, including the part mediated by NO (no significant differences between zofenopril (n=10) and lisinopril (n=8)).Zofenopril, but not lisinopril, additionally potentiated the effect of endogenous NO after A23187-induced release from the endothelium (+100%) as well as that of exogenous NO provided by nitroglycerin (+22%) and sodium nitrite (+36%) (for all P<0.05 versus no-MI).We conclude that ACE-inhibition with a SH-group has a potential advantage in improvement of endothelial dysfunction through increased activity of NO after release from the endothelium into the vessel wall. Furthermore, this is the first study demonstrating the selective normalizing effect of N-actylcysteine on NO-contribution to ACh-induced dilatation in experimental heart

  14. A retrospective study of the effects of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in diabetic nephropathy.

    PubMed

    Pathak, Jahnavi V; Dass, Ervilla E

    2015-01-01

    Till date, several studies have compared angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in terms of delaying the progression of diabetic nephropathy. But the superiority of one drug class over the other remains unsettled. This study has retrospectively compared the effects of ACE inhibitors and ARBs in diabetic nephropathy. The study aims to compare ACE inhibitors and ARBs in terms of delaying or preventing the progression of diabetic nephropathy, association between blood pressure (B.P) and urinary albumin and also B.P and serum creatinine with ACE inhibitor and ARB, know the percentage of hyperkalemia in patients of diabetic nephropathy receiving ACE inhibitor or ARB. A total of 134 patients diagnosed with diabetic nephropathy during the years 2001-2010 and having a complete follow-up were studied, out of which 99 were on ARB (63 patients of Losartan and 36 of Telmisartan) and 35 on ACE inhibitor (Ramipril). There was at least 1-month of interval between each observation made and also between the date of treatment started and the first reading that is, the observation of the 1(st) month. In total, three readings were taken that is, of the 1(st), 2(nd) and 3(rd) month after the treatment started. Comparison of the 1(st) and 3(rd) month after the treatment started was done. Mean ± standard deviation, Paired t-test, and Chi-square were used for the analysis of the data. The results reflect that ARBs (Losartan and Telmisartan) when compared to ACE inhibitor (Ramipril) are more effective in terms of delaying the progression of diabetic nephropathy and also in providing renoprotection. Also, ARBs have the property of simultaneously decreasing the systolic B.P and albuminuria when compared to ACE inhibitor (Ramipril). Angiotensin receptor blockers are more renoprotective than ACE inhibitors and also provide better cardioprotection.

  15. Renal tubular ACE-mediated tubular injury is the major contributor to microalbuminuria in early diabetic nephropathy.

    PubMed

    Eriguchi, Masahiro; Lin, Mercury; Yamashita, Michifumi; Zhao, Tuantuan V; Khan, Zakir; Bernstein, Ellen A; Gurley, Susan B; Gonzalez-Villalobos, Romer A; Bernstein, Kenneth E; Giani, Jorge F

    2018-04-01

    Diabetic nephropathy is a major cause of end-stage renal disease in developed countries. While angiotensin-converting enzyme (ACE) inhibitors are used to treat diabetic nephropathy, how intrarenal ACE contributes to diabetic renal injury is uncertain. Here, two mouse models with different patterns of renal ACE expression were studied to determine the specific contribution of tubular vs. glomerular ACE to early diabetic nephropathy: it-ACE mice, which make endothelial ACE but lack ACE expression by renal tubular epithelium, and ACE 3/9 mice, which lack endothelial ACE and only express renal ACE in tubular epithelial cells. The absence of endothelial ACE normalized the glomerular filtration rate and endothelial injury in diabetic ACE 3/9 mice. However, these mice developed tubular injury and albuminuria and displayed low renal levels of megalin that were similar to those observed in diabetic wild-type mice. In diabetic it-ACE mice, despite hyperfiltration, the absence of renal tubular ACE greatly reduced tubulointerstitial injury and albuminuria and increased renal megalin expression compared with diabetic wild-type and diabetic ACE 3/9 mice. These findings demonstrate that endothelial ACE is a central regulator of the glomerular filtration rate while tubular ACE is a key player in the development of tubular injury and albuminuria. These data suggest that tubular injury, rather than hyperfiltration, is the main cause of microalbuminuria in early diabetic nephropathy.

  16. Identification of ACE-inhibitory peptides from Phaseolus vulgaris after in vitro gastrointestinal digestion.

    PubMed

    Tagliazucchi, Davide; Martini, Serena; Bellesia, Andrea; Conte, Angela

    2015-01-01

    The objective of this study was to identify the angiotensin I-converting enzyme (ACE)-inhibitory peptides released from thermally treated Phaseolus vulgaris (pinto) whole beans after in vitro gastrointestinal digestion. The degree of hydrolysis increased during digestion reaching a value of 50% at the end of the pancreatic digestion. The <3 kDa fraction of the postpancreatic sample showed high ACE-inhibitory activity (IC50 = 105.6 ± 2.1 μg of peptides/mL). Peptides responsible for the ACE-inhibitory activity were isolated by reverse-phase high-performance liquid chromatography (HPLC). Three fractions, showing the highest inhibitory activity, were selected for tandem mass spectrometry (MS/MS) experiments. Eleven of the identified sequences have previously been described as ACE-inhibitors. Most of the identified bioactive peptides have a hydrophobic amino acid, (iso)leucine or phenylalanine, or proline at the C-terminal position, which is crucial for their ACE-inhibitory activity. The sequence of some peptides allowed us to anticipate the presence of ACE-inhibitory activity.

  17. Angiotensin-Converting Enzyme Inhibitors and the Risk of Congenital Malformations.

    PubMed

    Bateman, Brian T; Patorno, Elisabetta; Desai, Rishi J; Seely, Ellen W; Mogun, Helen; Dejene, Sara Z; Fischer, Michael A; Friedman, Alexander M; Hernandez-Diaz, Sonia; Huybrechts, Krista F

    2017-01-01

    To examine the association between first-trimester angiotensin-converting enzyme (ACE) inhibitor exposure and the risk of overall major congenital, cardiac, and central nervous system malformations. We used a cohort of completed pregnancies linked to liveborn neonates derived from Medicaid claims from 2000 to 2010. We examined the risk of malformations associated with first-trimester exposure to an ACE inhibitor. Propensity score-based methods were used to control for potential confounders including maternal demographics, medical conditions, exposure to other medications, and measures of health care utilization. The cohort included 1,333,624 pregnancies, of which 4,107 (0.31%) were exposed to ACE inhibitors during the first trimester. The prevalence of overall malformations in the ACE inhibitor-exposed pregnancies was 5.9% compared with 3.3% in the unexposed (unadjusted relative risk, 1.82; 95% confidence interval [CI] 1.61-2.06), of cardiac malformations was 3.4% compared with 1.2% (relative risk 2.95, 95% CI 2.50-3.47), and of central nervous system malformations was 0.27% compared with 0.18% (relative risk 1.46, 95% CI 0.81-2.64). After restricting the cohort to pregnancies complicated by chronic hypertension (both exposed and unexposed) and accounting for other confounding factors, there was no significant increase in the risk of any of the outcomes assessed. Relative risks associated with first-trimester ACE inhibitor exposure were 0.89 (95% CI 0.75-1.06) for overall malformations, 0.95 (95% CI 0.75-1.21) for cardiac malformations, and 0.54 (95% CI 0.26-1.11) for CNS malformations. After accounting for confounders, among women with hypertension, exposure to ACE inhibitors during the first trimester was not associated with an increased risk of major congenital malformations.

  18. Dipeptidyl peptidase IV deficiency increases susceptibility to angiotensin-converting enzyme inhibitor-induced peritracheal edema.

    PubMed

    Byrd, James Brian; Shreevatsa, Ajai; Putlur, Pradeep; Foretia, Denis; McAlexander, Laurie; Sinha, Tuhin; Does, Mark D; Brown, Nancy J

    2007-08-01

    Serum dipeptidyl peptidase IV (DPPIV) activity is decreased in some individuals with ACE inhibitor-associated angioedema. ACE and DPPIV degrade substance P, an edema-forming peptide. The contribution of impaired degradation of substance P by DPPIV to the pathogenesis of ACE inhibitor-associated angioedema is unknown. We sought to determine whether DPPIV deficiency results in increased edema formation during ACE inhibition. We also sought to develop an animal model using magnetic resonance imaging to quantify ACE inhibitor-induced edema. The effect of genetic DPPIV deficiency on peritracheal edema was assessed in F344 rats after treatment with saline, captopril (2.5 mg/kg), or captopril plus the neurokinin receptor antagonist spantide (100 mug/kg) by using serial T2-weighted magnetic resonance imaging. Serum dipeptidyl peptidase activity was dramatically decreased in DPPIV-deficient rats (P < .001). The volume of peritracheal edema was significantly greater in captopril-treated DPPIV-deficient rats than in saline-treated DPPIV-deficient rats (P = .001), saline-treated rats of the normal substrain (P < .001), or captopril-treated rats of the normal substrain (P = .001). Cotreatment with spantide attenuated peritracheal edema in captopril-treated DPPIV-deficient rats (P = .005 vs captopril-treated DPPIV-deficient rats and P = .57 vs saline-treated DPPIV-deficient rats). DPPIV deficiency predisposes to peritracheal edema formation when ACE is inhibited through a neurokinin receptor-dependent mechanism. Magnetic resonance imaging is useful for modeling ACE inhibitor-associated angioedema in rats. Genetic or environmental factors that decrease DPPIV activity might increase the risk of ACE inhibitor-associated angioedema.

  19. Associations of ACE Gene Insertion/Deletion Polymorphism, ACE Activity, and ACE mRNA Expression with Hypertension in a Chinese Population

    PubMed Central

    He, Qingfang; Fan, Chunhong; Yu, Min; Wallar, Gina; Zhang, Zuo-Feng; Wang, Lixin; Zhang, Xinwei; Hu, Ruying

    2013-01-01

    Background The present study was designed to explore the association of angiotensin converting enzyme (ACE) gene insertion/deletion (I/D, rs4646994) polymorphism, plasma ACE activity, and circulating ACE mRNA expression with essential hypertension (EH) in a Chinese population. In addition, a new detection method for circulating ACE mRNA expression was explored. Methods The research was approved by the ethics committee of Zhejiang Provincial Center for Disease Prevention and Control. Written informed consent was obtained prior to the investigation. 221 hypertensives (cases) and 221 normotensives (controls) were interviewed, subjected to a physical examination, and provided blood for biochemical and genetic tests. The ACE mRNA expression was analyzed by real time fluorescent quantitative Reverse Transcription PCR (FQ-RT-PCR). We performed logistic regression to assess associations of ACE I/D genotypes, ACE activity, and ACE mRNA expression levels with hypertension. Results The results of the multivariate logistic regression analysis showed that the additive model (ID, DD versus II) of the ACE genotype revealed an association with hypertension with adjusted OR of 1.43(95% CI: 1.04-1.97), and ACE ID genotype with adjusted OR of 1.72(95% CI: 1.01-2.92), DD genotype with adjusted OR of 1.94(95% CI: 1.01-3.73), respectively. In addition, our data also indicate that plasma ACE activity (adjusted OR was 1.13(95% CI: 1.08-1.18)) was significantly related to hypertension. However, the plasma ACE mRNA expressions were not different between the cases and controls. Conclusion ACE I/D polymorphism and ACE activity revealed significant influence on hypertension, while circulating ACE mRNA expression was not important factors associated with hypertension in this Chinese population. The detection of circulating ACE mRNA expression by FQ-RT-PCR might be a useful method for early screening and monitoring of EH. PMID:24098401

  20. Role of homocysteinylation of ACE in endothelial dysfunction of arteries

    PubMed Central

    Huang, An; Pinto, John T.; Froogh, Ghezal; Kandhi, Sharath; Qin, Jun; Wolin, Michael S.; Hintze, Thomas H.

    2014-01-01

    The direct impact of de novo synthesis of homocysteine (Hcy) and its reactive metabolites, Hcy-S-S-Hcy and Hcy thiolactone (HCTL), on vascular function has not been fully elucidated. We hypothesized that Hcy synthesized within endothelial cells affects activity of angiotensin-converting enzyme (ACE) by direct homocysteinylation of its amino- and/or sulfhydryl moieties. This covalent modification enhances ACE reactivity toward angiotensin II (ANG II)-NADPH oxidase-superoxide-dependent endothelial dysfunction. Mesenteric and coronary arteries isolated from normal rats were incubated for 3 days with or without exogenous methionine (Met, 0.1–0.3 mM), a precursor to Hcy. Incubation of arteries in Met-free media resulted in time-dependent decreases in vascular Hcy formation. By contrast, vessels incubated with Met produced Hcy in a dose-dependent manner. There was a notably greater de novo synthesis of Hcy from endothelial than from smooth muscle cells. Enhanced levels of Hcy production significantly impaired shear stress-induced dilation and release of nitric oxide, events that are associated with elevated production of vascular superoxide. Each of these processes was attenuated by ANG II type I receptor blocker or ACE and NADPH oxidase inhibitors. In addition, in vitro exposure of purified ACE to Hcy-S-S-Hcy/HCTL resulted in formation of homocysteinylated ACE and an enhanced ACE activity. The enhanced ACE activity was confirmed in isolated coronary and mesenteric arteries that had been exposed directly to Hcy-S-S-Hcy/HCTL or after Met incubation. In conclusion, vasculature-derived Hcy initiates endothelial dysfunction that, in part, may be mediated by ANG II-dependent activation of NADPH oxidase in association with homocysteinylation of ACE. PMID:25416191

  1. Relation of angiotensin-converting enzyme inhibitor treatment to insulin-like growth factor-1 serum levels in subjects >65 years of age (the InCHIANTI study).

    PubMed

    Maggio, Marcello; Ceda, Gian Paolo; Lauretani, Fulvio; Pahor, Marco; Bandinelli, Stefania; Najjar, Samer S; Ling, Shari M; Basaria, Shehzad; Ruggiero, Carmelinda; Valenti, Giorgio; Ferrucci, Luigi

    2006-05-15

    Observational studies have shown that the use of angiotensin-converting enzyme (ACE) inhibitors is associated with the maintenance of greater muscle strength and physical performance in older subjects. However, the mechanism that underlies these beneficial effects remains poorly understood. Because ACE inhibitors block the production of angiotensin II, which is a potent inhibitor of insulin-like growth factor-1 (IGF-1) production, it was hypothesized that treatment with ACE inhibitors is associated with higher levels of IGF-1. This hypothesis was tested in 745 subjects (417 women, 328 men) enrolled in the Invecchiare in Chianti study. Of these, 160 were receiving ACE inhibitors. The association between ACE inhibitor use and serum IGF-1 was tested by linear regression models. After adjusting for multiple potential confounders, serum levels of total IGF-1 were significantly higher in participants receiving ACE inhibitors (mean +/- SD 129.0 +/- 56.1 ng/ml) compared with the rest of the study population (mean +/- SD 116.5 +/- 54.8 ng/ml) (p <0.001). Participants with short (<3 years) and long (3 to 9 years) treatment durations had higher serum IGF-1 levels than participants who were not receiving ACE inhibitor treatment, but the difference was statistically significant only for the short-duration group (p <0.05). In conclusion, in older subjects, treatment with ACE inhibitors for <3 years is associated with significantly higher levels of IGF-1. This may be 1 of the mechanisms by which ACE inhibitors might slow the decreases in muscle strength and physical function that are often observed in older subjects.

  2. Targeted in-vivo computed tomography (CT) imaging of tissue ACE using concentrated lisinopril-capped gold nanoparticle solutions

    NASA Astrophysics Data System (ADS)

    Daniel, Marie-Christine; Aras, Omer; Smith, Mark F.; Nan, Anjan; Fleiter, Thorsten

    2010-04-01

    The development of cardiac and pulmonary fibrosis have been associated with overexpression of angiotensin-converting enzyme (ACE). Moreover, ACE inhibitors, such as lisinopril, have shown a benificial effect for patients diagnosed with heart failure or systemic hypertension. Thus targeted imaging of the ACE is of crucial importance for monitoring of the tissue ACE activity as well as the treatment efficacy in heart failure. In this respect, lisinopril-capped gold nanoparticles were prepared to provide a new type of probe for targeted molecular imaging of ACE by tuned K-edge computed tomography (CT) imaging. Concentrated solutions of these modified gold nanoparticles, with a diameter around 16 nm, showed high contrast in CT imaging. These new targeted imaging agents were thus used for in vivo imaging on rat models.

  3. Impact of clinically tested NEP/ACE inhibitors on tumor uptake of [(111)In-DOTA]MG11-first estimates for clinical translation.

    PubMed

    Kaloudi, Aikaterini; Nock, Berthold A; Lymperis, Emmanouil; Valkema, Roelf; Krenning, Eric P; de Jong, Marion; Maina, Theodosia

    2016-12-01

    We have recently shown that treatment of mice with the neutral endopeptidase (NEP) inhibitor phosphoramidon (PA) improves the bioavailability and tumor uptake of biodegradable radiopeptides. For the truncated gastrin radiotracer [(111)In-DOTA]MG11 ([(DOTA)DGlu(10)]gastrin(10-17)), this method led to impressively high tumor-to-kidney ratios. Translation of this concept in the clinic requires the use of certified NEP inhibitors, such as thiorphan (TO) and its orally administered prodrug racecadotril (Race). Besides NEP, angiotensin-converting enzyme (ACE) has also been implicated in the catabolism of gastrin analogs. In the present study, we first compared the effects induced by NEP inhibition (using PA, TO, or Race) and/or by ACE inhibition (using lisinopril, Lis) on the biodistribution profile of [(111)In-DOTA]MG11 in mice. In addition, we compared the efficacy of PA and TO at different administered doses to enhance tumor uptake. [(111)In-DOTA]MG11 was coinjected with (a) vehicle, (b) PA (300 μg), (c) TO (150 μg), (d) Lis (100 μg), (e) PA (300 μg) plus Lis (100 μg), or (f) 30-40 min after intraperitoneal (ip) injection of Race (3 mg) in SCID mice bearing AR42J xenografts. In addition, [(111)In-DOTA]MG11 was coinjected with vehicle, or with progressively increasing amounts of PA (3, 30, or 300 μg) or TO (1.5, 15, and 150 μg) in SCID mice bearing twin A431-CCK2R(+/-) tumors. In all above cases, biodistribution was conducted at 4 h postinjection (pi). During NEP inhibition, the uptake of [(111)In-DOTA]MG11 in the AR42J tumors impressively increased from 1.8 ± 1.0 % ID/g (controls) to 15.3 ± 4.7 % ID/g (PA) and 12.3 ± 3.6 % ID/g (TO), while with Race tumor values reached 6.8 ± 2.8 % ID/g. Conversely, Lis had no effect on tumor uptake and no additive effect when coinjected with PA. During the dose dependence study in mice, PA turned out to be more efficacious in enhancing tumor uptake of [(111)In-DOTA]MG11 in the CCK2R

  4. Race and Association of ACE/ARB Exposure with Outcome in Heart Failure

    PubMed Central

    El-Refai, Mostafa; Hrobowski, Tara; Peterson, Edward L.; Wells, Karen; Spertus, John A.; Williams, L. Keoki; Lanfear, David E.

    2015-01-01

    Purpose Angiotensin converting enzyme inhibitors (ACE) and angiotensin receptor blockers (ARB) have been established as a mainstay of heart failure (HF) treatment. Current data are limited and conflicting regarding the consistency of ACE/ARB benefit across race groups in HF. This study aims to clarify this point. Methods A retrospective study of insured patients with a documented ejection fraction of<50%, hospitalized for HF between January, 2000 and June, 2008. Pharmacy claims data was used to estimate ACE/ARB exposure over six-month rolling windows. The association between ACE/ARB exposure and all-cause hospitalization or death was assessed by proportional hazards regression, with adjustment for baseline covariates and beta blocker exposure. Further analyses were stratified by race, and included an ACE/ARB*Race interaction term. Results A total of 1,095 patients met inclusion criteria (619 African American individuals). Median follow up was 2.1 years. In adjusted models ACE/ARB exposure was associated with lower risk of death or hospitalization in both groups (African Americans HR 0.47, p<0.001; Caucasians HR 0.55, p<0.001). A formal test for interaction was consistent with similar effects in each group (p=0.861, β=0.04). Conclusion ACE/ARB exposure was equally associated with a protective effect in preventing death or re-hospitalization among HF patients with systolic dysfunction in both African American patients and Caucasians. PMID:24842464

  5. The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan

    PubMed Central

    Jhund, Pardeep S; McMurray, John J V

    2016-01-01

    Inhibition of neurohumoural pathways such as the renin angiotensin aldosterone and sympathetic nervous systems is central to the understanding and treatment of heart failure (HF). Conversely, until recently, potentially beneficial augmentation of neurohumoural systems such as the natriuretic peptides has had limited therapeutic success. Administration of synthetic natriuretic peptides has not improved outcomes in acute HF but modulation of the natriuretic system through inhibition of the enzyme that degrades natriuretic (and other vasoactive) peptides, neprilysin, has proven to be successful. After initial failures with neprilysin inhibition alone or dual neprilysin-angiotensin converting enzyme (ACE) inhibition, the Prospective comparison of angiotensin receptor neprilysin inhibitor (ARNI) with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) trial demonstrated that morbidity and mortality can be improved with the angiotensin receptor blocker neprilysin inhibitor sacubitril/valsartan (formerly LCZ696). In comparison to the ACE inhibitor enalapril, sacubitril/valsartan reduced the occurrence of the primary end point (cardiovascular death or hospitalisation for HF) by 20% with a 16% reduction in all-cause mortality. These findings suggest that sacubitril/valsartan should replace an ACE inhibitor or angiotensin receptor blocker as the foundation of treatment of symptomatic patients (NYHA II–IV) with HF and a reduced ejection fraction. This review will explore the background to neprilysin inhibition in HF, the results of the PARADIGM-HF trial and offer guidance on how to use sacubitril/valsartan in clinical practice. PMID:27207980

  6. Enhanced intestinal permeability and oral bioavailability of enalapril maleate upon complexation with the cationic polymethacrylate Eudragit E100.

    PubMed

    Ramírez-Rigo, María V; Olivera, María E; Rubio, Modesto; Manzo, Ruben H

    2014-05-13

    The low bioavailability of enalapril maleate associated to its instability in solid state motivated the development of a polyelectrolyte-drug complex between enalapril maleate and the cationic polymethacrylate Eudragit E100. The solid complexes were characterized by DSC-TG, FT-IR and X-ray diffraction. Their aqueous dispersions were evaluated for drug delivery in bicompartimental Franz cells and electrokinetic potentials. Stability in solid state was also evaluated using an HPLC-UV stability indicating method. Absorption of enalapril maleate was assessed thorough the rat everted gut sac model. In addition, urinary recovery after oral administration in rats was used as an indicator of systemic exposition. The solid materials are stable amorphous solids in which both moieties of enalapril maleate are ionically bonded to the polymer. Their aqueous dispersions exhibited controlled release over more than 7h in physiologic saline solution, being ionic exchange the fundamental mechanism that modified the extent and rate of drug release. Intestinal permeation of enalapril maleate was 1.7 times higher in the presence of the cationic polymer. This increase can be related with the capacity to adhere the mucosa due to the positive zeta potential of the complexes. As a consequence bioavailability was significantly improved (1.39 times) after oral administration of the complexes. In addition, no signs of chemical decomposition were observed after a 14months period. The results indicated that the products are new chemical entities that improve unfavorable properties of a useful drug. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Angiotensin-Converting Enzyme Inhibitors and the Risk of Congenital Malformations

    PubMed Central

    Bateman, Brian T; Patorno, Elisabetta; Desai, Rishi J; Seely, Ellen W; Mogun, Helen; Dejene, Sara Z; Fischer, Michael A; Friedman, Alexander M; Hernandez-Diaz, Sonia; Huybrechts, Krista F

    2016-01-01

    Objective To examine the association between first-trimester angiotensin-converting enzyme (ACE) inhibitor exposure and the risk for overall major congenital, cardiac, and central nervous system (CNS) malformations. Methods We used a cohort of completed pregnancies linked to liveborn infants derived from Medicaid claims from 2000 to 2010. We examined the risk of malformations associated with first-trimester exposure to an ACE inhibitor. Propensity score based methods were used to control for potential confounders including maternal demographics, medical conditions, exposure to other medications, and measures of health care utilization. Results The cohort included 1,333,624 pregnancies, of which 4,107 (0.31%) were exposed to ACE inhibitors during the first trimester. The prevalence of overall malformations in the ACE inhibitor–exposed was 5.9% versus 3.3% in the unexposed (unadjusted relative risk (RR), 1.82; 95% confidence interval (CI) 1.61 to 2.06), of cardiac malformations was 3.4% versus 1.2% (RR 2.95; 95% CI 2.50 to 3.47), and of CNS malformations was 0.27% versus 0.18% (RR 1.46; 95% CI 0.81 to 2.64). After restricting the cohort to pregnancies complicated by chronic hypertension (both exposed and unexposed) and accounting for other confounding factors, there was no significant increase in the risk for any of the outcomes assessed. Relative risks associated with first-trimester ACE inhibitor exposure were 0.89 (95% CI 0.75 to 1.06) for overall malformations, 0.95 (95% CI 0.75 to 1.21) for cardiac malformations, and 0.54 (95% CI 0.26 to 1.11) for CNS malformations. Conclusions After accounting for confounders, among women with hypertension, exposure to ACE inhibitors during the first trimester was not associated with an increased risk of major congenital malformations. PMID:27926639

  8. Optimized and Validated Spectrophotometric Methods for the Determination of Enalapril Maleate in Commercial Dosage Forms

    PubMed Central

    Rahman, Nafisur; Haque, Sk Manirul

    2008-01-01

    Four simple, rapid and sensitive spectrophotometric methods have been proposed for the determination of enalapril maleate in pharmaceutical formulations. The first method is based on the reaction of carboxylic acid group of enalapril maleate with a mixture of potassium iodate (KIO3) and iodide (KI) to form yellow colored product in aqueous medium at 25 ± 1°C. The reaction is followed spectrophotometrically by measuring the absorbance at 352 nm. The second, third and fourth methods are based on the charge transfer complexation reaction of the drug with p-chloranilic acid (pCA) in 1, 4-dioxan-methanol medium, 2, 3-dichloro 5, 6-dicyano 1, 4-benzoquinone (DDQ) in acetonitrile-1,4 dioxane medium and iodine in acetonitrile-dichloromethane medium. Under optimized experimental conditions, Beer’s law is obeyed in the concentration ranges of 2.5–50, 20–560, 5–75 and 10–200 μg mL−1, respectively. All the methods have been applied to the determination of enalapril maleate in pharmaceutical dosage forms. Results of analysis are validated statistically. PMID:19609388

  9. Relation of Angiotensin-Converting Enzyme Inhibitor Treatment to Insulin-Like Growth Factor-1 Serum Levels in Subjects >65 Years of Age (the InCHIANTI Study)

    PubMed Central

    Maggio, Marcello; Ceda, Gian Paolo; Lauretani, Fulvio; Pahor, Marco; Bandinelli, Stefania; Najjar, Samer S.; Ling, Shari M.; Basaria, Shehzad; Ruggiero, Carmelinda; Valenti, Giorgio; Ferrucci, Luigi

    2009-01-01

    Observational studies have shown that the use of angiotensin-converting enzyme (ACE) inhibitors is associated with the maintenance of greater muscle strength and physical performance in older subjects. However, the mechanism that underlies these beneficial effects remains poorly understood. Because ACE inhibitors block the production of angiotensin II, which is a potent inhibitor of insulin-like growth factor-1 (IGF-1) production, it was hypothesized that treatment with ACE inhibitors is associated with higher levels of IGF-1. This hypothesis was tested in 745 subjects (417 women, 328 men) enrolled in the Invecchiare in Chianti study. Of these, 160 were receiving ACE inhibitors. The association between ACE inhibitor use and serum IGF-1 was tested by linear regression models. After adjusting for multiple potential confounders, serum levels of total IGF-1 were significantly higher in participants receiving ACE inhibitors (mean ± SD 129.0 ± 56.1 ng/ml) compared with the rest of the study population (mean ± SD 116.5 ± 54.8 ng/ml) (p <0.001). Participants with short (<3 years) and long (3 to 9 years) treatment durations had higher serum IGF-1 levels than participants who were not receiving ACE inhibitor treatment, but the difference was statistically significant only for the short-duration group (p <0.05). In conclusion, in older subjects, treatment with ACE inhibitors for <3 years is associated with significantly higher levels of IGF-1. This may be 1 of the mechanisms by which ACE inhibitors might slow the decreases in muscle strength and physical function that are often observed in older subjects. PMID:16679098

  10. Sex dimorphism in ANGII-mediated crosstalk between ACE2 and ACE in diabetic nephropathy.

    PubMed

    Clotet-Freixas, Sergi; Soler, Maria Jose; Palau, Vanesa; Anguiano, Lidia; Gimeno, Javier; Konvalinka, Ana; Pascual, Julio; Riera, Marta

    2018-06-08

    Angiotensin-converting enzyme (ACE) and ACE2 play a critical role in the renin-angiotensin system (RAS) by altering angiotensin II (ANGII) levels, thus governing its deleterious effects. Both enzymes are altered by sex and diabetes, and play an important role in the development of diabetic nephropathy (DN). Importantly, previous evidence in diabetic and ACE2-deficient (ACE2KO) males suggest a sex-dependent crosstalk between renal ACE and ACE2. In the present work, we aimed to study the sex-specific susceptibility to diabetes and direct infusion of ANGII in kidney disease progression, with a special focus on its link to ACE2 and ACE. In our mouse model, ANGII promoted hypertension, albuminuria, reduced glomerular filtration, and glomerular histological alterations. ANGII adverse effects were accentuated by diabetes and ACE2 deficiency, in a sex-dependent fashion: ACE2 deficiency accentuated ANGII-induced hypertension, albuminuria, and glomerular hypertrophy in diabetic females, whereas in diabetic males exacerbated ANGII-mediated glomerular hypertrophy, mesangial expansion, and podocyte loss. At the molecular level, ANGII downregulated renal ACE gene and enzymatic activity levels, as well as renin gene expression in ACE2KO mice. Interestingly, male sex and diabetes accentuated this effect. Here we show sex dimorphism in the severity of diabetes- and ANGII-related renal lesions, and demonstrate that ACE2- and ACE-related compensatory mechanisms are sex-specific. Supporting our previous findings, the modulation and ANGII-mediated crosstalk between ACE2 and ACE in DN progression was more evident in males. This work increases the understanding of the sex-specific role of ACE2 and ACE in DN, reinforcing the necessity of more personalized treatments targeting RAS.

  11. ACE blood test

    MedlinePlus

    ... to help diagnose and monitor a disorder called sarcoidosis . People with sarcoidosis may have their ACE level tested regularly to ... normal ACE level may be a sign of sarcoidosis. ACE levels may rise or fall as sarcoidosis ...

  12. Cost-effectiveness of sacubitril/valsartan versus enalapril in patients with heart failure and reduced ejection fraction.

    PubMed

    Liang, Lin; Bin-Chia Wu, David; Aziz, Mohamed Ismail Abdul; Wong, Raymond; Sim, David; Leong, Kui Toh Gerard; Wei, Yong Quek; Tan, Doreen; Ng, Kwong

    2018-02-01

    Sacubitril/valsartan reduces cardiovascular death and hospitalizations for heart failure (HF). However, decision-makers need to determine whether its benefits are worth the additional costs, given the low-cost generic status of traditional standard of care. To evaluate the cost-effectiveness of sacubitril/valsartan compared to enalapril in patients with HF and reduced ejection fraction, from the Singapore healthcare payer perspective. A Markov model was developed to project clinical and economic outcomes of sacubitril/valsartan vs enalapril for 66-year-old patients with HF over 10 years. Key health states included New York Heart Association classes I-IV and deaths; patients in each state incurred a monthly risk of hospitalization for HF and cardiovascular death. Sacubitril/valsartan benefits were modeled by applying the hazard ratios (HRs) in PARADIGM-HF trial to baseline probabilities. Primary model outcomes were total and incremental costs and quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) for sacubitril/valsartan relative to enalapril Results: Compared to enalapril, sacubitril/valsartan was associated with an ICER of SGD 74,592 (USD 55,198) per QALY gained. A major driver of cost-effectiveness was the cardiovascular mortality benefit of sacubitril/valsartan. The uncertainty of this treatment benefit in the Asian sub-group was tested in sensitivity analyses using a HR of 1 as an upper limit, where the ICERs ranged from SGD 41,019 (USD 30,354) to SGD 1,447,103 (USD 1,070,856) per QALY gained. Probabilistic sensitivity analyses showed the probability of sacubitril/valsartan being cost-effective was below 1%, 12%, and 71% at SGD 20,000, SGD 50,000, and SGD 100,000 per QALY gained, respectively. At the current daily price sacubitril/valsartan may not represent good value for limited healthcare dollars compared to enalapril in reducing cardiovascular morbidity and mortality in HF in the Singapore healthcare setting. This study

  13. Effects of combined candesartan and ACE inhibitors on BNP, markers of inflammation and oxidative stress, and glucose regulation in patients with symptomatic heart failure.

    PubMed

    White, Michel; Lepage, Serge; Lavoie, Joel; De Denus, Simon; Leblanc, Marie-Hélène; Gossard, Denis; Whittom, Lucette; Racine, Normand; Ducharme, Anique; Dabouz, Farida; Rouleau, Jean-Lucien; Touyz, Rhian

    2007-03-01

    We assessed the effects of candesartan in addition to angiotensin-converting enzyme (ACE) inhibitors on N-terminal pro-type natriuretic peptide (Nt-proBNP), systemic markers of inflammation and oxidative stress as well as on glucose regulation in patients with heart failure (HF). Eighty patients with HF ages 62.5 +/- 8.4 years presenting mostly with New York Heart Association class II symptoms (class II = 57.5%, III = 41.3%), and mean left ventricular ejection fraction 27.1 +/- 7.3% were recruited. The patients were randomized to receive candesartan titrated to 32 mg 1 per day versus placebo in double-blind fashion for 6 months. Nt-proBNP, markers of inflammation and oxidative stress, glucose, insulin, and fasting insulin resistance index were analyzed. Candesartan decreased Nt-proBNP (median value = 12.4% versus -20.4%; [candesartan] P = .05), and high-sensitivity C-reactive protein (hsCRP) (+5.32% versus -20.3% [candesartan]; P = 0.046), without significantly influencing serum interleukin-6, interleukin-18, adhesion molecules, or markers of oxidative stress. Blood glucose decreased in patients treated with candesartan with a significantly greater effect in patients with higher blood glucose levels (P < .01 for interaction). The addition of candesartan to ACE inhibitor and beta-blocker decreases Nt-proBNP and hsCRP, but does not change the other markers of inflammation or oxidative stress in patients with heart failure. Dual angiotensin-II suppression also decreased blood glucose with a greater impact in patients with higher blood glucose level.

  14. Kinin B1 receptor blockade and ACE inhibition attenuate cardiac postinfarction remodeling and heart failure in rats

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

    Lin, Xinchun

    Introduction: The aim of the present study was to evaluate the effects of the novel kinin B1 receptor antagonist BI113823 on postinfarction cardiac remodeling and heart failure, and to determine whether B1 receptor blockade alters the cardiovascular effects of an angiotensin 1 converting enzyme (ACE) inhibitor in rats. Methods and results: Sprague Dawley rats were subjected to permanent occlusion of the left coronary artery. Cardiovascular function was determined at 6 weeks postinfarction. Treatment with either B1 receptor antagonist (BI113823) or an ACE inhibitor (lisinopril) alone or in combination significantly reduced the heart weight-to-body weight and lung weight-to-body weight ratios, andmore » improved postinfarction cardiac function as evidenced by greater cardiac output, the maximum rate of left ventricular pressure rise (± dP/dtmax), left ventricle ejection fraction, fractional shorting, better wall motion, and attenuation of elevated left ventricular end diastolic pressure (LVEDP). Furthermore, all three treatment groups exhibited significant reduction in cardiac interstitial fibrosis, collagen deposition, CD68 positive macrophages, neutrophils, and proinflammatory cytokine production (TNF-α and IL-1β), compared to vehicle controls. Conclusion: The present study shows that treatment with the novel kinin B1 receptor antagonist, BI113823, reduces postinfarction cardiac remodeling and heart failure, and does not influence the cardiovascular effects of the ACE inhibitor. - Highlights: • We examined the role of kinin B1 receptors in the development of heart failure. • Kinin B1 receptor blockade attenuates post-infarction cardiac remodeling. • Kinin B1 receptor blockade improves dysfunction, and prevented heart failure. • B1 receptor blockade does not affect the cardio-protection of an ACE inhibitor.« less

  15. Angiotensin-I converting enzyme (ACE): structure, biological roles, and molecular basis for chloride ion dependence.

    PubMed

    Masuyer, Geoffrey; Yates, Christopher J; Sturrock, Edward D; Acharya, K Ravi

    2014-10-01

    Somatic angiotensin-I converting enzyme (sACE) has an essential role in the regulation of blood pressure and electrolyte fluid homeostasis. It is a zinc protease that cleaves angiotensin-I (AngI), bradykinin, and a broad range of other signalling peptides. The enzyme activity is provided by two homologous domains (N- and C-), which display clear differences in substrate specificities and chloride activation. The presence of chloride ions in sACE and its unusual role in activity was identified early on in the characterisation of the enzyme. The molecular mechanisms of chloride activation have been investigated thoroughly through mutagenesis studies and shown to be substrate-dependent. Recent results from X-ray crystallography structural analysis have provided the basis for the intricate interactions between ACE, its substrate and chloride ions. Here we describe the role of chloride ions in human ACE and its physiological consequences. Insights into the chloride activation of the N- and C-domains could impact the design of improved domain-specific ACE inhibitors.

  16. Characterization of ACE and ACE2 Expression within Different Organs of the NOD Mouse

    PubMed Central

    Roca-Ho, Heleia; Riera, Marta; Palau, Vanesa; Pascual, Julio; Soler, Maria Jose

    2017-01-01

    Renin angiotensin system (RAS) is known to play a key role in several diseases such as diabetes, and renal and cardiovascular pathologies. Its blockade has been demonstrated to delay chronic kidney disease progression and cardiovascular damage in diabetic patients. In this sense, since local RAS has been described, the aim of this study is to characterize angiotensin converting enzyme (ACE) and ACE2 activities, as well as protein expression, in several tissues of the non-obese diabetic (NOD) mice model. After 21 or 40 days of diabetes onset, mouse serums and tissues were analyzed for ACE and ACE2 enzyme activities and protein expression. ACE and ACE2 enzyme activities were detected in different tissues. Their expressions vary depending on the studied tissue. Thus, whereas ACE activity was highly expressed in lungs, ACE2 activity was highly expressed in pancreas among the studied tissues. Interestingly, we also observed that diabetes up-regulates ACE mainly in serum, lung, heart, and liver, and ACE2 mainly in serum, liver, and pancreas. In conclusion, we found a marked serum and pulmonary alteration in ACE activity of diabetic mice, suggesting a common regulation. The increase of ACE2 activity within the circulation in diabetic mice may be ascribed to a compensatory mechanism of RAS. PMID:28273875

  17. Characterization of ACE and ACE2 Expression within Different Organs of the NOD Mouse.

    PubMed

    Roca-Ho, Heleia; Riera, Marta; Palau, Vanesa; Pascual, Julio; Soler, Maria Jose

    2017-03-05

    Renin angiotensin system (RAS) is known to play a key role in several diseases such as diabetes, and renal and cardiovascular pathologies. Its blockade has been demonstrated to delay chronic kidney disease progression and cardiovascular damage in diabetic patients. In this sense, since local RAS has been described, the aim of this study is to characterize angiotensin converting enzyme (ACE) and ACE2 activities, as well as protein expression, in several tissues of the non-obese diabetic (NOD) mice model. After 21 or 40 days of diabetes onset, mouse serums and tissues were analyzed for ACE and ACE2 enzyme activities and protein expression. ACE and ACE2 enzyme activities were detected in different tissues. Their expressions vary depending on the studied tissue. Thus, whereas ACE activity was highly expressed in lungs, ACE2 activity was highly expressed in pancreas among the studied tissues. Interestingly, we also observed that diabetes up-regulates ACE mainly in serum, lung, heart, and liver, and ACE2 mainly in serum, liver, and pancreas. In conclusion, we found a marked serum and pulmonary alteration in ACE activity of diabetic mice, suggesting a common regulation. The increase of ACE2 activity within the circulation in diabetic mice may be ascribed to a compensatory mechanism of RAS.

  18. Angiotensin-converting enzyme inhibition studies by natural leech inhibitors by capillary electrophoresis and competition assay.

    PubMed

    Deloffre, Laurence; Sautiere, Pierre-Eric; Huybrechts, Roger; Hens, Korneel; Vieau, Didier; Salzet, Michel

    2004-06-01

    A protocol to follow the processing of angiotensin I into angiotensin II by rabbit angiotensin-converting enzyme (ACE) and its inhibition by a novel natural antagonist, the leech osmoregulator factor (LORF) using capillary zonal electrophoresis is described. The experiment was carried out using the Beckman PACE system and steps were taken to determine (a) the migration profiles of angiotensin and its yielded peptides, (b) the minimal amount of angiotensin II detected, (c) the use of different electrolytes and (d) the concentration of inhibitor. We demonstrated that LORF (IPEPYVWD), a neuropeptide previously found in leech brain, is able to inhibit rabbit ACE with an IC(50) of 19.8 micro m. Interestingly, its cleavage product, IPEP exhibits an IC(50) of 11.5 micro m. A competition assay using p-benzoylglycylglycylglycine and insect ACE established that LORF and IPEP fragments are natural inhibitors for invertebrate ACE. Fifty-four percent of insect ACE activity is inhibited with 50 micro m IPEP and 35% inhibition with LORF (25 mm). Extending the peptide at both N- and C-terminus (GWEIPEPYVWDES) and the cleavage of IPEP in IP abolished the inhibitory activity of both peptides. Immunocytochemical data obtained with antisera raised against LORF and leech ACE showed a colocalization between the enzyme and its inhibitor in the same neurons. These results showed that capillary zonal electrophoresis is a useful technique for following enzymatic processes with small amounts of products and constitutes the first evidence of a natural ACE inhibitor in invertebrates.

  19. FIRE III ACE

    Atmospheric Science Data Center

    2013-01-23

    FIRE III ACE Data Sets The First International Satellite Cloud ... Regional Experiment (FIRE) - Arctic Cloud Experiment (ACE) was conducted April through July of 1998. It was held in conjunction with ... Heat Budget of the Arctic Ocean (SHEBA) Experiment. The FIRE-ACE focused on all aspects of Arctic cloud systems. The main facility was ...

  20. Isolation, Purification and Molecular Mechanism of a Peanut Protein-Derived ACE-Inhibitory Peptide

    PubMed Central

    Shi, Aimin; Liu, Hongzhi; Liu, Li; Hu, Hui; Wang, Qiang; Adhikari, Benu

    2014-01-01

    Although a number of bioactive peptides are capable of angiotensin I-converting enzyme (ACE) inhibitory effects, little is known regarding the mechanism of peanut peptides using molecular simulation. The aim of this study was to obtain ACE inhibiting peptide from peanut protein and provide insight on the molecular mechanism of its ACE inhibiting action. Peanut peptides having ACE inhibitory activity were isolated through enzymatic hydrolysis and ultrafiltration. Further chromatographic fractionation was conducted to isolate a more potent peanut peptide and its antihypertensive activity was analyzed through in vitro ACE inhibitory tests and in vivo animal experiments. MALDI-TOF/TOF-MS was used to identify its amino acid sequence. Mechanism of ACE inhibition of P8 was analyzed using molecular docking and molecular dynamics simulation. A peanut peptide (P8) having Lys-Leu-Tyr-Met-Arg-Pro amino acid sequence was obtained which had the highest ACE inhibiting activity of 85.77% (half maximal inhibitory concentration (IC50): 0.0052 mg/ml). This peanut peptide is a competitive inhibitor and show significant short term (12 h) and long term (28 days) antihypertensive activity. Dynamic tests illustrated that P8 can be successfully docked into the active pocket of ACE and can be combined with several amino acid residues. Hydrogen bond, electrostatic bond and Pi-bond were found to be the three main interaction contributing to the structural stability of ACE-peptide complex. In addition, zinc atom could form metal-carboxylic coordination bond with Tyr, Met residues of P8, resulting into its high ACE inhibiting activity. Our finding indicated that the peanut peptide (P8) having a Lys-Leu-Tyr-Met-Arg-Pro amino acid sequence can be a promising candidate for functional foods and prescription drug aimed at control of hypertension. PMID:25347076

  1. Combining neuroendocrine inhibitors in heart failure: reflections on safety and efficacy.

    PubMed

    Jneid, Hani; Moukarbel, George V; Dawson, Bart; Hajjar, Roger J; Francis, Gary S

    2007-12-01

    Neuroendocrine activation in heart failure has become the major target of pharmacotherapy for this growing epidemic. Agents targeting the renin-angiotensin-aldosterone and sympathetic nervous systems have shown cardiovascular and survival benefits in clinical trials. Beta-blockers and angiotensin-converting enzyme (ACE) inhibitors remain the mainstream initial therapy. The benefits of aldosterone antagonists have been demonstrated in advanced heart failure (spironolactone) and after myocardial infarction complicated by left ventricular dysfunction and heart failure (eplerenone). Emerging clinical evidence demonstrated that angiotensin receptor blockers may be a reasonable alternative to ACE inhibitors in patients with heart failure (candesartan) and following myocardial infarction complicated by heart failure or left ventricular dysfunction (valsartan). Angiotensin receptor blockers (candesartan) also provided incremental benefits when added to ACE inhibitors in chronic heart failure. Thus, combining neuroendocrine inhibitors in heart failure appears both biologically plausible and evidence-based. However, this approach raised concerns about side effects, such as hypotension, renal insufficiency, hyperkalemia, and others. Close follow-up and implementation of evidence-based medicine (ie, using agents and doses proven beneficial in clinical trials) should therefore be undertaken when combining neuroendocrine inhibitors.

  2. Prevention of salt induced hypertension and fibrosis by angiotensin converting enzyme inhibitors in Dahl S rats

    PubMed Central

    Liang, B; Leenen, F H H

    2007-01-01

    Background and purpose: In Dahl S rats, high salt increases activity of the tissue renin-angiotensin-aldosterone system (RAAS) in the CNS, heart and kidneys. Here, we assessed the effects of chronic angiotensin converting enzyme (ACE) inhibition on salt-induced hypertension and cardiovascular and renal hypertrophy and fibrosis, relative to the extent of ACE blockade. Experimental approach: From 4.5 weeks of age, Dahl S rats received either the lipophilic ACE inhibitor trandolapril (1 or 5 mg kg-1 day-1) or the hydrophilic ACE inhibitor lisinopril (10 or 50 mg kg-1 day-1) and a high salt diet was started 0.5 week later. Treatments ended at 9 weeks of age. Key results: High salt diet markedly increased blood pressure (BP), decreased plasma angiotensin II and increased ACE binding densities in brain, heart, aorta and kidneys. Trandolapril and lisinopril prevented 50% of the increase in BP in light and dark period of the day. After the last doses, trandolapril decreased ACE densities by ∼80% in brain nuclei and heart and lisinopril by ∼60% in the brain and by ∼70% in the heart. The two ACE inhibitors prevented right ventricular hypertrophy and attenuated left ventricular hypertrophy but did not affect renal hypertrophy caused by high salt. Both drugs prevented high salt-induced fibrosis in heart, kidney and aorta. Conclusion and implication: As the ACE inhibitors could completely prevent tissue fibrosis and partially prevent tissue hypertrophy and hypertension, the tissue RAAS may play a critical role in salt-induced fibrosis, but a lesser role in the hypertrophy. PMID:17906684

  3. Vitamin D receptor agonist VS-105 improves cardiac function in the presence of enalapril in 5/6 nephrectomized rats

    PubMed Central

    Chen, Yung-wu; Wessale, Jerry L.

    2014-01-01

    Vitamin D receptor (VDR) agonists (VDRAs) are commonly used to manage hyperparathyroidism secondary to chronic kidney disease (CKD). Patients with CKD experience extremely high risks of cardiovascular morbidity and mortality. Clinical observations show that VDRA therapy may be associated with cardio-renal protective and survival benefits in patients with CKD. The 5/6 nephrectomized (NX) Sprague-Dawley rat with established uremia exhibits elevated serum parathyroid hormone (PTH), hypertension, and abnormal cardiac function. Treatment of 5/6 NX rats with VS-105, a novel VDRA (0.05 and 0.5 μg/kg po by gavage), once daily for 8 wk in the presence or absence of enalapril (30 mg/kg po via drinking water) effectively suppressed serum PTH without raising serum calcium. VS-105 alone reduced systolic blood pressure (from 174 ± 6 to 145 ± 9 mmHg, P < 0.05) as effectively as enalapril (from 174 ± 6 to 144 ± 7 mmHg, P < 0.05). VS-105 improved cardiac functional parameters such as E/A ratio, ejection fraction, and fractional shortening with or without enalapril. Enalapril or VS-105 alone significantly reduced left ventricular hypertrophy (LVH); VS-105 plus enalapril did not further reduce LVH. VS-105 significantly reduced both cardiac and renal fibrosis. The lack of hypercalcemic toxicity of VS-105 is due to its lack of effects on stimulating intestinal calcium transport and inducing the expression of intestinal calcium transporter genes such as Calb3 and TRPV6. These studies demonstrate that VS-105 is a novel VDRA that may provide cardiovascular benefits via VDR activation. Clinical studies are required to confirm the cardiovascular benefits of VS-105 in CKD. PMID:25503724

  4. Sources of heterogeneity in case-control studies on associations between statins, ACE-inhibitors, and proton pump inhibitors and risk of pneumonia.

    PubMed

    de Groot, Mark C H; Klungel, Olaf H; Leufkens, Hubert G M; van Dijk, Liset; Grobbee, Diederick E; van de Garde, Ewoudt M W

    2014-10-01

    The heterogeneity in case-control studies on the associations between community-acquired pneumonia (CAP) and ACE-inhibitors (ACEi), statins, and proton pump inhibitors (PPI) hampers translation to clinical practice. Our objective is to explore sources of this heterogeneity by applying a common protocol in different data settings. We conducted ten case-control studies using data from five different health care databases. Databases varied on type of patients (hospitalised vs. GP), level of case validity, and mode of exposure ascertainment (prescription or dispensing based). Identified CAP patients and controls were matched on age, gender, and calendar year. Conditional logistic regression was used to calculate odds ratios (OR) for the associations between the drugs of interest and CAP. Associations were adjusted by a common set of potential confounders. Data of 38,742 cases and 118,019 controls were studied. Comparable patterns of variation between case-control studies were observed for ACEi, statins and PPI use and pneumonia risk with adjusted ORs varying from 1.04 to 1.49, 0.82 to 1.50 and 1.16 to 2.71, respectively. Overall, higher ORs were found for hospitalised CAP patients matched to population controls versus GP CAP patients matched to population controls. Prevalence of drug exposure was higher in dispensing data versus prescription data. We show that case-control selection and methods of exposure ascertainment induce bias that cannot be adjusted for and to a considerable extent explain the heterogeneity in results obtained in case-control studies on statins, ACEi and PPIs and CAP. The common protocol approach helps to better understand sources of variation in observational studies.

  5. [Conformational Fingerprinting Using Monoclonal Antibodies
    (on the Example of Angiotensin I-Converting Enzyme-ACE)].

    PubMed

    Danilov, S M

    2017-01-01

    During the past 30 years my laboratory has generated 40+ monoclonal antibodies (mAbs) directed to structural and conformational epitopes on human ACE as well as ACE from rats, mice and other species. These mAbs were successfully used for detection and quantification of ACE by ELISA, Western blotting, flow cytometry and immunohistochemistry. In all these applications mainly single mAbs were used. We hypothesized that we can obtain a completely new kind of information about ACE structure and function if we use the whole set of mAbs directed to different epitopes on the ACE molecule. When we finished epitope mapping of all mAbs to ACE (and especially, those recognizing conformational epitopes), we realized that we had obtained a new tool to study ACE. First, we demonstrated that binding of some mAbs is very sensitive to local conformational changes on the ACE surface-due to local denaturation, inactivation, ACE inhibitor or mAbs binding or due to diseases. Second, we were able to detect, localize and characterize several human ACE mutations. And, finally, we established a new concept - conformational fingerprinting of ACE using mAbs that in turn allowed us to obtain evidence for tissue specificity of ACE, which has promising scientific and diagnostic perspectives. The initial goal for the generation of mAbs to ACE 30 years ago was obtaining mAbs to organ-specific endothelial cells, which could be used for organ-specific drug delivery. Our systematic work on characterization of mAbs to numerous epitopes on ACE during these years has lead not only to the generation of the most effective mAbs for specific drug/gene delivery into the lung capillaries, but also to the establishment of the concept of conformational fingerprinting of ACE, which in turn gives a theoretical base for the generation of mAbs, specific for ACE from different organs. We believe that this concept could be applicable for any glycoprotein against which there is a set of mAbs to different epitopes.

  6. Potential role of eNOS in the therapeutic control of myocardial oxygen consumption by ACE inhibitors and amlodipine.

    PubMed

    Loke, K E; Messina, E J; Shesely, E G; Kaley, G; Hintze, T H

    2001-01-01

    Our aim was to investigate the potential therapeutic role of endothelial nitric oxide synthase (eNOS) in the modulation of cardiac O(2) consumption induced by the angiotensin converting enzyme (ACE) inhibitor ramiprilat and amlodipine. Three different groups of mice were used; wild type, wild type in the presence of N-nitro-L-arginine methyl ester (L-NAME, 10(-4) mol/l) or genetically altered mice lacking the eNOS gene (eNOS -/-). Myocardial O(2) consumption was measured using a Clark-type O(2) electrode in an air-tight stirred bath. Concentration-response curves to ramiprilat (RAM), amlodipine (AMLO), diltiazem (DIL), carbachol (CCL), substance P (SP) and S-nitroso-N-acetyl-penicillamine (SNAP) were performed. The rate of decrease in O(2) concentration was expressed as a percentage of the baseline. Baseline O(2) consumption was not different between the three groups of mice. In tissues from wild type mice, RAM (10(-5) mol/l), AMLO (10(-5) mol/l), DIL (10(-4) mol/l), CCL (10(-4) mol/l), SP (10(-7) mol/l) and SNAP (10(-4) mol/l) reduced myocardial O(2) consumption by -32+/-4, -27+/-10, -20+/-6, -25+/-2, -22+/-4 and -42+/-4%, respectively. The responses to RAM, AMLO, CCL and SP were absent in tissues taken from eNOS -/- mice (-7.1+/-4.3, -5.0+/-6.0, -5.2+/-5.1 and -0.4+/-0.2%, respectively). In addition, L-NAME significantly (P<0.05) inhibited the reduction in O(2) consumption induced by RAM (-9.8+/-4.4%), AMLO (-1.0+/-6.0%), CCL (-8.8+/-3.7%) and SP (-6.6+/-4.9%) in cardiac tissues from wild type mice. In contrast, NO-independent responses to the calcium channel antagonist, DIL, and responses to the NO donor, SNAP, were not affected in cardiac tissues taken from eNOS -/- (DIL: -20+/-4%; SNAP: -46+/-6%) or L-NAME-treated (DIL: -17+/-2%; SNAP: -33+/-5%) mice. These results suggest that endogenous endothelial NO synthase derived NO serves an important role in the regulation of myocardial O(2) consumption. This action may contribute to the therapeutic action of ACE

  7. Use of ACE-inhibitors and falls in patients with Parkinson's disease.

    PubMed

    Laudisio, Alice; Lo Monaco, Maria Rita; Silveri, Maria Caterina; Bentivoglio, Anna Rita; Vetrano, Davide L; Pisciotta, Maria Stella; Brandi, Vincenzo; Bernabei, Roberto; Zuccalà, Giuseppe

    2017-05-01

    Falls represent a major concern in patients with Parkinson's disease (PD); however, currently acknowledged treatments for PD are not effective in reducing the risk of falling. The aim was to assess the association of use of ACE-inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) with falls among patients with PD. We analysed data of 194 elderly with PD attending a geriatric Day Hospital. Self-reported history of falls that occurred over the last year, as well as use of drugs, including ACEIs and angiotensin II receptor blockers (ARBs) were recorded. The association of the occurrence of any falls with use of ACEIs, and ARBs was assessed by logistic regression analysis. The association between the number of falls and use of ACEIs, and ARBs was assessed according to Poisson regression. In logistic regression, after adjusting for potential confounders, use of ACEIs was associated with a reduced probability of falling over the last year (OR=0.15, 95% CI=0.03-0.81; P=0.028). This association did not vary with blood pressure levels (P for the interaction term=0.528). Also, using Poisson regression, use of ACEIs predicted a reduced number of falls among participants who fell (PR=0.31; 95% CI=0.10-0.94; P=0.039). No association was found between use of ARBs and falls. Our results indicate that use of ACEIs might be independently associated with reduced probability, and a reduced number of falls among patients with PD. Dedicated studies are needed to define the single agents and dosages that might most effectively reduce the risk of falling in clinical practice. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Effects of Prolonged Angiotensin-converting Enzyme Inhibitor Treatment on Amyloid β-Protein Metabolism in Mouse Models of Alzheimer Disease

    PubMed Central

    Hemming, Matthew L.; Selkoe, Dennis J.; Farris, Wesley

    2008-01-01

    Genetic and pathologic studies have associated angiotensin-converting enzyme (ACE) with Alzheimer disease. Previously, we and others have reported that ACE degrades in vitro the amyloid β-protein (Aβ), a putative upstream initiator of Alzheimer disease. These studies support the hypothesis that deficiency in ACE-mediated Aβ proteolysis could increase Alzheimer disease risk, and raise the question of whether ACE inhibitors, a commonly prescribed class of anti-hypertensive medications, can elevate Aβ levels in vivo. To test this hypothesis, we administered the ACE inhibitor captopril to two lines of APP transgenic mice harboring either low levels of Aβ or high levels of Aβ with associated plaque deposition. In both models, we show that captopril does not affect cerebral Aβ levels in either soluble or insoluble pools. Further, we find no change in plaque deposition or in peripheral Aβ levels. Data from these Alzheimer models suggest that captopril and similar ACE inhibitors do not cause Aβ accumulation in vivo. PMID:17321748

  9. Patients With Newly Diagnosed Hypertension Treated With the Renin Angiotensin Receptor Blocker Azilsartan Medoxomil vs Angiotensin-Converting Enzyme Inhibitors: The Prospective EARLY Registry.

    PubMed

    Schmieder, Roland E; Potthoff, Sebastian A; Bramlage, Peter; Baumgart, Peter; Mahfoud, Felix; Buhck, Hartmut; Ouarrak, Taoufik; Ehmen, Martina; Senges, Jochen; Gitt, Anselm K

    2015-12-01

    For patients with newly diagnosed hypertension, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are usually the first-line therapies. There is, however, no real-life data regarding the relative clinical effectiveness and tolerability of either drug class. The prospective registry, Treatment With Azilsartan Compared to ACE Inhibitors in Antihypertensive Therapy (EARLY), was conducted to evaluate the effectiveness of the ARB azilsartan medoxomil (AZL-M) vs ACE inhibitors in real-world patients. Of the 1153 patients with newly diagnosed hypertension who were included in the registry, 789 were prescribed AZL-M and 364 were prescribed an ACE inhibitor. After multivariate adjustment, AZL-M was found to provide superior blood pressure reduction and better target blood pressure (<140/90 mm Hg) achievement. The proportion of patients with adverse events was not statistically different between groups. The authors conclude that in newly diagnosed hypertensive patients, AZL-M provides superior blood pressure control with a similar safety profile compared with ACE inhibitors. © 2015 Wiley Periodicals, Inc.

  10. Diabetes and CVD risk during angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment in hypertension: a study of 15,990 patients.

    PubMed

    Hasvold, L P; Bodegård, J; Thuresson, M; Stålhammar, J; Hammar, N; Sundström, J; Russell, D; Kjeldsen, S E

    2014-11-01

    Differences in clinical effectiveness between angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) in the primary treatment of hypertension are unknown. The aim of this retrospective cohort study was to assess the prevention of type 2 diabetes and cardiovascular disease (CVD) in patients treated with ARBs or ACEis. Patients initiated on enalapril or candesartan treatment in 71 Swedish primary care centers between 1999 and 2007 were included. Medical records data were extracted and linked with nationwide hospital discharge and cause of death registers. The 11,725 patients initiated on enalapril and 4265 on candesartan had similar baseline characteristics. During a mean follow-up of 1.84 years, 36,482 patient-years, the risk of new diabetes onset was lower in the candesartan group (hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.69-0.96, P=0.01) compared with the enalapril group. No difference between the groups was observed in CVD risk (HR 0.99, 95% CI 0.87-1.13, P=0.86). More patients discontinued treatment in the enalapril group (38.1%) vs the candesartan group (27.2%). In a clinical setting, patients initiated on candesartan treatment had a lower risk of new-onset type 2 diabetes and lower rates of drug discontinuation compared with patients initiated on enalapril. No differences in CVD risk were observed.

  11. [Competition between branded and generic drugs in Austria: evidence from the market for ACE inhibitors].

    PubMed

    Mahlich, J C; Stadler, I

    2012-01-01

    The market for pharmaceuticals in Austria is highly regulated and manufacturers cannot set prices freely after patent expiration of the pioneer drug. We wanted to examine the effect of price regulation on price competition between branded and generic drugs in Austria. We examined the Austrian market for ACE inhibitors and describe competitive dynamics by means of 6 indices. We compared our results with those of Grabowski and Vernon who studied the US market. According to our analysis the competition amongst the producers of generic drugs is not great and consequently, compared to the USA, over time the prices for generic products decrease less and their market share increases less. This is due to a market-oriented system in the USA which waives most regulatory provisions. Our conclusions are in line with the findings by Danzon und Chao (2000) who argue that in a price-regulated market competitive dynamics are less strongly developed. From a politico-economic view, the necessity of price regulations in the pharmaceutical market seems questionable, as price regulations generally also cause other negative effects, such as distorted economic incentives for research and development investments. © Georg Thieme Verlag KG Stuttgart · New York.

  12. Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial.

    PubMed

    Vardeny, Orly; Claggett, Brian; Packer, Milton; Zile, Michael R; Rouleau, Jean; Swedberg, Karl; Teerlink, John R; Desai, Akshay S; Lefkowitz, Martin; Shi, Victor; McMurray, John J V; Solomon, Scott D

    2016-10-01

    In this analysis, we utilized data from PARADIGM-HF to test the hypothesis that participants who exhibited any dose reduction during the trial would have similar benefits from lower doses of sacubitril/valsartan relative to lower doses of enalapril. In a post-hoc analysis from PARADIGM-HF, we characterized patients by whether they received the maximal dose (200 mg sacubitril/valsartan or 10 mg enalapril twice daily) throughout the trial or had any dose reduction to lower doses (100/50/0 mg sacubitril/valsartan or 5/2.5/0 mg enalapril twice daily). The treatment effect for the primary outcome was estimated, stratified by dose level using time-updated Cox regression models. In the two treatment arms, participants with a dose reduction (43% of those randomized to enalapril and 42% of those randomized to sacubitril/valsartan) had similar baseline characteristics and similar baseline predictors of the need for dose reduction. In a time-updated analysis, any dose reduction was associated with a higher subsequent risk of the primary event [hazard ratio (HR) 2.5, 95% confidence interval (CI) 2.2-2.7]. However, the treatment benefit of sacubitril/valsartan over enalapril following a dose reduction was similar (HR 0.80, 95% CI 0.70-0.93, P < 0.001) to that observed in patients who had not experienced any dose reduction (HR 0.79, 95% CI 0.71-0.88, P < 0.001). In PARADIGM-HF, study medication dose reduction identified patients at higher risk of a major cardiovascular event. The magnitude of benefit for patients on lower doses of sacubitril/valsartan relative to those on lower doses of enalapril was similar to that of patients who remained on target doses of both drugs. © 2016 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

  13. Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress

    PubMed Central

    de Queiroz, Thyago Moreira; Sriramula, Srinivas; Feng, Yumei; Johnson, Tanya; Mungrue, Imran N.; Lazartigues, Eric

    2014-01-01

    Endoplasmic reticulum (ER) stress was previously reported to contribute to neurogenic hypertension while neuronal angiotensin-converting enzyme type 2 (ACE2) overexpression blunts the disease. To assess which brain regions are important for ACE2 beneficial effects and the contribution of ER stress to neurogenic hypertension, we first used transgenic mice harboring a floxed neuronal hACE2 transgene (SL) and tested the impact of hACE2 knockdown in the subfornical organ (SFO) and paraventricular nucleus (PVN) on deoxycorticosterone acetate (DOCA)-salt hypertension. SL and nontransgenic (NT) mice underwent DOCA-salt or sham treatment while infected with an adenoassociated virus (AAV) encoding Cre recombinase (AAV-Cre) or a control virus (AAV-green fluorescent protein) to the SFO or PVN. DOCA-salt-induced hypertension was reduced in SL mice, with hACE2 overexpression in the brain. This reduction was only partially blunted by knockdown of hACE2 in the SFO or PVN, suggesting that both regions are involved but not essential for ACE2 regulation of blood pressure (BP). DOCA-salt treatment did not increase the protein levels of ER stress and autophagy markers in NT mice, despite a significant increase in BP. In addition, these markers were not affected by hACE2 overexpression in the brain, despite a significant reduction of hypertension in SL mice. To further assess the role of ER stress in neurogenic hypertension, NT mice were infused intracerebroventricularlly with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, during DOCA-salt treatment. However, TUDCA infusion failed to blunt the development of hypertension in NT mice. Our data suggest that brain ER stress does not contribute to DOCA-salt hypertension and that ACE2 blunts neurogenic hypertension independently of ER stress. PMID:25519733

  14. Comparative Evaluation of Enalapril and Losartan in Pharmacological Correction of Experimental Osteoporosis and Fractures of Its Background

    PubMed Central

    Rajkumar, D. S. R.; Faitelson, A. V.; Gudyrev, O. S.; Dubrovin, G. M.; Pokrovski, M. V.; Ivanov, A. V.

    2013-01-01

    In the experiment on the white Wistar female rats (222 animals), the osteoprotective effect of enalapril and losartan was studied on experimental models of osteoporosis and osteoporotic fractures. It was revealed that in rats after ovariectomy, the endothelial dysfunction of microcirculation vessels of osteal tissue develops, resulting in occurrence of osteoporosis and delay of consolidation of experimental fractures. Enalapril and losartan prevented the reduction of microcirculation in bone, which was reflected in slowing the thinning of bone trabeculae and in preventing the occurrence of these microfractures, as well as increasing quality of experimental fractures healing. PMID:23401845

  15. Effects of long-term treatment with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: a systematic review.

    PubMed

    Teo, Koon K; Yusuf, Salim; Pfeffer, Marc; Torp-Pedersen, Christian; Kober, Lars; Hall, Alistair; Pogue, Janice; Latini, Roberto; Collins, Rory

    2002-10-05

    Results from a retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) study suggest that angiotensin-converting-enzyme (ACE) inhibitors may be less effective in patients receiving aspirin. We aimed to confirm or refute this theory. We used the Peto-Yusuf method to undertake a systematic overview of data for 22060 patients from six long-term randomised trials of ACE inhibitors to assess whether aspirin altered the effects of ACE inhibitor therapy on major clinical outcomes (composite of death, myocardial infarction, stroke, hospital admission for congestive heart failure, or revascularisation). Baseline characteristics, and prognosis in patients allocated placebo, differed strikingly between those who were and were not taking aspirin at baseline. Results from analyses of all trials, except SOLVD, did not suggest any significant differences between the proportional reductions in risk with ACE inhibitor therapy in the presence or absence of aspirin for the major clinical outcomes (p=0.15), or in any of its individual components, except myocardial infarction (interaction p=0.01). Overall, ACE inhibitor therapy significantly reduced the risk of the major clinical outcomes by 22% (p<0.0001), with clear reductions in risk both among those receiving aspirin at baseline (odds ratio 0.80, [99% CI 0.73-0.88]) and those who were not (0.71 [99% CI 0.62-0.81], interaction p=0.07). Considering the totality of evidence on all major vascular outcomes in these trials, there is only weak evidence of any reduction in the benefit of ACE-inhibitor therapy when added to aspirin. However, there is definite evidence of clinically important benefits with respect to these major clinical outcomes with ACE-inhibitor therapy, irrespective of whether concomitant aspirin is used.

  16. Angiotensin I-Converting Enzyme Inhibitor Activity on Egg Albumen Fermentation

    PubMed Central

    Nahariah, N.; Legowo, A. M.; Abustam, E.; Hintono, A.

    2015-01-01

    Lactobacillus plantarum is used for fermentation of fish products, meat and milk. However, the utilization of these bacteria in egg processing has not been done. This study was designed to evaluate the potential of fermented egg albumen as a functional food that is rich in angiotensin I-converting enzyme inhibitors activity (ACE-inhibitor activity) and is antihypertensive. A completely randomized design was used in this study with six durations of fermentation (6, 12, 18, 24, 30, and 36 h) as treatments. Six hundred eggs obtained from the same chicken farm were used in the experiment as sources of egg albumen. Bacteria L. plantarum FNCC 0027 used in the fermentation was isolated from cow’s milk. The parameters measured were the total bacteria, dissolved protein, pH, total acid and the activity of ACE-inhibitors. The results showed that there were significant effects of fermentation time on the parameters tested. Total bacteria increased significantly during fermentation for 6, 12, 18, and 24 h and then decreased with the increasing time of fermentation to 30 and 36 h. Soluble protein increased significantly during fermentation to 18 h and then subsequently decreased during of fermentation to 24, 30, and 36 h. The pH value decreased markedly during fermentation. The activities of ACE-inhibitor in fermented egg albumen increased during fermentation to 18 h and then decreased with the increasing of the duration of fermentation to 24, 30, and 36 h. The egg albumen which was fermented for 18 h resulted in a functional food that was rich in ACE-inhibitor activity. PMID:25715689

  17. Expression and evolutionary analyses of three acetylcholinesterase genes (Mi-ace-1, Mi-ace-2, Mi-ace-3) in the root-knot nematode Meloidogyne incognita.

    PubMed

    Cui, Ruqiang; Zhang, Lei; Chen, Yuyan; Huang, Wenkun; Fan, Chengming; Wu, Qingsong; Peng, Deliang; da Silva, Washington; Sun, Xiaotang

    2017-05-01

    The full cDNA of Mi-ace-3 encoding an acetylcholinesterase (AChE) in Meloidogyne incognita was cloned and characterized. Mi-ace-3 had an open reading frame of 1875 bp encoding 624 amino acid residues. Key residues essential to AChE structure and function were conserved. The deduced Mi-ACE-3 protein sequence had 72% amino acid similarity with that of Ditylenchus destructor Dd-AChE-3. Phylogenetic analyses using 41 AChEs from 24 species showed that Mi-ACE-3 formed a cluster with 4 other nematode AChEs. Our results revealed that the Mi-ace-3 cloned in this study, which is orthologous to Caenorhabditis elegans AChE, belongs to the nematode ACE-3/4 subgroup. There was a significant reduction in the number of galls in transgenic tobacco roots when Mi-ace-1, Mi-ace-2, and Mi-ace-3 were knocked down simultaneously, whereas little or no effect were observed when only one or two of these genes were knocked down. This is an indication that the functions of these three genes are redundant. Copyright © 2017. Published by Elsevier Inc.

  18. Effect of quercetin on plasma extravasation in rat CNS and dura mater by ACE and NEP inhibition.

    PubMed

    Cyrino, Luiz A R; Cardoso, Ronie C F; Hackl, Luciane P N; Nicolau, Mauro

    2002-09-01

    The effects of quercetin on substance P-induced plasma protein extravasation (PE) in the rat dura mater, cerebellum, olfactory bulb and cortex and also its modulation by endopeptidases, angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) were studied. PE was assessed by photometric measurement of extravasated Evans blue. Substance P (SP) and NEP or ACE inhibitors increased the PE in dura mater. Pretreatment with captopril or phosphoramidon potentiated PE induced by SP in the dura mater and cerebellum, respectively. Quercetin increased the PE in the dura mater, cerebellum and cortex. Further results suggested that the PE induced by SP in the dura mater was enhanced by pretreatment with quercetin, similar to that observed with selective peptidase inhibitors. Quercetin-stimulated extravasation in all tissues was abolished by NK-1 receptor blockade. These results suggest that quercetin increases PE in the dura mater and CNS tissues by inhibiting NEP and/or ACE, showing that the effect induced in the dura mater, cerebellum and cortex occurs through endogenous SP accumulation. Copyright 2002 John Wiley & Sons, Ltd.

  19. Anoctamin 6 Contributes to Cl− Secretion in Accessory Cholera Enterotoxin (Ace)-stimulated Diarrhea

    PubMed Central

    Aoun, Joydeep; Hayashi, Mikio; Sheikh, Irshad Ali; Sarkar, Paramita; Saha, Tultul; Ghosh, Priyanka; Bhowmick, Rajsekhar; Ghosh, Dipanjan; Chatterjee, Tanaya; Chakrabarti, Pinak; Chakrabarti, Manoj K.; Hoque, Kazi Mirajul

    2016-01-01

    Accessory cholera enterotoxin (Ace) of Vibrio cholerae has been shown to contribute to diarrhea. However, the signaling mechanism and specific type of Cl− channel activated by Ace are still unknown. We have shown here that the recombinant Ace protein induced ICl of apical plasma membrane, which was inhibited by classical CaCC blockers. Surprisingly, an Ace-elicited rise of current was neither affected by ANO1 (TMEM16A)-specific inhibitor T16A(inh)-AO1(TAO1) nor by the cystic fibrosis transmembrane conductance regulator (CFTR) blocker, CFTR inh-172. Ace stimulated whole-cell current in Caco-2 cells. However, the apical ICl was attenuated by knockdown of ANO6 (TMEM16F). This impaired phenotype was restored by re-expression of ANO6 in Caco-2 cells. Whole-cell patch clamp recordings of ANO currents in HEK293 cells transiently expressing mouse ANO1-mCherry or ANO6-GFP confirmed that Ace induced Cl− secretion. Application of Ace produced ANO6 but not the ANO1 currents. Ace was not able to induce a [Ca2+]i rise in Caco-2 cells, but cellular abundance of phosphatidylinositol 4,5-bisphosphate (PIP2) increased. Identification of the PIP2-binding motif at the N-terminal sequence among human and mouse ANO6 variants along with binding of PIP2 directly to ANO6 in HEK293 cells indicate likely PIP2 regulation of ANO6. The biophysical and pharmacological properties of Ace stimulated Cl− current along with intestinal fluid accumulation, and binding of PIP2 to the proximal KR motif of channel proteins, whose mutagenesis correlates with altered binding of PIP2, is comparable with ANO6 stimulation. We conclude that ANO6 is predominantly expressed in intestinal epithelia, where it contributes secretory diarrhea by Ace stimulation in a calcium-independent mechanism of RhoA-ROCK-PIP2 signaling. PMID:27799301

  20. Safety and Efficacy of the ACE-Inhibitor Ramipril in Alport Syndrome: The Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase III EARLY PRO-TECT Alport Trial in Pediatric Patients.

    PubMed

    Gross, Oliver; Friede, Tim; Hilgers, Reinhard; Görlitz, Anke; Gavénis, Karsten; Ahmed, Raees; Dürr, Ulrike

    2012-01-01

    Introduction. Retrospective observational data show that ACE-inhibitor therapy delays renal failure and improves life expectancy in Alport patients with proteinuria. The EARLY PRO-TECT Alport trial assesses the safety and efficacy of early therapy onset with ramipril in pediatric Alport patients. Methods and analysis. This double-blind, randomized, placebo-controlled, multicenter phase III trial (NCT01485978; EudraCT-number 2010-024300-10) includes 120 pediatric patients aged 24 months to 18 years with early stages of Alport syndrome (isolated hematuria or microalbuminuria). From March 2012, up to 80 patients will be randomized 1:1 to ramipril or placebo. In the event of disease progression during 3-year treatment, patients are unblinded and ramipril is initiated, if applicable. Approximately 40 patients receive open-label ramipril contributing to the safety database. Primary end-points are "time to progression to next disease level" and "incidence of adverse drug events before disease progression." Treatment effect estimates from the randomized comparison and Alport registry data will be combined in supportive analyses to maximize evidence. Conclusion. Without this trial, ACE inhibitors may become standard off-label treatment in Alport syndrome without satisfactory evidence base. The results are expected to be of relevance for therapy of all pediatric patients with kidney disease, and the trial protocol might serve as a model for other rare pediatric glomerulopathies.

  1. Effect of long-term treatment with urocortin on the activity of somatic angiotensin-converting enzyme in spontaneously hypertensive rats.

    PubMed

    Yang, Cui; Liu, Xiuxia; Li, Shengnan

    2010-02-01

    Our previous acute study on urocortin (Ucn) demonstrated that Ucn altered serum and tissue angiotensin-converting enzyme (ACE) activity in rats. Therefore, the present investigation was designed to explore the effect of long-term treatment with Ucn on somatic ACE (sACE) and other components of the renin-angiotensin system (RAS). After 8 weeks of intravenous administration of Ucn in spontaneously hypertensive rats (SHR), serum and tissue sACE, angiotensin II (Ang II), nitric oxide (NO), Ang-(1-7), and tissue chymase activities were evaluated. RT-PCR analysis was performed to determine the quantity of tissue sACE mRNA. Serum sACE activity was reduced by Ucn, although tissue sACE activity and tissue sACE mRNA were elevated. Chymase activity was observed to be enhanced by Ucn, whereas the ACE inhibitor enalapril failed to influence chymase. Serum and tissue Ang II activity was reduced, but NO and Ang-(1-7) production was increased in a concentration-dependent manner after Ucn treatment. Meanwhile, a significant decrease of the systolic blood pressure (SBP) was observed after the long-term Ucn administration, and there was a significant positive correlation (r2 = 0.6993) between serum ACE activity and SBP. Pretreatment with the corticotropin-releasing factor (CRF) blocker astressin and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway blocker PD98059 abolished these effects of Ucn. Our findings further support the hypothesis that the changes of sACE activity and the production of other RAS components may play roles in the vasodilatory property of Ucn via the activation of the ERK1/2 pathway.

  2. High-Throughput and Rapid Screening of Novel ACE Inhibitory Peptides from Sericin Source and Inhibition Mechanism by Using in Silico and in Vitro Prescriptions.

    PubMed

    Sun, Huaju; Chang, Qing; Liu, Long; Chai, Kungang; Lin, Guangyan; Huo, Qingling; Zhao, Zhenxia; Zhao, Zhongxing

    2017-11-22

    Several novel peptides with high ACE-I inhibitory activity were successfully screened from sericin hydrolysate (SH) by coupling in silico and in vitro approaches for the first time. Most screening processes for ACE-I inhibitory peptides were achieved through high-throughput in silico simulation followed by in vitro verification. QSAR model based predicted results indicated that the ACE-I inhibitory activity of these SH peptides and six chosen peptides exhibited moderate high ACE-I inhibitory activities (log IC 50 values: 1.63-2.34). Moreover, two tripeptides among the chosen six peptides were selected for ACE-I inhibition mechanism analysis which based on Lineweaver-Burk plots indicated that they behave as competitive ACE-I inhibitors. The C-terminal residues of short-chain peptides that contain more H-bond acceptor groups could easily form hydrogen bonds with ACE-I and have higher ACE-I inhibitory activity. Overall, sericin protein as a strong ACE-I inhibition source could be deemed a promising agent for antihypertension applications.

  3. New ACE-Inhibitory Peptides from Hemp Seed (Cannabis sativa L.) Proteins.

    PubMed

    Orio, Lara P; Boschin, Giovanna; Recca, Teresa; Morelli, Carlo F; Ragona, Laura; Francescato, Pierangelo; Arnoldi, Anna; Speranza, Giovanna

    2017-12-06

    A hemp seed protein isolate, prepared from defatted hemp seed meals by alkaline solubilization/acid precipitation, was subjected to extensive chemical hydrolysis under acid conditions (6 M HCl). The resulting hydrolysate was fractionated by semipreparative RP-HPLC, and the purified fractions were tested as inhibitors of angiotensin converting enzyme (ACE). Mono- and bidimensional NMR experiments and LC-MS analyses led to the identification of four potentially bioactive peptides, i.e. GVLY, IEE, LGV, and RVR. They were prepared by solid-phase synthesis, and tested for ACE-inhibitory activity. The IC 50 values were GVLY 16 ± 1.5 μM, LGV 145 ± 13 μM, and RVR 526 ± 33 μM, confirming that hemp seed may be a valuable source of hypotensive peptides.

  4. ACES--Today and Tomorrow.

    ERIC Educational Resources Information Center

    Hackney, Harold

    1991-01-01

    Presents text of Presidential Address delivered March 24, 1991, at the Association for Counselor Education and Supervision (ACES) luncheon, part of the American Association for Counseling and Development Convention held in Reno, Nevada. Comments on past, present, and future of ACES, particularly on future challenges and role of ACES. (ABL)

  5. Chromatographic behavior of zwitterionic enalapril-exploring the conditions for lipophilicity assessment.

    PubMed

    Gikas, Spyros; Tsopelas, Fotios; Giaginis, Costas; Dimitrakopoulos, John; Livadara, Theodora; Archontaki, Helen; Tsantili-Kakoulidou, Anna

    2008-11-04

    The chromatographic behavior of enalapril was investigated under different stationary and mobile phase conditions in an effort to unravel interferences in the underlying retention mechanism, which would affect its relation to octanol-water partitioning. Extrapolated retention factors, logk(w), were used as relevant chromatographic indices. The retention/pH profile was established and the peak split phenomenon, associated with cis/trans interconversion, was also monitored as a function of pH. The pH at maximum retention and minimum peak split occurrence was chosen for further investigation, so that the presence of zwitterionic structure was guaranteed and any effect of cis/trans interconversion could be ignored. Retention of zwitterionic enalapril was found to be very sensitive to mobile phase conditions in regard to organic modifier as well to the aqueous component. The use of morpholine-propanesulfonic acid (MOPS) as buffer and the presence of n-octanol as mobile phase additive proved critical factors for maximum suppression of secondary interactions. Nevertheless, the corresponding extrapolated retention factor was considerably larger than octanol-water logD value at the isoelectric point. However, logk(w) could be successfully converted to logD by means of a calibration equation established for ionized acidic compounds.

  6. Physicochemical stability of captopril and enalapril extemporaneous formulations for pediatric patients.

    PubMed

    Casas, Marta; Álvarez, José; Lucero, María Jesús

    2015-05-01

    The prevalence of hypertension among children has been increasing. Community and Hospital Pharmacists are often challenged to provide an oral liquid extemporaneous formulation for pediatric patients, because there are no appropriate dosage drugs to the specific needs of the child. The objective of this study is to choose and develop suitable pediatric extemporaneous formulations for captopril and enalapril maleate and to determine their physicochemical stability. A survey was carried out to evaluate the extent of dispensation of these drugs in Hospitals in Spain. Stability studies of formulations have been studied according to ICH normative at 5, 25 and 40 °C. Three samples from each temperature were withdrawn and assessed for stability on days 0, 15, 30, 50 and 90 using a high-performance liquid chromatography (HPLC) mass spectrometer assay. Rheological studies were carried out to ensure the maintenance of the physical characteristics of these non-Newtonian fluids. Captopril and enalapril maleate formulations used the pure drug and were stable during 50 days at 5 °C. We have developed easy antihypertensive oral liquid extemporaneous formulations for pediatric patients with physical and chemical stability higher than those provided by the majority of Hospitals.

  7. The role of enzyme and substrate concentration in the evaluation of serum angiotensin converting enzyme (ACE) inhibition by enalaprilat in vitro.

    PubMed

    Weisser, K; Schloos, J

    1991-10-09

    The relationship between serum angiotensin converting enzyme (ACE) activity and concentration of the ACE inhibitor enalaprilat was determined in vitro in the presence of different concentrations (S = 4-200 mM) of the substrate Hip-Gly-Gly. From Henderson plots, a competitive tight-binding relationship between enalaprilat and serum ACE was found yielding a value of approximately 5 nM for serum ACE concentration (Et) and an inhibition constant (Ki) for enalaprilat of approximately 0.1 nM. A plot of reaction velocity (Vi) versus total inhibitor concentration (It) exhibited a non-parallel shift of the inhibition curve to the right with increasing S. This was reflected by apparent Hill coefficients greater than 1 when the commonly used inhibitory sigmoid concentration-effect model (Emax model) was applied to the data. Slopes greater than 1 were obviously due to discrepancies between the free inhibitor concentration (If) present in the assay and It plotted on the abscissa and could, therefore, be indicators of tight-binding conditions. Thus, the sigmoid Emax model leads to an overestimation of Ki. Therefore, a modification of the inhibitory sigmoid Emax model (called "Emax tight model") was applied, which accounts for the depletion of If by binding, refers to It and allows estimation of the parameters Et and IC50f (free concentration of inhibitor when 50% inhibition occurs) using non-linear regression analysis. This model could describe the non-symmetrical shape of the inhibition curves and the results for Ki and Et correlated very well with those derived from the Henderson plots. The latter findings confirm that the degree of ACE inhibition measured in vitro is, in fact, dependent on the concentration of substrate and enzyme present in the assay. This is of importance not only for the correct evaluation of Ki but also for the interpretation of the time course of serum ACE inhibition measured ex vivo. The non-linear model has some advantages over the linear Henderson

  8. Non-disulfide-bridged peptides from Tityus serrulatus venom: Evidence for proline-free ACE-inhibitors.

    PubMed

    Pucca, Manuela Berto; Cerni, Felipe Augusto; Pinheiro-Junior, Ernesto Lopes; Zoccal, Karina Furlani; Bordon, Karla de Castro Figueiredo; Amorim, Fernanda Gobbi; Peigneur, Steve; Vriens, Kim; Thevissen, Karin; Cammue, Bruno Philippe Angelo; Júnior, Ronaldo Bragança Martins; Arruda, Eurico; Faccioli, Lúcia Helena; Tytgat, Jan; Arantes, Eliane Candiani

    2016-08-01

    The present study purifies two T. serrulatus non-disulfide-bridged peptides (NDBPs), named venom peptides 7.2 (RLRSKG) and 8 (KIWRS) and details their synthesis and biological activity, comparing to the synthetic venom peptide 7.1 (RLRSKGKK), previously identified. The synthetic replicate peptides were subjected to a range of biological assays: hemolytic, antifungal, antiviral, electrophysiological, immunological and angiotensin-converting enzyme (ACE) inhibition activities. All venom peptides neither showed to be cytolytic nor demonstrated significant antifungal or antiviral activities. Interestingly, peptides were able to modulate macrophages' responses, increasing IL-6 production. The three venom peptides also demonstrated potential to inhibit ACE in the following order: 7.2>7.1>8. The ACE inhibition activity was unexpected, since peptides that display this function are usually proline-rich peptides. In attempt to understand the origin of such small peptides, we discovered that the isolated peptides 7.2 and 8 are fragments of the same molecule, named Pape peptide precursor. Furthermore, the study discusses that Pape fragments could be originated from a post-splitting mechanism resulting from metalloserrulases and other proteinases cleavage, which can be seen as a clever mechanism used by the scorpion to enlarge its repertoire of venom components. Scorpion venom remains as an interesting source of bioactive proteins and this study advances our knowledge about three NDBPs and their biological activities. Copyright © 2016. Published by Elsevier Inc.

  9. Angiotensin-converting enzyme activity in Cavalier King Charles Spaniels with an ACE gene polymorphism and myxomatous mitral valve disease.

    PubMed

    Meurs, Kathryn M; Olsen, Lisbeth H; Reimann, Maria J; Keene, Bruce W; Atkins, Clarke E; Adin, Darcy; Aona, Brent; Condit, Julia; DeFrancesco, Teresa; Reina-Doreste, Yamir; Stern, Joshua A; Tou, Sandra; Ward, Jessica; Woodruff, Kathleen

    2018-02-01

    Myxomatous mitral valve disease (MMVD) is the most common heart disease in the dog. It is particularly common in the Cavalier King Charles Spaniel (CKCS) breed and affected dogs are frequently managed with angiotensin-converting enzyme inhibitors (ACE-I). We have previously identified a canine ACE gene polymorphism associated with a decrease in angiotensin-converting enzyme (ACE) activity. The aim of this study was to evaluate for the prevalence of the ACE polymorphism in CKCS with mitral valve disease and to determine whether the presence of the polymorphism is associated with alterations in ACE activity at different stages of cardiac disease. Seventy-three dogs with a diagnosis of mitral valve disease were evaluated and a blood sample was drawn for ACE polymorphism genotyping and ACE activity measurement. Forty-three dogs were homozygous for the ACE polymorphism; five were heterozygous and 25 were homozygous wild type. The mean age and the median severity of disease were not different for dogs with the polymorphism and dogs with the wild-type sequence. The median baseline ACE activity was significantly lower for the ACE polymorphism (27.0 U/l) than the wild-type sequence dogs (31.0 U/l) (P=0.02). Dogs with more severe disease and the ACE polymorphism had significantly lower levels of ACE activity than dogs with the wild-type sequence (P=0.03). The CKCS appears to have a high prevalence of the ACE variant. Dogs with the ACE variant had lower levels of ACE activity even in more advanced mitral valve disease than dogs without the variant. The clinical significance of this finding and its impact on the need for ACE-I in dogs with the polymorphism and heart disease deserves further study.

  10. Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis

    PubMed Central

    Caldeira, Daniel; Alarcão, Joana; Vaz-Carneiro, António

    2012-01-01

    Objective To systematically review longitudinal studies evaluating use of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and risk of pneumonia. Design Systematic review and meta-analysis. Data sources Medline through PubMed, Web of Science with conference proceedings (inception to June 2011), and US Food and Drug Administration website (June 2011). Systematic reviews and references of retrieved articles were also searched. Study selection Two reviewers independently selected randomised controlled trials and cohort and case-control studies evaluating the use of ACE inhibitors or ARBs and risk of pneumonia and retrieved characteristics of the studies and data estimates. Data synthesis The primary outcome was incidence of pneumonia and the secondary outcome was pneumonia related mortality. Subgroup analyses were carried according to baseline morbidities (stroke, heart failure, and chronic kidney disease) and patients’ characteristics (Asian and non-Asian). Pooled estimates of odds ratios and 95% confidence intervals were derived by random effects meta-analysis. Adjusted frequentist indirect comparisons between ACE inhibitors and ARBs were estimated and combined with direct evidence whenever available. Heterogeneity was assessed using the I2 test. Results 37 eligible studies were included. ACE inhibitors were associated with a significantly reduced risk of pneumonia compared with control treatment (19 studies: odds ratio 0.66, 95% confidence interval 0.55 to 0.80; I2=79%) and ARBs (combined direct and indirect odds ratio estimate 0.69, 0.56 to 0.85). In patients with stroke, the risk of pneumonia was also lower in those treated with ACE inhibitors compared with control treatment (odds ratio 0.46, 0.34 to 0.62) and ARBs (0.42, 0.22 to 0.80). ACE inhibitors were associated with a significantly reduced risk of pneumonia among Asian patients (0.43, 0.34 to 0.54) compared with non-Asian patients (0.82, 0.67 to 1.00; P<0

  11. Molecular recognition and regulation of human angiotensin-I converting enzyme (ACE) activity by natural inhibitory peptides

    PubMed Central

    Masuyer, Geoffrey; Schwager, Sylva L. U.; Sturrock, Edward D.; Isaac, R. Elwyn; Acharya, K. Ravi

    2012-01-01

    Angiotensin-I converting enzyme (ACE), a two-domain dipeptidylcarboxypeptidase, is a key regulator of blood pressure as a result of its critical role in the renin-angiotensin-aldosterone and kallikrein-kinin systems. Hence it is an important drug target in the treatment of cardiovascular diseases. ACE is primarily known for its ability to cleave angiotensin I (Ang I) to the vasoactive octapeptide angiotensin II (Ang II), but is also able to cleave a number of other substrates including the vasodilator bradykinin and N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), a physiological modulator of hematopoiesis. For the first time we provide a detailed biochemical and structural basis for the domain selectivity of the natural peptide inhibitors of ACE, bradykinin potentiating peptide b and Ang II. Moreover, Ang II showed selective competitive inhibition of the carboxy-terminal domain of human somatic ACE providing evidence for a regulatory role in the human renin-angiotensin system (RAS). PMID:23056909

  12. Effects of angiotensin-converting enzyme inhibitor versus valsartan on cellular signaling events in heart transplant.

    PubMed

    White, Michel; Ross, Heather; Levesque, Sylvie; Whittom, Lucette; Pelletier, Guy B; Racine, Normand; Meloche, Sylvain; Voisin, Laure

    2009-05-01

    Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) provide similar biologic effects in model systems and similar clinical impacts in humans. The changes in the cardiac angiotensin system signaling pathways in the human heart in response to ACE inhibitors versus ARBs have been incompletely studied. To investigate the effects of ACE inhibitors versus valsartan on the angiotensin II signal transduction pathways in the transplanted human heart. Twenty-seven stable cardiac transplant recipients were randomized to remain on ACE inhibitor therapy (n = 8) or to receive valsartan (n = 19). Two additional endomyocardial biopsy samples were obtained at baseline and after 9 months of therapy. The expression of cardiac angiotensin type I and II receptors and atrial natriuretic factor (ANF) was measured by quantitative polymerase chain reaction. The expression and phosphorylation levels of selected signal transduction pathways were analyzed by immunoblotting. The mean dose of valsartan was 114 +/- 41 mg/day. The use of valsartan resulted in a similar impact on blood pressure and biochemistry profile. There were no significant changes in the expression of angiotensin type I and II receptors and ANF with valsartan. Similarly, no significant changes in the expression and phosphorylation of Jun N-terminal kinase, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinases or AKT, and mammalian target of rapamycin was observed in the valsartan-treated group. Valsartan use is associated with similar clinical and molecular cardiac effects as ACE inhibitor therapy in stable long-term cardiac transplant recipients.

  13. Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE

    PubMed Central

    Rella, Monika; Elliot, Joann L; Revett, Timothy J; Lanfear, Jerry; Phelan, Anne; Jackson, Richard M; Turner, Anthony J; Hooper, Nigel M

    2007-01-01

    Background Mammalian angiotensin converting enzyme (ACE) plays a key role in blood pressure regulation. Although multiple ACE-like proteins exist in non-mammalian organisms, to date only one other ACE homologue, ACE2, has been identified in mammals. Results Here we report the identification and characterisation of the gene encoding a third homologue of ACE, termed ACE3, in several mammalian genomes. The ACE3 gene is located on the same chromosome downstream of the ACE gene. Multiple sequence alignment and molecular modelling have been employed to characterise the predicted ACE3 protein. In mouse, rat, cow and dog, the predicted protein has mutations in some of the critical residues involved in catalysis, including the catalytic Glu in the HEXXH zinc binding motif which is Gln, and ESTs or reverse-transcription PCR indicate that the gene is expressed. In humans, the predicted ACE3 protein has an intact HEXXH motif, but there are other deletions and insertions in the gene and no ESTs have been identified. Conclusion In the genomes of several mammalian species there is a gene that encodes a novel, single domain ACE-like protein, ACE3. In mouse, rat, cow and dog ACE3, the catalytic Glu is replaced by Gln in the putative zinc binding motif, indicating that in these species ACE3 would lack catalytic activity as a zinc metalloprotease. In humans, no evidence was found that the ACE3 gene is expressed and the presence of deletions and insertions in the sequence indicate that ACE3 is a pseudogene. PMID:17597519

  14. The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan.

    PubMed

    Jhund, Pardeep S; McMurray, John J V

    2016-09-01

    Inhibition of neurohumoural pathways such as the renin angiotensin aldosterone and sympathetic nervous systems is central to the understanding and treatment of heart failure (HF). Conversely, until recently, potentially beneficial augmentation of neurohumoural systems such as the natriuretic peptides has had limited therapeutic success. Administration of synthetic natriuretic peptides has not improved outcomes in acute HF but modulation of the natriuretic system through inhibition of the enzyme that degrades natriuretic (and other vasoactive) peptides, neprilysin, has proven to be successful. After initial failures with neprilysin inhibition alone or dual neprilysin-angiotensin converting enzyme (ACE) inhibition, the Prospective comparison of angiotensin receptor neprilysin inhibitor (ARNI) with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) trial demonstrated that morbidity and mortality can be improved with the angiotensin receptor blocker neprilysin inhibitor sacubitril/valsartan (formerly LCZ696). In comparison to the ACE inhibitor enalapril, sacubitril/valsartan reduced the occurrence of the primary end point (cardiovascular death or hospitalisation for HF) by 20% with a 16% reduction in all-cause mortality. These findings suggest that sacubitril/valsartan should replace an ACE inhibitor or angiotensin receptor blocker as the foundation of treatment of symptomatic patients (NYHA II-IV) with HF and a reduced ejection fraction. This review will explore the background to neprilysin inhibition in HF, the results of the PARADIGM-HF trial and offer guidance on how to use sacubitril/valsartan in clinical practice. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  15. Impact of the PPAR-γ2 Pro12Ala Polymorphism and ACE Inhibitor Therapy on New-Onset Microalbuminuria in Type 2 Diabetes: Evidence From BENEDICT

    PubMed Central

    De Cosmo, Salvatore; Motterlini, Nicola; Prudente, Sabrina; Pellegrini, Fabio; Trevisan, Roberto; Bossi, Antonio; Remuzzi, Giuseppe; Trischitta, Vincenzo; Ruggenenti, Piero

    2009-01-01

    OBJECTIVE Cross-sectional studies found less microalbuminuria in type 2 diabetic patients with the Ala12 allele of the peroxisome proliferator–activated receptor-γ2 (PPAR-γ2) Pro12Ala polymorphism. We prospectively evaluated the association between Pro12Ala polymorphism (rs1801282) and new-onset microalbuminuria. RESEARCH DESIGN AND METHODS Pro12Ala polymorphism was genotyped by TaqMan-based assay in genomic DNA of 1,119 consenting patients from BErgamo NEphrologic DIabetic Complications Trial (BENEDICT)—a prospective, randomized trial evaluating ACE inhibition effect on new-onset microalbuminuria (albuminuria 20–200 μg/min in at least two of three consecutive overnight urine collections in two consecutive visits) in hypertensive type 2 diabetes with albuminuria <20 μg/min at inclusion. RESULTS Baseline characteristics of Ala (Ala/Ala or Ala/Pro) carriers and Pro/Pro homozygotes were similar, with a nonsignificant trend to lower albuminuria (P = 0.1107) in the 177 Ala carriers. Over a median (interquartile range) of 44.0 (17.1–51.9) months, 7 (4%) Ala carriers and 86 (9.1%) Pro/Pro homozygotes developed microalbuminuria (hazard ratio [HR] 0.45 [95% CI 0.21–0.97]; P = 0.042). Final albuminuria was significantly lower in Ala carriers than Pro/Pro homozygotes (7.3 ± 9.1 vs. 10.5 ± 24.9 μg/min, respectively), even after adjustment for baseline albuminuria (P = 0.048). Baseline and follow-up blood pressure and metabolic control were similar in both groups. Incidence of microalbuminuria was significantly decreased by ACE versus non-ACE inhibitor therapy in Pro/Pro homozygotes (6.3 vs. 11.9%, respectively, HR 0.46 [0.29–0.72]; P < 0.001). CONCLUSIONS In type 2 diabetes, the Ala allele protects from worsening albuminuria and new-onset microalbuminuria, and ACE inhibition blunts the excess risk of microalbuminuria associated with the Pro/Pro genotype. Evaluating Pro12Ala polymorphism may help identifying patients at risk who may benefit the most from

  16. An Angiotensin I-Converting Enzyme Mutation (Y465D) Causes a Dramatic Increase in Blood ACE via Accelerated ACE Shedding

    PubMed Central

    Gordon, Kerry; Nesterovitch, Andrew B.; Lünsdorf, Heinrich; Chen, Zhenlong; Castellon, Maricela; Popova, Isolda A.; Kalinin, Sergey; Mendonca, Emma; Petukhov, Pavel A.; Schwartz, David E.

    2011-01-01

    Background Angiotensin I-converting enzyme (ACE) metabolizes a range of peptidic substrates and plays a key role in blood pressure regulation and vascular remodeling. Thus, elevated ACE levels may be associated with an increased risk for different cardiovascular or respiratory diseases. Previously, a striking familial elevation in blood ACE was explained by mutations in the ACE juxtamembrane region that enhanced the cleavage-secretion process. Recently, we found a family whose affected members had a 6-fold increase in blood ACE and a Tyr465Asp (Y465D) substitution, distal to the stalk region, in the N domain of ACE. Methodology/Principal Findings HEK and CHO cells expressing mutant (Tyr465Asp) ACE demonstrate a 3- and 8-fold increase, respectively, in the rate of ACE shedding compared to wild-type ACE. Conformational fingerprinting of mutant ACE demonstrated dramatic changes in ACE conformation in several different epitopes of ACE. Cell ELISA carried out on CHO-ACE cells also demonstrated significant changes in local ACE conformation, particularly proximal to the stalk region. However, the cleavage site of the mutant ACE - between Arg1203 and Ser1204 - was the same as that of WT ACE. The Y465D substitution is localized in the interface of the N-domain dimer (from the crystal structure) and abolishes a hydrogen bond between Tyr465 in one monomer and Asp462 in another. Conclusions/Significance The Y465D substitution results in dramatic increase in the rate of ACE shedding and is associated with significant local conformational changes in ACE. These changes could result in increased ACE dimerization and accessibility of the stalk region or the entire sACE, thus increasing the rate of cleavage by the putative ACE secretase (sheddase). PMID:21998728

  17. Clinical pharmacokinetics and efficacy of renin inhibitors.

    PubMed

    Rongen, G A; Lenders, J W; Smits, P; Thien, T

    1995-07-01

    The successful introduction of angiotensin converting enzyme (ACE) inhibitors in the treatment of patients with essential hypertension or heart failure has increased interest in the (patho)physiological role of the renin-angiotensin system (RAS). ACE is not only involved in the formation of angiotensin II from angiotensin I, but also inactivates vasoactive substances such as bradykinin and substance P. Accumulation of these substances during treatment with ACE inhibitors may contribute to both their therapeutic action and certain adverse effects associated with their use, such as cough and angioneurotic oedema. Renin inhibitors offer an alternative approach to inhibit the RAS. The major advantage of these, still experimental, drugs is their high specificity for the RAS since angiotensinogen is the only known substrate of renin. The currently available renin inhibitors are pseudopeptides that are rapidly taken up by the liver and excreted in the bile. Consequently, these drugs are subjected to a considerable first pass effect which limits their oral bioavailability. Additionally, plasma elimination half-life times are short and the duration of action is limited. Despite these shortcomings, single oral or intravenous administration results in a 80 to 90% inhibition of plasma renin activity and a slight reduction in blood pressure in patients with hypertension. The extent of blood pressure reduction is dependent on the patient's salt balance. After 1 week of oral treatment with the renin inhibitor remikiren, the antihypertensive effect was reduced in salt-repleted hypertensive patients. Subsequent intravenous administration of the drug did not further affect blood pressure, indicating that it was not the first pass effect that was limiting the efficacy of remikiren.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. High Incidence of ACE/PAI-1 in Association to a Spectrum of Other Polymorphic Cardiovascular Genes Involving PBMCs Proinflammatory Cytokines in Hypertensive Hypercholesterolemic Patients: Reversibility with a Combination of ACE Inhibitor and Statin

    PubMed Central

    Mouawad, Charbel; Haddad, Katia; Hamoui, Samar; Azar, Albert; Fajloun, Ziad; Makdissy, Nehman

    2015-01-01

    Cardiovascular diseases (CVDs) are significantly high in the Lebanese population with the two most predominant forms being atherosclerosis and venous thrombosis. The purpose of our study was to assess the association of a spectrum of CVD related genes and combined state of hypertension hypercholesterolemia (HH) in unrelated Lebanese. Twelve polymorphisms were studied by multiplex PCR and reverse hybridization of DNA from 171 healthy individuals and 144 HH subjects. Two genes were significantly associated with HH: ACE (OR: 9.20, P<0.0001) and PAI-1 (OR: 2.29, P = 0.007), respectively with the occurrence of the risky alleles “Del” and “4G”. The frequencies of the Del and 4G alleles were found to be 0.98 and 0.90 in the HH group versus 0.84 and 0.79 in the healthy group, respectively. Serum ACE activity and PAI-I increased significantly with Del/Del and 4G/5G genotypes. The co-expression of Del/4G(+/+) was detected in 113 out of 171 (66.0%) controls and 125 out of 144 (86.8%) HH subjects. Del/4G(-/-) was detected in only 6 (3.5%) controls and undetected in the HH group. Three venous thrombosis related genes [FV(Leiden), MTHFR(A1298C) and FXIII(V34L)] were significantly related to the prominence of the co-expression of Del/4G(+/+). A range of 2 to 8 combined polymorphisms co-expressed per subject where 5 mutations were the most detected. In Del/4G(+/+) subjects, peripheral blood mononuclear cells (PBMCs) produced significant elevated levels of IFN-γ and TNF-α contrary to IL-10, and no variations occurred for IL-4. ACE inhibitor (ramipril) in combination with statin (atorvastatin) and not alone reversed significantly the situation. This first report from Lebanon sheds light on an additional genetic predisposition of a complex spectrum of genes involved in CVD and suggests that the most requested gene FVL by physicians may not be sufficient to diagnose eventual future problems that can occur in the cardiovascular system. Subjects expressing the double mutations

  19. High Incidence of ACE/PAI-1 in Association to a Spectrum of Other Polymorphic Cardiovascular Genes Involving PBMCs Proinflammatory Cytokines in Hypertensive Hypercholesterolemic Patients: Reversibility with a Combination of ACE Inhibitor and Statin.

    PubMed

    AlBacha, Jeanne d'Arc; Khoury, Mira; Mouawad, Charbel; Haddad, Katia; Hamoui, Samar; Azar, Albert; Fajloun, Ziad; Makdissy, Nehman

    2015-01-01

    Cardiovascular diseases (CVDs) are significantly high in the Lebanese population with the two most predominant forms being atherosclerosis and venous thrombosis. The purpose of our study was to assess the association of a spectrum of CVD related genes and combined state of hypertension hypercholesterolemia (HH) in unrelated Lebanese. Twelve polymorphisms were studied by multiplex PCR and reverse hybridization of DNA from 171 healthy individuals and 144 HH subjects. Two genes were significantly associated with HH: ACE (OR: 9.20, P<0.0001) and PAI-1 (OR: 2.29, P = 0.007), respectively with the occurrence of the risky alleles "Del" and "4G". The frequencies of the Del and 4G alleles were found to be 0.98 and 0.90 in the HH group versus 0.84 and 0.79 in the healthy group, respectively. Serum ACE activity and PAI-I increased significantly with Del/Del and 4G/5G genotypes. The co-expression of Del/4G(+/+) was detected in 113 out of 171 (66.0%) controls and 125 out of 144 (86.8%) HH subjects. Del/4G(-/-) was detected in only 6 (3.5%) controls and undetected in the HH group. Three venous thrombosis related genes [FV(Leiden), MTHFR(A1298C) and FXIII(V34L)] were significantly related to the prominence of the co-expression of Del/4G(+/+). A range of 2 to 8 combined polymorphisms co-expressed per subject where 5 mutations were the most detected. In Del/4G(+/+) subjects, peripheral blood mononuclear cells (PBMCs) produced significant elevated levels of IFN-γ and TNF-α contrary to IL-10, and no variations occurred for IL-4. ACE inhibitor (ramipril) in combination with statin (atorvastatin) and not alone reversed significantly the situation. This first report from Lebanon sheds light on an additional genetic predisposition of a complex spectrum of genes involved in CVD and suggests that the most requested gene FVL by physicians may not be sufficient to diagnose eventual future problems that can occur in the cardiovascular system. Subjects expressing the double mutations (Del/4G

  20. Interaction of angiotensin-converting enzyme (ACE) with membrane-bound carboxypeptidase M (CPM) - a new function of ACE.

    PubMed

    Sun, Xiaoou; Wiesner, Burkhard; Lorenz, Dorothea; Papsdorf, Gisela; Pankow, Kristin; Wang, Po; Dietrich, Nils; Siems, Wolf-Eberhard; Maul, Björn

    2008-12-01

    Angiotensin-converting enzyme (ACE) demonstrates, besides its typical dipeptidyl-carboxypeptidase activity, several unusual functions. Here, we demonstrate with molecular, biochemical, and cellular techniques that the somatic wild-type murine ACE (mACE), stably transfected in Chinese Hamster Ovary (CHO) or Madin-Darby Canine Kidney (MDCK) cells, interacts with endogenous membranal co-localized carboxypeptidase M (CPM). CPM belongs to the group of glycosylphosphatidylinositol (GPI)-anchored proteins. Here we report that ACE, completely independent of its known dipeptidase activities, has GPI-targeted properties. Our results indicate that the spatial proximity between mACE and the endogenous CPM enables an ACE-evoked release of CPM. These results are discussed with respect to the recently proposed GPI-ase activity and function of sperm-bound ACE.

  1. Gender difference of serum angiotensin-converting enzyme (ACE) activity in DD genotype of ACE insertion/deletion polymorphism in elderly Chinese.

    PubMed

    Zhang, Ya-Feng; Cheng, Qiong; Tang, Nelson L S; Chu, Tanya T W; Tomlinson, Brian; Liu, Fan; Kwok, Timothy C Y

    2014-12-01

    In this study we investigated the gender difference of serum angiotensin-converting enzyme (ACE) activity in a population of Hong Kong-dwelling elderly Chinese. A total of 1767 (843 male, 924 female) Hong Kong-dwelling elderly Chinese were recruited. ACE I/D genotypes were identified by polymerase chain reaction amplification and serum ACE activity was determined using a commercially available kinetic kit. ACE I/D genotype distribution was compared by chi-square test, the correlation between ACE I/D polymorphism and serum ACE activity was analysed by ANOVA test and gender difference of serum ACE activity of different genotypes was compared by independent sample t-test. No statistically significant difference of genotype distribution between male and female subjects was found. Serum ACE activity was significantly correlated with ACE genotype. Overall, there was no gender difference of serum ACE activity; however, when sub-grouping the subjects by ACE I/D genotype, male subjects with DD genotype had higher serum ACE activity than female subjects with DD genotype. No significant gender difference of genotype distribution was found in elderly Chinese. Serum ACE activity was significantly correlated with ACE I/D polymorphism in elderly Chinese. Male subjects with DD genotype had higher serum ACE activity than female subjects with DD genotype. © The Author(s) 2013.

  2. Angiotensin-converting enzyme (ACE) inhibitory potential of standardized Mucuna pruriens seed extract.

    PubMed

    Chaudhary, Sushil Kumar; De, Apurba; Bhadra, Santanu; Mukherjee, Pulok K

    2015-01-01

    Mucuna pruriens Linn. (Fabaceae) is a tropical legume, traditionally used for controlling blood pressure. Inhibition of angiotensin-converting enzyme (ACE) is one of the successful strategies for controlling hypertension. The present study evaluated the ACE inhibition potential of the standardized extract of M. pruriens seeds. Standardization of the extract and its fractions were carried out by RP-HPLC method [methanol and 1% v/v acetic acid in water (5:95 v/v)] using levodopa as a marker. The ACE inhibition activity of the extract and fractions was evaluated at different concentrations (20, 40, 60, 80, and 100 µg/mL) using the HPLC-DAD and the UV spectrophotometric method. The liberation of hippuric acid (HA) from hippuryl-L-histidyl-L-leucine (HHL) was estimated in the spectrophotometric method and RP-HPLC assay at 228 nm. Methanol extract and aqueous fraction showed a maximum activity with IC50 values of 38.44 ± 0.90 and 57.07 ± 2.90 µg/mL (RP-HPLC), and 52.68 ± 2.02 and 67.65 ± 2.40 µg/mL (spectrophotometry), respectively. The study revealed that the aqueous extract contains the highest amount of levodopa. Eventually the methanol extract showed highest ACE inhibition activity except levodopa alone. It was further observed that the inhibition was altered with respect to the change in the content of levodopa in the extract. Thus, it can be assumed that levodopa may be responsible for the ACE inhibition activity of M. pruriens seeds. It can be concluded that M. pruriens seed is a potential ACE inhibitor can be explored further as an effective antihypertensive agent.

  3. Combining aspirin with angiotensin converting enzyme inhibitors in heart failure: how safe is it?

    PubMed

    Mehta, H; Mahajan, A; Bansal, N; Vaidya, S; Pathak, L

    1998-11-01

    The above discussion on the interaction of aspirin and ACE inhibitors seems to suggest that aspirin in high doses may have adverse interaction with ACE inhibitors in patients with heart failure but the data obtained is not sufficient or conclusive to recommended omission of aspirin in patients with heart failure. This raises a query in the mind of the physician whether to use a combination or not? The role of aspirin in the early period after myocardial infarction is well established so is the role of ACE inhibitors. Hence in patients with myocardial infarction and preserved left ventricular function it would not be wrong to administer combination of ACE inhibitors and aspirin. Albeit at a lower dose. In patients with large myocardial infarction or heart failure, warfarin may be an option but still needs to be documented in large trials. As suggested long term use of aspirin after infarction is still ambiguous and may be harmful in patients with heart failure with its anticedent side effects. But long term benefits of ACE inhibitors in heart failure are well documented. Hence if a choice has to be made whether to discontinue either of the two drugs it would be preferable to stop the aspirin. To answer the issue of use of aspirin in patients with heart failure it would be essential to conduct a double blind randomized trial comparing known anti-thrombotic treatment, aspirin and anti-coagulants on mortality in patients with heart failure, especially caused by coronary artery disease. Such a trial is underway at the present and till the results are available it should be left to clinical judgement of the physician whether to administer aspirin in patients with heart failure after weighing the benefits versus risk.

  4. Inhibition of angiotensin convertin enzyme (ACE) activity by the anthocyanins delphinidin- and cyanidin-3-O-sambubiosides from Hibiscus sabdariffa.

    PubMed

    Ojeda, Deyanira; Jiménez-Ferrer, Enrique; Zamilpa, Alejandro; Herrera-Arellano, Armando; Tortoriello, Jaime; Alvarez, Laura

    2010-01-08

    The beverages of Hibiscus sabdariffa calyces are widely used in Mexico as diuretic, for treating gastrointestinal disorders, liver diseases, fever, hypercholesterolemia and hypertension. Different works have demonstrated that Hibiscus sabdariffa extracts reduce blood pressure in humans, and recently, we demonstrated that this effect is due to angiotensin converting enzyme (ACE) inhibitor activity. The aim of the current study was to isolate and characterizer the constituents responsible of the ACE activity of the aqueous extract of Hibiscus sabdariffa. Bioassay-guided fractionation of the aqueous extract of dried calyces of Hibiscus sabdariffa using preparative reversed-phase HPLC, and the in vitro ACE Inhibition assay, as biological monitor model, were used for the isolation. The isolated compounds were characterized by spectroscopic methods. The anthocyanins delphinidin-3-O-sambubioside (1) and cyanidin-3-O-sambubioside (2) were isolated by bioassay-guided purification. These compounds showed IC(50) values (84.5 and 68.4 microg/mL, respectively), which are similar to those obtained by related flavonoid glycosides. Kinetic determinations suggested that these compounds inhibit the enzyme activity by competing with the substrate for the active site. The competitive ACE inhibitor activity of the anthocyanins 1 and 2 is reported for the first time. This activity is in good agreement with the folk medicinal use of Hibiscus sabdariffa calyces as antihypertensive. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  5. Expression of Magnaporthe grisea Avirulence Gene ACE1 Is Connected to the Initiation of Appressorium-Mediated Penetration▿

    PubMed Central

    Fudal, Isabelle; Collemare, Jérôme; Böhnert, Heidi U.; Melayah, Delphine; Lebrun, Marc-Henri

    2007-01-01

    Magnaporthe grisea is responsible for a devastating fungal disease of rice called blast. Current control of this disease relies on resistant rice cultivars that recognize M. grisea signals corresponding to specific secreted proteins encoded by avirulence genes. The M. grisea ACE1 avirulence gene differs from others, since it controls the biosynthesis of a secondary metabolite likely recognized by rice cultivars carrying the Pi33 resistance gene. Using a transcriptional fusion between ACE1 promoter and eGFP, we showed that ACE1 is only expressed in appressoria during fungal penetration into rice and barley leaves, onion skin, and cellophane membranes. ACE1 is almost not expressed in appressoria differentiated on Teflon and Mylar artificial membranes. ACE1 expression is not induced by cellophane and plant cell wall components, demonstrating that it does not require typical host plant compounds. Cyclic AMP (cAMP) signaling mutants ΔcpkA and Δmac1 sum1-99 and tetraspanin mutant Δpls1::hph differentiate melanized appressoria with normal turgor but are unable to penetrate host plant leaves. ACE1 is normally expressed in these mutants, suggesting that it does not require cAMP signaling or a successful penetration event. ACE1 is not expressed in appressoria of the buf1::hph mutant defective for melanin biosynthesis and appressorial turgor. The addition of hyperosmotic solutes to buf1::hph appressoria restores appressorial development and ACE1 expression. Treatments of young wild-type appressoria with actin and tubulin inhibitors reduce both fungal penetration and ACE1 expression. These experiments suggest that ACE1 appressorium-specific expression does not depend on host plant signals but is connected to the onset of appressorium-mediated penetration. PMID:17142568

  6. Comparative effectiveness of angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers in patients with type 2 diabetes and retinopathy.

    PubMed

    Shih, Chia-Jen; Chen, Hung-Ta; Kuo, Shu-Chen; Li, Szu-Yuan; Lai, Pi-Hsiang; Chen, Shu-Chen; Ou, Shuo-Ming; Chen, Yung-Tai

    2016-05-17

    Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are effective treatments for diabetic retinopathy, but randomized trials and meta-analyses comparing their effects on macrovascular complications have yielded conflicting results. We compared the effectiveness of these drugs in patients with pre-existing diabetic retinopathy in a large population-based cohort. We conducted a propensity score-matched cohort study using Taiwan's National Health Insurance Research Database. We included adult patients prescribed an ACE inhibitor or ARB within 90 days after diagnosis of diabetic retinopathy between 2000 and 2010. Primary outcomes were all-cause death and major adverse cardiovascular events (myocardial infarction, ischemic stroke or cardiovascular death). Secondary outcomes were hospital admissions with acute kidney injury or hyperkalemia. We identified 11 246 patients receiving ACE inhibitors and 15 173 receiving ARBs, of whom 9769 patients in each group were matched successfully by propensity scores. In the intention-to-treat analyses, ARBs were similar to ACE inhibitors in risk of all-cause death (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.87-1.01) and major adverse cardiovascular events (HR 0.95, 95% CI 0.87-1.04), including myocardial infarction (HR 1.03, 95% CI 0.88-1.20), ischemic stroke (HR 0.94, 95% CI 0.85-1.04) and cardiovascular death (HR 1.01, 95% CI 0.88-1.16). They also did not differ from ACE inhibitors in risk of hospital admission with acute kidney injury (HR 1.01, 95% CI 0.91-1.13) and hospital admission with hyperkalemia (HR 1.01, 95% CI 0.86-1.18). Results were similar in as-treated analyses. Our study showed that ACE inhibitors were similar to ARBs in risk of all-cause death, major adverse cardiovascular events and adverse effects among patients with pre-existing diabetic retinopathy. © 2016 Canadian Medical Association or its licensors.

  7. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials.

    PubMed

    Abuissa, Hussam; Jones, Philip G; Marso, Steven P; O'Keefe, James H

    2005-09-06

    We sought to investigate the role of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in preventing the new onset of type 2 diabetes mellitus. Diabetes is a public health problem of epidemic proportions and its prevalence is on the rise. The typical American born today has a one in three chance of developing type 2 diabetes. This diagnosis is associated with an adverse cardiovascular prognosis and is considered the risk equivalent of established coronary disease. Even in high-risk individuals, diabetes is a preventable disease. Several studies have shown that ACE inhibitors and ARBs decrease the incidence of new-onset type 2 diabetes. However, the exact role of these agents in diabetes prevention has not yet been fully elucidated. We conducted a meta-analysis of 12 randomized controlled clinical trials of ACE inhibitors or ARBs, identified through a MEDLINE search and a review of reports from scientific meetings, to study the efficacy of these medications in diabetes prevention. This showed that ACE inhibitors and ARBs were associated with reductions in the incidence of newly diagnosed diabetes by 27% and 23%, respectively, and by 25% in the pooled analysis. The use of an ACE inhibitor or ARB should be considered in patients with pre-diabetic conditions such as metabolic syndrome, hypertension, impaired fasting glucose, family history of diabetes, obesity, congestive heart failure, or coronary heart disease.

  8. Angiotensin-Converting Inhibitors and Angiotensin II Receptor Blockers and Longitudinal Change in Percent Emphysema on Computed Tomography. The Multi-Ethnic Study of Atherosclerosis Lung Study

    PubMed Central

    Parikh, Megha A.; Aaron, Carrie P.; Hoffman, Eric A.; Schwartz, Joseph E.; Madrigano, Jaime; Austin, John H. M.; Lovasi, Gina; Watson, Karol; Stukovsky, Karen Hinckley

    2017-01-01

    Rationale: Although emphysema on computed tomography (CT) is associated with increased morbidity and mortality in patients with and without spirometrically defined chronic obstructive pulmonary disease, no available medications target emphysema outside of alpha-1 antitrypsin deficiency. Transforming growth factor-β and endothelial dysfunction are implicated in emphysema pathogenesis, and angiotensin II receptor blockers (ARBs) inhibit transforming growth factor-β, improve endothelial function, and restore airspace architecture in murine models. Evidence in humans is, however, lacking. Objectives: To determine whether angiotensin-converting enzyme (ACE) inhibitor and ARB dose is associated with slowed progression of percent emphysema by CT. Methods: The Multi-Ethnic Study of Atherosclerosis researchers recruited participants ages 45–84 years from the general population from 2000 to 2002. Medication use was assessed by medication inventory. Percent emphysema was defined as the percentage of lung regions less than −950 Hounsfield units on CTs. Mixed-effects regression models were used to adjust for confounders. Results: Among 4,472 participants, 12% used an ACE inhibitor and 6% used an ARB at baseline. The median percent emphysema was 3.0% at baseline, and the rate of progression was 0.64 percentage points over a median of 9.3 years. Higher doses of ACE or ARB were independently associated with a slower change in percent emphysema (P = 0.03). Over 10 years, in contrast to a predicted mean increase in percent emphysema of 0.66 percentage points in those who did not take ARBs or ACE inhibitors, the predicted mean increase in participants who used maximum doses of ARBs or ACE inhibitors was 0.06 percentage points (P = 0.01). The findings were of greatest magnitude among former smokers (P < 0.001). Indications for ACE inhibitor or ARB drugs (hypertension and diabetes) and other medications for hypertension and diabetes were not associated independently

  9. Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo-controlled clinical trial.

    PubMed

    Campbell, Craig; McMillan, Hugh J; Mah, Jean K; Tarnopolsky, Mark; Selby, Kathryn; McClure, Ty; Wilson, Dawn M; Sherman, Matthew L; Escolar, Diana; Attie, Kenneth M

    2017-04-01

    ACE-031 is a fusion protein of activin receptor type IIB and IgG1-Fc, which binds myostatin and related ligands. It aims to disrupt the inhibitory effect on muscle development and provide potential therapy for myopathies like Duchenne muscular dystrophy (DMD). ACE-031 was administered subcutaneously every 2-4 weeks to DMD boys in a randomized, double-blind, placebo-controlled, ascending-dose trial. The primary objective was safety evaluation. Secondary objectives included characterization of pharmacokinetics and pharmacodynamics. ACE-031 was not associated with serious or severe adverse events. The study was stopped after the second dosing regimen due to potential safety concerns of epistaxis and telangiectasias. A trend for maintenance of the 6-minute walk test (6MWT) distance in the ACE-031 groups compared with a decline in the placebo group (not statistically significant) was noted, as was a trend for increased lean body mass and bone mineral density (BMD) and reduced fat mass. ACE-031 use demonstrated trends for pharmacodynamic effects on lean mass, fat mass, BMD, and 6MWT. Non-muscle-related adverse events contributed to the decision to discontinue the study. Myostatin inhibition is a promising therapeutic approach for DMD. Muscle Nerve 55: 458-464, 2017. © 2016 Wiley Periodicals, Inc.

  10. Tissue-specific expression of transgenic secreted ACE in vasculature can restore normal kidney functions, but not blood pressure, of Ace-/- mice.

    PubMed

    Chattopadhyay, Saurabh; Kessler, Sean P; Colucci, Juliana Almada; Yamashita, Michifumi; Senanayake, Preenie deS; Sen, Ganes C

    2014-01-01

    Angiotensin-converting enzyme (ACE) regulates normal blood pressure and fluid homeostasis through its action in the renin-angiotensin-system (RAS). Ace-/- mice are smaller in size, have low blood pressure and defective kidney structure and functions. All of these defects are cured by transgenic expression of somatic ACE (sACE) in vascular endothelial cells of Ace-/- mice. sACE is expressed on the surface of vascular endothelial cells and undergoes a natural cleavage secretion process to generate a soluble form in the body fluids. Both the tissue-bound and the soluble forms of ACE are enzymatically active, and generate the vasoactive octapeptide Angiotensin II (Ang II) with equal efficiency. To assess the relative physiological roles of the secreted and the cell-bound forms of ACE, we expressed, in the vascular endothelial cells of Ace-/- mice, the ectodomain of sACE, which corresponded to only the secreted form of ACE. Our results demonstrated that the secreted form of ACE could normalize kidney functions and RAS integrity, growth and development of Ace-/- mice, but not their blood pressure. This study clearly demonstrates that the secreted form of ACE cannot replace the tissue-bound ACE for maintaining normal blood pressure; a suitable balance between the tissue-bound and the soluble forms of ACE is essential for maintaining all physiological functions of ACE.

  11. Tissue-Specific Expression of Transgenic Secreted ACE in Vasculature Can Restore Normal Kidney Functions, but Not Blood Pressure, of Ace-/- Mice

    PubMed Central

    Chattopadhyay, Saurabh; Kessler, Sean P.; Colucci, Juliana Almada; Yamashita, Michifumi; Senanayake, Preenie deS; Sen, Ganes C.

    2014-01-01

    Angiotensin-converting enzyme (ACE) regulates normal blood pressure and fluid homeostasis through its action in the renin-angiotensin-system (RAS). Ace-/- mice are smaller in size, have low blood pressure and defective kidney structure and functions. All of these defects are cured by transgenic expression of somatic ACE (sACE) in vascular endothelial cells of Ace-/- mice. sACE is expressed on the surface of vascular endothelial cells and undergoes a natural cleavage secretion process to generate a soluble form in the body fluids. Both the tissue-bound and the soluble forms of ACE are enzymatically active, and generate the vasoactive octapeptide Angiotensin II (Ang II) with equal efficiency. To assess the relative physiological roles of the secreted and the cell-bound forms of ACE, we expressed, in the vascular endothelial cells of Ace-/- mice, the ectodomain of sACE, which corresponded to only the secreted form of ACE. Our results demonstrated that the secreted form of ACE could normalize kidney functions and RAS integrity, growth and development of Ace-/- mice, but not their blood pressure. This study clearly demonstrates that the secreted form of ACE cannot replace the tissue-bound ACE for maintaining normal blood pressure; a suitable balance between the tissue-bound and the soluble forms of ACE is essential for maintaining all physiological functions of ACE. PMID:24475296

  12. [Effect of altitude chronic hypoxia on liver enzymes and its correlation with ACE/ACE2 in yak and migrated cattle].

    PubMed

    Liu, Feng-yun; Hu, Lin; Li, Yu-xian; Liu, Shi-ming; Tang, Yong-ping; Qi, Sheng-gui; Yang, Lei; Wu, Tian-yi

    2015-05-01

    To investigate the difference of liver enzyme levels and its correlation with serum ACE/ACE2 among yak and cattle on Qinghai-Tibetan plateau, and to further explore the biochemical mechanism of their liver of altitude adaptation. The serum samples of yak were collected at 3,000 m, 3,500 m, 4,000 m and 4,300 m respectively, meanwhile the serum samples of migrated cattle on plateau (2,500 m) and lowland cattle (1,300 m) were also collected. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholinesterase (CHE), gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), serum lipase (LPS), angiotensin converting enzyme(ACE), angiotensin converting enzyme-2 (ACE2) in serum were measured by using fully automatic blood biochemcal analyzer. We analysed the differences of the above enzymes and its correlation with ACE/ACE2. We used one way analysis of variance (ANOVA). The levels of ALT in 4,000 m group and 4,300 m group of yak increased significantly compared with other groups, there were no statistically significant differences in AST, CHE, GGT, ACE/ACE2 levels of yaks at different altitudes. As compared to lowland cattle, the serum levels of AST and CHE were increased, the level of LPS and ACE was decreased significantly, respectively, and especially, the ratio of ACE/ACE2 of migranted cattle reduced nearly two times. The levels of LPS were significantly correlated to the ratio of ACE/ACE2 in yak (r = 0.357, P < 0.01), and a high correlation between ALP and ACE/ACE2 in lowland cattle( r = 0.418, P < 0.05), But the biggest contribution rate of the ratio of ACE/ACE2 was only 17.5% for the changes of the levels of liver enzyme. The results indicated that with the altitude increased did not significantly influence the changes of liver enzymes' activities in mountainous yaks but not in cattle. However, all above these changes weren't actually correlated to the ratio of ACE/ACE2.

  13. The effects of drug market regulation on pharmaceutical prices in Europe: overview and evidence from the market of ACE inhibitors

    PubMed Central

    2011-01-01

    This study provides an overview of policy measures targeting pharmaceutical expenditure in Europe and analyses their impact on originator pharmaceutical prices. Panel data methods are used to examine the market of ACE Inhibitors in six European countries (Denmark, France, Germany, Netherlands, Sweden, United Kingdom) over period 1991-2006. We find that although some measures are effective in reducing originator prices, others appear to have an insignificant effect. Results suggest that supply side measures such as mandatory generic substitution, regressive pharmacy mark-ups and claw-backs are effective in reducing pharmaceuticals prices. Results are not as strong for demand side measures. Profit controls and the use of cost-effectiveness analysis appear to have a negative effect on prices, while results on reference pricing are inconclusive. Findings also indicate that, although originator prices are not immediately affected by generic entry, they may be influenced by changes in generic prices post patent expiry. PMID:22828053

  14. Comparison of Clinical Factors Between Patients With Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema and Cough.

    PubMed

    Hallberg, Pär; Nagy, Julia; Karawajczyk, Malgorzata; Nordang, Leif; Islander, Gunilla; Norling, Pia; Johansson, Hans-Erik; Kämpe, Mary; Hugosson, Svante; Yue, Qun-Ying; Wadelius, Mia

    2017-04-01

    Angioedema is a rare and serious adverse drug reaction (ADR) to angiotensin-converting enzyme (ACE) inhibitor treatment. Dry cough is a common side effect of ACE inhibitors and has been identified as a possible risk factor for angioedema. We compared characteristics between patients with ACE inhibitor-induced angioedema and cough with the aim of identifying risk factors that differ between these adverse events. Data on patients with angioedema or cough induced by ACE inhibitors were collected from the Swedish database of spontaneously reported ADRs or from collaborating clinicians. Wilcoxon rank sum test, Fisher's exact test, and odds ratios (ORs) with 95% CIs were used to test for between-group differences. The significance threshold was set to P <0.00128 to correct for multiple comparisons. Clinical characteristics were compared between 168 patients with angioedema and 121 with cough only. Smoking and concomitant selective calcium channel blocker treatment were more frequent among patients with angioedema than cough: OR = 4.3, 95% CI = 2.1-8.9, P = 2.2 × 10 -5 , and OR = 3.7, 95% CI = 2.0-7.0, P = 1.7 × 10 -5 . Angioedema cases were seen more often in male patients (OR = 2.2, 95% CI = 1.4-3.6, P = 1.3 × 10 -4 ) and had longer time to onset and higher doses than those with cough ( P = 3.2 × 10 -10 and P = 2.6 × 10 -4 ). A multiple model containing the variables smoking, concurrent calcium channel blocker treatment, male sex, and time to onset accounted for 26% of the variance between the groups. Smoking, comedication with selective calcium channel blockers, male sex, and longer treatment time were associated with ACE inhibitor-induced angioedema rather than cough.

  15. ACE2 alterations in kidney disease.

    PubMed

    Soler, María José; Wysocki, Jan; Batlle, Daniel

    2013-11-01

    Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that degrades angiotensin (Ang) II to Ang-(1-7). ACE2 is highly expressed within the kidneys, it is largely localized in tubular epithelial cells and less prominently in glomerular epithelial cells and in the renal vasculature. ACE2 activity has been shown to be altered in diabetic kidney disease, hypertensive renal disease and in different models of kidney injury. There is often a dissociation between tubular and glomerular ACE2 expression, particularly in diabetic kidney disease where ACE2 expression is increased at the tubular level but decreased at the glomerular level. In this review, we will discuss alterations in circulating and renal ACE2 recently described in different renal pathologies and disease models as well as their possible significance.

  16. ACE2 alterations in kidney disease

    PubMed Central

    Soler, María José; Wysocki, Jan; Batlle, Daniel

    2013-01-01

    Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that degrades angiotensin (Ang) II to Ang-(1–7). ACE2 is highly expressed within the kidneys, it is largely localized in tubular epithelial cells and less prominently in glomerular epithelial cells and in the renal vasculature. ACE2 activity has been shown to be altered in diabetic kidney disease, hypertensive renal disease and in different models of kidney injury. There is often a dissociation between tubular and glomerular ACE2 expression, particularly in diabetic kidney disease where ACE2 expression is increased at the tubular level but decreased at the glomerular level. In this review, we will discuss alterations in circulating and renal ACE2 recently described in different renal pathologies and disease models as well as their possible significance. PMID:23956234

  17. Omapatrilat, a dual angiotensin-converting enzyme and neutral endopeptidase inhibitor, prevents fatty streak deposit in apolipoprotein E-deficient mice.

    PubMed

    Arnal, J F; Castano, C; Maupas, E; Mugniot, A; Darblade, B; Gourdy, P; Michel, J B; Bayard, F

    2001-04-01

    Angiotensin-converting enzyme (ACE) is mainly responsible for converting angiotensin I (AI) to angiotensin II (AII), and ACE inhibitors prevent atherosclerosis in animal models. Neutral endopeptidase 24.11 (NEP) degrades substance P, kinins and atrial natriuretic peptide (ANP), and aortic wall NEP activity was found to be increased in atherosclerosis. In the present study, we have evaluated the effect of candoxatril, a NEP inhibitor, and of omapatrilat, a dual ACE and NEP inhibitor, on the development of fatty streak in apolipoprotein E (apoE)-deficient mice. Groups of ten male apoE-deficient mice were given either placebo, candoxatril 50 mg/kg per day, or omapatrilat 10, or 100 mg/kg per day for 4 months. None of the treatments influenced body weight, serum total or HDL-cholesterol. Compared with the placebo, candoxatril did not protect the mice from fatty streak deposit. In contrast, omapatrilat dose dependently inhibited the constitution of fatty streak in apoE-deficient mice. The precise advantages of the dual ACE and NEP inhibition versus the inhibition of only ACE should now be considered in the prevention of atherosclerosis as well as in the occurrence of its complications.

  18. Pharmacologic modulation of ACE2 expression.

    PubMed

    Soler, María José; Barrios, Clara; Oliva, Raymond; Batlle, Daniel

    2008-10-01

    Angiotensin-converting enzyme 2 (ACE2) is an enzymatically active homologue of angiotensin-converting enzyme that degrades angiotensin I, angiotensin II, and other peptides. Recent studies have shown that under pathologic conditions, ACE2 expression in the kidney is altered. In this review, we briefly summarize recent studies dealing with pharmacologic interventions that modulate ACE2 expression. ACE2 amplification may have a potential therapeutic role for kidney disease and hypertension.

  19. Synthesis and biological studies of highly concentrated lisinopril-capped gold nanoparticles for CT tracking of angiotensin converting enzyme (ACE)

    NASA Astrophysics Data System (ADS)

    Ghann, William E.; Aras, Omer; Fleiter, Thorsten; Daniel, Marie-Christine

    2011-05-01

    For patients with a history of heart attack or stroke, the prevention of another cardiovascular or cerebrovascular event is crucial. The development of cardiac and pulmonary fibrosis has been associated with overexpression of tissue angiotensin-converting enzyme (ACE). Recently, gold nanoparticles (GNPs) have shown great potential as X-ray computed tomography (CT) contrast agents. Since lisinopril is an ACE inhibitor, it has been used as coating on GNPs for targeted imaging of tissue ACE in prevention of fibrosis. Herein, lisinopril-capped gold nanoparticles (LIS-GNPs) were synthesized up to a concentration of 55 mgAu/mL. Their contrast was measured using CT and the results were compared to Omnipaque, a commonly used iodine-based contrast agent. The targeting ability of these LIS-GNPs was also assessed.

  20. Identification of ace inhibitory cryptides in Tilapia protein hydrolysate by UPLC-MS/MS coupled to database analysis.

    PubMed

    Yesmine, Ben Henda; Antoine, Bonnet; da Silva Ortência Leocádia, Nunes Gonzalez; Rogério, Boscolo Wilson; Ingrid, Arnaudin; Nicolas, Bridiau; Thierry, Maugard; Jean-Marie, Piot; Frédéric, Sannier; Stéphanie, Bordenave-Juchereau

    2017-05-01

    An ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry method was developed and applied to identify short angiotensin-I-converting enzyme (ACE) inhibitory cryptides in Tilapia (Oreochromis Niloticus) protein hydrolyzate. A database was created with previously identified ACE-inhibitory di- and tripeptides and the lowest molecular weight fraction of Tilapia hydrolysate was analysed for coincidences. Only VW and VY were identified. Further analysis of collected fractions conducted to the identification of 51 different peptides in major fractions. 19 peptides selected were synthesised and tested for their ACE inhibitory potential. TL, TI, IK, LR, LD, IQ, DI, AILE, ALLE, ALIE and AIIE were identified as new ACE inhibitors. The findings from this study point UPLC-MS/MS combined with the creation of a database as an efficient technique to identify specific short peptides within a complex hydrolysate, in addition with de novo sequencing. This efficient characterisation of bioactive factors like cryptides in protein hydrolysates will extend their use as functional foods. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Oxygen radical system in chronic infarcted rat heart: the effect of combined beta blockade and ACE inhibition.

    PubMed

    Theres, H; Wagner, K D; Schulz, S; Strube, S; Leiterer, K P; Romberg, D; Günther, J; Scholz, H; Baumann, G; Schimke, I

    2000-05-01

    In vitro experiments suggest that beta blockade and angiotensin-converting enzyme (ACE) inhibition may protect the failing heart by reduction of myocardial oxidative stress. To test this hypothesis in an in vivo model, the beta blocker metoprolol (350 mg) and the ACE inhibitor ramipril (1 mg) were given either alone or in combination to rats (per kilogram body weight per day) for 6 weeks after myocardial infarction. Left ventricular end-diastolic pressure (LVEDP), contractile function of papillary muscles, enzymatic antioxidative defense (indicated by the activities of the superoxide dismutase isoenzymes and glutathione peroxidase), and the extent of lipid peroxidation were studied. Placebo-treated rats showed cardiac hypertrophy, increased LVEDP, lower rates of contraction and relaxation, as well as a deficit in the myocardial antioxidative defense associated with increased lipid peroxide levels, when compared with sham-operated animals. Combined beta blockade and ACE inhibition improved the antioxidative defense, reduced hypertrophy and LVEDP, and enhanced rates of contraction. Thus prolonged beta blockade and ACE inhibition after infarction may decrease myocardial oxidative stress and thereby could be beneficial in heart failure.

  2. Kinetics of degradation of enalapril maleate in dosage forms.

    PubMed

    Stanisz, Beata

    2004-01-01

    The effect of humidity and temperature on the stability of enalapril maleate (ENA) in tablets have been studied. Tablets with ENA were stored in final packs (blisters) and without final packs in the atmosphere of increased humidity (76.4 % RH) and in the temperature range from 313 K to 333 K (forced degradation test). Degradation of ENA in tablets stored in final packs and without final packs followed the first order reaction model. During this study, the product of hydrolysis of the ester group and intramolecular cyclization have been observed. Thermodynamic parameters (activation energies, enthalpy and entropy) for the decomposition of ENA in tablets were calculated.

  3. FIRE III ACE Info

    Atmospheric Science Data Center

    2014-03-18

    ... Regional Experiment (FIRE) - Arctic Cloud Experiment (ACE) was conducted April through July of 1998. It was held in conjunction with ... Heat Budget of the Arctic Ocean (SHEBA) Experiment. The FIRE-ACE focused on all aspects of Arctic cloud systems. The main facility was ...

  4. Phytochemical and in vitro and in vivo biological investigation on the antihypertensive activity of mango leaves (Mangifera indica L.).

    PubMed

    Ronchi, Silas Nascimento; Brasil, Girlandia Alexandre; do Nascimento, Andrews Marques; de Lima, Ewelyne Miranda; Scherer, Rodrigo; Costa, Helber B; Romão, Wanderson; Boëchat, Giovanna Assis Pereira; Lenz, Dominik; Fronza, Marcio; Bissoli, Nazaré Souza; Endringer, Denise Coutinho; de Andrade, Tadeu Uggere

    2015-10-01

    The aim of this study was to investigate the antihypertensive effect of leaves Mangifera indica L. using in vitro and in vivo assays. The ethanol extract of leaves of M. indica was fractionated to dichloromethanic, n-butyl alcohol and aqueous fractions. The chemical composition of ethanolic extract and dichloromethanic fraction were evaluated by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Antioxidant activity was evaluated in the DPPH scavenging activity assay. Angiotensin-converting enzyme (ACE) inhibitory activity was investigated using in vitro and in vivo assays. The chronic antihypertensive assay was performed in spontaneously hypertensive rats (SHRs) and Wistar rats treated with enalapril (10 mg/kg), dichloromethanic fraction (100 mg/kg; twice a day) or vehicle control for 30 days. The baroreflex sensitivity was evaluated through the use of sodium nitroprusside and phenylephrine. Cardiac hypertrophy was evaluated by morphometric analysis. The dichloromethanic fraction exhibited the highest flavonoid, total phenolic content and high antioxidant activity. Dichloromethanic fraction elicited ACE inhibitory activity in vitro (99 ± 8%) similar to captopril. LC-MS/MS analysis revealed the presence of ferulic acid (48.3 ± 0.04 µg/g) caffeic acid (159.8 ± 0.02 µg/g), gallic acid (142.5 ± 0.03 µg/g), apigenin (11.0 ± 0.01 µg/g) and quercetin (203.3 ± 0.05 µg/g). The chronic antihypertensive effects elicited by dichloromethanic fraction were similar to those of enalapril, and the baroreflex sensitivity was normalized in SHR. Plasma ACE activity and cardiac hypertrophy were comparable with animals treated with enalapril. Dichloromethanic fraction of M. indica presented an antihypertensive effect, most likely by ACE inhibition, with benefits in baroreflex sensitivity and cardiac hypertrophy. Altogether, the results of the present study suggest that the dichloromethanic fraction of M. indica leaves may have potential as a promoting

  5. Association of Angiotensin-Converting Enzyme ACE Gene Polymorphism with ACE Activity and Susceptibility to Vitiligo in Egyptian Population.

    PubMed

    Badran, Dahlia I; Nada, Hesham; Hassan, Ranya

    2015-05-01

    The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is associated with vitiligo in the Indians and Koreans, but not in those of English or Turkish background. We investigated the ACE (I/D) polymorphism in vitiligo patients for the first time in Egypt and compared serum ACE levels between vitiligo patients and controls. The present study was carried out in 100 vitiligo patients (40 males and 60 females) and in 100 healthy controls of an Egyptian population using the polymerase chain reaction genotyping method. The ACE genotype and allele frequency was significantly different between vitiligo patients and controls. Our results revealed a significant increase in the frequency of the ACE I allele (p=0.002; odds ratio: 1.99; 95% confidence intervals: 1.207-3.284) with an overrepresentation of I/D genotype in the vitiligo patient group. Furthermore, there was a significant difference between the segmental, nonsegmental, and focal vitiligo in ACE gene genotype distribution. Serum ACE levels were significantly increased in vitiligo patients compared to controls (p=0.034). This study suggests that, for the first time, ACE gene polymorphism confers susceptibility to vitiligo in the Egyptian population.

  6. Crystal structure of the N domain of human somatic angiotensin I-converting enzyme provides a structural basis for domain-specific inhibitor design.

    PubMed

    Corradi, Hazel R; Schwager, Sylva L U; Nchinda, Aloysius T; Sturrock, Edward D; Acharya, K Ravi

    2006-03-31

    Human somatic angiotensin I-converting enzyme (sACE) is a key regulator of blood pressure and an important drug target for combating cardiovascular and renal disease. sACE comprises two homologous metallopeptidase domains, N and C, joined by an inter-domain linker. Both domains are capable of cleaving the two hemoregulatory peptides angiotensin I and bradykinin, but differ in their affinities for a range of other substrates and inhibitors. Previously we determined the structure of testis ACE (C domain); here we present the crystal structure of the N domain of sACE (both in the presence and absence of the antihypertensive drug lisinopril) in order to aid the understanding of how these two domains differ in specificity and function. In addition, the structure of most of the inter-domain linker allows us to propose relative domain positions for sACE that may contribute to the domain cooperativity. The structure now provides a platform for the design of "domain-specific" second-generation ACE inhibitors.

  7. Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1-FoxM1 complex.

    PubMed

    Yang, Jin; Feng, Xuhui; Zhou, Qiong; Cheng, Wei; Shang, Ching; Han, Pei; Lin, Chiou-Hong; Chen, Huei-Sheng Vincent; Quertermous, Thomas; Chang, Ching-Pin

    2016-09-20

    Genes encoding angiotensin-converting enzymes (Ace and Ace2) are essential for heart function regulation. Cardiac stress enhances Ace, but suppresses Ace2, expression in the heart, leading to a net production of angiotensin II that promotes cardiac hypertrophy and fibrosis. The regulatory mechanism that underlies the Ace2-to-Ace pathological switch, however, is unknown. Here we report that the Brahma-related gene-1 (Brg1) chromatin remodeler and forkhead box M1 (FoxM1) transcription factor cooperate within cardiac (coronary) endothelial cells of pathologically stressed hearts to trigger the Ace2-to-Ace enzyme switch, angiotensin I-to-II conversion, and cardiac hypertrophy. In mice, cardiac stress activates the expression of Brg1 and FoxM1 in endothelial cells. Once activated, Brg1 and FoxM1 form a protein complex on Ace and Ace2 promoters to concurrently activate Ace and repress Ace2, tipping the balance to Ace2 expression with enhanced angiotensin II production, leading to cardiac hypertrophy and fibrosis. Disruption of endothelial Brg1 or FoxM1 or chemical inhibition of FoxM1 abolishes the stress-induced Ace2-to-Ace switch and protects the heart from pathological hypertrophy. In human hypertrophic hearts, BRG1 and FOXM1 expression is also activated in endothelial cells; their expression levels correlate strongly with the ACE/ACE2 ratio, suggesting a conserved mechanism. Our studies demonstrate a molecular interaction of Brg1 and FoxM1 and an endothelial mechanism of modulating Ace/Ace2 ratio for heart failure therapy.

  8. Imbalanced plasma ACE and ACE2 level in the uremic patients with cardiovascular diseases and its change during a single hemodialysis session.

    PubMed

    Yang, Chung-Wei; Lu, Li-Che; Chang, Chia-Chu; Cho, Ching-Chang; Hsieh, Wen-Yeh; Tsai, Chin-Hung; Lin, Yi-Chang; Lin, Chih-Sheng

    2017-11-01

    The renin-angiotensin system (RAS) has significant influences on heart and renal disease progression. Angiotensin converting enzyme (ACE) and angiotensin converting enzyme II (ACE2) are major peptidases of RAS components and play counteracting functions through angiotensin II (Ang II)/ATIR and angiotensin-(1-7) (Ang-(1-7))/Mas axis, respectively. There were 360 uremic patients on regular hemodialysis (HD) treatment (inclusive of 119 HD patients with cardiovascular diseases (CVD) and 241 HD patients without CVD and 50 healthy subjects were enrolled in this study. Plasma ACE, ACE2, Ang II and Ang-(1-7) levels of the HD patients were determined. We compared pre-HD levels of plasma ACE, ACE2, Ang II and Ang-(1-7) in the HD patients with and without CVD to those of the controls. The HD patients, particularly those with CVD, showed a significant increase in the levels of ACE and Ang II, whereas ACE2 and Ang-(1-7) levels were lower than those in the healthy controls. Therefore, imbalanced ACE/ACE2 was observed in the HD patients with CVD. In the course of a single HD session, the plasma ACE, ACE/ACE2 and Ang II levels in the HD patients with CVD were increased from pre-HD to post-HD. On the contrary, ACE2 levels were decreased after the HD session. These changes were not detected in the HD patients without CVD. Pathogenically imbalanced circulating ACE/ACE2 was detected in the HD patients, particularly those with CVD. HD session could increase ACE/Ang II/AT1R axis and decrease ACE2/Ang-(1-7)/Mas axis activity in the circulation of HD patients with CVD.

  9. Comparative effectiveness of angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers in patients with type 2 diabetes and retinopathy

    PubMed Central

    Shih, Chia-Jen; Chen, Hung-Ta; Kuo, Shu-Chen; Li, Szu-Yuan; Lai, Pi-Hsiang; Chen, Shu-Chen; Ou, Shuo-Ming; Chen, Yung-Tai

    2016-01-01

    Background: Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are effective treatments for diabetic retinopathy, but randomized trials and meta-analyses comparing their effects on macrovascular complications have yielded conflicting results. We compared the effectiveness of these drugs in patients with pre-existing diabetic retinopathy in a large population-based cohort. Methods: We conducted a propensity score–matched cohort study using Taiwan’s National Health Insurance Research Database. We included adult patients prescribed an ACE inhibitor or ARB within 90 days after diagnosis of diabetic retinopathy between 2000 and 2010. Primary outcomes were all-cause death and major adverse cardiovascular events (myocardial infarction, ischemic stroke or cardiovascular death). Secondary outcomes were hospital admissions with acute kidney injury or hyperkalemia. Results: We identified 11 246 patients receiving ACE inhibitors and 15 173 receiving ARBs, of whom 9769 patients in each group were matched successfully by propensity scores. In the intention-to-treat analyses, ARBs were similar to ACE inhibitors in risk of all-cause death (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.87–1.01) and major adverse cardiovascular events (HR 0.95, 95% CI 0.87–1.04), including myocardial infarction (HR 1.03, 95% CI 0.88–1.20), ischemic stroke (HR 0.94, 95% CI 0.85–1.04) and cardiovascular death (HR 1.01, 95% CI 0.88–1.16). They also did not differ from ACE inhibitors in risk of hospital admission with acute kidney injury (HR 1.01, 95% CI 0.91–1.13) and hospital admission with hyperkalemia (HR 1.01, 95% CI 0.86–1.18). Results were similar in as-treated analyses. Interpretation: Our study showed that ACE inhibitors were similar to ARBs in risk of all-cause death, major adverse cardiovascular events and adverse effects among patients with pre-existing diabetic retinopathy. PMID:27001739

  10. Marketing ACE in Victoria.

    ERIC Educational Resources Information Center

    2001

    This publication presents options raised through various forums for marketing adult and community education (ACE) in Victoria, Australia, and suggested strategies. After an introduction (chapter 1), chapters 2 and 3 provide a broad view of the current situation for marketing ACE. Chapter 2 discusses general issues in the current position--ACE…

  11. Cost-Effectiveness of Sacubitril-Valsartan Combination Therapy Compared With Enalapril for the Treatment of Heart Failure With Reduced Ejection Fraction.

    PubMed

    King, Jordan B; Shah, Rashmee U; Bress, Adam P; Nelson, Richard E; Bellows, Brandon K

    2016-05-01

    The objective of this study was to determine the cost-effectiveness and cost per quality-adjusted life year (QALY) gained of sacubitril-valsartan relative to enalapril for treatment of heart failure with reduced ejection fraction (HFrEF). Compared with enalapril, combination angiotensin receptor-neprilysin inhibition (ARNI), as is found in sacubitril-valsartan, reduces cardiovascular death and heart failure hospitalization rates in patients with HFrEF. Using a Markov model, costs, effects, and cost-effectiveness were estimated for sacubitril-valsartan and enalapril therapies for the treatment of HFrEF. Patients were 60 years of age at model entry and were modeled over a lifetime (40 years) from a third-party payer perspective. Clinical probabilities were derived predominantly from PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). All costs and effects were discounted at a 3% rate annually and are presented in 2015 U.S. dollars. In the base case, sacubitril-valsartan, compared with enalapril, was more costly ($60,391 vs. $21,758) and more effective (6.49 vs. 5.74 QALYs) over a lifetime. The cost-effectiveness of sacubitril-valsartan was highly dependent on duration of treatment, ranging from $249,411 per QALY at 3 years to $50,959 per QALY gained over a lifetime. Sacubitril-valsartan may be a cost-effective treatment option depending on the willingness-to-pay threshold. Future investigations should incorporate real-world evidence with sacubitril-valsartan to further inform decision making. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  12. ACE inhibition with captopril retards the development of signs of neurodegeneration in an animal model of Alzheimer's disease.

    PubMed

    AbdAlla, Said; Langer, Andreas; Fu, Xuebin; Quitterer, Ursula

    2013-08-16

    Increased generation of reactive oxygen species (ROS) is a significant pathological feature in the brains of patients with Alzheimer's disease (AD). Experimental evidence indicates that inhibition of brain ROS could be beneficial in slowing the neurodegenerative process triggered by amyloid-beta (Abeta) aggregates. The angiotensin II AT1 receptor is a significant source of brain ROS, and AD patients have an increased brain angiotensin-converting enzyme (ACE) level, which could account for an excessive angiotensin-dependent AT1-induced ROS generation. Therefore, we analyzed the impact of ACE inhibition on signs of neurodegeneration of aged Tg2576 mice as a transgenic animal model of AD. Whole genome microarray gene expression profiling and biochemical analyses demonstrated that the centrally active ACE inhibitor captopril normalized the excessive hippocampal ACE activity of AD mice. Concomitantly, the development of signs of neurodegeneration was retarded by six months of captopril treatment. The neuroprotective profile triggered by captopril was accompanied by reduced amyloidogenic processing of the amyloid precursor protein (APP), and decreased hippocampal ROS, which is known to enhance Abeta generation by increased activation of beta- and gamma-secretases. Taken together, our data present strong evidence that ACE inhibition with a widely used cardiovascular drug could interfere with Abeta-dependent neurodegeneration.

  13. Decreased Risk of Radiation Pneumonitis With Incidental Concurrent Use of Angiotensin-Converting Enzyme Inhibitors and Thoracic Radiation Therapy

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

    Kharofa, Jordan; Cohen, Eric P.; Tomic, Rade

    2012-09-01

    Purpose: Angiotensin-converting enzyme (ACE) inhibitors have been shown to mitigate radiation-induced lung injury in preclinical models. The aim of this study was to evaluate whether ACE inhibitors decrease the risk of radiation pneumonitis in lung cancer patients receiving thoracic irradiation. Methods and Materials: Patients with Stage I through III small-cell and non-small-cell lung cancer treated definitively with radiation from 2004-2009 at the Clement J. Zablocki Veterans Affairs Medical Center were retrospectively reviewed. Acute pulmonary toxicity was quantified within 6 months of completion of treatment according to the Common Terminology Criteria for Adverse Events version 4. The use of ACE inhibitors,more » nonsteroidal anti-inflammatory drugs, inhaled glucocorticosteroids, statins, and angiotensin receptor blockers; dose-volume histogram parameters; and patient factors were assessed for association with Grade 2 or higher pneumonitis. Results: A total of 162 patients met the criteria for inclusion. The majority of patients had Stage III disease (64%) and received concurrent chemotherapy (61%). Sixty-two patients were identified as ACE inhibitor users (38%). All patients had acceptable radiation plans based on dose-volume histogram constraints (V20 [volume of lung receiving at least 20 Gy] {<=}37% and mean lung dose {<=}20 Gy) with the exception of 2 patients who did not meet both criteria. Grade 2 or higher pulmonary toxicity occurred in 12 patients (7.4%). The rate of Grade 2 or higher pneumonitis was lower in ACE inhibitor users vs. nonusers (2% vs. 11%, p = 0.032). Rates of Grade 2 or higher pneumonitis were significantly increased in patients aged greater than 70 years (16% vs. 2%, p = 0.005) or in whom V5 (volume of lung receiving at least 5 Gy) was 50% or greater (13% vs. 4%, p = 0.04). V10 (volume of lung receiving at least 10 Gy), V20, V30 (volume of lung receiving at least 30 Gy), and mean lung dose were not independently associated with Grade

  14. Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study).

    PubMed

    Shaddy, Robert; Canter, Charles; Halnon, Nancy; Kochilas, Lazaros; Rossano, Joseph; Bonnet, Damien; Bush, Christopher; Zhao, Ziqiang; Kantor, Paul; Burch, Michael; Chen, Fabian

    2017-11-01

    Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor approved for the treatment of adult heart failure (HF); however, the benefit of sacubitril/valsartan in pediatric HF patients is unknown. This global multi-center study will use an adaptive, seamless two-part design. Part 1 will assess the pharmacokinetics/pharmacodynamics of single ascending doses of sacubitril/valsartan in pediatric (1 month to <18 years) HF patients with systemic left ventricle and reduced left ventricular systolic function stratified into 3 age groups (Group 1: 6 to <18 years; Group 2: 1 to <6 years; Group 3: 1 month to <1 year). Part 2 is a 52-week, efficacy and safety study where 360 eligible patients will be randomized to sacubitril/valsartan or enalapril. A novel global rank primary endpoint derived by ranking patients (worst-to-best outcome) based on clinical events such as death, initiation of mechanical life support, listing for urgent heart transplant, worsening HF, measures of functional capacity (NYHA/Ross scores), and patient-reported HF symptoms will be used to assess efficacy. The PANORAMA-HF study, which will be the largest prospective pediatric HF trial conducted to date and the first to use a global rank primary endpoint, will determine whether sacubitril/valsartan is superior to enalapril for treatment of pediatric HF patients with reduced systemic left ventricular systolic function. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  15. ACE-1 experiment

    NASA Image and Video Library

    2013-06-24

    In the International Space Stations Destiny laboratory,NASA astronaut Karen Nyberg,Expedition 36 flight engineer,speaks into a microphone while conducting a session with the Advanced Colloids Experiment (ACE)-1 sample preparation at the Light Microscopy Module (LMM) in the Fluids Integrated Rack / Fluids Combustion Facility (FIR/FCF). ACE-1 is a series of microscopic imaging investigations that uses the microgravity environment to examine flow characteristics and the evolution and ordering effects within a group of colloidal materials.

  16. Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1–FoxM1 complex

    PubMed Central

    Yang, Jin; Feng, Xuhui; Zhou, Qiong; Cheng, Wei; Shang, Ching; Han, Pei; Lin, Chiou-Hong; Chen, Huei-Sheng Vincent; Quertermous, Thomas; Chang, Ching-Pin

    2016-01-01

    Genes encoding angiotensin-converting enzymes (Ace and Ace2) are essential for heart function regulation. Cardiac stress enhances Ace, but suppresses Ace2, expression in the heart, leading to a net production of angiotensin II that promotes cardiac hypertrophy and fibrosis. The regulatory mechanism that underlies the Ace2-to-Ace pathological switch, however, is unknown. Here we report that the Brahma-related gene-1 (Brg1) chromatin remodeler and forkhead box M1 (FoxM1) transcription factor cooperate within cardiac (coronary) endothelial cells of pathologically stressed hearts to trigger the Ace2-to-Ace enzyme switch, angiotensin I-to-II conversion, and cardiac hypertrophy. In mice, cardiac stress activates the expression of Brg1 and FoxM1 in endothelial cells. Once activated, Brg1 and FoxM1 form a protein complex on Ace and Ace2 promoters to concurrently activate Ace and repress Ace2, tipping the balance to Ace2 expression with enhanced angiotensin II production, leading to cardiac hypertrophy and fibrosis. Disruption of endothelial Brg1 or FoxM1 or chemical inhibition of FoxM1 abolishes the stress-induced Ace2-to-Ace switch and protects the heart from pathological hypertrophy. In human hypertrophic hearts, BRG1 and FOXM1 expression is also activated in endothelial cells; their expression levels correlate strongly with the ACE/ACE2 ratio, suggesting a conserved mechanism. Our studies demonstrate a molecular interaction of Brg1 and FoxM1 and an endothelial mechanism of modulating Ace/Ace2 ratio for heart failure therapy. PMID:27601681

  17. Sacubitril/Valsartan: From Clinical Trials to Real-world Experience.

    PubMed

    Joly, Joanna M; Desai, Akshay S

    2018-04-23

    Compared to enalapril, use of angiotensin-receptor blocker and neprilysin inhibitor sacubitril/valsartan to treat patients with heart failure and reduced ejection fraction (HFrEF) is associated with substantial reductions in both cardiovascular mortality and heart failure progression. The purpose of this review is to discuss the real-world experience of sacubitril/valsartan. In the years following the publication of the landmark PARADIGM-HF trial in 2014 and its subsequent FDA approval, a growing evidence base supports the safety and efficacy of sacubitril/valsartan in a broad spectrum of patients with HFrEF. Updated clinical practice guidelines have embraced the use of sacubitril/valsartan in preference to ACE inhibitors or ARBs in selected patients. In this review, we highlight the clinical trials that led to these key updates to clinical guidelines, offer practical strategies for patient selection and utilization in clinical practice, and identify important areas of uncertainty that require future research.

  18. The influence of enalapril and spironolactone on electrolyte concentrations in Doberman pinschers with dilated cardiomyopathy.

    PubMed

    Thomason, J D; Rapoport, G; Fallaw, T; Calvert, C A

    2014-12-01

    The combination of an angiotensin-converting enzyme inhibitor (ACEI) with an aldosterone receptor antagonist can increase serum potassium and magnesium and lower serum sodium concentrations. The objective of this study was to retrospectively determine whether an ACEI and spironolactone can be co-administered to Doberman pinschers with occult dilated cardiomyopathy without serious adverse influences on serum electrolyte concentrations. Between 2001 and 2007, 26 client-owned Doberman pinschers were given enalapril, spironolactone, and carvedilol and followed for at least 6 months. Most dogs had been prescribed mexiletine for ventricular tachyarrhythmia suppression. Dogs were treated with pimobendan when congestive heart failure was imminent. Baseline and follow-up (3-10 visits) color-flow Doppler echocardiograms, serum urea nitrogen (SUN), creatinine, sodium, potassium, and magnesium concentration data were tabulated. Compared to baseline data, there were no significant changes in serum sodium or serum creatinine concentrations. Serum magnesium (P = 0.003), serum potassium (P = 0.0001), and SUN (P = 0.0001) concentrations increased significantly with time. Although the combination of ACEI and spironolactone was associated with significant increases in magnesium, potassium, and SUN concentrations, these changes were of no apparent clinical relevance. At the dosages used in this study, this combination of drugs appears safe. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. ACE Inhibition in Anti-Thy1 Glomerulonephritis Limits Proteinuria but Does Not Improve Renal Function and Structural Remodeling

    PubMed Central

    Westerweel, Peter E.; Joles, Jaap A.; den Ouden, Krista; Goldschmeding, Roel; Rookmaaker, Maarten B.; Verhaar, Marianne C.

    2012-01-01

    Background/Aims ACE inhibitor (ACE-I) treatment effectively inhibits proteinuria and ameliorates the course of various renal diseases. In experimental glomerulonephritis, however, angiotensin II (AngII) infusion has also been shown to be renoprotective. We evaluated the long-term (28 days) course of anti-Thy1 glomerulonephritis in animals with suppressed AngII formation by ACE-I treatment. Methods Brown Norway rats received perindopril (2.8 mg/kg/day, n = 12), dihydropyridine calcium-antagonist amlodipine (Ca-A; 13 mg/kg/day, n = 6) or were left untreated (n = 14). All animals were monitored for blood pressure, proteinuria, and creatinine clearance after anti-Thy1 injection. Renal histology was assessed at day 7 and 28. Results Systolic blood pressure was equally reduced by ACE-I and Ca-A treatment. AngII suppression prevented development of proteinuria, but did not protect against glomerular microaneurysm formation or reduction in creatinine clearance. After resolution of the microaneurysms, animals with suppressed AngII production showed a modest increase in glomerulosclerosis and vasculopathic thickening of intrarenal vessels. Conclusions In anti-Thy1 glomerulonephritis, suppression of AngII formation does not protect against the induction of glomerular damage and is associated with mild aggravation of adverse renal fibrotic remodeling. Proteinuria, however, is effectively prevented by ACE-I treatment. Ca-A treatment did not affect the course of glomerulonephritis, indicating that ACE-I effects are blood pressure independent. PMID:22479264

  20. ACE-1 experiment

    NASA Image and Video Library

    2013-06-24

    ISS036-E-019760 (24 June 2013) --- In the International Space Station’s Destiny laboratory, NASA astronaut Karen Nyberg, Expedition 36 flight engineer, conducts a session with the Advanced Colloids Experiment (ACE)-1 sample preparation at the Light Microscopy Module (LMM) in the Fluids Integrated Rack / Fluids Combustion Facility (FIR/FCF). ACE-1 is a series of microscopic imaging investigations that uses the microgravity environment to examine flow characteristics and the evolution and ordering effects within a group of colloidal materials.

  1. Inequity of access to ACE inhibitors in Swedish heart failure patients: a register-based study

    PubMed Central

    Lindahl, Bertil; Hanning, Marianne; Westerling, Ragnar

    2016-01-01

    Background Several international studies suggest inequity in access to evidence-based heart failure (HF) care. Specifically, studies of ACE inhibitors (ACEIs) point to reduced ACEI access related to female sex, old age and socioeconomic position. Thus far, most studies have either been rather small, lacking diagnostic data, or lacking the possibility to account for several individual-based sociodemographic factors. Our aim was to investigate differences, which could reflect inequity in access to ACEIs based on sex, age, socioeconomic status or immigration status in Swedish patients with HF. Methods Individually linked register data for all Swedish adults hospitalised for HF in 2005–2010 (n=93 258) were analysed by multivariate regression models to assess the independent risk of female sex, high age, low employment status, low income level, low educational level or foreign country of birth, associated with lack of an ACEI dispensation within 1 year of hospitalisation. Adjustment for possible confounding was made for age, comorbidity, Angiotensin receptor blocker therapy, period and follow-up time. Results Analysis revealed an adjusted OR for no ACEI dispensation for women of 1.31 (95% CI 1.27 to 1.35); for the oldest patients of 2.71 (95% CI 2.53 to 2.91); and for unemployed patients of 1.59 (95% CI 1.46 to 1.73). Conclusions Access to ACEI treatment was reduced in women, older patients and unemployed patients. We conclude that access to ACEIs is inequitable among Swedish patients with HF. Future studies should include clinical data, as well as mortality outcomes in different groups. PMID:26261264

  2. Neprilysin Inhibitors in Cardiovascular Disease.

    PubMed

    Kang, Guson; Banerjee, Dipanjan

    2017-02-01

    Mortality from heart failure remains high despite advances in medical therapy over the last three decades. Angiotensin receptor-neprilysin inhibitor (ARNI) combinations are the latest addition to the heart failure medical armamentarium, which is built on the cornerstone regimen of beta blockers, angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers, and aldosterone antagonists. Recent trial data have shown a significant mortality benefit from ARNIs, which, as of May 2016, have now received a class I recommendation for use in patients with heart failure and reduced ejection fraction from the major American and European cardiology societies.

  3. Short term safety assessment of cilazapril.

    PubMed

    Coulter, D M

    1993-11-24

    To undertake an event monitoring study of cilazapril in general practice during the early marketing period, to provide some comparisons with other angiotensin converting enzyme inhibitors and to assess the monitoring method. The monitoring was undertaken in the Intensive Medicines Monitoring Programme. Cilazapril was prescribed for mild to moderate hypertension in 996 patients at a recommended dose of 2.5-5.0 mg daily. The monitoring period was six months and practitioners were asked to report all adverse events. A reaction profile was prepared and compared with profiles for lisinopril, enalapril and captopril. The chi-square test was applied to differences in proportions. There were 84 (8.4%) reports describing 133 adverse events; 124 (93%) were assessed as reactions. Withdrawals totalled 53 (5.3%). The most common reactions were cough (2.9%), nausea and vomiting (1.3%) and lethargy (1.1%). Cilazapril had a higher proportion of neurological reactions (p < 0.001) (mainly headache) but a lower proportion of skin reactions (p = 0.001) than the other ACE inhibitors. It also had relatively less diarrhoea and there were differences in the patterns of psychiatric reactions. Cilazapril has a similar reaction profile to other ACE inhibitors but this paper shows differences, some not previously reported, that may assist selection when prescribing. Although there was a high rate of reporting of known adverse reactions, other events were reported at a very low rate and spontaneous reporting is thus confirmed as an unreliable method of monitoring for unexpected adverse reactions.

  4. Heart failure.

    PubMed

    Metra, Marco; Teerlink, John R

    2017-10-28

    Heart failure is common in adults, accounting for substantial morbidity and mortality worldwide. Its prevalence is increasing because of ageing of the population and improved treatment of acute cardiovascular events, despite the efficacy of many therapies for patients with heart failure with reduced ejection fraction, such as angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), β blockers, and mineralocorticoid receptor antagonists, and advanced device therapies. Combined angiotensin receptor blocker neprilysin inhibitors (ARNIs) have been associated with improvements in hospital admissions and mortality from heart failure compared with enalapril, and guidelines now recommend substitution of ACE inhibitors or ARBs with ARNIs in appropriate patients. Improved safety of left ventricular assist devices means that these are becoming more commonly used in patients with severe symptoms. Antidiabetic therapies might further improve outcomes in patients with heart failure. New drugs with novel mechanisms of action, such as cardiac myosin activators, are under investigation for patients with heart failure with reduced left ventricular ejection fraction. Heart failure with preserved ejection fraction is a heterogeneous disorder that remains incompletely understood and will continue to increase in prevalence with the ageing population. Although some data suggest that spironolactone might improve outcomes in these patients, no therapy has conclusively shown a significant effect. Hopefully, future studies will address these unmet needs for patients with heart failure. Admissions for acute heart failure continue to increase but, to date, no new therapies have improved clinical outcomes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF.

    PubMed

    Böhm, Michael; Young, Robin; Jhund, Pardeep S; Solomon, Scott D; Gong, Jianjian; Lefkowitz, Martin P; Rizkala, Adel R; Rouleau, Jean L; Shi, Victor C; Swedberg, Karl; Zile, Michael R; Packer, Milton; McMurray, John J V

    2017-04-14

    Compared to heart failure patients with higher systolic blood pressure (SBP), those with lower SBP have a worse prognosis. To make matters worse, the latter patients often do not receive treatment with life-saving therapies that might lower blood pressure further. We examined the association between SBP and outcomes in the Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with an angiotensin-converting enzyme (ACE) inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF), as well as the effect of sacubitril/valsartan, compared with enalapril, according to baseline SBP. We analysed the effect of treatment on SBP and on the primary composite outcome (cardiovascular death or heart failure hospitalization), its components and all-cause death. We examined baseline SBP as a categorical (<110, 110 to < 120, 120 to < 130, 130 to < 140 and ≥140 mmHg) and continuous variable, as well as average in-trial SBP and time-updated SBP. All-cause and cardiovascular mortality rates were highest in patients with the lowest SBP whereas there was a U-shaped relationship between SBP and the rate of heart failure hospitalization. The benefit of sacubitril/valsartan over enalapril was consistent across all baseline SBP categories for all outcomes. For example, the sacubitril/valsartan versus enalapril hazard ratio for the primary endpoint was 0.88 (95%CI 0.74-1.06) in patients with a baseline SBP <110 mmHg and 0.81 (0.65-1.02) for those with a SBP ≥140 mmHg (P for interaction = 0.55). Symptomatic hypotension, study drug dose-reduction and discontinuation were more frequent in patients with a lower SBP. In PARADIGM-HF, patients with lower SBP at randomization, notably after tolerating full doses of both study drugs during a run-in period, were at higher risk but generally tolerated sacubitril/valsartan and had the same relative benefit over enalapril as patients with higher baseline SBP

  6. ACE Inhibition with Captopril Retards the Development of Signs of Neurodegeneration in an Animal Model of Alzheimer’s Disease

    PubMed Central

    AbdAlla, Said; Langer, Andreas; Fu, Xuebin; Quitterer, Ursula

    2013-01-01

    Increased generation of reactive oxygen species (ROS) is a significant pathological feature in the brains of patients with Alzheimer’s disease (AD). Experimental evidence indicates that inhibition of brain ROS could be beneficial in slowing the neurodegenerative process triggered by amyloid-beta (Abeta) aggregates. The angiotensin II AT1 receptor is a significant source of brain ROS, and AD patients have an increased brain angiotensin-converting enzyme (ACE) level, which could account for an excessive angiotensin-dependent AT1-induced ROS generation. Therefore, we analyzed the impact of ACE inhibition on signs of neurodegeneration of aged Tg2576 mice as a transgenic animal model of AD. Whole genome microarray gene expression profiling and biochemical analyses demonstrated that the centrally active ACE inhibitor captopril normalized the excessive hippocampal ACE activity of AD mice. Concomitantly, the development of signs of neurodegeneration was retarded by six months of captopril treatment. The neuroprotective profile triggered by captopril was accompanied by reduced amyloidogenic processing of the amyloid precursor protein (APP), and decreased hippocampal ROS, which is known to enhance Abeta generation by increased activation of beta- and gamma-secretases. Taken together, our data present strong evidence that ACE inhibition with a widely used cardiovascular drug could interfere with Abeta-dependent neurodegeneration. PMID:23959119

  7. ACE-1 experiment

    NASA Image and Video Library

    2013-06-24

    ISS036-E-019830 (24 June 2013) --- In the International Space Station’s Destiny laboratory, NASA astronaut Karen Nyberg, Expedition 36 flight engineer, speaks into a microphone while conducting a session with the Advanced Colloids Experiment (ACE)-1 sample preparation at the Light Microscopy Module (LMM) in the Fluids Integrated Rack / Fluids Combustion Facility (FIR/FCF). ACE-1 is a series of microscopic imaging investigations that uses the microgravity environment to examine flow characteristics and the evolution and ordering effects within a group of colloidal materials.

  8. Angiotensin-converting enzyme inhibitor and statin use and incident mobility limitation in community-dwelling older adults: the Health, Aging and Body Composition study.

    PubMed

    Gray, Shelly L; Boudreau, Robert M; Newman, Anne B; Studenski, Stephanie A; Shorr, Ronald I; Bauer, Douglas C; Simonsick, Eleanor M; Hanlon, Joseph T

    2011-12-01

    To evaluate whether the use of angiotensin-converting enzyme (ACE) inhibitors and statins is associated with a lower risk of incident mobility limitation in older community dwelling adults. Longitudinal cohort study. Health, Aging and Body Composition (Health ABC) study. Three thousand fifty-five participants who were well functioning at baseline (no mobility limitations). Summated standardized daily doses (low, medium, high) and duration of ACE inhibitor and statin use were computed. Mobility limitation (two consecutive self-reports of having any difficulty walking one-quarter of a mile or climbing 10 steps without resting) was assessed every 6 months after baseline. Multivariable Cox proportional hazards analyses were conducted, adjusting for demographics, health status, and health behaviors. At baseline, 15.2% used ACE inhibitors and 12.9% used statins; use of both was greater than 25% by Year 6. Over 6.5 years of follow-up, 49.8% had developed mobility limitation. In separate multivariable models, neither ACE inhibitor (multivariate hazard ratio (HR) = 0.95, 95% confidence interval (CI) = 0.82-1.09) nor statin use (multivariate HR = 1.02, 95% CI = 0.87-1.17) was associated with lower risk of mobility limitation. Similar findings were seen in analyses examining dose-response and duration-response relationships and a sensitivity analysis restricted to those with hypertension. ACE inhibitors and statins widely prescribed to treat hypertension and hypercholesterolemia, respectively, do not lower risk of mobility limitation, an important indicator of quality of life. © 2011, Copyright the Authors Journal compilation © 2011, The American Geriatrics Society.

  9. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials.

    PubMed

    Teo, Koon; Yusuf, Salim; Sleight, Peter; Anderson, Craig; Mookadam, Farouk; Ramos, Barbara; Hilbrich, Lutz; Pogue, Janice; Schumacher, Helmut

    2004-07-01

    Angiotensin-converting enzyme (ACE) inhibitors reduce mortality, myocardial infarction, stroke, heart failure, need for revascularization, nephropathy, and diabetes and its complications. Although angiotensin-II receptor blockers (ARBs) have been less extensively evaluated, theoretically they may have "protective" effects similar to those of ACE inhibitors, but with better tolerability. Currently, there is uncertainty about the role of ARBs when used alone or in combination with an ACE inhibitor in high-risk populations with controlled hypertension. Primary objectives of the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) are to determine if the combination of the ARB telmisartan and the ACE inhibitor ramipril is more effective than ramipril alone, and if telmisartan is at least as effective as ramipril. The Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease (TRANSCEND) will determine if telmisartan is superior to placebo in patients who are intolerant of ACE inhibitors. The primary outcome for both trials is the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. High-risk patients with coronary, peripheral, or cerebrovascular disease or diabetes with end-organ damage are being recruited and followed for 3.5 to 5.5 years in 2 parallel, randomized, double-blind clinical trials. Recruitment from 730 centers in 40 countries for ONTARGET (n = 25,620) was completed in July 2003. For TRANSCEND, 5776 patients (out of a projected total of 6000) have been recruited (by May 10, 2004). Baseline patient characteristics are comparable to the Heart Outcomes Prevention Evaluation (HOPE) trial, the basis of the design of the current study, confirming that patients are at high-risk.

  10. The relationship between angiotensin-converting enzyme (ACE) insertion (I) / deletion (D) polymorphism, serum ACE activity and bone mineral density (BMD) in older Chinese.

    PubMed

    Zhang, Ya-Feng; Wang, Hong; Cheng, Qiong; Qin, Ling; Tang, Nelson Ls; Leung, Ping-Chong; Kwok, Timothy Cy

    2017-01-01

    In this study, we set out to investigate the relationship between angiotensin-converting enzyme ( ACE) I/D polymorphism, serum ACE activity and bone mineral density (BMD) in older Chinese. A standardized, structured, face-to-face interview was performed to collect demographic information. BMD was measured using dual-energy X-ray absorptiometry (DXA). I/D genotypes of ACE were determined by polymerase chain reaction (PCR) amplification. Serum ACE activity was determined photometrically by a commercially available kinetic kit. Multiple linear regression analysis was used to examine the relationship between ACE I/D polymorphism, serum ACE activity and BMD. A total of 1567 males and 1760 females were selected for analyzing the relationship between ACE I/D polymorphism and BMD. There was no significant difference in spine BMD, total hip BMD and femur neck BMD among different ACE I/D genotypes both in males and females. A total of 1699 males and 1739 females were selected for analyzing the relationship between serum ACE activity and BMD. There was also no significant difference in spine BMD, total hip BMD and femur neck BMD among different serum ACE activity groups both in males and females. There was no relationship between ACE I/D polymorphism, serum ACE activity and BMD in older Chinese.

  11. Angiotensin converting enzyme (ACE) and neprilysin hydrolyze neuropeptides: a brief history, the beginning and follow-ups to early studies.

    PubMed

    Skidgel, Randal A; Erdös, Ervin G

    2004-03-01

    and to the very broad and beneficial therapeutic applications of ACE inhibitors.

  12. Role of ACE and PAI-1 Polymorphisms in the Development and Progression of Diabetic Retinopathy

    PubMed Central

    Saleem, Saba; Azam, Aisha; Maqsood, Sundus Ijaz; Muslim, Irfan; Bashir, Shaheena; Fazal, Nosheen; Riaz, Moeen; Ali, Syeda Hafiza Benish; Niazi, Muhammad Khizar; Ishaq, Mazhar; Waheed, Nadia Khalida; Qamar, Raheel; Azam, Maleeha

    2015-01-01

    In the present study we determined the association of angiotensin converting enzyme (ACE) and plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms with diabetic retinopathy (DR) and its sub-clinical classes in Pakistani type 2 diabetic patients. A total of 353 diabetic subjects including 160 DR and 193 diabetic non retinopathy (DNR) as well as 198 healthy controls were genotyped by allele specific polymerase chain reaction (PCR) for ACE Insertion/Deletion (ID) polymorphism, rs4646994 in intron 16 and PAI-1 4G/5G (deletion/insertion) polymorphism, rs1799768 in promoter region of the gene. To statistically assess the genotype-phenotype association, multivariate logistic regression analysis was applied to the genotype data of DR, DNR and control individuals as well as the subtypes of DR. The ACE genotype ID was found to be significantly associated with DR (p = 0.009, odds ratio (OR) 1.870 [95% confidence interval (CI) = 1.04–3.36]) and its sub-clinical class non-proliferative DR (NPDR) (p = 0.006, OR 2.250 [95% CI = 1.098–4.620]), while PAI polymorphism did not show any association with DR in the current cohort. In conclusion in Pakistani population the ACE ID polymorphism was observed to be significantly associated with DR and NPDR, but not with the severe form of the disease i.e. proliferative DR (PDR). PMID:26658948

  13. Perindopril increases the swallowing reflex by inhibiting substance P degradation and tyrosine hydroxylase activation in a rat model of dysphagia.

    PubMed

    Ikeda, Jun-ichi; Kojima, Natsuki; Saeki, Kohji; Ishihara, Miki; Takayama, Makoto

    2015-01-05

    Patients with hypertension have a high risk of ischemic stroke and subsequent stroke-associated pneumonia. Stroke-associated pneumonia is most likely to develop in patients with dysphagia. The present study was designed to compare the ameliorative effects of different treatments in rat model of dysphagia. Spontaneously hypertensive rats were treated with bilateral common carotid artery occlusion (BCAO) to induce chronic cerebral hypoperfusion causing disorders of the swallowing reflex. Angiotensin-converting enzyme (ACE) inhibitors (perindopril, imidapril and enalapril), an angiotensin II type 1-receptor blocker (losartan), a vasodilator (hydralazine) and an indirect dopamine agonist (amantadine) were dissolved in drinking water and administered to the rats for six weeks. The blood pressure, the swallowing reflex under anesthesia, the substance P content in the striatum and the tyrosine hydroxylase (TH) expression in the substantial nigra were measured. Compared to the vehicle control, the decrease in the swallowing reflex induced by BCAO was attenuated significantly by enalapril, imidapril and perindopril, but only slightly by losartan. Hydralazine had no effect on the swallowing reflex. Amantadine significantly attenuated the decreased swallowing reflex but increased the blood pressure. Cerebral hypoperfusion for six weeks decreased the TH expression and substance P level. Perindopril improved both the TH expressions and substance P level, but imidapril, enalapril and amantadine only improved the substance P level. The present findings indicate that perindopril could be useful for preventing dysphagia in the chronic stage of stroke by attenuating the decrease in TH expression and the decrease in the substance P level. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. The Aerosol/Cloud/Ecosystems Mission (ACE)

    NASA Technical Reports Server (NTRS)

    Schoeberl, Mark

    2008-01-01

    The goals and measurement strategy of the Aerosol/Cloud/Ecosystems Mission (ACE) are described. ACE will help to answer fundamental science questions associated with aerosols, clouds, air quality and global ocean ecosystems. Specifically, the goals of ACE are: 1) to quantify aerosol-cloud interactions and to assess the impact of aerosols on the hydrological cycle and 2) determine Ocean Carbon Cycling and other ocean biological processes. It is expected that ACE will: narrow the uncertainty in aerosol-cloud-precipitation interaction and quantify the role of aerosols in climate change; measure the ocean ecosystem changes and precisely quantify ocean carbon uptake; and, improve air quality forecasting by determining the height and type of aerosols being transported long distances. Overviews are provided of the aerosol-cloud community measurement strategy, aerosol and cloud observations over South Asia, and ocean biology research goals. Instruments used in the measurement strategy of the ACE mission are also highlighted, including: multi-beam lidar, multiwavelength high spectra resolution lidar, the ocean color instrument (ORCA)--a spectroradiometer for ocean remote sensing, dual frequency cloud radar and high- and low-frequency micron-wave radiometer. Future steps for the ACE mission include refining measurement requirements and carrying out additional instrument and payload studies.

  15. ACE2-Independent Action Of Presumed ACE2 Activators: Studies In Vivo, Ex Vivo and In Vitro

    PubMed Central

    Haber, Philipp K.; Ye, Minghao; Wysocki, Jan; Maier, Christoph; Haque, Syed K.; Batlle, Daniel

    2014-01-01

    Angiotensin converting enzyme 2, (ACE2), is a key enzyme in the metabolism of angiotensin II. 1-[[2-(dimetilamino)ethyl]amino]-4-(hidroximetil)-7-[[(4-metilfenil)sulfonil]oxi]-9H-xantona-9 (XNT)and Diminazene (DIZE)have been reported to exert various organ-protective effects that have been attributed to activation of ACE2. To test the effect of these compounds we studied Ang II degradation in vivo and in vitro as well as their effect on ACE2 activity in vivo and in vitro. In a model of Ang II induced acute hypertension, blood pressure recovery was markedly enhanced by XNT (slope with XNT -3.26±0.2 vs.-1.6±0.2 mmHg/min without XNT, p<0.01). After Ang II infusion, neither plasma nor kidney ACE2 activity was affected by XNT. Plasma Ang II and Ang (1-7) levels also were not significantly affected by XNT. The blood pressure lowering effect of XNT seen in WT animals was also observed in ACE2 KO mice (slope with XNT -3.09±0.30 mmHg/min vs. -1.28±0.22 mmHg/min without XNT, p<0.001). These findings show that the blood pressure lowering effect of XNT in Ang II induced hypertension cannot be due to activation of ACE2. In vitro and ex vivo experiments in both mice and rat kidney confirmed a lack of enhancement of ACE2 enzymatic activity by XNT and DIZE. Moreover, Ang II degradation in vitro and ex vivo was unaffected by XNT and DIZE. We conclude that the biologic effects of these compounds are ACE2 independent and should not be attributed to activation of this enzyme. PMID:24446061

  16. Circulating plasma vascular endothelial growth factor and microvascular complications of type 1 diabetes mellitus: the influence of ACE inhibition.

    PubMed

    Chaturvedi, N; Fuller, J H; Pokras, F; Rottiers, R; Papazoglou, N; Aiello, L P

    2001-04-01

    To determine whether circulating plasma vascular endothelial growth factor (VEGF) is elevated in the presence of diabetic microvascular complications, and whether the impact of angiotensin-converting enzyme (ACE) inhibitors on these complications can be accounted for by changes in circulating VEGF. Samples (299/354 of those with retinal photographs) from the EUCLID placebo-controlled clinical trial of the ACE inhibitor lisinopril in mainly normoalbuminuric non-hypertensive Type 1 diabetic patients were used. Albumin excretion rate (AER) was measured 6 monthly. Geometric mean VEGF levels by baseline retinopathy status, change in retinopathy over 2 years, and by treatment with lisinopril were calculated. No significant correlation was observed between VEGF at baseline and age, diabetes duration, glycaemic control, blood pressure, smoking, fibrinogen and von Willebrand factor. Mean VEGF concentration at baseline was 11.5 (95% confidence interval 6.0--27.9) pg/ml in those without retinopathy, 12.9 (6.0--38.9) pg/ml in those with non-proliferative retinopathy, and 16.1 (8.1--33.5) pg/ml in those with proliferative retinopathy (P = 0.06 for trend). Baseline VEGF was 15.2 pg/ml in those who progressed by at least one level of retinopathy by 2 years compared to 11.8 pg/ml in those who did not (P = 0.3). VEGF levels were not altered by lisinopril treatment. Results were similar for AER. Circulating plasma VEGF concentration is not strongly correlated with risk factor status or microvascular disease in Type 1 diabetes, nor is it affected by ACE inhibition. Changes in circulating VEGF cannot account for the beneficial effect of ACE inhibition on retinopathy.

  17. Comparison of the diabetes guidelines from the ADA/EASD and the AACE/ACE.

    PubMed

    Cornell, Susan

    To compare recent diabetes guideline updates from the American Diabetes Association-European Association for the Study of Diabetes (ADA/EASD) and the American Association of Clinical Endocrinologists-American College of Endocrinology (AACE/ACE). The ADA/EASD guideline continues to advocate a stepwise approach to glycemic control that initiates with metformin and intensifies treatment incrementally to dual and triple therapy at 3-month intervals until the patient is at their individualized goal. The AACE/ACE guideline provides a broader choice of first-line medications, with a suggested hierarchy of use, and it encourages initial dual and triple therapy if the glycated hemoglobin (A1C) level is high enough at diagnosis (7.5%-9.0% and >9.0%, respectively). Target A1C levels are higher in the ADA/EASD guideline (≤7.0%) compared with the AACE/ACE guideline (≤6.5%), although both statements indicate that targets should be adjusted to specific clinical scenarios based on safety. Both guidelines now include the new sodium-glucose cotransporter-2 inhibitors among their choices of acceptable glucose-lowering medications and endorse the overall cardiovascular and pancreatic safety of incretin therapies, and the safety of pioglitazone vis-a-vis bladder cancer. In practice, the ADA/EASD guidelines tend to be more user-friendly for general practitioners because of the simple stepwise intensification regimen, whereas the AACE/ACE guidelines are more commonly followed by specialists (endocrinologists) because of the more aggressive A1C targets. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  18. Drug Repositioning and Pharmacophore Identification in the Discovery of Hookworm MIF Inhibitors

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

    Y Cho; J Vermeire; J Merkel

    The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new pharmacophores. Hookworms are blood-feeding, intestinal nematode parasites that infect up to 600 million people worldwide. Vaccination with recombinant Ancylostoma ceylanicum macrophage migration inhibitory factor (rAceMIF) provided partial protection from disease, thus establishing a 'proof-of-concept' for targeting AceMIF to prevent or treat infection. A high-throughput screen (HTS) against rAceMIF identified six AceMIF-specific inhibitors. A nonsteroidal anti-inflammatory drug (NSAID), sodium meclofenamate, could be tested in an animal model to assess the therapeutic efficacy in treating hookworm disease. Furosemide, an FDA-approved diuretic, exhibited submicromolar inhibitionmore » of rAceMIF tautomerase activity. Structure-activity relationships of a pharmacophore based on furosemide included one analog that binds similarly to the active site, yet does not inhibit the Na-K-Cl symporter (NKCC1) responsible for diuretic activity.« less

  19. Effect of angiotensin-converting enzyme (ACE) gene polymorphism on progression of renal disease and the influence of ACE inhibition in IDDM patients: findings from the EUCLID Randomized Controlled Trial. EURODIAB Controlled Trial of Lisinopril in IDDM.

    PubMed

    Penno, G; Chaturvedi, N; Talmud, P J; Cotroneo, P; Manto, A; Nannipieri, M; Luong, L A; Fuller, J H

    1998-09-01

    We examined whether the ACE gene insertion/deletion (I/D) polymorphism modulates renal disease progression in IDDM and how ACE inhibitors influence this relationship. The EURODIAB Controlled Trial of Lisinopril in IDDM is a multicenter randomized placebo-controlled trial in 530 nonhypertensive, mainly normoalbuminuric IDDM patients aged 20-59 years. Albumin excretion rate (AER) was measured every 6 months for 2 years. Genotype distribution was 15% II, 58% ID, and 27% DD. Between genotypes, there were no differences in baseline characteristics or in changes in blood pressure and glycemic control throughout the trial. There was a significant interaction between the II and DD genotype groups and treatment on change in AER (P = 0.05). Patients with the II genotype showed the fastest rate of AER progression on placebo but had an enhanced response to lisinopril. AER at 2 years (adjusted for baseline AER) was 51.3% lower on lisinopril than placebo in the II genotype patients (95% CI, 15.7 to 71.8; P = 0.01), 14.8% in the ID group (-7.8 to 32.7; P = 0.2), and 7.7% in the DD group (-36.6 to 37.6; P = 0.7). Absolute differences in AER between placebo and lisinopril at 2 years were 8.1, 1.7, and 0.8 microg/min in the II, ID, and DD groups, respectively. The significant beneficial effect of lisinopril on AER in the II group persisted when adjusted for center, blood pressure, and glycemic control, and also for diastolic blood pressure at 1 month into the study. Progression from normoalbuminuria to microalbuminuria (lisinopril versus placebo) was 0.27 (0.03-2.26; P = 0.2) in the II group, and 1.30 (0.33-5.17; P = 0.7) in the DD group (P = 0.6 for interaction). Knowledge of ACE genotype may be of value in determining the likely impact of ACE inhibitor treatment.

  20. Angiotensin-converting Enzyme Inhibitor and Statin Medication Use and Incident Mobility Limitation in Community Older Adults. The Health, Aging and Body Composition Study

    PubMed Central

    Gray, Shelly L.; Boudreau, Robert M.; Newman, Anne B.; Studenski, Stephanie A.; Shorr, Ronald I; Bauer, Douglas C.; Simonsick, Eleanor M.; Hanlon, Joseph T

    2012-01-01

    Objective Angiotensin-converting enzyme (ACE) inhibitors and statin medications have been proposed as potential agents to prevent or delay physical disability; yet limited research has evaluated whether such use in older community dwelling adults is associated with a lower risk of incident mobility limitation. Design Longitudinal cohort study Setting Health, Aging and Body Composition (Health ABC) Participants 3055 participants who were well functioning at baseline (e.g., no mobility limitations). Measurements Summated standardized daily doses (low, medium and high) and duration of ACE inhibitor and statin use was computed. Mobility limitation (two consecutive self-reports of having any difficulty walking 1/4 mile or climbing 10 steps without resting) was assessed every 6 months after baseline. Multivariable Cox proportional hazard analyses were conducted adjusting for demographics, health status, and health behaviors. Results At baseline, ACE inhibitors and statins were used by 15.2% and 12.9%, respectively and both increased to over 25% by year 6. Over 6.5 years of follow-up, 49.8% had developed mobility limitation. In separate multivariable models, neither ACE inhibitor (multivariate hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.82–1.09) nor statin use (multivariate HR 1.02; 95% CI 0.87–1.17) was associated with a lower risk for mobility limitation. Similar findings were seen in analyses examining dose- and duration-response relationships and sensitivity analyses restricted to those with hypertension. Conclusions These findings indicate that ACE inhibitors and statins widely prescribed to treat hypertension and hypercholesterolemia, respectively do not lower risk of mobility limitation, an important life quality indicator. PMID:22092102

  1. ACE-1 experiment

    NASA Image and Video Library

    2013-06-24

    ISS036-E-019783 (24 June 2013) --- In the International Space Station’s Destiny laboratory, a fisheye lens attached to an electronic still camera was used to capture this image of NASA astronaut Karen Nyberg, Expedition 36 flight engineer, as she conducts a session with the Advanced Colloids Experiment (ACE)-1 sample preparation at the Light Microscopy Module (LMM) in the Fluids Integrated Rack / Fluids Combustion Facility (FIR/FCF). ACE-1 is a series of microscopic imaging investigations that uses the microgravity environment to examine flow characteristics and the evolution and ordering effects within a group of colloidal materials.

  2. ALTUS Cumulus Electrification Study (ACES)

    NASA Technical Reports Server (NTRS)

    Kim, Tony; Blakeslee, Richard; Russell, Larry W. (Technical Monitor)

    2002-01-01

    The ALTUS Cumulus Electrification Study (ACES) is an uninhabited aerial vehicle (UAV)-based project that will investigate thunderstorms in the vicinity of the Florida Everglades in August 2002. ACES is being conducted to both investigate storm electrical activity and its relationship to storm morphology, and validate Tropical Rainfall Measurement Mission (TRMM) satellite measurements. In addition, as part of NASA's UAV-based science demonstration program, this project will provide a scientifically useful demonstration of the utility and promise of UAV platforms for Earth science and applications observations. Part of the demonstration involves getting approvals from the Federal Aviation Administration and the NASA airworthiness flight safety review board. ACES will employ the ALTUS II aircraft, built by General Atomics - Aeronautical Systems, Inc. Key science objectives simultaneously addressed by ACES are to: (1) investigate lightning-storm relationships, (2) study storm electrical budgets, and (3) provide Lightning Imaging Sensor validation. The ACES payload, already developed and flown on ALTUS, includes electrical, magnetic, and optical sensors to remotely characterize the lightning activity and the electrical environment within and around thunderstorms. ACES will contribute important electrical and optical measurements not available from other sources. Also, the high altitude vantage point of the UAV observing platform (up to 55,000 feet) offers a useful 'cloud-top' perspective. By taking advantage of its slow flight speed (70 to 100 knots), long endurance, and high altitude flight, the ALTUS will be flown near, and when possible, above (but never into) thunderstorms for long periods of time, allowing investigations to be conducted over entire storm life cycles. In addition, concurrent ground-based observations will enable the UAV measurements to be more completely interpreted and evaluated in the context of the thunderstorm structure, evolution, and

  3. Comparative clinical evaluation of Boerhavia diffusa root extract with standard Enalapril treatment in Canine chronic renal failure

    PubMed Central

    Oburai, Nethaji Lokeswar; Rao, V. Vaikunta; Bonath, Ram Babu Naik

    2015-01-01

    Background: Complementing herbal drugs with conservative modern treatment could improve renal condition in canine chronic renal failure (CRF). Objective: In this study, clinical evaluation of Boerhavia diffusa root extract was carried out in CRF in dogs in comparison with standard enalapril. Materials and Methods: A total of 20 dogs of mixed breeds suffering from CRF from 1 to 2 months were divided into two groups (n = 10) and treated as follows: Group I - Enalapril at 0.5 mg/kg p.o. once daily for 90 days + amoxicillin and cloxacillin at 25 mg/kg i.m. once daily for 1-week; Group II - B. diffusa root extract at 500 mg p.o per dog daily for 90 days. Both groups were maintained on a supportive fluid therapy. The data were analyzed using paired t-test and one-way ANOVA followed by Dunnett's post-hoc test. Results: CRF caused a significant (P < 0.05) increase in systolic and diastolic blood pressure, serum creatinine, urea nitrogen, sodium, potassium, phosphorus, urinary protein, alkaline phosphatase (ALP), and glutamyl transferase (GGT). A significant (P < 0.05) decrease in hemoglobin and total erythrocyte count (TEC) was also observed. Nephrosonography revealed indistinct corticomedullary junction, altered renal architecture, hyper-echoic cortex, medulla, and sunken kidneys. Both the treatments significantly (P < 0.05) reduced systolic and diastolic blood pressure by day 30. Serum Creatinine, urea nitrogen, phosphorus, urinary protein, ALP, and GGT showed significant (P < 0.05) reduction by day 60 in both the treatments. However, potassium levels were normalized only by B. diffusa root extract treatment by day 30. Both the treatments failed to show a significant improvement in nephrosonographic picture even after 90 days posttreatment. Conclusion: In conclusion, the efficacy of B. diffusa root extract was comparable to standard enalapril treatment of CRF in dogs. PMID:26604549

  4. ACE/DD genotype is associated with hemostasis balance disturbances reflecting hypercoagulability and endothelial dysfunction in patients with untreated hypertension.

    PubMed

    Makris, T K; Stavroulakis, G A; Dafni, U G; Gialeraki, A E; Krespi, P G; Hatzizacharias, A N; Tsoukala, C G; Vythoulkas, J S; Kyriakidis, M K

    2000-11-01

    Angiotensin-converting enzyme (ACE) gene polymorphism has been associated with an increased incidence of myocardial infarction. Recent studies have investigated a potential influence of ACE gene polymorphism on fibrinolysis or endothelial function. It has been previously established that essential hypertension is accompanied by endothelial dysfunction and fibrinolytic balance disorders. The aim of our study was to study the relation between ACE gene polymorphism and fibrinolytic/hemostatic factors as well as endothelial cell damage markers in patients with hypertension. The following parameters were evaluated in 104 patients with previously untreated hypertension: plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) antigen, fibrinogen, D-dimer, and von Willebrand factor (vWF). The genotype of the ACE gene was also determined (by the polymerase chain reaction method), and patients were characterized according to the observed alleles as deletion/deletion (DD), insertion/insertion (II), or insertion/deletion (ID). Those with DD genotype (n = 42) had significantly higher plasma levels of PAI-1 antigen (P =. 012), tPA antigen (P =.0001), fibrinogen (P =.0002), D-dimer (P =. 0001) and vWF (P =.0004) compared with ID (n = 30) or II (n = 32) genotypes. The ACE gene genotypes appeared to be significant predictors for plasma PAI-1 antigen, tPA antigen, fibrinogen, D -dimer, and vWF even after adjustment for age, sex, body mass index, triglyceride and cholesterol levels, and blood pressure. Our findings suggest that the ACE/DD genotype is associated with hemostasis balance disturbances reflecting hypercoagulability and endothelial damage in patients with untreated hypertension.

  5. Influence of several peptidase inhibitors on the pro-inflammatory effects of substance P, capsaicin and collagenase.

    PubMed

    Damas, J; Bourdon, V; Liégeois, J F; Simmons, W H

    1996-11-01

    Injection of substance P (SP) in a rat hindpaw induced extravasation of 125I-labelled albumin in both hindpaws and salivation. Intravenous injection of SP dose-dependently increased vascular permeability. This latter effect was increased in rat paws by captopril, an inhibitor of angiotensin-converting enzyme (ACE), administered locally in combination with diprotin A, an inhibitor of an dipeptidyl(amino)peptidase IV (DAP IV) or phosphoramidon, an inhibitor of neutral endopeptidase (NEP). The increase in permeability induced by SP was inhibited by RP 67580, a NK-1-receptor antagonist. Intravenous injection of capsaicin induced labelled albumin extravasation in rat paws. This effect was increased by combination of captopril with diprotin A or phosphoramidon, but not by captopril associated with amastatin, an inhibitor of aminopeptidase M (AmM). It was suppressed by RP 67580. Injection of collagenase in rat paws triggered a swelling and a local plasma exudation. These responses were reduced by RP 67580 but not by RP 68651, its inactive enantiomer. They were increased by combination of captopril with diprotin A or phosphoramidon in normal rats. The potentiating effects of captopril and diprotin A were suppressed by RP 67580 in normal rats but did not develop in kininogen-deficient rats. The oedema induced by collagenase was also increased by lisinopril, another ACE inhibitor, administered locally in combination with apstatin, an inhibitor of aminopeptidase P (AmP). In rats pretreated by methysergide, collagenase-induced oedema was reduced and can be increased by captopril, by lisinopril, administered alone or by lisinopril associated with apstatin. It is concluded that SP is mainly inactivated in rat paws by ACE, DAP IV and NEP. In collagenase-induced oedema, a low amount of SP would be released from afferent nerve terminals by bradykinin formed in low amounts. Bradykinin is inactivated in rat paws by ACE and AmP. In collagenase-oedema, the pro-inflammatory effects of

  6. A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure

    PubMed Central

    McMurray, John; Packer, Milton; Desai, Akshay; Gong, Jianjian; Greenlaw, Nicola; Lefkowitz, Martin; Rizkala, Adel; Shi, Victor; Rouleau, Jean; Solomon, Scott; Swedberg, Karl; Zile, Michael R.; Andersen, Karl; Arango, Juan Luis; Arnold, Malcolm; Be˘lohlávek, Jan; Böhm, Michael; Boytsov, Sergey; Burgess, Lesley; Cabrera, Walter; Chen, Chen-Huan; Erglis, Andrejs; Fu, Michael; Gomez, Efrain; Gonzalez, Angel; Hagege, Albert-Alain; Katova, Tzvetana; Kiatchoosakun, Songsak; Kim, Kee-Sik; Bayram, Edmundo; Martinez, Felipe; Merkely, Bela; Mendoza, Iván; Mosterd, Arend; Negrusz-Kawecka, Marta; Peuhkurinen, Keijo; Ramires, Felix; Refsgaard, Jens; Senni, Michele; Sibulo, Antonio S.; Silva-Cardoso, José; Squire, Iain; Starling, Randall C.; Vinereanu, Dragos; Teerlink, John R.; Wong, Raymond

    2015-01-01

    Aims Although active-controlled trials with renin–angiotensin inhibitors are ethically mandated in heart failure with reduced ejection fraction, clinicians and regulators often want to know how the experimental therapy would perform compared with placebo. The angiotensin receptor-neprilysin inhibitor LCZ696 was compared with enalapril in PARADIGM-HF. We made indirect comparisons of the effects of LCZ696 with putative placebos. Methods and results We used the treatment-arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an ACE inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alternative) as the reference trial for comparison of an ARB to placebo. The hazard ratio of LCZ696 vs. a putative placebo was estimated through the product of the hazard ratio of LCZ696 vs. enalapril (active-control) and that of the historical active-control (enalapril or candesartan) vs. placebo. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 34–50%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 21–44%; P < 0.0001) and heart failure hospitalization (49%, 39–58%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 15–39%; P < 0.0001). Putative placebo analyses based on CHARM-Alternative gave relative risk reductions of 39% (95%CI 27–48%; P < 0.0001) for the composite outcome of cardiovascular death or heart failure hospitalization, 32% (95%CI 16–45%; P < 0.0001) for cardiovascular death, 46% (33–56%; P < 0.0001) for heart failure hospitalization, and 26% (95%CI 11–39%; P < 0.0001) for all-cause mortality. Conclusion These indirect comparisons of LCZ696 with a putative placebo show that the strategy of combined angiotensin

  7. Apricot and other seed stones: amygdalin content and the potential to obtain antioxidant, angiotensin I converting enzyme inhibitor and hypocholesterolemic peptides.

    PubMed

    García, M C; González-García, E; Vásquez-Villanueva, R; Marina, M L

    2016-11-09

    Stones from olives and Prunus genus fruits are cheap and sustainable sources of proteins and could be potential sources of bioactive peptides. The main limitation to the use of these seeds is the presence of amygdalin. This work proposes to determine amygdalin in olive and Prunus seeds and in protein isolates obtained from them. Moreover, antioxidant, angiotensin I converting enzyme (ACE) inhibitor, and hypocholesterolemic properties will be evaluated in hydrolysates obtained from these seeds. Despite some seeds contained amygdalin, all protein isolates were free of this substance. Two different procedures to obtain bioactive peptides from protein isolates were examined: gastrointestinal digestion and processing with Alcalase, Flavourzyme or Thermolysin. Higher antioxidant, ACE inhibitor and hypocholesterolemic activities were observed when proteins were processed with Alcalase, Flavourzyme or Thermolysin. The highest antioxidant and ACE inhibitor capacities were observed for the Prunus genus seed hydrolysates while the highest capacity to reduce micellar cholesterol solubility was observed for the apricot and olive seed hydrolysates.

  8. Role of angiotensin converting enzyme in the vascular effects of an endopeptidase 24.15 inhibitor.

    PubMed Central

    Telford, S E; Smith, A I; Lew, R A; Perich, R B; Madden, A C; Evans, R G

    1995-01-01

    1. We investigated the role of angiotensin converting enzyme (ACE) in the cardiovascular effects of N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP), a peptidase inhibitor selective for metalloendopeptidase (EP) E.C. 3.4.24.15. 2. In conscious rabbits, cFP (5 mg kg-1, i.v.) markedly slowed the degradation of [3H]-bradykinin, potentiated the depressor response to right atrial administration of bradykinin (10-1000 ng kg-1), and inhibited the pressor response to right atrial angiotensin I (10-100 ng kg-1). In each of these respects, the effects of cFP were indistinguishable from those of the ACE inhibitor, captopril (0.5 mg plus 10 mg kg-1h-1 i.v.). Furthermore, the effects of combined administration of cFP and captopril were indistinguishable from those of captopril alone. 3. In experimentally naive anaesthetized rats, cFP administration (9.3 mg kg-1, i.v.) was followed by a moderate but sustained fall in arterial pressure of 13 mmHg. However, in rats pretreated with bradykinin (50 micrograms kg-1) a more pronounced fall of 30 mmHg was observed. Captopril (5 mg kg-1) had similar hypotensive effects to those of cFP, and cFP had no effect when it was administered after captopril. 4. CFP displaced the binding of [125I]-351A (the p-hydroxybenzamidine derivative of lisinopril) from preparations of rat plasma ACE and solubilized lung membrane ACE (KD = 1.2 and 0.14 microM respectively), and inhibited rat plasma ACE activity (KI = 2.4 microM). Addition of phosphoramidon (10 microM), an inhibitor of a range of metalloendopeptidases, including neutral endopeptidase (E.C.3.4.24.11), markedly reduced the potency of cFP in these systems.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7620708

  9. Risk of hyperkalemia in patients with moderate chronic kidney disease initiating angiotensin converting enzyme inhibitors or angiotensin receptor blockers: a randomized study

    PubMed Central

    2013-01-01

    Background Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are renoprotective but both may increase serum potassium concentrations in patients with chronic kidney disease (CKD). The proportion of affected patients, the optimum follow-up period and whether there are differences between drugs in the development of this complication remain to be ascertained. Methods In a randomized, double-blind, phase IV, controlled, crossover study we recruited 30 patients with stage 3 CKD under restrictive eligibility criteria and strict dietary control. With the exception of withdrawals, each patient was treated with olmesartan and enalapril separately for 3 months each, with a 1-week wash-out period between treatments. Patients were clinically assessed on 10 occasions via measurements of serum and urine samples. We used the Cochran–Mantel–Haenszel statistics for comparison of categorical data between groups. Comparisons were also made using independent two-sample t-tests and Welch’s t-test. Analysis of variance (ANOVA) was performed when necessary. We used either a Mann–Whitney or Kruskal-Wallis test if the distribution was not normal or the variance not homogeneous. Results Enalapril and olmesartan increased serum potassium levels similarly (0.3 mmol/L and 0.24 mmol/L respectively). The percentage of patients presenting hyperkalemia higher than 5 mmol/L did not differ between treatments: 37% for olmesartan and 40% for enalapril. The mean e-GFR ranged 46.3 to 48.59 ml/mint/1.73 m2 in those treated with olmesartan and 46.8 to 48.3 ml/mint/1.73 m2 in those with enalapril and remained unchanged at the end of the study. The decreases in microalbuminuria were also similar (23% in olmesartan and 29% in enalapril patients) in the 4 weeks time point. The percentage of patients presenting hyperkalemia, even after a two month period, did not differ between treatments. There were no appreciable changes in sodium and potassium urinary excretion

  10. Design, synthesis, and antihypertensive activity of curcumin-inspired compounds via ACE inhibition and vasodilation, along with a bioavailability study for possible benefit in cardiovascular diseases

    PubMed Central

    Zhuang, Xiao-dong; Liao, Li-zhen; Dong, Xiao-bian; Hu, Xun; Guo, Yue; Du, Zhi-min; Liao, Xin-xue; Wang, Li-chun

    2016-01-01

    This study describes the synthesis of a novel series of curcumin-inspired compounds via a facile synthetic route. The structures of these derivatives were ascertained using various spectroscopic and analytic techniques. The pharmacological effects of the target analogs were assessed by assaying their inhibition of angiotensin-converting enzyme (ACE). All of the synthesized derivatives exhibited considerable inhibition of ACE, with half-maximal inhibitory concentrations ranging from 1.23 to 120.32 μM. In a docking analysis with testicular ACE (tACE), the most promising inhibitor (4j) was efficiently accommodated in the deep cleft of the protein cavity, making close interatomic contacts with Glu162, His353, and Ala356, comparable with lisinopril. Compounds 4i, 4j, 4k, and 4l were further selected for determination of their vasodilator activity (cardiac output and stroke volume) on isolated rat hearts using the Langendorff technique. The bioavailability of compound 4j was determined in experimental mice. PMID:26792980

  11. Design, synthesis, and antihypertensive activity of curcumin-inspired compounds via ACE inhibition and vasodilation, along with a bioavailability study for possible benefit in cardiovascular diseases.

    PubMed

    Zhuang, Xiao-Dong; Liao, Li-Zhen; Dong, Xiao-Bian; Hu, Xun; Guo, Yue; Du, Zhi-Min; Liao, Xin-Xue; Wang, Li-Chun

    2016-01-01

    This study describes the synthesis of a novel series of curcumin-inspired compounds via a facile synthetic route. The structures of these derivatives were ascertained using various spectroscopic and analytic techniques. The pharmacological effects of the target analogs were assessed by assaying their inhibition of angiotensin-converting enzyme (ACE). All of the synthesized derivatives exhibited considerable inhibition of ACE, with half-maximal inhibitory concentrations ranging from 1.23 to 120.32 μM. In a docking analysis with testicular ACE (tACE), the most promising inhibitor (4j) was efficiently accommodated in the deep cleft of the protein cavity, making close interatomic contacts with Glu162, His353, and Ala356, comparable with lisinopril. Compounds 4i, 4j, 4k, and 4l were further selected for determination of their vasodilator activity (cardiac output and stroke volume) on isolated rat hearts using the Langendorff technique. The bioavailability of compound 4j was determined in experimental mice.

  12. Comparison of the effects of candesartan cilexetil and enalapril maleate on right ventricular myocardial remodeling in dogs with experimentally induced pulmonary stenosis.

    PubMed

    Yamane, Tsuyoshi; Fujii, Yoko; Orito, Kensuke; Osamura, Kaori; Kanai, Takao; Wakao, Yoshito

    2008-12-01

    To compare the effects of candesartan cilexetil and enalapril maleate on right ventricular myocardial remodeling in dogs with experimentally induced pulmonary stenosis. 24 Beagles. 18 dogs underwent pulmonary arterial banding (PAB) to induce right ventricular pressure overload, and 6 healthy dogs underwent sham operations (thoracotomy only [sham-operated group]). Dogs that underwent PAB were allocated to receive 1 of 3 treatments (6 dogs/group): candesartan (1 mg/kg, PO, q 24 h [PABC group]), enalapril (0.5 mg/kg, PO, q 24 h [PABE group]), or no treatment (PABNT group). Administration of treatments was commenced the day prior to surgery; control dogs received no cardiac medications. Sixty days after surgery, right ventricular wall thickness was assessed echocardiographically and plasma renin activity, angiotensin-converting enzyme activity, and angiotensin I and II concentrations were assessed; all dogs were euthanatized, and collagenous fiber area, cardiomyocyte diameter, and tissue angiotensin-converting enzyme and chymase-like activities in the right ventricle were evaluated. After 60 days of treatment, right ventricular wall thickness, cardiomyocyte diameter, and collagenous fiber area in the PABNT and PABE groups were significantly increased, compared with values in the PABC and sham-operated groups. Chymase-like activity was markedly greater in the PABE group than in other groups. Results indicated that treatment with candesartan but not enalapril effectively prevented myocardial remodeling in dogs with experimentally induced subacute right ventricular pressure overload.

  13. Milk-derived peptide Val-Pro-Pro (VPP) inhibits obesity-induced adipose inflammation via an angiotensin-converting enzyme (ACE) dependent cascade.

    PubMed

    Sawada, Yoko; Sakamoto, Yuri; Toh, Mariko; Ohara, Nozomi; Hatanaka, Yuiko; Naka, Ayano; Kishimoto, Yoshimi; Kondo, Kazuo; Iida, Kaoruko

    2015-12-01

    This study aimed to examine the effects of Val-Pro-Pro (VPP), a food-derived peptide with an angiotensin-converting enzyme (ACE) inhibitory property, on obesity-linked insulin resistance, and adipose inflammation in vivo and in vitro. C57BL/6J mice were fed high-fat high-sucrose diet and VPP (0.1% in water) for 4 months. For in vitro analysis, coculture of 3T3-L1 adipocytes overexpressing either ACE (3T3-ACE) or green fluorescent protein (3T3-GFP) and RAW264 macrophages was conducted with VPP. In diet-induced obese mice, VPP improved insulin sensitivity, concomitant with a significant decrease in tumor necrosis factor α (TNF-α) and IL-1β expression in adipose tissue, with a tendency (p = 0.06) toward decreased CC chemokine ligand 5 expression. Additionally, VPP administration inhibited macrophage accumulation and activation in fat tissues. In vitro, VPP attenuated TNF-α mRNA induced by ACE overexpression in 3T3-L1 adipocytes. TNF-α and IL-1β expression decreased following VPP treatment of RAW264 macrophage and 3T3-ACE adipocyte cocultures, but not in RAW264-3T3-GFP adipocyte cocultures. Our data suggest that VPP inhibits adipose inflammation in the interaction between adipocytes and macrophages, acting as an ACE inhibitor, thereby improving obesity-related insulin resistance. Thus, ingestion of VPP may be a viable protective and therapeutic strategy for insulin resistance and obesity-associated adipose inflammation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Efficacy of lycopene on modulation of renal antioxidant enzymes, ACE and ACE gene expression in hyperlipidaemic rats.

    PubMed

    Khan, Nazish Iqbal; Noori, Shafaq; Mahboob, Tabassum

    2016-07-01

    We aimed to evaluate the efficacy of lycopene on renal tissue antioxidant enzymes and angiotensin converting enzyme (ACE) gene expression and serum activity in diet-induced hyperlipidaemia. Thirty-two female Wistar albino rats (200-250 g weight), 5-6 months of age, were randomly selected and divided into four groups. Group I received normal diet; group II received 24 g high fat diet/100 g of daily diet; group III received 24 g high fat diet/100 g daily diet and 200 ml of lycopene extract (twice a week) for 8 weeks; and group IV received 200 ml oral lycopene extract twice a week for 8 weeks. A marked increase was observed in plasma urea and creatinine levels, serum C-reactive protein, kidney weight, tissue renal malonyldialdehyde level, ACE gene expression and serum level, while a decrease catalase level among hyperlipidaemic rats was observed. Histologically, interstitial inflammation and proliferation was seen. Lycopene supplementation significantly decreased plasma urea and creatinine, serum ACE, renal tissue malonyldialdehyde level and C-reactive protein level, while it increased tissue antioxidant enzymes level and total protein. Tissue inflammation and proliferation was improved. This finding suggests that supplementation of lycopene is effective for renal antioxidant enzymes, ACE gene expression and ACE serum level in hyperlipidaemic rats. © The Author(s) 2016.

  15. (99m)Tc-labeled gastrins of varying peptide chain length: Distinct impact of NEP/ACE-inhibition on stability and tumor uptake in mice.

    PubMed

    Kaloudi, Aikaterini; Nock, Berthold A; Lymperis, Emmanouil; Krenning, Eric P; de Jong, Marion; Maina, Theodosia

    2016-06-01

    In situ inhibition of neutral endopeptidase (NEP) has been recently shown to impressively increase the bioavailability and tumor uptake of biodegradable gastrin radioligands. Furthermore, angiotensin converting enzyme (ACE) has been previously shown to cleave gastrin analogs in vitro. In the present study, we have assessed the effects induced by single or dual NEP/ACE-inhibition on the pharmacokinetic profile of three (99m)Tc-labeled gastrins of varying peptide chain length: [(99m)Tc]SG6 ([(99m)Tc-N4-Gln(1)]gastrin(1-17)), [(99m)Tc]DG2 ([(99m)Tc-N4-Gly(4),DGlu(5)]gastrin(4-17)) and [(99m)Tc]DG4 ([(99m)Tc-N4-DGlu(10)]gastrin(10-17)). Mouse blood samples were collected 5min after injection of each of [(99m)Tc]SG6/DG2/DG4 together with: a) vehicle, b) the NEP-inhibitor phosphoramidon (PA), c) the ACE-inhibitor lisinopril (Lis), or d) PA plus Lis and were analyzed by RP-HPLC for radiometabolite detection. Biodistribution was studied in SCID mice bearing A431-CCK2R(+/-) xenografts at 4h postinjection (pi). [(99m)Tc]SG6 or [(99m)Tc]DG4 was coinjected with either vehicle or the above described NEP/ACE-inhibitor regimens; for [(99m)Tc]DG2 control and PA animal groups were only included. Treatment of mice with PA induced significant stabilization of (99m)Tc-radiotracers in peripheral blood, while treatment with Lis or Lis+PA affected the stability of des(Glu)5 [(99m)Tc]DG4 only. In line with these findings, PA coinjection led to notable amplification of tumor uptake of radiopeptides compared to controls (P<0.01). Only [(99m)Tc]DG4 profited by single Lis (2.06±0.39%ID/g vs 0.99±0.13%ID/g in controls) or combined Lis+PA coinjection (8.91±1.61%ID/g vs 4.89±1.33%ID/g in PA-group). Furthermore, kidney uptake remained favourably low and unaffected by PA and/or Lis coinjection only in the case of [(99m)Tc]DG4 (<1.9%ID/g) resulting in the most optimal tumor-to-kidney ratios. In situ NEP/ACE-inhibition diversely affected the in vivo profile of (99m)Tc-radioligands based on

  16. Desert Dust Layers Over Polluted Marine Boundary Layers: ACE-2 Measurements and ACE-Asia Plans

    NASA Technical Reports Server (NTRS)

    Russell, Philip B.; Schmid, B.; Livingston, J. M.; Redemann, J.; Bergstrom, R. W.; Condon, Estelle P. (Technical Monitor)

    2000-01-01

    Aerosols in ACE-Asia are expected to have some commonalties with those in ACE-2, along with important differences. Among the commonalities are occurrences of desert dust layers over polluted marine boundary layers. Differences include the nature of the dust (yellowish in the East Asia desert outflow, vs. reddish-brown in the Sahara Outflow measured in ACE-2) and the composition of boundary-layer aerosols (e.g., more absorbing, soot and organic aerosol in-the Asian plume, caused by coal and biomass burning, with limited controls). In this paper we present ACE-2 measurements and analyses as a guide to our plans for ACE-2 Asia. The measurements include: (1) Vertical profiles of aerosol optical depth and extinction (380-1558 nm), and of water vapor column and concentration, from the surface through the elevated desert dust, measured by the 14-channel Ames Airborne Tracking Sunphotometer (AATS-14); (2) Comparisons of airborne and shipborne sunphotometer optical depths to satellite-retrieved values, with and without desert dust; (3) Comparisons between airborne Sunphotometer optical depth and extinction spectra and those derived from coincident airborne in situ measurements of aerosol size distribution, scattering and absorption; (4) Comparisons between size distributions measured in situ and retrieved from sunphotometer optical depth spectra; (5) Comparisons between aerosol single scattering albedo values obtained by several techniques, using various combinations of measurements of backscatter, extinction, size distribution, scattering, absorption, and radiative flux. We show how analyses of these data can be used to address questions important to ACE-Asia, such as: (1) How do dust and other absorbing aerosols affect the accuracy of satellite optical depth retrievals? How important are asphericity effects? (2) How important are supermicron dust and seasalt aerosols to overall aerosol optical depth and radiative forcing? How well are these aerosols sampled by aircraft

  17. The Atmospheric Chemistry Experiment (ACE): Status and Latest Results

    NASA Astrophysics Data System (ADS)

    Bernath, P. F.; Boone, C. D.; McElroy, C. T.

    2017-12-01

    ACE (also known as SCISAT) is making a comprehensive set of simultaneous measurements of numerous trace gases, thin clouds, aerosols and temperature by solar occultation from a satellite in low earth orbit. A high inclination (74°) orbit gives ACE coverage of tropical, mid-latitudes and polar regions. The primary instrument is a high-resolution (0.02 cm-1) infrared Fourier Transform Spectrometer (FTS) operating in the 750-4400 cm-1 region, which provides the vertical distribution of trace gases, and the meteorological variables of temperature and pressure. A second instrument, a dual spectrophotometer called MAESTRO, extends the wavelength coverage to the 400-1000 nm spectral region. Aerosols and clouds are being monitored through the extinction of solar radiation using two filtered imagers and by MAESTRO as well as by their infrared spectra. After 14 years in orbit, the ACE is still operating well. A short overview of the ACE mission will be presented (see http://www.ace.uwaterloo.ca for more information). The current version (v. 3.5/3.6) of ACE-FTS processing includes more than 30 molecules and twenty isotopologues; v.3.5/3.6 is now available in near-real time. This talk will focus on recent ACE results and the new version 4.0 of ACE-FTS processing.

  18. ACE Gene in Egyptian Ischemic Stroke Patients.

    PubMed

    Mostafa, Magdy A; El-Nabiel, Lobna M; Fahmy, Nagia Aly; Aref, Hany; Shreef, Edrees; Abd El-Tawab, Fathy; Abdulghany, Osama M

    2016-09-01

    Angiotensin-1-converting enzyme (ACE) is a crucial player in vascular homeostasis and in the pathogenesis of atherosclerosis and hypertension. The present study was conducted to determine whether there is an association between the ACE insertion/deletion (I/D) polymorphism and ischemic stroke in Egyptian population. Also, we analyzed the ACE gene I/D polymorphism as a risk factor for small-vessel (SV) versus large-vessel (LV) disease. Sixty patients with ischemic stroke were included: 30 with SV disease and 30 with LV disease. In addition, a control group of 30 apparent healthy subjects were studied. Clinical assessment, computed tomography, magnetic resonance imaging brain, and genetic study using the polymerase chain reaction of ACE gene were done for all subjects. We found that the distribution of ACE gene polymorphism frequency was significantly different between the 3 groups. The DD genotype was far more common in stroke patients compared to controls. It was also significantly more common in each of the patient groups compared to controls but rather similar in the 2 patient groups with SV and LV diseases. We found that the ACE gene deletion/deletion genotype is common in Egyptian patients with non-cardioembolic ischemic stroke but does not appear to be specific neither to SV nor to LV disease. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  19. Regulation of the aceI multidrug efflux pump gene in Acinetobacter baumannii.

    PubMed

    Liu, Qi; Hassan, Karl A; Ashwood, Heather E; Gamage, Hasinika K A H; Li, Liping; Mabbutt, Bridget C; Paulsen, Ian T

    2018-06-01

    To investigate the function of AceR, a putative transcriptional regulator of the chlorhexidine efflux pump gene aceI in Acinetobacter baumannii. Chlorhexidine susceptibility and chlorhexidine induction of aceI gene expression were determined by MIC and quantitative real-time PCR, respectively, in A. baumannii WT and ΔaceR mutant strains. Recombinant AceR was prepared as both a full-length protein and as a truncated protein, AceR (86-299), i.e. AceRt, which has the DNA-binding domain deleted. The binding interaction of the purified AceR protein and its putative operator region was investigated by electrophoretic mobility shift assays and DNase I footprinting assays. The binding of AceRt with its putative ligand chlorhexidine was examined using surface plasmon resonance and tryptophan fluorescence quenching assays. MIC determination assays indicated that the ΔaceI and ΔaceR mutant strains both showed lower resistance to chlorhexidine than the parental strain. Chlorhexidine-induced expression of aceI was abolished in a ΔaceR background. Electrophoretic mobility shift assays and DNase I footprinting assays demonstrated chlorhexidine-stimulated binding of AceR with two sites upstream of the putative aceI promoter. Surface plasmon resonance and tryptophan fluorescence quenching assays suggested that the purified ligand-binding domain of the AceR protein was able to bind with chlorhexidine with high affinity. This study provides strong evidence that AceR is an activator of aceI gene expression when challenged with chlorhexidine. This study is the first characterization, to our knowledge, of a regulator controlling expression of a PACE family multidrug efflux pump.

  20. FIR ACE samples

    NASA Image and Video Library

    2014-06-04

    ISS040-E-007368 (5 June 2014) --- NASA astronaut Reid Wiseman, Expedition 40 flight engineer, works with Advanced Colloids Experiment (ACE) samples in the Destiny laboratory of the International Space Station.

  1. 5 years after an ACE: what happens then?

    PubMed

    Chong, Clara; Featherstone, Neil; Sharif, Shazia; Cherian, Abraham; Cuckow, Peter; Mushtaq, Imran; De Coppi, Paolo; Cross, Kate; Curry, Joseph

    2016-04-01

    Antegrade continence enema (ACE) revolutionised the lives of children with chronic constipation and soiling. Parents often ask how long the ACE will be required. We looked at our patients 5 years after ACE formation to answer the question. We reviewed clinical notes of all patients undergoing ACE procedure during January 1990 to December 2010. Only patients with >5 years follow-up were included. Data are given as median (range). 133 patients were included with >5 years of follow-up. Primary pathology was anorectal anomaly (ARA) 64 (48%); spinal dysraphism (SD) 40 (30%); functional constipation (FC) 14 (10%); Hirschsprung's Disease (HD) 10 (8%) and others 5 (4%). Median follow-up was 7 years (5-17 years). Overall 74% still use their ACE; whilst 26% no longer access their stoma, of whom 47% recovered normal colonic function. 50% of HD patient recover colonic function. FC has the highest failure rate at 21%. Overall 86% achieved excellent clinical outcome with 74% of patient still using their ACE at 5 years. HD has the highest recovery rate of 50%. FC has a more unreliable clinical outcome with 21% recovered colonic function and 21% failed. Outcome varied dependent on the background diagnosis.

  2. ACE insertion/deletion polymorphism and submaximal exercise hemodynamics in postmenopausal women.

    PubMed

    Hagberg, James M; McCole, Steve D; Brown, Michael D; Ferrell, Robert E; Wilund, Kenneth R; Huberty, Andrea; Douglass, Larry W; Moore, Geoffrey E

    2002-03-01

    We sought to determine whether the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism is associated with submaximal exercise cardiovascular hemodynamics. Postmenopausal healthy women (20 sedentary, 20 physically active, 22 endurance athletes) had cardiac output (acetylene rebreathing) measured during 40, 60, and 80% VO(2 max) exercise. The interaction of ACE genotype and habitual physical activity (PA) level was significantly associated with submaximal exercise systolic blood pressure, with only sedentary women exhibiting differences among genotypes. No significant effects of ACE genotype or its interaction with PA levels was observed for submaximal exercise diastolic blood pressure. ACE genotype was significantly associated with submaximal exercise heart rate (HR) with ACE II having approximately 10 beats/min higher HR than ACE ID/DD genotype women. ACE genotype did not interact significantly with habitual PA level to associate with submaximal exercise HR. ACE genotype was not independently, but was interactively with habitual PA levels, associated with differences in submaximal exercise cardiac output and stroke volume. For cardiac output, ACE II genotype women athletes had ~25% greater cardiac output than ACE DD genotype women athletes, whereas for stroke volume genotype-dependent differences were observed in both the physically active and athletic women. ACE genotype was not significantly associated, either independently or interactively with habitual PA levels, with submaximal exercise total peripheral resistance or arteriovenous O(2) difference. Thus the common ACE locus polymorphic variation is associated with many submaximal exercise cardiovascular hemodynamic responses.

  3. Inhibitors of endopeptidase and angiotensin-converting enzyme lead to an amplification of the morphological changes and an upregulation of the substance P system in a muscle overuse model.

    PubMed

    Song, Yafeng; Stål, Per S; Yu, Ji-Guo; Lorentzon, Ronny; Backman, Clas; Forsgren, Sture

    2014-04-11

    We have previously observed, in studies on an experimental overuse model, that the tachykinin system may be involved in the processes of muscle inflammation (myositis) and other muscle tissue alterations. To further evaluate the significance of tachykinins in these processes, we have used inhibitors of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), substances which are known to terminate the activity of various endogenously produced substances, including tachykinins. Injections of inhibitors of NEP and ACE, as well as the tachykinin substance P (SP), were given locally outside the tendon of the triceps surae muscle of rabbits subjected to marked overuse of this muscle. A control group was given NaCl injections. Evaluations were made at 1 week, a timepoint of overuse when only mild inflammation and limited changes in the muscle structure are noted in animals not treated with inhibitors. Both the soleus and gastrocnemius muscles were examined morphologically and with immunohistochemistry and enzyme immunoassay (EIA). A pronounced inflammation (myositis) and changes in the muscle fiber morphology, including muscle fiber necrosis, occurred in the overused muscles of animals given NEP and ACE inhibitors. The morphological changes were clearly more prominent than for animals subjected to overuse and NaCl injections (NaCl group). A marked SP-like expression, as well as a marked expression of the neurokinin-1 receptor (NK-1R) was found in the affected muscle tissue in response to injections of NEP and ACE inhibitors. The concentration of SP in the muscles was also higher than that for the NaCl group. The observations show that the local injections of NEP and ACE inhibitors led to marked SP-like and NK-1R immunoreactions, increased SP concentrations, and an amplification of the morphological changes in the tissue. The injections of the inhibitors thus led to a more marked myositis process and an upregulation of the SP system. Endogenously produced

  4. ACE and AGTR1 polymorphisms in elite rhythmic gymnastics.

    PubMed

    Di Cagno, Alessandra; Sapere, Nadia; Piazza, Marina; Aquino, Giovanna; Iuliano, Enzo; Intrieri, Mariano; Calcagno, Giuseppe

    2013-02-01

    In the angiotensin-converting enzyme (ACE) gene, Alu deletion, in intron 16, is associated with higher concentrations of ACE serum activity and this may be associated with elite sprint and power performance. The Alu insertion is associated with lower ACE levels and this could lead to endurance performance. Moreover, recent studies have identified a single-nucleotide polymorphism of the angiotensin type 1 receptor gene AGTR1, which seems to be related to ACE activity. The aim of this study was to examine the involvement of the ACE and the AGTR1 gene polymorphisms in 28 Italian elite rhythmic gymnasts (age range 21 ± 7.6 years), and compare them to 23 middle level rhythmic gymnasts (age range 17 ± 10.9 years). The ACE D allele was significantly more frequent in elite athletes than in the control population (χ(2)=4.07, p=0.04). Comparisons between the middle level and elite athletes revealed significant differences (p<0.0001) for the ACE DD genotype (OR=6.48, 95% confidence interval=1.48-28.34), which was more frequent in elite athletes. There were no significant differences in the AGTR1 A/C genotype or allele distributions between the middle level and elite athletes. In conclusion, the ACE D allele genotype could be a contributing factor to high-performance rhythmic gymnastics that should be considered in athlete development and could help to identify which skills should be trained for talent promotion.

  5. Brain ACE2 shedding contributes to the development of neurogenic hypertension

    PubMed Central

    Chhabra, Kavaljit H.; Lazartigues, Eric

    2015-01-01

    Rationale Over-activity of the brain Renin Angiotensin System (RAS) is a major contributor to neurogenic hypertension. While over-expression of Angiotensin-Converting Enzyme type 2 (ACE2) has been shown to be beneficial in reducing hypertension by transforming Angiotensin (Ang)-II into Ang-(1-7), several groups have reported decreased brain ACE2 expression and activity during the development of hypertension. Objective We hypothesized that ADAM17-mediated ACE2 shedding results in decreased membrane-bound ACE2 in the brain, thus promoting the development of neurogenic hypertension. Methods and Results To test this hypothesis, we used the DOCA-salt model of neurogenic hypertension in non-transgenic (NT) and syn-hACE2 mice over-expressing ACE2 in neurons. DOCA-salt treatment in NT mice led to significant increases in blood pressure, hypothalamic Ang-II levels, inflammation, impaired baroreflex sensitivity, autonomic dysfunction, as well as decreased hypothalamic ACE2 activity and expression, while these changes were blunted or prevented in syn-hACE2 mice. In addition, reduction of ACE2 expression and activity in the brain paralleled a rise in ACE2 activity in the cerebrospinal fluid of NT mice following DOCA-salt treatment and was accompanied by enhanced ADAM17 expression and activity in the hypothalamus. Chronic knockdown of ADAM17 in the brain blunted the development of hypertension and restored ACE2 activity and baroreflex function. Conclusions Our data provide the first evidence that ADAM17-mediated shedding impairs brain ACE2 compensatory activity, thus contributing to the development of neurogenic hypertension. PMID:24014829

  6. The Atmospheric Chemistry Experiment (ACE): Mission Overview

    NASA Astrophysics Data System (ADS)

    Bernath, P. F.; Boone, C.; Walker, K.; McLeod, S.; Nassar, R.

    2003-12-01

    The ACE mission goals are: (1) to measure and to understand the chemical and dynamical processes that control the distribution of ozone in the upper troposphere and stratosphere, with a particular emphasis on the Arctic region; (2) to explore the relationship between atmospheric chemistry and climate change; (3) to study the effects of biomass burning in the free troposphere; (4) to measure aerosol number density, size distribution and composition in order to reduce the uncertainties in their effects on the global energy balance. ACE will make a comprehensive set of simultaneous measurements of trace gases, thin clouds, aerosols, and temperature by solar occultation from a satellite in low earth orbit. A high inclination (74 degrees) low earth orbit (650 km) gives ACE coverage of tropical, mid-latitudes and polar regions. The solar occultation advantages are high sensitivity and self-calibration. A high-resolution (0.02 cm-1) infrared Fourier Transform Spectrometer (FTS) operating from 2 to 13 microns (750-4100 cm-1) will measure the vertical distribution of trace gases, and the meteorological variables of temperature and pressure. The ACE concept is derived from the now-retired ATMOS FTS instrument, which flew on the Space Shuttle in 1985, 1992, 1993, 1994. Climate-chemistry coupling may lead to the formation of an Arctic ozone hole. ACE will provide high quality data to confront these model predictions and will monitor polar chemistry as chlorine levels decline. The ACE-FTS can measure water vapor and HDO in the tropical tropopause region to study dehydration and strat-trop exchange. The molecular signatures of massive forest fires will evident in the ACE infrared spectra. The CO2 in our spectra can be used to either retrieve atmospheric pressure or (if the instrument pointing knowledge proves to be satisfactory) for an independent retrieval of a CO2 profile for carbon cycle science. Aerosols and clouds will be monitored using the extinction of solar radiation at

  7. The Atmospheric Chemistry Experiment (ACE): Mission Overview

    NASA Astrophysics Data System (ADS)

    Bernath, P.

    2003-04-01

    The ACE mission goals are: (1) to measure and to understand the chemical and dynamical processes that control the distribution of ozone in the upper troposphere and stratosphere, with a particular emphasis on the Arctic region; (2) to explore the relationship between atmospheric chemistry and climate change; (3) to study the effects of biomass burning in the free troposphere; (4) to measure aerosol number density, size distribution and composition in order to reduce the uncertainties in their effects on the global energy balance. ACE will make a comprehensive set of simultaneous measurements of trace gases, thin clouds, aerosols, and temperature by solar occultation from a satellite in low earth orbit. A high inclination (74 degrees) low earth orbit (650 km) will give ACE coverage of tropical, mid-latitudes and polar regions. The solar occultation advantages are high sensitivity and self-calibration. A high-resolution (0.02 cm-1) infrared Fourier Transform Spectrometer (FTS) operating from 2 to 13 microns (750-4100 cm-1) will measure the vertical distribution of trace gases, and the meteorological variables of temperature and pressure. The ACE concept is derived from the now-retired ATMOS FTS instrument, which flew on the Space Shuttle in 1985, 1992, 1993, 1994. Climate-chemistry coupling may lead to the formation of an Arctic ozone hole. ACE will provide high quality data to confront these model predictions and will monitor polar chemistry as chlorine levels decline. The ACE-FTS can measure water vapor and HDO in the tropical tropopause region to study dehydration and strat-trop exchange. The molecular signatures of massive forest fires will evident in the ACE infrared spectra. The CO_2 in our spectra can be used to either retrieve atmospheric pressure or (if the instrument pointing knowledge proves to be satisfactory) for an independent retrieval of a CO_2 profile for carbon cycle science. Aerosols and clouds will be monitored using the extinction of solar

  8. The relationship between ACE polymorphism and panic disorder.

    PubMed

    Gulec-Yılmaz, Seda; Gulec, Huseyın; Dalan, Altay Burak; Cetın, Bugra; Tımırcı-Kahraman, Ozlem; Ogut, Dıcle Bılge; Atasoy, Hande; Dırımen, Gulız Arikan; Gultekın, Guldal Inal; Isbır, Turgay

    2014-01-01

    The angiotensin converting enzyme (ACE) gene, which has been found to have an insertion and deletion polymorphism (I/D), is of increasing interest in etiology and treatment of various psychiatric disorders such as panic disorder. The present study aimed to investigate the relationship between ACE polymorphism and panic disorder. In this study, 43 patients diagnosed with panic disorder at the Erenköy Mental and Neurological Diseases Training and Research Hospital, Istanbul and 41 healthy controls were enrolled. The ACE gene insertion/deletion polymorphism of exon 16 was evaluated using the polymerase chain reaction method. There was a significant association between I/D genotype and panic disorder (p=0.003). However, the frequency of the I allele was found to be significantly higher in patients compared to controls (p=0.002). In addition, we recognized a significant association between I/D polymorphism and respiratory-type panic disorder in patients. Carriers of the D allele also had an increased risk of respiratory type panic disorder patients (p=0.034). Moreover, the result of Spearman correlation analysis showed an association with ACE D allele and severity of panic disorder (p<0.001). We suggest that the I/D polymorphism of the ACE gene is associated with panic disorder and particularly respiratory-type panic disorder in patients. The I/D polymorphism of the ACE gene seems to influence therapeutic outcome in patients suffering from panic disorder. Our results indicate that ACE D allele is associated with the severity of panic disorder. Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  9. Identification of Novel Saccharomyces cerevisiae Proteins with Nuclear Export Activity: Cell Cycle-Regulated Transcription Factor Ace2p Shows Cell Cycle-Independent Nucleocytoplasmic Shuttling

    PubMed Central

    Jensen, Torben Heick; Neville, Megan; Rain, Jean Christophe; McCarthy, Terri; Legrain, Pierre; Rosbash, Michael

    2000-01-01

    Nuclear export of proteins containing leucine-rich nuclear export signals (NESs) is mediated by the NES receptor CRM1/Crm1p. We have carried out a yeast two-hybrid screen with Crm1p as a bait. The Crm1p-interacting clones were subscreened for nuclear export activity in a visual assay utilizing the Crm1p-inhibitor leptomycin B (LMB). This approach identified three Saccharomyces cerevisiae proteins not previously known to have nuclear export activity. These proteins are the 5′ RNA triphosphatase Ctl1p, the cell cycle-regulated transcription factor Ace2p, and a protein encoded by the previously uncharacterized open reading frame YDR499W. Mutagenesis analysis show that YDR499Wp contains an NES that conforms to the consensus sequence for leucine-rich NESs. Mutagenesis of Ctl1p and Ace2p were unable to identify specific NES residues. However, a 29-amino-acid region of Ace2p, rich in hydrophobic residues, contains nuclear export activity. Ace2p accumulates in the nucleus at the end of mitosis and activates early-G1-specific genes. We now provide evidence that Ace2p is nuclear not only in late M-early G1 but also during other stages of the cell cycle. This feature of Ace2p localization explains its ability to activate genes such as CUP1, which are not expressed in a cell cycle-dependent manner. PMID:11027275

  10. Angiotensin I-converting enzyme (ACE) inhibitory activity of Fucus spiralis macroalgae and influence of the extracts storage temperature-A short report.

    PubMed

    Paiva, Lisete; Lima, Elisabete; Neto, Ana Isabel; Baptista, José

    2016-11-30

    Recently, increasing attention has been paid to the marine algae as a natural source of novel angiotensin-I converting enzyme (ACE) inhibitors, such as the phlorotannins that are the predominant polyphenols in brown algae. This study reports, for the first time, the ACE inhibition of methanol extract/fractions from Azorean brown algae Fucus spiralis (Fs) determined by HPLC-UV method, their total phenolic content (TPC) quantified as phloroglucinol equivalents (PE) and the effect of the Fs dry powder methanol extracts (Fs-DME) storage temperature on ACE inhibition. The results indicate that the ACE inhibition of Fs-DME decreased by 28.8% and 78.2% when stored during 15days at -80°C and -13°C, respectively, as compared with the activity of Fs-DME at a refrigerated temperature of 6°C and assayed immediately after extraction that showed a value of 80.1±2.1%. This Fs-DME sample was fractionated by ultrafiltration membranes into three molecular weight ranges (<1kDa, 1-3kDa and >3kDa), presenting the fraction>3kDa remarkably high ACE inhibition (88.8±2.4%), TPC value (156.6±1.4mg PE/g of dry weight fraction) and yield. Furthermore, chromatographic and spectrophotometric analyses corroborate that phenolic compounds were present in Fs methanol extract/fractions, and also revealed that phloroglucinol occurs in Fs. The results seem to suggest that Azorean Fs can be a source of powerful ACE-inhibitory phlorotannins with potential impact on public health, particularly on hypertensive patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Listing of Available ACE Data Tables

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

    Conlin, Jeremy Lloyd

    This document is divided into multiple sections. Section 2 lists some of the more frequently used ENDF/B reaction types that can be used with the FM input card. The remaining sections (described below) contain tables showing the available ACE data tables for various types of data. These ACE data libraries are distributed by the Radiation Safety Information Computational Center (RSICC) with MCNP6.

  12. A SOAP Web Services Interface to ACE Data

    NASA Astrophysics Data System (ADS)

    Davis, A. J.; Hamell, G. R.

    2005-05-01

    Since early in 1998, NASA's Advanced Composition Explorer (ACE) spacecraft has provided continuous measurements of solar wind and energetic particle activity from L1, located approximately 0.01 AU sunward of Earth. ACE data from nine instruments are being used to measure and compare the elemental and isotopic composition of the solar corona, the nearby interstellar medium, and the Galaxy, and to study particle acceleration processes that occur in a wide range of environments. The spacecraft has enough fuel to stay in orbit about L1 until at least 2020. The ACE Science Center (ASC) provides access to ACE data, and performs level 1 and browse data processing for the science instruments. Available on-line are solar wind, solar energetic particle, and galactic cosmic ray intensity and composition data, as well as solar wind and magnetic field parameters on a variety of time scales. We describe our recent efforts to provide enhanced access to ACE data via a SOAP Web Services interface. The interface utilizes the Space Physics Archive Search and Extract (SPASE) dictionary, and will be compatible with emerging virtual observatories.

  13. Systolic versus diastolic heart failure in community practice: clinical features, outcomes, and the use of angiotensin-converting enzyme inhibitors.

    PubMed

    Philbin, E F; Rocco, T A; Lindenmuth, N W; Ulrich, K; Jenkins, P L

    2000-12-01

    Among patients with heart failure, there is controversy about whether there are clinical features and laboratory tests that can differentiate patients who have low ejection fractions from those with normal ejection fractions. The usefulness of angiotensin-converting enzyme (ACE) inhibitors among heart failure patients who have normal left ventricular ejection fractions is also not known. From a registry of 2,906 unselected consecutive patients with heart failure who were admitted to 10 acute-care community hospitals during 1995 and 1997, we identified 1291 who had a quantitative measurement of their left ventricular ejection fraction. Patients were separated into three groups based on ejection fraction: < or =0.39 (n = 741, 57%), 0.40 to 0.49 (n = 238, 18%), and > or =0.50 (n = 312, 24%). In-hospital mortality, prescription of ACE inhibitors at discharge, subsequent rehospitalization, quality of life, and survival were measured; survivors were observed for at least 6 months after hospitalization. The mean (+/- SD) age of the sample was 75+/-11 years; the majority (55%) of patients were women. In multivariate models, age >75 years, female sex, weight >72.7 kg, and a valvular etiology for heart failure were associated with an increased probability of having an ejection fraction > or =0.50; a prior history of heart failure, an ischemic or idiopathic cause of heart failure, and radiographic cardiomegaly were associated with a lower probability of having an ejection fraction > or =0.50. Total mortality was lower in patients with an ejection fraction > or =0.50 than in those with an ejection fraction < or =0.39 (odds ratio [OR] = 0.69, 95% confidence interval [CI 0.49 to 0.98, P = 0.04). Among hospital survivors with an ejection fraction of 0.40 to 0.49, the 65% who were prescribed ACE inhibitors at discharge had better mean adjusted quality-of-life scores (7.0 versus 6.2, P = 0.02), and lower adjusted mortality (OR = 0.34, 95% CI: 0.17 to 0.70, P = 0.01) during follow

  14. The presence of PAI-1 4G/5G and ACE DD genotypes increases the risk of early-stage AVF thrombosis in hemodialysis patients.

    PubMed

    Güngör, Yahya; Kayataş, Mansur; Yıldız, Gürsel; Özdemir, Öztürk; Candan, Ferhan

    2011-01-01

    In this study, we investigated the relationship between early arteriovenous fistula (AVF) thrombosis with angiotensin-converting enzyme (ACE) gene and thrombophilic factor gene polymorphisms. Thirty-five patients who suffered from three or more fistula thrombosis episodes in the early period after AVF operation and 33 control patients with no history of thrombosis for at least 3 years were enrolled in this study. Factor V G1691A Leiden, factor V H1299R (R2), prothrombin G20210A, factor XIIIV34L, β-fibrinogen-455 G-A, glycoprotein IIIa L33P human platelet antigens (HPA-1), methylenetetrahydrofolate reductase C677T, and methylenetetrahydrofolate reductase A1298C gene polymorphisms were similar in both groups (p > 0.05). Plasminogen activator inhibitor 1 (PAI-1) 4G/5G genotype in the study group and 4G/4G genotype in the control group were significantly higher (p = 0.014). No significant difference was detected in terms of the 5G/5G genotype. With regard to the ACE gene polymorphism, the control group showed more ID genotype (19/33, 57.6%), whereas the study group showed more DD genotype (17/35, 48.6%). II genotype was similar in both groups (x(2) = 7.40, p = 0.025). The rate of ACE inhibitor-angiotensin II receptor blockers use was 5/35 in the study group (14.3%) and 5/33 in the control group (15.2%). Individuals with PAI-1 4G/5G genotype showed 5.03 times more risk of thrombosis when compared with 4G/4G and 5G/5G genotypes [p = 0.008, OR = 5.03, 95% confidence interval (1.44:17.64)]. Individuals with ACE DD genotype showed 4.25 times more risk of thrombosis when compared with II and ID [p = 0.008, OR = 4.25, 95% confidence interval (1.404:12.83)]. PAI-1 4G/5G and ACE DD genotypes are associated with increased risk for early AVF thrombosis.

  15. Acute Care for Elders (ACE) Tracker and e-Geriatrician: Methods to Disseminate ACE Concepts to Hospitals with No Geriatricians on Staff

    PubMed Central

    Malone, Michael L.; Vollbrecht, Marsha; Stephenson, Jeff; Burke, Laura; Pagel, Patti; Goodwin, James S.

    2014-01-01

    This article describes an innovative method to disseminate the Acute Care for Elders (ACE) model of care for hospitalized older patients implemented at 11 community hospitals in Wisconsin. The ACE Tracker is a computer-generated checklist of all older patients in a facility that takes information from multiple areas of the electronic medical record to identify the older patients’ risk factors for functional decline and poor outcomes. The ACE Tracker report was validated against in-person observation of the older patients and found to be accurate. Interdisciplinary teams on medical–surgical units use this summary report to review each patient’s plan of care and to efficiently assess the patients who are vulnerable to poor hospital outcomes. The ACE Tracker is also used during regular consultation provided through teleconferencing between an off-site geriatrician (e-Geriatrician) and the local ACE team. The effect of the ACE Tracker and e-Geriatrician models was assessed by measuring use of urinary catheters, physical restraints, high-risk medications, and social service evaluation at a single hospital for the 6 months before and after implementation of the models. There were significant improvements in urinary catheter and physical therapy referrals but no significant changes in the other outcomes. There was no change in the length of stay or in the rate of hospital readmission within 30 days. PMID:20122048

  16. Aerobic exercise training differentially affects ACE C- and N-domain activities in humans: Interactions with ACE I/D polymorphism and association with vascular reactivity.

    PubMed

    Alves, Cléber Rene; Fernandes, Tiago; Lemos, José Ribeiro; Magalhães, Flávio de Castro; Trombetta, Ivani Credidio; Alves, Guilherme Barreto; Mota, Glória de Fátima Alves da; Dias, Rodrigo Gonçalves; Pereira, Alexandre Costa; Krieger, José Eduardo; Negrão, Carlos Eduardo; Oliveira, Edilamar Menezes

    2018-01-01

    Previous studies have linked angiotensin-converting enzyme ( ACE) insertion (I)/deletion (D) polymorphism (II, ID and DD) to physical performance. Moreover, ACE has two catalytic domains: NH2 (N) and COOH (C) with distinct functions, and their activity has been found to be modulated by ACE polymorphism. The aim of the present study is to investigate the effects of the interaction between aerobic exercise training (AET) and ACE I/D polymorphism on ACE N- and C-domain activities and vascular reactivity in humans. A total of 315 pre-selected healthy males were genotyped for II, ID and DD genotypes. Fifty completed the full AET (II, n = 12; ID, n = 25; and DD, n = 13), performed in three 90-minute sessions weekly, in the four-month exercise protocol. Pre- and post-training resting heart rate (HR), peak O 2 consumption (VO 2 peak), mean blood pressure (MBP), forearm vascular conduction (FVC), total circulating ACE and C- and N-domain activities were assessed. One-way ANOVA and two -way repeated-measures ANOVA were used. In pre-training, all variables were similar among the three genotypes. In post-training, a similar increase in FVC (35%) was observed in the three genotypes. AET increased VO 2 peak similarly in II, ID and DD (49±2 vs. 57±1; 48±1 vs. 56±3; and 48±5 vs. 58±2 ml/kg/min, respectively). Moreover, there were no changes in HR and MBP. The DD genotype was also associated with greater ACE and C-domain activities at pre- and post-training when compared to II. AET decreased similarly the total ACE and C-domain activities in all genotypes, while increasing the N-domain activity in the II and DD genotypes. However, interestingly, the measurements of N-domain activity after training indicate a greater activity than the other genotypes. These results suggest that the vasodilation in response to AET may be associated with the decrease in total ACE and C-domain activities, regardless of genotype, and that the increase in N-domain activity is dependent on the DD

  17. What proportion of patients with chronic heart failure are eligible for sacubitril-valsartan?

    PubMed

    Pellicori, Pierpaolo; Urbinati, Alessia; Shah, Parin; MacNamara, Alexandra; Kazmi, Syed; Dierckx, Riet; Zhang, Jufen; Cleland, John G F; Clark, Andrew L

    2017-06-01

    The PARADIGM-HF trial showed that sacubitril-valsartan, an ARB-neprilysin inhibitor, is more effective than enalapril for some patients with heart failure (HF). It is uncertain what proportion of patients with HF would be eligible for sacubitril-valsartan in clinical practice. Between 2001 and 2014, 6131 patients consecutively referred to a community HF clinic with suspected HF were assessed. The criteria required to enter the randomized phase of PARADIGM-HF, including symptoms, NT-proBNP, and current treatment with or without target doses of ACE inhibitors or ARBs, were applied to identify the proportion of patients eligible for sacubitril-valsartan. Recognizing the diversity of clinical opinion and guideline recommendations concerning this issue, entry criteria were applied singly and in combination. Of 1396 patients with reduced left ventricular ejection fraction (≤40%, HFrEF) and contemporary measurement of NT-proBNP, 379 were on target doses of an ACE inhibitor or ARB at their initial visit and, of these, 172 (45%) fulfilled the key entry criteria for the PARADIGM-HF trial. Lack of symptoms (32%) and NT-proBNP <600 ng/L (49%) were common reasons for failure to fulfil criteria. A further 122 patients became eligible during follow-up (n = 294, 21%). However, if background medication and doses were ignored, then 701 (50%) were eligible initially and a further 137 became eligible during follow-up. Of patients with HFrEF referred to a clinic such as ours, only 21% fulfilled the PARADIGM-HF randomization criteria, on which the ESC Guidelines are based; this proportion rises to 60% if background medication is ignored. © 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.

  18. Cost-utility analysis of eprosartan compared to enalapril in primary prevention and nitrendipine in secondary prevention in Europe--the HEALTH model.

    PubMed

    Schwander, Björn; Gradl, Birgit; Zöllner, York; Lindgren, Peter; Diener, Hans-Christoph; Lüders, Stephan; Schrader, Joachim; Villar, Fernando Antoñanzas; Greiner, Wolfgang; Jönsson, Bengt

    2009-09-01

    To investigate the cost-utility of eprosartan versus enalapril (primary prevention) and versus nitrendipine (secondary prevention) on the basis of head-to-head evidence from randomized controlled trials. The HEALTH model (Health Economic Assessment of Life with Teveten for Hypertension) is an object-oriented probabilistic Monte Carlo simulation model. It combines a Framingham-based risk calculation with a systolic blood pressure approach to estimate the relative risk reduction of cardiovascular and cerebrovascular events based on recent meta-analyses. In secondary prevention, an additional risk reduction is modeled for eprosartan according to the results of the MOSES study ("Morbidity and Mortality after Stroke--Eprosartan Compared to Nitrendipine for Secondary Prevention"). Costs and utilities were derived from published estimates considering European country-specific health-care payer perspectives. Comparing eprosartan to enalapril in a primary prevention setting the mean costs per quality adjusted life year (QALY) gained were highest in Germany (Euro 24,036) followed by Belgium (Euro 17,863), the UK (Euro 16,364), Norway (Euro 13,834), Sweden (Euro 11,691) and Spain (Euro 7918). In a secondary prevention setting (eprosartan vs. nitrendipine) the highest costs per QALY gained have been observed in Germany (Euro 9136) followed by the UK (Euro 6008), Norway (Euro 1695), Sweden (Euro 907), Spain (Euro -2054) and Belgium (Euro -5767). Considering a Euro 30,000 willingness-to-pay threshold per QALY gained, eprosartan is cost-effective as compared to enalapril in primary prevention (patients >or=50 years old and a systolic blood pressure >or=160 mm Hg) and cost-effective as compared to nitrendipine in secondary prevention (all investigated patients).

  19. Tailored Assays for Pharmacokinetic and Pharmacodynamic Investigations of Aliskiren and Enalapril in Children: An Application in Serum, Urine, and Saliva.

    PubMed

    Burckhardt, Bjoern B; Tins, Jutta; Ramusovic, Sergej; Läer, Stephanie

    2015-01-01

    Drugs that are effectively used to treat hypertension in adults (e.g., enalapril) have not been sufficiently investigated in children. Studies required for pediatric approval require special consideration regarding ethics, study design, and conduct and are also associated with special demands for the bioanalytic method. Pediatric-appropriate assays can overcome these burdens and enable systematic investigations of pharmacokinetics and pharmacodynamic in all pediatric age groups. Tailored assays were developed for pharmacokinetic investigation of a drug in 100 μL of serum, saliva, and urine. All assays were applied in a proof-of-concept study to 22 healthy volunteers who had been given 300 mg aliskiren hemifumarate or 20 mg enalapril maleate and allowed for dense sampling. Changes in humoral parameters of the renin-angiotensin-aldosterone system were also evaluated with 6 parameters in 2.1 mL blood per time point. The pharmacokinetic results of aliskiren and enalapril obtained by low-volume assays in serum and urine were comparable to that noted in the literature. The dense sampling enabled very detailed concentration-time profiles that showed high intersubject variability and biphasic absorption behavior of aliskiren. The replacement of invasive sampling by saliva collection appears inappropriate for both drugs because the correlations of drug concentrations in both fluids were low. A low-volume assay was also used to determine values for in the renin-angiotensin-aldosterone system and to compare those results with the published literature. These results support both the use of low-volume assays in pediatric research and the systematic investigation of their use in neonates and infants. Use of this assay methodology will increase information about drug pharmacokinetics and pharmacodynamics in this vulnerable population and might contribute to safe and effective use of pharmacotherapy.

  20. Tailored Assays for Pharmacokinetic and Pharmacodynamic Investigations of Aliskiren and Enalapril in Children: An Application in Serum, Urine, and Saliva

    PubMed Central

    Tins, Jutta; Ramusovic, Sergej; Läer, Stephanie

    2015-01-01

    OBJECTIVES: Drugs that are effectively used to treat hypertension in adults (e.g., enalapril) have not been sufficiently investigated in children. Studies required for pediatric approval require special consideration regarding ethics, study design, and conduct and are also associated with special demands for the bioanalytic method. Pediatric-appropriate assays can overcome these burdens and enable systematic investigations of pharmacokinetics and pharmacodynamic in all pediatric age groups. METHODS: Tailored assays were developed for pharmacokinetic investigation of a drug in 100 μL of serum, saliva, and urine. All assays were applied in a proof-of-concept study to 22 healthy volunteers who had been given 300 mg aliskiren hemifumarate or 20 mg enalapril maleate and allowed for dense sampling. Changes in humoral parameters of the renin-angiotensin-aldosterone system were also evaluated with 6 parameters in 2.1 mL blood per time point. RESULTS: The pharmacokinetic results of aliskiren and enalapril obtained by low-volume assays in serum and urine were comparable to that noted in the literature. The dense sampling enabled very detailed concentration-time profiles that showed high intersubject variability and biphasic absorption behavior of aliskiren. The replacement of invasive sampling by saliva collection appears inappropriate for both drugs because the correlations of drug concentrations in both fluids were low. A low-volume assay was also used to determine values for in the renin-angiotensin-aldosterone system and to compare those results with the published literature. CONCLUSION: These results support both the use of low-volume assays in pediatric research and the systematic investigation of their use in neonates and infants. Use of this assay methodology will increase information about drug pharmacokinetics and pharmacodynamics in this vulnerable population and might contribute to safe and effective use of pharmacotherapy. PMID:26766933

  1. Engineering Development Tests Airdrop Controlled Exit System (ACES)

    DTIC Science & Technology

    1980-09-01

    AIRDROP CONTROLLED EXIT SYSTEM ( ACES ) RECOVERY PARACHUTES TELEMETERING DATA 20. D5TFAC c• Cat •u•u am revers e• ift n•ceesafy ad Ide•lityf by block...rTECHNICAL REPORT , NATICK /TR-82 /017 f C’n Engineering Development Tests Airdropý Controlled Exit System ( ACES ) COPY CLV40ble to DTIC doe’ io C...and,50.,,,10) s. TYPE OF REPORT A PERIOn COVEnEo Test Report ENCINEERTNG DEVELOPMENT TESTS Oct 79 - Apr 80 AIRDROP CONTROLLED EXIT SYSTEM ( ACES ) 6

  2. AceCloud: Molecular Dynamics Simulations in the Cloud.

    PubMed

    Harvey, M J; De Fabritiis, G

    2015-05-26

    We present AceCloud, an on-demand service for molecular dynamics simulations. AceCloud is designed to facilitate the secure execution of large ensembles of simulations on an external cloud computing service (currently Amazon Web Services). The AceCloud client, integrated into the ACEMD molecular dynamics package, provides an easy-to-use interface that abstracts all aspects of interaction with the cloud services. This gives the user the experience that all simulations are running on their local machine, minimizing the learning curve typically associated with the transition to using high performance computing services.

  3. ACE Objectives, Current Status and the 2017 Decadal Survey

    NASA Technical Reports Server (NTRS)

    Da Silva, Arlindo

    2018-01-01

    In this talk we present an overview of the Aerosol-Cloud-Ecosystems (ACE) preformulation studies, a tier-2 satellite mission recommended by the 2007 Decadal Survey. We discuss the current status of ACE measurement concepts and associated retrieval algorithms. We conclude with a brief discussion of the recommendations by the 2017 Decadal Survey and how ACE accomplishments can inform the future Aerosol and Cloud, Convection & Precipitation Designated Observables.

  4. Anoctamin 6 Contributes to Cl- Secretion in Accessory Cholera Enterotoxin (Ace)-stimulated Diarrhea: AN ESSENTIAL ROLE FOR PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE (PIP2) SIGNALING IN CHOLERA.

    PubMed

    Aoun, Joydeep; Hayashi, Mikio; Sheikh, Irshad Ali; Sarkar, Paramita; Saha, Tultul; Ghosh, Priyanka; Bhowmick, Rajsekhar; Ghosh, Dipanjan; Chatterjee, Tanaya; Chakrabarti, Pinak; Chakrabarti, Manoj K; Hoque, Kazi Mirajul

    2016-12-23

    Accessory cholera enterotoxin (Ace) of Vibrio cholerae has been shown to contribute to diarrhea. However, the signaling mechanism and specific type of Cl - channel activated by Ace are still unknown. We have shown here that the recombinant Ace protein induced I Cl of apical plasma membrane, which was inhibited by classical CaCC blockers. Surprisingly, an Ace-elicited rise of current was neither affected by ANO1 (TMEM16A)-specific inhibitor T16A (inh) -AO1(TAO1) nor by the cystic fibrosis transmembrane conductance regulator (CFTR) blocker, CFTR inh-172. Ace stimulated whole-cell current in Caco-2 cells. However, the apical I Cl was attenuated by knockdown of ANO6 (TMEM16F). This impaired phenotype was restored by re-expression of ANO6 in Caco-2 cells. Whole-cell patch clamp recordings of ANO currents in HEK293 cells transiently expressing mouse ANO1-mCherry or ANO6-GFP confirmed that Ace induced Cl - secretion. Application of Ace produced ANO6 but not the ANO1 currents. Ace was not able to induce a [Ca 2+ ] i rise in Caco-2 cells, but cellular abundance of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) increased. Identification of the PIP 2 -binding motif at the N-terminal sequence among human and mouse ANO6 variants along with binding of PIP 2 directly to ANO6 in HEK293 cells indicate likely PIP 2 regulation of ANO6. The biophysical and pharmacological properties of Ace stimulated Cl - current along with intestinal fluid accumulation, and binding of PIP 2 to the proximal KR motif of channel proteins, whose mutagenesis correlates with altered binding of PIP 2 , is comparable with ANO6 stimulation. We conclude that ANO6 is predominantly expressed in intestinal epithelia, where it contributes secretory diarrhea by Ace stimulation in a calcium-independent mechanism of RhoA-ROCK-PIP 2 signaling. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. Inhibitors of endopeptidase and angiotensin-converting enzyme lead to an amplification of the morphological changes and an upregulation of the substance P system in a muscle overuse model

    PubMed Central

    2014-01-01

    Background We have previously observed, in studies on an experimental overuse model, that the tachykinin system may be involved in the processes of muscle inflammation (myositis) and other muscle tissue alterations. To further evaluate the significance of tachykinins in these processes, we have used inhibitors of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), substances which are known to terminate the activity of various endogenously produced substances, including tachykinins. Methods Injections of inhibitors of NEP and ACE, as well as the tachykinin substance P (SP), were given locally outside the tendon of the triceps surae muscle of rabbits subjected to marked overuse of this muscle. A control group was given NaCl injections. Evaluations were made at 1 week, a timepoint of overuse when only mild inflammation and limited changes in the muscle structure are noted in animals not treated with inhibitors. Both the soleus and gastrocnemius muscles were examined morphologically and with immunohistochemistry and enzyme immunoassay (EIA). Results A pronounced inflammation (myositis) and changes in the muscle fiber morphology, including muscle fiber necrosis, occurred in the overused muscles of animals given NEP and ACE inhibitors. The morphological changes were clearly more prominent than for animals subjected to overuse and NaCl injections (NaCl group). A marked SP-like expression, as well as a marked expression of the neurokinin-1 receptor (NK-1R) was found in the affected muscle tissue in response to injections of NEP and ACE inhibitors. The concentration of SP in the muscles was also higher than that for the NaCl group. Conclusions The observations show that the local injections of NEP and ACE inhibitors led to marked SP-like and NK-1R immunoreactions, increased SP concentrations, and an amplification of the morphological changes in the tissue. The injections of the inhibitors thus led to a more marked myositis process and an upregulation of

  6. Antihypertensive drug prescription trends at the primary health care centres in Bahrain.

    PubMed

    Jassim al Khaja, K A; Sequeira, R P; Wahab, A W; Mathur, V S

    2001-05-01

    To determine the antihypertensive drug prescribing pattern by primary care physicians in patients with uncomplicated essential hypertension; to identify whether such pattern of prescription is appropriate and in accordance with international guidelines for pharmacotherapy of hypertension; and to estimate the impact of such prescriptions on cost of treatment. A prescription-based survey among patients with uncomplicated essential hypertension was conducted in seven out of a total of 18 health centres in Bahrain. The relevant data for our study was collected using cards, designed for chronically-ill patients. A total of 1019 male and 1395 female (62.9%) out of 3838 of the study population were on monotherapy, whereas 596 male and 828 female (37.1%) were on antihypertensive combination therapy. Among the monotherapy category, the various antihypertensive drugs used were as follows: beta-blockers (58.8%), angiotensin converting enzyme (ACE) inhibitors (14.2%), calcium channel blockers (11.1%), diuretics (8.1%) and alpha-methyldopa (7.0%). With respect to overall utilization pattern, beta-blockers were the most frequently prescribed (65.5%), diuretics ranked second (27.4%), followed by ACE inhibitors (20.6%), calcium channel blockers (19.9%) and alpha-methyldopa (8.5%). Within each class of antihypertensives used, the most frequently used individual agents were as follows: (a) among beta-blockers 97.7% used atenolol; (b) among the diuretics, indapamide (35.4%), hydrochlorothiazide (HCTZ) (32.7%), HCTZ in combination with triamterene (25.7%), and chlorthalidone (4.6%); (c) among the ACE inhibitors, captopril (44.9%), enalapril (29.7%), and lisinopril (19.0%); (d) among the calcium channel blockers, nifedipine (98.2%). Significant age- and gender-related differences in prescribing patterns were seen. Short-acting nifedipine monotherapy was inappropriately prescribed in a significant number of patients above the age of 50 years. ACE inhibitors accounted for approximately

  7. A relationship between proteinuria and acute tubulointerstitial disease in rats with experimental nephrotic syndrome

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

    Eddy, A.A.; McCulloch, L.; Liu, E.

    1991-05-01

    The relationship between tubulointerstitial nephritis and proteinuria was characterized in experimental nephrosis in rats. In one group, proteinuria induced by aminonucleoside of puromycin (PAN) was reduced by using an 8% protein diet and adding the angiotensin I-converting enzyme (ACE) inhibitor enalapril to the drinking water. Two control groups were injected with saline and PAN, respectively, and fed a 27% protein diet. The first group had significantly reduced albuminuria and a definite attenuation of tubular cell injury. There was a strong positive correlation between the number of interstitial macrophages and albuminuria. The beneficial effect was reproduced by dietary-protein restriction alone, whereasmore » ACE inhibition alone had an insignificant effect on the degree of proteinuria. Depletion of circulating T lymphocytes in one group of nephrotic rats eliminated interstitial lymphocytes but did not affect interstitial macrophage influx. Inhibition of the in situ proliferation of resident interstitial macrophages by unilateral kidney irradiation failed to change the intensity of the macrophage infiltration. Treatment of rats with sodium maleate produced proximal tubular cell toxicity but interstitial inflammation did not develop, suggesting that the latter is not a nonspecific response to tubular injury. These studies demonstrate a strong relationship between tubulointerstitial nephritis and the severity of proteinuria in experimental nephrosis.« less

  8. Identification of new polymorphisms of the angiotensin I-converting enzyme (ACE) gene, and study of their relationship to plasma ACE levels by two-QTL segregation-linkage analysis

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

    Villard, E.; Soubrier, F.; Tiret, L.

    1996-06-01

    Plasma angiotensin I-converting enzyme (ACE) levels are highly genetically determined. A previous segregation-linkage analysis suggested the existence of a functional mutation located within or close to the ACE locus, in almost complete linkage disequilibrium (LD) with the ACE insertion/deletion (I/D) polymorphism and accounting for half the ACE variance. In order to identify the functional variant at the molecular level, we compared ACE gene sequences between four subjects selected for having contrasted ACE levels and I/D genotypes. We identified 10 new polymorphisms, among which 8 were genotyped in 95 healthy nuclear families, in addition to the I/D polymorphism. These polymorphisms couldmore » be divided into two groups: five polymorphisms in the 5{prime} region and three in the coding sequence and the 3{prime} UTR. Within each group, polymorphisms were in nearly complete association, whereas polymorphisms from the two groups were in strong negative LD. After adjustment for the I/D polymorphism, all polymorphisms of the 5{prime} group remained significantly associated with ACE levels, which suggests the existence of two quantitative trait loci (QTL) acting additively on ACE levels. Segregation-linkage analyses including one or two ACE-linked QTLs in LD with two ACE markers were performed to test this hypothesis. The two QTLs and the two markers were assumed to be in complete LD. Results supported the existence of two ACE-linked QTLs, which would explain 38% and 49% of the ACE variance in parents and offspring, respectively. One of these QTLs might be the I/D polymorphism itself or the newly characterized 4656(CT){sub 2/3} polymorphism. The second QTL would have a frequency of {approximately}.20, which is incompatible with any of the yet-identified polymorphisms. More extensive sequencing and extended analyses in larger samples and in other populations will be necessary to characterize definitely the functional variants. 30 refs., 1 fig., 6 tabs.« less

  9. Aerobic exercise training differentially affects ACE C- and N-domain activities in humans: Interactions with ACE I/D polymorphism and association with vascular reactivity

    PubMed Central

    Alves, Cléber Rene; Fernandes, Tiago; Lemos, José Ribeiro; Magalhães, Flávio de Castro; Trombetta, Ivani Credidio; Alves, Guilherme Barreto; da Mota, Glória de Fátima Alves; Dias, Rodrigo Gonçalves; Pereira, Alexandre Costa; Krieger, José Eduardo; Negrão, Carlos Eduardo; Oliveira, Edilamar Menezes

    2018-01-01

    Introduction: Previous studies have linked angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism (II, ID and DD) to physical performance. Moreover, ACE has two catalytic domains: NH2 (N) and COOH (C) with distinct functions, and their activity has been found to be modulated by ACE polymorphism. The aim of the present study is to investigate the effects of the interaction between aerobic exercise training (AET) and ACE I/D polymorphism on ACE N- and C-domain activities and vascular reactivity in humans. Materials and methods: A total of 315 pre-selected healthy males were genotyped for II, ID and DD genotypes. Fifty completed the full AET (II, n = 12; ID, n = 25; and DD, n = 13), performed in three 90-minute sessions weekly, in the four-month exercise protocol. Pre- and post-training resting heart rate (HR), peak O2 consumption (VO2 peak), mean blood pressure (MBP), forearm vascular conduction (FVC), total circulating ACE and C- and N-domain activities were assessed. One-way ANOVA and two-way repeated-measures ANOVA were used. Results: In pre-training, all variables were similar among the three genotypes. In post-training, a similar increase in FVC (35%) was observed in the three genotypes. AET increased VO2 peak similarly in II, ID and DD (49±2 vs. 57±1; 48±1 vs. 56±3; and 48±5 vs. 58±2 ml/kg/min, respectively). Moreover, there were no changes in HR and MBP. The DD genotype was also associated with greater ACE and C-domain activities at pre- and post-training when compared to II. AET decreased similarly the total ACE and C-domain activities in all genotypes, while increasing the N-domain activity in the II and DD genotypes. However, interestingly, the measurements of N-domain activity after training indicate a greater activity than the other genotypes. These results suggest that the vasodilation in response to AET may be associated with the decrease in total ACE and C-domain activities, regardless of genotype, and that the increase in N

  10. Evaluation of ACE gene I/D polymorphism in Iranian elite athletes.

    PubMed

    Shahmoradi, Somayeh; Ahmadalipour, Ali; Salehi, Mansoor

    2014-01-01

    Angiotensin converting enzyme (ACE) is an important gene, which is associated with the successful physical activity. The ACE gene has a major polymorphism (I/D) in intron 16 that determines its plasma and tissue levels. In this study, we aimed to determine whether there is an association between this polymorphism and sports performance in our studied population including elite athletes of different sports disciplines. We investigated allele frequency and genotype distribution of the ACE gene in 156 Iranian elite athletes compared to 163 healthy individuals. We also investigated this allele frequency between elite athletes in three functional groups of endurance, power, and mixed sports performances. DNA was extracted from peripheral blood, and polymerase chain reaction (PCR) method was performed on intron 16 of the ACE gene. The ACE genotype was determined for each subject. Statistical analysis was performed by SPSS 15, and results were analyzed by Chi-Square test. There was a significant difference in genotype distribution and allele frequency of the ACE gene in athletes and control group (P = 0.05, P = 0.03, respectively). There was also a significant difference in allele frequency of the ACE gene in 3 groups of athletes with different sports disciplines (P = 0.045). Proportion of the ACE gene D allele was greater in elite endurance athletes (37 high-distance cyclists) than two other groups. Findings of the present study demonstrated that there is an association between the ACE gene I/D polymorphism and sports performance in Iranian elite athletes.

  11. Adverse Childhood Experiences (ACEs), Stress and Mental Health in College Students.

    PubMed

    Karatekin, Canan

    2018-02-01

    The goal of this short-term longitudinal study was to examine whether adverse childhood experiences (ACEs) could be used to identify college students at risk for mental health problems and whether current level of stress mediates the relationship between ACEs and mental health. Data on ACEs and mental health (depression, anxiety and suicidality) were collected at the beginning of the semester, and data on current stressors and mental health were collected toward the end of the semester (n = 239). Findings indicated that ACEs predicted worsening of mental health over the course of a semester and suggested current number of stressors as a mediator of the relationship between ACEs and mental health. Results suggest that screening for ACEs might be useful to identify students at high risk for deterioration in mental health. Results further suggest that stress-related interventions would be beneficial for students with high levels of ACEs and point to the need for more research and strategies to increase help-seeking in college students. Copyright © 2017 John Wiley & Sons, Ltd.

  12. The PAI-1 4G/5G and ACE I/D polymorphisms and risk of recurrent pregnancy loss: a case-control study.

    PubMed

    Kim, Jin Ju; Choi, Young Min; Lee, Sung Ki; Yang, Kwang Moon; Paik, Eun Chan; Jeong, Hyeon Jeong; Jun, Jong Kwan; Han, Ae Ra; Hong, Min A

    2014-12-01

    Thrombophilia has been postulated to be a contributor to the pathophysiology of recurrent pregnancy loss (RPL). We investigated the role of the plasminogen activator inhibitor type 1 (PAI-1) 4G/5G and angiotensin converting enzyme (ACE) I/D polymorphisms in Korean patients with RPL. Genotyping was performed using the TaqMan assay in 227 RPL patients and 304 controls. The genotype distributions of both polymorphisms in the RPL group did not differ from those of controls. Because the frequency of being homozygous for ACE D/D and the PAI-I 4G/4G combination has been reported to be significantly higher in RPL patients, this was also analyzed. However, no significant difference was noted; 3.1% of RPL patients had both ACE D/D and PAI-I 4G/4G, as did 4.9% of controls (P = 0.791). The current study suggests that both polymorphisms, either alone or in combination, are not major determinants of the development of RPL in Korean women. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. ACES microwave link requirements.

    PubMed

    Uhrich, P M; Guillernot, P; Aubry, P; Gonzalez, F; Salomon, C

    2000-01-01

    Atomic Clock Ensemble in Space (ACES) is a project of the European Space Agency on-board the future International Space Station (ISS). The payload consists mainly of two atomic frequency standards, one space hydrogen maser (SHM) prepared by the Observatoire de Neuchatel (Switzerland), and one cold atom caesium clock called PHARAO prepared by the CNES (France), with the participation of the BNM-LPTF, the ENS-LKB, and the CNRS-LHA. Because of the anticipated performances of these clocks on-board the ISS, the requirements of the links between the payload and the clocks on the Earth are at the limits of the known potential of the optical or microwave techniques. The microwave link (MWL) requirements are described in this paper. Taking into account the characteristics of the ISS orbit, and fixing an arbitrary limit to the additional noise brought to the clock readings by the MWL, the computation of the required stability leads to two kinds of requirements: the first one at the subpicosecond level over each single continuous pass of the ISS above any Earth station, and the second one at the level of one part in 10(16) and below over a one day or more averaging period. Moreover, the ISS orbit parameters should lead to a knowledge of the ACES clock position at the m level, and of the ACES clock speed at the mm/s level.

  14. The absence of intrarenal ACE protects against hypertension

    PubMed Central

    Gonzalez-Villalobos, Romer A.; Janjoulia, Tea; Fletcher, Nicholas K.; Giani, Jorge F.; Nguyen, Mien T.X.; Riquier-Brison, Anne D.; Seth, Dale M.; Fuchs, Sebastien; Eladari, Dominique; Picard, Nicolas; Bachmann, Sebastian; Delpire, Eric; Peti-Peterdi, Janos; Navar, L. Gabriel; Bernstein, Kenneth E.; McDonough, Alicia A.

    2013-01-01

    Activation of the intrarenal renin-angiotensin system (RAS) can elicit hypertension independently from the systemic RAS. However, the precise mechanisms by which intrarenal Ang II increases blood pressure have never been identified. To this end, we studied the responses of mice specifically lacking kidney angiotensin-converting enzyme (ACE) to experimental hypertension. Here, we show that the absence of kidney ACE substantially blunts the hypertension induced by Ang II infusion (a model of high serum Ang II) or by nitric oxide synthesis inhibition (a model of low serum Ang II). Moreover, the renal responses to high serum Ang II observed in wild-type mice, including intrarenal Ang II accumulation, sodium and water retention, and activation of ion transporters in the loop of Henle (NKCC2) and distal nephron (NCC, ENaC, and pendrin) as well as the transporter activating kinases SPAK and OSR1, were effectively prevented in mice that lack kidney ACE. These findings demonstrate that ACE metabolism plays a fundamental role in the responses of the kidney to hypertensive stimuli. In particular, renal ACE activity is required to increase local Ang II, to stimulate sodium transport in loop of Henle and the distal nephron, and to induce hypertension. PMID:23619363

  15. Identification of natural inhibitors against angiotensin I converting enzyme for cardiac safety using induced fit docking and MM-GBSA studies

    PubMed Central

    Vijayakumar, Balakrishnan; Parasuraman, Subramani; Raveendran, Ramasamy; Velmurugan, Devadasan

    2014-01-01

    Background: Cleistanthins A and B are isolated compounds from the leaves of Cleistanthus collinus Roxb (Euphorbiaceae). This plant is poisonous in nature which causes cardiovascular abnormalities such as hypotension, nonspecific ST-T changes and QTc prolongation. The biological activity predictions spectra of the compounds show the presence of antihypertensive, diuretic and antitumor activities. Objective: Objective of the present study was to determine the in silico molecular interaction of cleistanthins A and B with Angiotensin I- Converting Enzyme (ACE-I) using Induced Fit Docking (IFD) protocols. Materials and Methods: All the molecular modeling calculations like IFD docking, binding free energy calculation and ADME/Tox were carried out using Glide software (Schrödinger LLC 2009, USA) in CentOS EL-5 workstation. Results: The IFD complexes showed favorable docking score, glide energy, glide emodel, hydrogen bond and hydrophobic interactions between the active site residues of ACE-I and the compounds. Binding free energy was calculated for the IFD complexes using Prime MM-GBSA method. The conformational changes induced by the inhibitor at the active site of ACE-I were observed based on changes of the back bone Cα atoms and side-chain chi (x) angles. The various physicochemical properties were calculated for these compounds. Both cleistanthins A and B showed better docking score, glide energy and glide emodel when compared to captopril inhibitor. Conclusion: These compounds have successively satisfied all the in silico parameters and seem to be potent inhibitors of ACE-I and potential candidates for hypertension. PMID:25298685

  16. A novel angiotensin-І converting enzyme (ACE) inhibitory peptide from gastrointestinal protease hydrolysate of silkworm pupa (Bombyx mori) protein: Biochemical characterization and molecular docking study.

    PubMed

    Wu, Qiongying; Jia, Junqiang; Yan, Hui; Du, Jinjuan; Gui, Zhongzheng

    2015-06-01

    Silkworm pupa (Bombyx mori) protein was hydrolyzed using gastrointestinal endopeptidases (pepsin, trypsin and α-chymotrypsin). Then, the hydrolysate was purified sequentially by ultrafiltration, gel filtration chromatography and RP-HPLC. A novel ACE inhibitory peptide, Ala-Ser-Leu, with the IC50 value of 102.15μM, was identified by IT-MS/MS. This is the first report of Ala-Ser-Leu from natural protein. Lineweaver-Burk plots suggest that the peptide is a competitive inhibitor against ACE. The molecular docking studies revealed that the ACE inhibition of Ala-Ser-Leu is mainly attributed to forming very strong hydrogen bonds with the S1 pocket (Ala354) and the S2 pocket (Gln281 and His353). The results indicate that silkworm pupa (B. mori) protein or its gastrointestinal protease hydrolysate could be used as a functional ingredient in auxiliary therapeutic foods against hypertension. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Two quantitative trait loci affect ACE activities in Mexican-Americans.

    PubMed

    Kammerer, Candace M; Gouin, Nicolas; Samollow, Paul B; VandeBerg, Jane F; Hixson, James E; Cole, Shelley A; MacCluer, Jean W; Atwood, Larry D

    2004-02-01

    Angiotensin-converting enzyme (ACE) activity is highly heritable and has been associated with cardiovascular disease. We are studying the effects of genes and environmental factors on hypertension and related phenotypes, such as ACE activity, in Mexican-American families. In the current study, we performed multipoint linkage analysis to search for quantitative trait loci (QTLs) that affect ACE activities on data from 793 individuals from 29 pedigrees from the San Antonio Family Heart Study. As expected, we obtained strong evidence (maximum log of the odds [LOD]=4.57, genomic P=0.003) that a QTL for ACE activity is located on chromosome 17 near the ACE structural locus. We subsequently performed linkage analyses conditional on the effect of this QTL and obtained strong evidence (LOD=3.34) for a second QTL on chromosome 4 near D4S1548. We next incorporated the ACEIns/Del genotypes in our analyses and removed the evidence for the chromosome 17 QTL (maximum LOD=0.60); however, we retained our evidence for the QTL on chromosome 4q. We conclude that the QTL on chromosome 17 is tightly linked to ACE and is in strong disequilibrium with the insertion/deletion polymorphism, which is consistent with other reports. We also have evidence that an additional QTL affects ACE activity. Identification of this additional QTL might lead to alternate means of prophylaxis.

  18. ACE DD genotype: a predisposing factor for abdominal aortic aneurysm.

    PubMed

    Fatini, C; Pratesi, G; Sofi, F; Gensini, F; Sticchi, E; Lari, B; Pulli, R; Dorigo, W; Azas, L; Pratesi, C; Gensini, G F; Abbate, R

    2005-03-01

    To examine the role of polymorphisms in angiotensin converting enzyme (ACE, I/D) and angiotensin II receptor (AT1R, A1166C) in the development of abdominal aortic aneurysm (AAA). We investigated 250 consecutive patients, 217 males and 33 females (median age 72, range 50-83), undergone AAA elective repair and 250 healthy controls, comparable for sex and age. ACE and AT1R polymorphisms were studied by PCR-RFLP analysis. The genotype distribution was in Hardy-Weinberg equilibrium for all polymorphisms. The genotype distribution and allele frequency of ACE I/D, but not AT1R A1166C polymorphism were significantly different between patients and controls (ACE I/D: p=0.0002 and p<0.0001, respectively, and AT1R A1166C: p=0.6 and p=0.4, respectively). An association between the ACE DD genotype and the predisposition to AAA was found (OR DD vs. ID+II=1.9 95% CI 1.3-2.9, p<0.0001). Multivariate analysis adjusted for age, sex, traditional vascular risk factors and other atherosclerotic localizations, showed ACE DD genotype to be independently related to the disease (OR DD vs. ID+II=2.4, 95% CI 1.3-4.2 p=0.003). Our findings document that ACE DD genotype represents a susceptibility factor for AAA.

  19. Lisinopril. A review of its pharmacology and clinical efficacy in the early management of acute myocardial infarction.

    PubMed

    Goa, K L; Balfour, J A; Zuanetti, G

    1996-10-01

    Following establishment of its efficacy in hypertension and congestive heart failure, the ACE inhibitor lisinopril has now been shown to reduce mortality and cardiovascular morbidity in patients with myocardial infarction when administered as early treatment. The ability of lisinopril to attenuate the detrimental effects of left ventricular remodelling is a key mechanism; however, additional cardioprotective and vasculoprotective actions are postulated to play a role in mediating the early benefit. The GISSI-3 trial in > 19 000 patients has demonstrated that, when given orally within 24 hours of symptom onset and continued for 6 weeks, lisinopril (with or without nitrates) produces measurable survival benefits within 1 to 2 days of starting treatment. Compared with no lisinopril treatment, reductions of 11% in risk of mortality and 7.7% in a combined end-point (death plus severe left ventricular dysfunction) were evident at 6 weeks. Advantages were apparent in all types of patients. Thus, those at high risk-women, the elderly, patients with diabetes mellitus and those with anterior infarct and/or Killip class > 1 -also benefited. These gains in combined end-point events persisted in the longer term, despite treatment withdrawal after 6 weeks in most patients. At 6 months, the incidence rate for the combined end-point remained lower than with control (a 6.2% reduction). The GISSI-3 results concur with those from recent large investigations (ISIS-4, CCS-1, SMILE) of other ACE inhibitors as early management in myocardial infarction. However, the results of the CONSENSUS II trial (using intravenous enalaprilat then oral enalapril) were unfavourable in some patients. These findings, together with the development of persistent hypotension and, to a lesser extent, renal dysfunction among patients in the GISSI-3 trial, have prompted considerable debate over optimum treatment strategies. Present opinion generally holds that therapy with lisinopril or other ACE inhibitors

  20. The ACE2 gene: its potential as a functional candidate for cardiovascular disease.

    PubMed

    Burrell, Louise M; Harrap, Stephen B; Velkoska, Elena; Patel, Sheila K

    2013-01-01

    The RAS (renin-angiotensin system) plays an important role in the pathophysiology of CVD (cardiovascular disease), and RAS blockade is an important therapeutic strategy in the management of CVD. A new counterbalancing arm of the RAS is now known to exist in which ACE (angiotensin-converting enzyme) 2 degrades Ang (angiotensin) II, the main effector of the classic RAS, and generates Ang-(1-7). Altered ACE2 expression is associated with cardiac and vascular disease in experimental models of CVD, and ACE2 is increased in failing human hearts and atherosclerotic vessels. In man, circulating ACE2 activity increases with coronary heart disease, as well as heart failure, and a large proportion of the variation in plasma ACE2 levels has been attributed to hereditary factors. The ACE2 gene maps to chromosome Xp22 and this paper reviews the evidence associating ACE2 gene variation with CVD and considers clues to potential functional ACE2 variants that may alter gene expression or transcriptional activity. Studies to date have investigated ACE2 gene associations in hypertension, left ventricular hypertrophy and coronary artery disease, but the results have been inconsistent. The discrepancies may reflect the sample size of the studies, the gender or ethnicity of subjects, the cardiovascular phenotype or the ACE2 SNP investigated. The frequent observation of apparent sex-dependence might be of special importance, if confirmed. As yet, there are no studies to concurrently assess ACE2 gene polymorphisms and circulating ACE2 activity. Large-scale carefully conducted clinical studies are urgently needed to clarify more precisely the potential role of ACE2 in the CVD continuum.

  1. Statins, Angiotensin-Converting Enzyme Inhibitors and Physical Performance in Older Women

    PubMed Central

    Gray, Shelly L.; Aragaki, Aaron K.; LaMonte, Michael J.; Cochrane, Barbara B.; Kooperberg, Charles; Robinson, Jennifer G.; Woods, Nancy F.; LaCroix, Andrea Z.

    2012-01-01

    OBJECTIVES Angiotensin-converting enzyme (ACE) inhibitor and statin medications may preserve skeletal muscle. We examined associations between each medication class and baseline and mean annual change in physical performance measures and muscle strength in older women. DESIGN Prospective cohort study PARTICIPANTS Participants from the Women’s Health Initiative Clinical Trials who were aged 65–79 at baseline and had physical performance measures, self-report of health insurance and no prior history of stroke or congestive heart failure were included (n=5777). Women were recruited between 1993 and 1998. MEASUREMENTS Medication use was ascertained through a baseline inventory. Physical performance measures (timed 6-meter walk, repeated chair stands in 15 seconds) and grip strength were assessed at baseline and follow-up years 1, 3 and 6. Multivariable adjusted linear repeated- measures models adjusted for demographic and health characteristics. RESULTS ACE inhibitor use was negatively associated with mean grip strength at baseline (22.40 kg, 95% confidence interval [CI] 21.89, 22.91 versus 23.18 kg, 95% CI 23.02, 23.34; P = .005) and a greater mean annual change in number of chair stands (−.182, 95% CI −.217, −.147 versus −.145, 95% CI −.156, −.133; P = .05) compared to non-use. Statin use was not significantly associated with baseline or mean annual change for any outcome. A subgroup analysis suggested that statin use was associated with less mean annual change in chair stands (P = .006) in the oldest women. CONCLUSION These results do not support an association of statin or ACE inhibitor use with slower decline in physical performance or muscle strength, and thus do not support the use of these medications for preserving functional status in older adults. PMID:23176078

  2. Heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease.

    PubMed

    Wang, Wang; Patel, Vaibhav B; Parajuli, Nirmal; Fan, Dong; Basu, Ratnadeep; Wang, Zuocheng; Ramprasath, Tharmarajan; Kassiri, Zamaneh; Penninger, Josef M; Oudit, Gavin Y

    2014-08-01

    Angiotensin-converting enzyme 2 (ACE2) metabolizes Ang II into Ang 1-7 thereby negatively regulating the renin-angiotensin system. However, heart disease in humans and in animal models is associated with only a partial loss of ACE2. ACE2 is an X-linked gene; and as such, we tested the clinical relevance of a partial loss of ACE2 by using female ACE2(+/+) (wildtype) and ACE2(+/-) (heterozygote) mice. Pressure overload in ACE2(+/-) mice resulted in greater LV dilation and worsening systolic and diastolic dysfunction. These changes were associated with increased myocardial fibrosis, hypertrophy, and upregulation of pathological gene expression. In response to Ang II infusion, there was increased NADPH oxidase activity and myocardial fibrosis resulting in the worsening of Ang II-induced diastolic dysfunction with a preserved systolic function. Ang II-mediated cellular effects in cultured adult ACE2(+/-) cardiomyocytes and cardiofibroblasts were exacerbated. Ang II-mediated pathological signaling worsened in ACE2(+/-) hearts characterized by an increase in the phosphorylation of ERK1/2 and JNK1/2 and STAT-3 pathways. The ACE2(+/-) mice showed an exacerbated pressor response with increased vascular fibrosis and stiffness. Vascular superoxide and nitrotyrosine levels were increased in ACE2(+/-) vessels consistent with increased vascular oxidative stress. These changes occurred with increased renal fibrosis and superoxide production. Partial heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease secondary to pressure overload and Ang II infusion. Heart disease in humans with idiopathic dilated cardiomyopathy is associated with a partial loss of ACE2. Heterozygote female ACE2 mutant mice showed enhanced susceptibility to pressure overload-induced heart disease. Heterozygote female ACE2 mutant mice showed enhanced susceptibility to Ang II-induced heart and vascular diseases. Partial loss of ACE2 is sufficient to enhance the susceptibility to

  3. Acute effect of the dual angiotensin-converting enzyme and neutral endopeptidase 24-11 inhibitor mixanpril on insulin sensitivity in obese Zucker rat

    PubMed Central

    Arbin, V; Claperon, N; Fournié-Zaluski, M -C; Roques, B P; Peyroux, J

    2001-01-01

    The aim of this study was to determine whether acute dual angiotensin-converting enzyme (ACE)/neutral endopeptidase 24-11 (NEP) inhibition could improve whole body insulin-mediated glucose disposal (IMGD) more than ACE inhibition alone and whether this effect was mediated by the kinin-nitric oxide (NO) pathway activation.We therefore compared in anaesthetized obese (fa/fa) Zucker rats (ZOs) the effects of captopril (2 mg kg−1, i.v.+2 mg kg−1 h−1), retrothiorphan (25 mg kg−1, i.v. +25 mg  kg−1 h−1), a selective NEP inhibitor, and mixanpril (25 mg kg−1, i.v.+25 mg kg−1 h−1), a dual ACE/NEP inhibitor, on IMGD using hyperinsulinaemic euglycaemic clamp technique. The role of the kinin-NO pathway in the effects of mixanpril was tested using a bradykinin B2 receptor antagonist (Hoe-140, 300 μg kg−1) and a NO-synthase inhibitor (Nω-nitro-L-arginine methyl ester, L-NAME, 10 mg kg−1 i.v. +10 mg kg−1 h−1) as pretreatments.Insulin sensitivity index (ISI) was lower in ZO controls than in lean littermates. Increases in ISI were observed in captopril- and retrothiorphan-treated ZOs. In mixanpril-treated ZOs, ISI was further increased, compared to captopril- and retrothiorphan-treated ZOs.In ZOs, Hoe-140 and L-NAME alone did not significantly alter and slightly reduced the ISI respectively. Hoe-140 and L-NAME markedly inhibited the ISI improvement induced by mixanpril.These results show that in obese insulin-resistant Zucker rats, under acute conditions, NEP or ACE inhibition can improve IMGD and that dual ACE/NEP inhibition improves IMGD more effectively than does either single inhibition. This effect is linked to an increased activation of the kinin-NO pathway. PMID:11399666

  4. The ACE gene and human performance: 12 years on.

    PubMed

    Puthucheary, Zudin; Skipworth, James R A; Rawal, Jai; Loosemore, Mike; Van Someren, Ken; Montgomery, Hugh E

    2011-06-01

    Some 12 years ago, a polymorphism of the angiotensin I-converting enzyme (ACE) gene became the first genetic element shown to impact substantially on human physical performance. The renin-angiotensin system (RAS) exists not just as an endocrine regulator, but also within local tissue and cells, where it serves a variety of functions. Functional genetic polymorphic variants have been identified for most components of RAS, of which the best known and studied is a polymorphism of the ACE gene. The ACE insertion/deletion (I/D) polymorphism has been associated with improvements in performance and exercise duration in a variety of populations. The I allele has been consistently demonstrated to be associated with endurance-orientated events, notably, in triathlons. Meanwhile, the D allele is associated with strength- and power-orientated performance, and has been found in significant excess among elite swimmers. Exceptions to these associations do exist, and are discussed. In theory, associations with ACE genotype may be due to functional variants in nearby loci, and/or related genetic polymorphism such as the angiotensin receptor, growth hormone and bradykinin genes. Studies of growth hormone gene variants have not shown significant associations with performance in studies involving both triathletes and military recruits. The angiotensin type-1 receptor has two functional polymorphisms that have not been shown to be associated with performance, although studies of hypoxic ascent have yielded conflicting results. ACE genotype influences bradykinin levels, and a common gene variant in the bradykinin 2 receptor exists. The high kinin activity haplotye has been associated with increased endurance performance at an Olympic level, and similar results of metabolic efficiency have been demonstrated in triathletes. Whilst the ACE genotype is associated with overall performance ability, at a single organ level, the ACE genotype and related polymorphism have significant

  5. Angiotensin-converting enzyme inhibitors delay the occurrence of renal involvement and are associated with a decreased risk of disease activity in patients with systemic lupus erythematosus--results from LUMINA (LIX): a multiethnic US cohort.

    PubMed

    Durán-Barragán, S; McGwin, G; Vilá, L M; Reveille, J D; Alarcón, G S

    2008-07-01

    To examine if angiotensin-converting enzyme (ACE) inhibitor use delays the occurrence of renal involvement and decreases the risk of disease activity in SLE patients. SLE patients (Hispanics, African Americans and Caucasians) from the lupus in minorities: nature vs nurture (LUMINA) cohort were studied. Renal involvement was defined as ACR criterion and/or biopsy-proven lupus nephritis. Time-to-renal involvement was examined by univariable and multivariable Cox proportional hazards regression analyses. Disease activity was examined with a case-crossover design and a conditional logistic regression model; in the case intervals, a decrease in the SLAM-R score >or=4 points occurred but not in the control intervals. Eighty of 378 patients (21%) were ACE inhibitor users; 298 (79%) were not. The probability of renal involvement free-survival at 10 yrs was 88.1% for users and 75.4% for non-users (P = 0.0099, log rank test). Users developed persistent proteinuria and/or biopsy-proven lupus nephritis (7.1%) less frequently than non-users (22.9%), P = 0.016. By multivariable Cox proportional hazards regression analyses, ACE inhibitors use [hazard ratio (HR) 0.27; 95% CI 0.09, 0.78] was associated with a longer time-to-renal involvement occurrence whereas African American ethnicity (HR 3.31; 95% CI 1.44, 7.61) was with a shorter time. ACE inhibitor use (54/288 case and 254/1148 control intervals) was also associated with a decreased risk of disease activity (HR 0.56; 95% CI 0.34, 0.94). ACE inhibitor use delays the development of renal involvement and associates with a decreased risk of disease activity in SLE; corroboration of these findings in other lupus cohorts is desirable before practice recommendations are formulated.

  6. Issues in hypertension: drug tolerability and special populations.

    PubMed

    Gavras, H P

    2001-07-01

    Improvements in the death rate from coronary heart disease and in the control of hypertension have leveled off in recent years, reversing a trend toward steady improvement that began in 1972. Of the roughly 20% of Americans who suffer from hypertension, only 29% achieve adequate control (<140/90 mm Hg) with treatment and nearly half receive no treatment at all. Poor adherence to therapy doubtless plays a key role in this failure. As a major cause of poor adherence, tolerability becomes an extremely important element in any discussion of effective antihypertensive treatment. Despite their efficacy in treating hypertension, diuretics, beta-blockers, and calcium channel blockers have all been associated with numerous side effects, including increased serum lipid levels, insulin resistance, and edema. With the introduction of the angiotensin converting enzyme (ACE) inhibitors, patients were able to achieve blood pressure goals with fewer side effects. These agents, however, cause an irritating cough in up to 19% of patients. A newer class of drugs, the angiotensin receptor blockers (ARB), have similar effects to the ACE inhibitors, but their highly selective nature produces even fewer side effects. Eprosartan is a structurally unique ARB. Like the other ARB, this promising new agent has a side effect profile similar to placebo, and its response rate rivals or exceeds that of enalapril. Although it remains to be seen whether the ARB can significantly reduce morbidity and mortality from cardiovascular disease, preliminary data from the Evaluation of Losartan in the Elderly (ELITE) trial appear to be promising.

  7. Contemplating Synergistic Algorithms for the NASA ACE Mission

    NASA Technical Reports Server (NTRS)

    Mace, Gerald G.; Starr, David O.; Marchand, Roger; Ackerman, Steven A.; Platnick, Steven E.; Fridlind, Ann; Cooper, Steven; Vane, Deborah G.; Stephens, Graeme L.

    2013-01-01

    ACE is a proposed Tier 2 NASA Decadal Survey mission that will focus on clouds, aerosols, and precipitation as well as ocean ecosystems. The primary objective of the clouds component of this mission is to advance our ability to predict changes to the Earth's hydrological cycle and energy balance in response to climate forcings by generating observational constraints on future science questions, especially those associated with the effects of aerosol on clouds and precipitation. ACE will continue and extend the measurement heritage that began with the A-Train and that will continue through Earthcare. ACE planning efforts have identified several data streams that can contribute significantly to characterizing the properties of clouds and precipitation and the physical processes that force these properties. These include dual frequency Doppler radar, high spectral resolution lidar, polarimetric visible imagers, passive microwave and submillimeter wave radiometry. While all these data streams are technologically feasible, their total cost is substantial and likely prohibitive. It is, therefore, necessary to critically evaluate their contributions to the ACE science goals. We have begun developing algorithms to explore this trade space. Specifically, we will describe our early exploratory algorithms that take as input the set of potential ACE-like data streams and evaluate critically to what extent each data stream influences the error in a specific cloud quantity retrieval.

  8. A Discussion of Aerodynamic Control Effectors (ACEs) for Unmanned Air Vehicles (UAVs)

    NASA Technical Reports Server (NTRS)

    Wood, Richard M.

    2002-01-01

    A Reynolds number based, unmanned air vehicle classification structure has been developed which identifies four classes of unmanned air vehicle concepts. The four unmanned air vehicle (UAV) classes are; Micro UAV, Meso UAV, Macro UAV, and Mega UAV. In a similar fashion a labeling scheme for aerodynamic control effectors (ACE) was developed and eleven types of ACE concepts were identified. These eleven types of ACEs were laid out in a five (5) layer scheme. The final section of the paper correlated the various ACE concepts to the four UAV classes and ACE recommendations are offered for future design activities.

  9. Effectiveness and tolerability of fixed-dose combination enalapril plus nitrendipine in hypertensive patients: results of the 3-month observational, post-marketing, multicentre, prospective CENIT study.

    PubMed

    Sierra, Alejandro de la; Roca-Cusachs, Alejandro; Redón, Josep; Marín, Rafael; Luque, Manuel; Figuera, Mariano de la; Garcia-Garcia, Margarida; Falkon, Liliana

    2009-01-01

    Monotherapy with any class of antihypertensive drug effectively controls blood pressure (BP) in only about 50% of patients. Consequently, the majority of patients with hypertension require combined therapy with two or more medications. This study aimed to evaluate the effectiveness (systolic BP [SBP]/diastolic BP [DBP] control) and tolerability of the fixed-dose combination enalapril/nitrendipine 10 mg/20 mg administered as a single daily dose in hypertensive patients. This was a post-authorization, multicentre, prospective, observational study conducted in primary care with a 3-month follow-up. Patients throughout Spain with uncontrolled hypertension (> or =140/90 mmHg for patients without diabetes mellitus, or > or =130/85 mmHg for patients with diabetes) on monotherapy or with any combination other than enalapril + nitrendipine, or who were unable to tolerate their previous antihypertensive therapy, were recruited. Change from previous to study treatment was according to usual clinical practice. BP was measured once after 5 minutes of rest in the sitting position. Therapeutic response was defined as follows: 'controlled' meant controlled BP (<140/90 mmHg for nondiabetic patients, or <130/85 mmHg for diabetic patients); 'response' meant controlled BP, or a decrease in SBP of > or =20 mmHg and in DBP of > or =10 mmHg. The main laboratory test parameters were documented at baseline and after 3 months. Patients aged >65 years, with diabetes, with isolated systolic hypertension (ISH; SBP > or =140 mmHg for patients without diabetes, SBP > or =130 mmHg for patients with diabetes) and who were obese (body mass index [BMI] > or =30 kg/m2) were analysed separately. Of 6537 patients included, 5010 and 6354 patients were assessed in effectiveness and tolerability analyses, respectively. In the tolerability analysis population, there were 3023 men (47.6%) and 3321 women (52.4%). The mean (+/- SD) age of the tolerability analysis group was 62.8 (+/- 10.7) years. A total of

  10. The solar array is installed on ACE in SAEF-2

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Applied Physics Laboratory engineers and technicians from Johns Hopkins University install solar array panels on the Advanced Composition Explorer (ACE) in KSC's Spacecraft Assembly and Encapsulation Facility-II. The panel on which they are working is identical to the panel (one of four) seen in the foreground on the ACE spacecraft. Scheduled for launch on a Delta II rocket from Cape Canaveral Air Station on Aug. 25, ACE will study low- energy particles of solar origin and high-energy galactic particles for a better understanding of the formation and evolution of the solar system as well as the astrophysical processes involved. The ACE observatory will be placed into an orbit almost a million miles (1.5 million kilometers) away from the Earth, about 1/100 the distance from the Earth to the Sun. The collecting power of instrumentation aboard ACE is at least 100 times more sensitive than anything previously flown to collect similar data by NASA.

  11. Tissue-specific modulation of angiotensin-converting enzyme (ACE) in hyperthyroidism.

    PubMed

    Carneiro-Ramos, M S; Silva, V B; Santos, R A S; Barreto-Chaves, M L M

    2006-11-01

    We have previously demonstrated the interaction between the RAS and thyroid hormones (TH). The present study was designed to determine the role of TH in the local regulation of ACE activity and expression in different tissues. Adult male Wistar rats were randomized into three groups: T4-25 and T4-100 (0.025 and 0.100mg/kg of body weight/day of l-thyroxine for 14 days, respectively) and control. Hemodynamic parameters as well as cardiac and renal hypertrophy were evaluated. ACE activity and mRNA levels were determined by Fluorimetric and Northern blot assays, respectively. Both doses increased SBP and HR, as well as inducing cardiac and renal hypertrophy. Pulmonary and serum ACE levels were comparable among the groups. Both doses promoted increased renal ACE activity and expression but surprisingly ACE was diminished in the heart in both hyperthyroid groups. This change was mediated by a tissue-specific transcription mechanism.

  12. Synthesis and evaluation of chalcone analogues based pyrimidines as angiotensin converting enzyme inhibitors.

    PubMed

    Bukhari, S N A; Butt, A M; Amjad, M W B; Ahmad, W; Shah, V H; Trivedi, A R

    2013-11-01

    Hypertension is a widespread and frequently progressive ailment that imparts a foremost threat for cardiovascular and renal disorders. Mammoth efforts are needed for the synthesis of innovative antihypertensive agents to combat this lethal disease. Chalcones have shown antihypertensive activity through inhibition of Angiotensin Converting Enzyme (ACE). Hence, a series of chalcone analogues is synthesized and used as precursor for the synthesis of novel series of pyrimidines. Precursor chalcones were prepared by reacting aldehydes and ketones in presence of sodium hydroxide followed by synthesis of corresponding pyrimidines by reaction with urea in presence of potassium hydroxide. Both groups were then evaluated for their effects on ACE. The results depicted that pyrimidines were more active than chalcones with methoxy (C5 and P5) substitution showing best results to inhibit ACE. Given that chalcone analogues and pyrimidines show a potential as the angiotensin converting enzyme inhibitors.

  13. Identification of Potent ACE Inhibitory Peptides from Wild Almond Proteins.

    PubMed

    Mirzapour, Mozhgan; Rezaei, Karamatollah; Sentandreu, Miguel Angel

    2017-10-01

    In this study, the production, fractionation, purification and identification of ACE (angiotensin-I-converting enzyme) inhibitory peptides from wild almond (Amygdalus scoparia) proteins were investigated. Wild almond proteins were hydrolyzed using 5 different enzymes (pepsin, trypsin, chymotrypsin, alcalase and flavourzyme) and assayed for their ACE inhibitory activities. The degree of ACE inhibiting activity obtained after hydrolysis was found to be in the following order: alcalase > chymotrypsin > trypsin/pepsin > flavourzyme. The hydrolysates obtained from alcalase (IC 50 = 0.8 mg/mL) were fractionated by sequential ultrafiltration at 10 and 3 kDa cutoff values and the most active fraction (<3 kDa) was further separated using reversed phase high-performance liquid chromatography (RP-HPLC). Peptide sequence identifications were carried out on highly potential fractions obtained from RP-HPLC by means of liquid chromatography coupled to electrospray ionization and tandem mass spectrometry (LC-ESI-MS/MS). Sequencing of ACE inhibitory peptides present in the fraction 26 of RP-HPLC resulted in the identification of 3 peptide sequences (VVNE, VVTR, and VVGVD) not reported previously in the literature. Sequence identification of fractions 40 and 42 from RP-HPLC, which showed the highest ACE inhibitory activities (84.1% and 86.9%, respectively), resulted in the identification of more than 40 potential ACE inhibitory sequences. The results indicate that wild almond protein is a rich source of potential antihypertensive peptides and can be suggested for applications in functional foods and drinks with respect to hindrance and mitigation of hypertension after in vivo assessment. This study has shown the potential of wild almond proteins as good sources for producing ACE-inhibitory active peptides. According to this finding, peptides with higher ACE inhibitory activities could be released during the gastrointestinal digestion and contribute to the health- promoting

  14. Efficiency and specificity of RAAS inhibitors in cardiovascular diseases: how to achieve better end-organ protection?

    PubMed

    Nehme, Ali; Zibara, Kazem

    2017-11-01

    RAAS, a major pharmacological target in cardiovascular medicine, is inhibited by pharmacological classes including angiotensin converting enzyme (ACE) inhibitors (ACEIs), angiotensin-II type 1 blockers (ARBs) and aldosterone receptors antagonists, in addition to the recently introduced direct renin inhibitors (DRIs). However, currently used RAAS inhibitors still cannot achieve their desired effects and are associated with certain drawbacks, such as adverse side effects, incomplete blockage of the system and poor end-organ protection. In this review, we discuss the efficiency and specificity of the current RAAS inhibitors and propose some recommendations for achieving better treatments with better end-organ protection.

  15. Myoglobin microplate assay to evaluate prevention of protein peroxidation.

    PubMed

    Marques, Sara S; Magalhães, Luís M; Mota, Ana I P; Soares, Tânia R P; Korsak, Barbara; Reis, Salette; Segundo, Marcela A

    2015-10-10

    The current therapeutic strategies are based on the design of multifunctional drug candidates able to interact with various disease related targets. Drugs that have the ability to scavenge reactive oxygen species (ROS), beyond their main therapeutic action, may prevent the oxidative damage of biomolecules. Therefore, analytical approaches that monitor in a continuous mode the ability of drugs to counteract peroxidation of physiologically relevant biotargets are required. In the present work, a microplate spectrophotometric assay is proposed to evaluate the ability of selected cardiovascular drugs, including angiotensin-converting enzyme (ACE) inhibitors, β -blockers and statins to prevent protein peroxidation. Myoglobin, which is a heme protein, and peroxyl radicals generated from thermolysis of 2,2'-azo-bis(2-amidinopropane) dihydrochloride at 37 °C, pH 7.4 were selected as protein model and oxidative species, respectively. Myoglobin peroxidation was continuously monitored by the absorbance decrease at 409 nm and the ability of drugs to counteract protein oxidation was determined by the calculation of the area under the curve upon the myoglobin oxidation. Fluvastatin (AUC₅₀=12.5 ± 1.2 μM) and enalapril (AUC₅₀=15.2 ± 1.8 μM) showed high ability to prevent myoglobin peroxidation, providing even better efficiency than endogenous antioxidants such as reduced glutathione. Moreover, labetalol, enalapril and fluvastatin prevent the autoxidation of myoglobin, while glutathione showed a pro-oxidant effect. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. The solar array is installed on ACE in SAEF-2

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Applied Physics Laboratory engineers and technicians from Johns Hopkins University assist in guiding the Advanced Composition Explorer (ACE) as it is hoisted over a platform for solar array installation in KSC's Spacecraft Assembly and Encapsulation Facility-II. Scheduled for launch on a Delta II rocket from Cape Canaveral Air Station on Aug. 25, ACE will study low-energy particles of solar origin and high-energy galactic particles. The ACE observatory will contribute to the understanding of the formation and evolution of the solar system as well as the astrophysical processes involved. The collecting power of instruments aboard ACE is 10 to 1,000 times greater than anything previously flown to collect similar data by NASA.

  17. Single nucleotide polymorphisms of the angiotensin-converting enzyme (ACE) gene are associated with essential hypertension and increased ACE enzyme levels in Mexican individuals.

    PubMed

    Martínez-Rodríguez, Nancy; Posadas-Romero, Carlos; Villarreal-Molina, Teresa; Vallejo, Maite; Del-Valle-Mondragón, Leonardo; Ramírez-Bello, Julian; Valladares, Adan; Cruz-López, Miguel; Vargas-Alarcón, Gilberto

    2013-01-01

    To explore the role of the ACE gene polymorphisms in the risk of essential hypertension in Mexican Mestizo individuals and evaluate the correlation between these polymorphisms and the serum ACE levels. Nine ACE gene polymorphisms were genotyped by 5' exonuclease TaqMan genotyping assays and polymerase chain reaction (PCR) in 239 hypertensive and 371 non- hypertensive Mexican individuals. Haplotypes were constructed after linkage disequilibrium analysis. ACE serum levels were determined in selected individuals according to different haplotypes. Under a dominant model, rs4291 rs4335, rs4344, rs4353, rs4362, and rs4363 polymorphisms were associated with an increased risk of hypertension after adjusting for age, gender, BMI, triglycerides, alcohol consumption, and smoking. Five polymorphisms (rs4335, rs4344, rs4353, rs4362 and rs4363) were in strong linkage disequilibrium and were included in four haplotypes: H1 (AAGCA), H2 (GGATG), H3 (AGATG), and H4 (AGACA). Haplotype H1 was associated with decreased risk of hypertension, while haplotype H2 was associated with an increased risk of hypertension (OR = 0.77, P = 0.023 and OR = 1.41, P = 0.004 respectively). According to the codominant model, the H2/H2 and H1/H2 haplotype combinations were significantly associated with risk of hypertension after adjusted by age, gender, BMI, triglycerides, alcohol consumption, and smoking (OR = 2.0; P = 0.002 and OR = 2.09; P = 0.011, respectively). Significant elevations in serum ACE concentrations were found in individuals with the H2 haplotype (H2/H2 and H2/H1) as compared to H1/H1 individuals (P = 0.0048). The results suggest that single nucleotide polymorphisms and the "GGATG" haplotype of the ACE gene are associated with the development of hypertension and with increased ACE enzyme levels.

  18. Fixed-Dose Combinations of Renin–Angiotensin System Inhibitors and Calcium Channel Blockers in the Treatment of Hypertension

    PubMed Central

    Hsiao, Fu-Chih; Tung, Ying-Chang; Chou, Shing-Hsien; Wu, Lung-Sheng; Lin, Chia-Pin; Wang, Chun-Li; Lin, Yu-Sheng; Chang, Chee-Jen; Chu, Pao-Hsien

    2015-01-01

    Abstract Fixed-dose combinations (FDCs) of different regimens are recommended in guidelines for the treatment of hypertension. However, clinical studies comparing FDCs of angiotensin receptor blocker (ARB)/calcium channel blocker (CCB) and angiotensin-converting enzyme inhibitor (ACE inhibitor)/CCB in hypertensive patients are lacking. Using a propensity score matching of 4:1 ratio, this retrospective claims database study compared 2 FDC regimens, ARB/CCB and ACE inhibitor/CCB, in treating hypertensive patients with no known atherosclerotic cardiovascular disease. All patients were followed for at least 3 years or until the development of major adverse cardiovascular events (MACEs) during the study period. In addition, the effect of medication adherence on clinical outcomes was evaluated in subgroup analysis based on different portions of days covered. There was no significant difference in MACE-free survival (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 0.98–1.50; P = 0.08) and survival free from hospitalization for heart failure (HR: 1.15; 95% CI: 082–1.61; P = 0.431), new diagnosis of chronic kidney disease (HR: 0.98; 95% CI: 071–1.36; P = 0.906), and initiation of dialysis (HR: 0.99; 95% CI: 050–1.92; P = 0.965) between the 2 study groups. The results remained the same within each subgroup of patients with different adherence statuses. ARBs in FDC regimens with CCBs in the present study were shown to be as effective as ACE inhibitors at reducing the risks of MACEs, hospitalization for heart failure, new diagnosis of chronic kidney disease, and new initiation of dialysis in hypertensive patients, regardless of the medication adherence status. PMID:26705234

  19. ACE inhibitors

    MedlinePlus

    ... Diabetes - keeping active Diabetes - low blood sugar - self-care Diabetes - preventing heart attack and stroke Diabetes - taking care of your feet Diabetes - tests and checkups Diabetes - when you are sick ...

  20. Tissue angiotensin-converting enzyme inhibitors for the prevention of cardiovascular disease in patients with diabetes mellitus without left ventricular systolic dysfunction or clinical evidence of heart failure: a pooled meta-analysis of randomized placebo-controlled clinical trials.

    PubMed

    Saha, S A; Molnar, J; Arora, R R

    2008-01-01

    The aim of this study was to determine the role of tissue angiotensin-converting enzyme (ACE) inhibitors in the prevention of cardiovascular disease in patients with diabetes mellitus without left ventricular systolic dysfunction or clinical evidence of heart failure in randomized placebo-controlled clinical trials using pooled meta-analysis techniques. Randomized placebo-controlled clinical trials of at least 12 months duration in patients with diabetes mellitus without left ventricular systolic dysfunction or heart failure who had experienced a prior cardiovascular event or were at high cardiovascular risk were selected. A total of 10 328 patients (43 517 patient-years) from four selected trials were used for meta-analysis. Relative risk estimations were made using data pooled from the selected trials and statistical significance was determined using the Chi-squared test (two-sided alpha error <0.05). The number of patients needed to treat was also calculated. Tissue ACE inhibitors significantly reduced the risk of cardiovascular mortality by 14.9% (p = 0.022), myocardial infarction by 20.8% (p = 0.002) and the need for invasive coronary revascularization by 14% (p = 0.015) when compared to placebo. The risk of all-cause mortality also tended to be lower among patients randomized to tissue ACE inhibitors, whereas the risks of stroke and hospitalization for heart failure were not significantly affected. Treating about 65 patients with tissue ACE inhibitors for about 4.2 years would prevent one myocardial infarction, whereas treating about 85 patients would prevent one cardiovascular death. Pooled meta-analysis of randomized placebo-controlled trials suggests that tissue ACE inhibitors modestly reduce the risk of myocardial infarction and cardiovascular death and tend to reduce overall mortality in diabetic patients without left ventricular systolic dysfunction or heart failure.

  1. Association of angiotensin-converting enzyme (ACE) gene polymorphism with elevated serum ACE activity and major depression in an Iranian population.

    PubMed

    Firouzabadi, Negar; Shafiei, Massoumeh; Bahramali, Ehsan; Ebrahimi, Soltan Ahmed; Bakhshandeh, Hooman; Tajik, Nader

    2012-12-30

    Genetic factors contribute substantially to the likelihood of developing major depressive disorder (MDD). The importance of renin-angiotensin system (RAS) elements in cognition and behaviour and their involvement in aetiology and treatment of depression imply that RAS gene polymorphism(s) associated with RAS overactivity might also be associated with depression. In the present study, genotype and allele frequencies of six common polymorphisms of genes encoding for RAS components were determined in DNAs extracted from venous blood of 191 depressed and 104 healthy individuals using polymerase chain reaction (PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and serum angiotensin-converting enzyme (ACE) activity was assayed using a high-performance liquid chromatography (HPLC) method. The results showed, for the first time, that GG genotype of ACE A2350G was significantly associated with MDD among Iranian participants (P=0.001; odds ratio (OR)=6.2; 95% confidence interval (CI)=2.1-18.3). Significant higher serum ACE activity (P=0.0001) as well as higher diastolic blood pressure (P=0.036) were observed in depressed patients compared to the healthy control group. Depressed patients carrying GG genotype of the A2350G polymorphism had a significantly higher serum ACE activity (P=0.02) than individuals with either AA or AG genotype. In conclusion, this study supports the hypothesis of RAS overactivity in depression in that the genotype associated with higher serum ACE activity in an Iranian population was also associated with MDD. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  2. Blood type gene locus has no influence on ACE association with Alzheimer's disease.

    PubMed

    Braae, Anne; Medway, Christopher; Carrasquillo, Minerva; Younkin, Steven; Kehoe, Patrick G; Morgan, Kevin

    2015-04-01

    The ABO blood group locus was recently found to contribute independently and via interactions with angiotensin-converting enzyme (ACE) gene variation to plasma levels of ACE. Variation in ACE has previously been not only implicated as individually conferring susceptibility for Alzheimer's disease (AD) but also proposed to confer risk via interactions with other as yet unknown genes. More recently, larger studies have not supported ACE as a risk factor for AD, whereas the role of ACE pathway in AD has come under increased levels of scrutiny with respect to various aspects of AD pathology and possible therapies. We explored the potential combined involvement of ABO and ACE variations in the genetic susceptibility of 2067 AD cases compared with 1376 nondemented elderly. Including the effects of ABO haplotype did not provide any evidence for the genetic association of ACE with AD. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Does Angiotensin-Converting Enzyme Inhibitor and β-Blocker Use Reduce the Risk of Primary Liver Cancer? A Case-Control Study Using the U.K. Clinical Practice Research Datalink.

    PubMed

    Hagberg, Katrina Wilcox; Sahasrabuddhe, Vikrant V; McGlynn, Katherine A; Jick, Susan S

    2016-02-01

    It has been suggested that use of the antihypertensive drugs angiotensin-converting enzyme (ACE) inhibitors and β-blockers may decrease the risk of primary liver cancer; thus, the objective of this study was to evaluate whether use of ACE inhibitors and/or β-blockers is associated with a lower risk of liver cancer. Nested case-control study. United Kingdom Clinical Practice Research Datalink. We identified 490 cases with hypertension and a first-time (incident) diagnosis of primary liver cancer between 1988 and 2011. To account for an induction period, the index date was defined as the date of the first recorded liver cancer diagnosis minus 1 year. Controls were selected from patients with hypertension in the CPRD during the study period with a recorded diagnosis of hypertension who had no diagnosis of liver cancer and were free of any other cancer (except nonmelanoma skin cancer) before the index date; they were matched up to a 4:1 ratio to cases based on index date (same index date as that of their matched case), age (same year of birth), sex, general practice, and number of years of recorded history in the CPRD before the index date (1909 controls). Both cases and controls were required to have at least 2 years of recorded activity in the database before the index date. Exposure was defined as receipt of two or more prescriptions for ACE inhibitors and/or β-blockers before the index date; the reference group was nonuse (0-1 prescription) of ACE or β-blocker prescriptions before the index date. We also examined the effect of duration of use and, separately, the effect of individual drugs within each medication class on risk of liver cancer, and conducted analyses restricted to patients without liver disease or diabetes mellitus. Conditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). No association was found between use of ACE inhibitors and/or β-blockers and the risk of liver cancer compared

  4. Activation pattern of ACE2/Ang-(1-7) and ACE/Ang II pathway in course of heart failure assessed by multiparametric MRI in vivo in Tgαq*44 mice.

    PubMed

    Tyrankiewicz, Urszula; Olkowicz, Mariola; Skórka, Tomasz; Jablonska, Magdalena; Orzylowska, Anna; Bar, Anna; Gonet, Michal; Berkowicz, Piotr; Jasinski, Krzysztof; Zoladz, Jerzy A; Smolenski, Ryszard T; Chlopicki, Stefan

    2018-01-01

    Here, we analyzed systemic (plasma) and local (heart/aorta) changes in ACE/ACE-2 balance in Tgαq*44 mice in course of heart failure (HF). Tgαq*44 mice with cardiomyocyte-specific Gαq overexpression and late onset of HF were analyzed at different age for angiotensin pattern in plasma, heart, and aorta using liquid chromatography/mass spectrometry, for progression of HF by in vivo magnetic resonance imaging under isoflurane anesthesia, and for physical activity by voluntary wheel running. Six-month-old Tgαq*44 mice displayed decreased ventricle radial strains and impaired left atrial function. At 8-10 mo, Tgαq*44 mice showed impaired systolic performance and reduced voluntary wheel running but exhibited preserved inotropic reserve. At 12 mo, Tgαq*44 mice demonstrated a severe impairment of basal cardiac performance and modestly compromised inotropic reserve with reduced voluntary wheel running. Angiotensin analysis in plasma revealed an increase in concentration of angiotensin-(1-7) in 6- to 10-mo-old Tgαq*44 mice. However, in 12- to 14-mo-old Tgαq*44 mice, increased angiotensin II was noted with a concomitant increase in Ang III, Ang IV, angiotensin A, and angiotensin-(1-10). The pattern of changes in the heart and aorta was also compatible with activation of ACE2, followed by activation of the ACE pathway. In conclusion, mice with cardiomyocyte Gαq protein overexpression develop HF that is associated with activation of the systemic and the local ACE/Ang II pathway. However, it is counterbalanced by a prominent ACE2/Ang-(1-7) activation, possibly allowing to delay decompensation. NEW & NOTEWORTHY Changes in ACE/ACE-2 balance were analyzed based on measurements of a panel of nine angiotensins in plasma, heart, and aorta of Tgαq*44 mice in relation to progression of heart failure (HF) characterized by multiparametric MRI and exercise performance. The early stage of HF was associated with upregulation of the ACE2/angiotensin-(1-7) pathway, whereas the end

  5. DNA Methylation Analysis of the Angiotensin Converting Enzyme (ACE) Gene in Major Depression

    PubMed Central

    Zill, Peter; Baghai, Thomas C.; Schüle, Cornelius; Born, Christoph; Früstück, Clemens; Büttner, Andreas; Eisenmenger, Wolfgang; Varallo-Bedarida, Gabriella; Rupprecht, Rainer; Möller, Hans-Jürgen; Bondy, Brigitta

    2012-01-01

    Background The angiotensin converting enzyme (ACE) has been repeatedly discussed as susceptibility factor for major depression (MD) and the bi-directional relation between MD and cardiovascular disorders (CVD). In this context, functional polymorphisms of the ACE gene have been linked to depression, to antidepressant treatment response, to ACE serum concentrations, as well as to hypertension, myocardial infarction and CVD risk markers. The mostly investigated ACE Ins/Del polymorphism accounts for ∼40%–50% of the ACE serum concentration variance, the remaining half is probably determined by other genetic, environmental or epigenetic factors, but these are poorly understood. Materials and Methods The main aim of the present study was the analysis of the DNA methylation pattern in the regulatory region of the ACE gene in peripheral leukocytes of 81 MD patients and 81 healthy controls. Results We detected intensive DNA methylation within a recently described, functional important region of the ACE gene promoter including hypermethylation in depressed patients (p = 0.008) and a significant inverse correlation between the ACE serum concentration and ACE promoter methylation frequency in the total sample (p = 0.02). Furthermore, a significant inverse correlation between the concentrations of the inflammatory CVD risk markers ICAM-1, E-selectin and P-selectin and the degree of ACE promoter methylation in MD patients could be demonstrated (p = 0.01 - 0.04). Conclusion The results of the present study suggest that aberrations in ACE promoter DNA methylation may be an underlying cause of MD and probably a common pathogenic factor for the bi-directional relationship between MD and cardiovascular disorders. PMID:22808171

  6. An investigation of the concomitant use of angiotensin-converting enzyme inhibitors, non-steroidal anti-inflammatory drugs and diuretics.

    PubMed

    Bucsa, C; Moga, D C; Farcas, A; Mogosan, C; Dumitrascu, D L

    2015-08-01

    To determine in retrospective data the prevalence at hospital discharge of co-prescribing angiotensin-converting enzyme inhibitors (ACE-I) and non-steroidal anti-inflammatory drugs (NSAIDs) and ACE-I/NSAIDs and diuretics and to identify factors associated with the co-prescription. Secondary, we evaluated the extent of serum creatinine and potassium monitoring in patients treated with ACE-I and these associations and determined the prevalence of values above the upper normal limit (UNL) in monitored patients. Hospitalized patients with ACE-I in their therapy at discharge were included in 3 groups as follows: ACE-I, DT (double therapy with ACE-I and NSAIDs) and TT (triple therapy with ACE-I, NSAIDs and diuretics) groups. We evaluated differences on demographic characteristics, co-morbidities, medications, laboratory monitoring and quantified the patients with serum creatinine and potassium levels above the UNL using descriptive statistics. Logistic regression analysis with backward elimination was performed to identify significant predictors of combination therapy. Of 9960 admitted patients, 1214 were prescribed ACE-I, 40 were prescribed ACE-I/NSAIDs and 22 were prescribed ACE-I/NSAIDs/diuretics (3.13% and 1.72%, respectively, of the patients prescribed with ACE-I). Serum creatinine and potassium were monitored for the great majority of patients from all groups. The highest percentage of hyperkalemia was found in the DT group (10% of the patients) and of serum creatinine above UNL in the TT group (45.45%). The logistic regression final model showed that younger patients and monitoring for potassium were significantly associated with combination therapy. The prevalence of patients receiving DT/TT was relatively low and their monitoring during hospitalization was high. Factors associated with the combinations were younger patients and patients not tested for serum potassium.

  7. A Data Services Upgrade for Advanced Composition Explorer (ACE) Data

    NASA Astrophysics Data System (ADS)

    Davis, A. J.; Hamell, G.

    2008-12-01

    Since early in 1998, NASA's Advanced Composition Explorer (ACE) spacecraft has provided continuous measurements of solar wind, interplanetary magnetic field, and energetic particle activity from L1, located approximately 0.01 AU sunward of Earth. The spacecraft has enough fuel to stay in orbit about L1 until ~2024. The ACE Science Center (ASC) provides access to ACE data, and performs level 1 and browse data processing for the science instruments. Thanks to a NASA Data Services Upgrade grant, we have recently retooled our legacy web interface to ACE data, enhancing data subsetting capabilities and improving online plotting options. We have also integrated a new application programming interface (API) and we are working to ensure that it will be compatible with emerging Virtual Observatory (VO) data services standards. The new API makes extensive use of metadata created using the Space Physics Archive Search and Extract (SPASE) data model. We describe these recent improvements to the ACE Science Center data services, and our plans for integrating these services into the VO system.

  8. Lactoferricin-related peptides with inhibitory effects on ACE-dependent vasoconstriction.

    PubMed

    Centeno, José M; Burguete, María C; Castelló-Ruiz, María; Enrique, María; Vallés, Salvador; Salom, Juan B; Torregrosa, Germán; Marcos, José F; Alborch, Enrique; Manzanares, Paloma

    2006-07-26

    A selection of lactoferricin B (LfcinB)-related peptides with an angiotensin I-converting enzyme (ACE) inhibitory effect have been examined using in vitro and ex vivo functional assays. Peptides that were analyzed included a set of sequence-related antimicrobial hexapeptides previously reported and two representative LfcinB-derived peptides. In vitro assays using hippuryl-L-histidyl-L-leucine (HHL) and angiotensin I as substrates allowed us to select two hexapeptides, PACEI32 (Ac-RKWHFW-NH2) and PACEI34 (Ac-RKWLFW-NH2), and also a LfcinB-derived peptide, LfcinB17-31 (Ac-FKCRRWQWRMKKLGA-NH2). Ex vivo functional assays using rabbit carotid arterial segments showed PACEI32 (both D- and L-enantiomers) and LfcinB17-31 have inhibitory effects on ACE-dependent angiotensin I-induced contraction. None of the peptides exhibited in vitro ACE inhibitory activity using bradykinin as the substrate. In conclusion, three bioactive lactoferricin-related peptides exhibit inhibitory effects on both ACE activity and ACE-dependent vasoconstriction with potential to modulate hypertension that deserves further investigation.

  9. Absence of cell surface expression of human ACE leads to perinatal death

    PubMed Central

    Michaud, Annie; Acharya, K. Ravi; Masuyer, Geoffrey; Quenech'du, Nicole; Gribouval, Olivier; Morinière, Vincent; Gubler, Marie-Claire; Corvol, Pierre

    2014-01-01

    Renal tubular dysgenesis (RTD) is a recessive autosomal disease characterized most often by perinatal death. It is due to the inactivation of any of the major genes of the renin-angiotensin system (RAS), one of which is the angiotensin I-converting enzyme (ACE). ACE is present as a tissue-bound enzyme and circulates in plasma after its solubilization. In this report, we present the effect of different ACE mutations associated with RTD on ACE intracellular trafficking, secretion and enzymatic activity. One truncated mutant, R762X, responsible for neonatal death was found to be an enzymatically active, secreted form, not inserted in the plasma membrane. In contrast, another mutant, R1180P, was compatible with life after transient neonatal renal insufficiency. This mutant was located at the plasma membrane and rapidly secreted. These results highlight the importance of tissue-bound ACE versus circulating ACE and show that the total absence of cell surface expression of ACE is incompatible with life. In addition, two missense mutants (W594R and R828H) and two truncated mutants (Q1136X and G1145AX) were also studied. These mutants were neither inserted in the plasma membrane nor secreted. Finally, the structural implications of these ACE mutations were examined by molecular modelling, which suggested some important structural alterations such as disruption of intra-molecular non-covalent interactions (e.g. salt bridges). PMID:24163131

  10. Preparing GMAT for Operational Maneuver Planning of the Advanced Composition Explorer (ACE)

    NASA Technical Reports Server (NTRS)

    Qureshi, Rizwan Hamid; Hughes, Steven P.

    2014-01-01

    The General Mission Analysis Tool (GMAT) is an open-source space mission design, analysis and trajectory optimization tool. GMAT is developed by a team of NASA, private industry, public and private contributors. GMAT is designed to model, optimize and estimate spacecraft trajectories in flight regimes ranging from low Earth orbit to lunar applications, interplanetary trajectories and other deep space missions. GMAT has also been flight qualified to support operational maneuver planning for the Advanced Composition Explorer (ACE) mission. ACE was launched in August, 1997 and is orbiting the Sun-Earth L1 libration point. The primary science objective of ACE is to study the composition of both the solar wind and the galactic cosmic rays. Operational orbit determination, maneuver operations and product generation for ACE are conducted by NASA Goddard Space Flight Center (GSFC) Flight Dynamics Facility (FDF). This paper discusses the entire engineering lifecycle and major operational certification milestones that GMAT successfully completed to obtain operational certification for the ACE mission. Operational certification milestones such as gathering of the requirements for ACE operational maneuver planning, gap analysis, test plans and procedures development, system design, pre-shadow operations, training to FDF ACE maneuver planners, shadow operations, Test Readiness Review (TRR) and finally Operational Readiness Review (ORR) are discussed. These efforts have demonstrated that GMAT is flight quality software ready to support ACE mission operations in the FDF.

  11. Coexistence of ACE (I/D) and PAI-1 (4G/5G) gene variants in recurrent miscarriage in Polish population.

    PubMed

    Kurzawińska, Grażyna; Barlik, Magdalena; Drews, Krzysztof; Różycka, Agata; Seremak-Mrozikiewicz, Agnieszka; Ożarowski, Marcin; Klejewski, Andrzej; Czerny, Bogusław; Wolski, Hubert

    2016-01-01

    Recurrent miscarriage (RM) is one of the most common obstetric complications. Numerous studies have suggested that genetic variants leading to an impaired balance between coagulation and fibrinolysis may contribute to elevated risk of pregnancy loss. The aim of the study was to investigate a possible association between angiotensin-converting enzyme (ACE, rs1799752) I/D and plasminogen activator inhibitor type 1 (PAI-1, rs1799768) 4G/5G polymorphisms with RM among Polish women. DNA was extracted from peripheral blood samples of 152 women with a history of ≥ 2 consecutive pregnancy losses before 22 weeks of gestation, and 180 healthy controls with at least 1 live birth at term and no history of pregnancy loss. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to identify the polymorphisms. No statistically significant differences were found in genotype and allele frequencies of the studied polymorphisms. The most relevant difference between the study group and controls was found for the ID genotype distribution of the ACE gene (52.6 vs. 46.7%, OR = 1.27, p = 0.28). The analysis of genotype coexistence revealed a higher incidence of the combination of the ACE II and the PAI-1 4G/4G genotypes in the control group (10.0 vs.5.9% in control group; p = 0.17). The obtained results suggest no apparent association between the ACE I/D, PAI-1 4G/5G polymorphisms and increased RM susceptibility in the analyzed Polish population.

  12. Adverse childhood experiences (ACE) and adult attachment interview (AAI) in a non-clinical population.

    PubMed

    Thomson, Paula; Jaque, S Victoria

    2017-08-01

    Adverse childhood experiences (ACE) tend to be interrelated rather than independently occurring. There is a graded effect associated with ACE exposure and pathology, with an increase when ACE exposure is four or more. This study examined a sample of active individuals (n=129) to determine distribution patterns and relationships between ACEs, attachment classification, unresolved mourning (U), and disclosure difficulty. The results of this study demonstrated a strong relationship between increased ACEs and greater unresolved mourning. Specifically, the group differences for individuals who experienced no ACE (n=42, 33%), those with 1-3 ACEs (n=48, 37.8%), and those with ≥4 ACEs (n=37, 29.1%) revealed a pattern in which increased group ACE exposure was associated with greater lack of resolution for past trauma/loss experiences, more adult traumatic events, and more difficulty disclosing past trauma. Despite ≥4 ACEs, 51.4% of highly exposed individuals were classified as secure in the Adult Attachment Interview. Resilience in this group may be related to a combination of attachment security, college education, and engagement in meaningful activities. Likewise, adversity may actually encourage the cultivation of more social support, goal efficacy, and planning behaviors; factors that augment resilience to adversity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Identification and the molecular mechanism of a novel myosin-derived ACE inhibitory peptide.

    PubMed

    Yu, Zhipeng; Wu, Sijia; Zhao, Wenzhu; Ding, Long; Shiuan, David; Chen, Feng; Li, Jianrong; Liu, Jingbo

    2018-01-24

    The objective of this work was to identify a novel ACE inhibitory peptide from myosin using a number of in silico methods. Myosin was evaluated as a substrate for use in the generation of ACE inhibitory peptides using BIOPEP and ExPASy PeptideCutter. Then the ACE inhibitory activity prediction of peptides in silico was evaluated using the program peptide ranker, following the database search of known and unknown peptides using the program BIOPEP. In addition, the interaction mechanisms of the peptide and ACE were evaluated by DS. All of the tripeptides were predicted to be nontoxic. Results suggested that the tripeptide NCW exerted potent ACE inhibitory activity with an IC 50 value of 35.5 μM. Furthermore, the results suggested that the peptide NCW comes into contact with Zn 701, Tyr 523, His 383, Glu 384, Glu 411, and His 387. The potential molecular mechanism of the NCW/ACE interaction was investigated. Results confirmed that the higher inhibitory potency of NCW might be attributed to the formation of more hydrogen bonds with the ACE's active site. Therefore, the in silico method is effective to predict and identify novel ACE inhibitory peptides from protein hydrolysates.

  14. Effect of Angiotensin-Converting Enzyme Inhibitor/Calcium Antagonist Combination Therapy on Renal Function in Hypertensive Patients With Chronic Kidney Disease: Chikushi Anti-Hypertension Trial - Benidipine and Perindopril.

    PubMed

    Okuda, Tetsu; Okamura, Keisuke; Shirai, Kazuyuki; Urata, Hidenori

    2018-02-01

    Appropriate blood pressure control suppresses progression of chronic kidney disease (CKD). If an angiotensin-converting enzyme (ACE) inhibitor is ineffective, adding a calcium antagonist is recommended. We compared the long-term effect of two ACE inhibitor/calcium antagonist combinations on renal function in hypertensive patients with CKD. Patients who failed to achieve the target blood pressure (systolic/diastolic: < 130/80 mm Hg) with perindopril monotherapy were randomized to either combined therapy with perindopril and the L-type calcium antagonist amlodipine (group A) or perindopril and the T/L type calcium antagonist benidipine (group B). The primary endpoint was the change of the estimated glomerular filtration rate (eGFR) after 2 years. Eligible patients had a systolic pressure ≥ 130 mm Hg and/or diastolic pressure ≥ 80 mm Hg and CKD (urine protein (+) or higher, eGFR < 60 min/mL/1.73 m 2 ). After excluding 38 patients achieving the target blood pressure with perindopril monotherapy, 121 patients were analyzed (62 in group A and 59 in group B). Blood pressure decreased significantly in both groups, but there was no significant change of the eGFR. However, among patients with diabetes, eGFR unchanged in group B (n = 37, 59.1 ± 15.1 vs. 61.2 ± 27.9, P = 0.273), whereas decreased significantly in group A (n = 31, 57.3 ± 16.0 vs. 53.7 ± 16.7, P = 0.005). In hypertensive patients with diabetic nephropathy, combined therapy with an ACE inhibitor and T/L type calcium antagonist may prevent deterioration of renal function more effectively than an ACE inhibitor/L type calcium antagonist combination.

  15. Single Nucleotide Polymorphisms of the Angiotensin-Converting Enzyme (ACE) Gene Are Associated with Essential Hypertension and Increased ACE Enzyme Levels in Mexican Individuals

    PubMed Central

    Martínez-Rodríguez, Nancy; Posadas-Romero, Carlos; Villarreal-Molina, Teresa; Vallejo, Maite; Del-Valle-Mondragón, Leonardo; Ramírez-Bello, Julian; Valladares, Adan; Cruz-López, Miguel; Vargas-Alarcón, Gilberto

    2013-01-01

    Aim To explore the role of the ACE gene polymorphisms in the risk of essential hypertension in Mexican Mestizo individuals and evaluate the correlation between these polymorphisms and the serum ACE levels. Methods Nine ACE gene polymorphisms were genotyped by 5′ exonuclease TaqMan genotyping assays and polymerase chain reaction (PCR) in 239 hypertensive and 371 non- hypertensive Mexican individuals. Haplotypes were constructed after linkage disequilibrium analysis. ACE serum levels were determined in selected individuals according to different haplotypes. Results Under a dominant model, rs4291 rs4335, rs4344, rs4353, rs4362, and rs4363 polymorphisms were associated with an increased risk of hypertension after adjusting for age, gender, BMI, triglycerides, alcohol consumption, and smoking. Five polymorphisms (rs4335, rs4344, rs4353, rs4362 and rs4363) were in strong linkage disequilibrium and were included in four haplotypes: H1 (AAGCA), H2 (GGATG), H3 (AGATG), and H4 (AGACA). Haplotype H1 was associated with decreased risk of hypertension, while haplotype H2 was associated with an increased risk of hypertension (OR = 0.77, P = 0.023 and OR = 1.41, P = 0.004 respectively). According to the codominant model, the H2/H2 and H1/H2 haplotype combinations were significantly associated with risk of hypertension after adjusted by age, gender, BMI, triglycerides, alcohol consumption, and smoking (OR = 2.0; P = 0.002 and OR = 2.09; P = 0.011, respectively). Significant elevations in serum ACE concentrations were found in individuals with the H2 haplotype (H2/H2 and H2/H1) as compared to H1/H1 individuals (P = 0.0048). Conclusion The results suggest that single nucleotide polymorphisms and the “GGATG” haplotype of the ACE gene are associated with the development of hypertension and with increased ACE enzyme levels. PMID:23741507

  16. A human GRPr-transfected Ace-1 canine prostate cancer model in mice.

    PubMed

    Ding, Haiming; Kothandaraman, Shankaran; Gong, Li; Williams, Michelle M; Dirksen, Wessel P; Rosol, Thomas J; Tweedle, Michael F

    2016-06-01

    A versatile drug screening system was developed to simplify early targeted drug discovery in mice and then translate readily from mice to a dog prostate cancer model that more fully replicates the features of human prostate cancer. We stably transfected human cDNA of the GRPr bombesin (BBN) receptor subtype to canine Ace-1 prostate cancer cells (Ace-1(huGRPr) ). Expression was examined by (125) I-Tyr(4) -BBN competition, calcium stimulation assay, and fluorescent microscopy. A dual tumor nude mouse xenograft model was developed from Ace-1(CMV) (vector transfected Ace-1) and Ace-1(huGRPr) cells. The model was used to explore the in vivo behavior of two new IRDye800-labeled GRPr binding optical imaging agents: 800-G-Abz4-t-BBN, from a GRPr agonist peptide, and 800-G-Abz4-STAT, from a GRPr antagonist peptide, by imaging the tumor mice and dissected organs. Both agents bound Ace-1(huGRPr) and PC-3, a known GRPr-expressing human prostate cancer cell line, with 4-13 nM IC50 against (125) I-Tyr(4) -BBN, but did not bind Ace-1(CMV) cells (vector transfected). Binding was blocked by bombesin. Ca(2+) activation assays demonstrated that Ace-1(huGPRr) expressed biologically active GRPr. Both Ace-1 cell lines grew in the flanks of 100% of the nude mice and formed tumors of ∼0.5 cm diameter in 1 week. In vivo imaging of the mice at 800 nm emission showed GRPr+: GRPr- tumor signal brighter by a factor of two at 24 h post IV administration of 10 nmol of the imaging agents. Blood retention (4-8% ID at 1 h) was greater by a factor >10 and cumulative urine accumulation (28-30% at 4 h) was less by a factor 2 compared to a radioactive analog of the t-BBN containing agent, (177) LuAMBA, probably due to binding to blood albumin, which we confirmed in a mouse serum assay. The dual tumor Ace-1(CMV) /Ace-1(huGRPr) model system provides a rapid test of specific to nonspecific binding of new GRPr avid agents in a model that will extend logically to the known Ace-1 orthotopic

  17. Antihypertensive effect of Carica papaya via a reduction in ACE activity and improved baroreflex.

    PubMed

    Brasil, Girlandia Alexandre; Ronchi, Silas Nascimento; do Nascimento, Andrews Marques; de Lima, Ewelyne Miranda; Romão, Wanderson; da Costa, Helber Barcellos; Scherer, Rodrigo; Ventura, José Aires; Lenz, Dominik; Bissoli, Nazaré Souza; Endringer, Denise Coutinho; de Andrade, Tadeu Uggere

    2014-11-01

    The aims of this study were to evaluate the antihypertensive effects of the standardised methanolic extract of Carica papaya, its angiotensin converting enzyme inhibitory effects in vivo, its effect on the baroreflex and serum angiotensin converting enzyme activity, and its chemical composition. The chemical composition of the methanolic extract of C. papaya was evaluated by liquid chromatography-mass/mass and mass/mass spectrometry. The angiotensin converting enzyme inhibitory effect was evaluated in vivo by Ang I administration. The antihypertensive assay was performed in spontaneously hypertensive rats and Wistar rats that were treated with enalapril (10 mg/kg), the methanolic extract of C. papaya (100 mg/kg; twice a day), or vehicle for 30 days. The baroreflex was evaluated through the use of sodium nitroprusside and phenylephrine. Angiotensin converting enzyme activity was measured by ELISA, and cardiac hypertrophy was evaluated by morphometric analysis. The methanolic extract of C. papaya was standardised in ferulic acid (203.41 ± 0.02 µg/g), caffeic acid (172.60 ± 0.02 µg/g), gallic acid (145.70 ± 0.02 µg/g), and quercetin (47.11 ± 0.03 µg/g). The flavonoids quercetin, rutin, nicotiflorin, clitorin, and manghaslin were identified in a fraction of the extract. The methanolic extract of C. papaya elicited angiotensin converting enzyme inhibitory activity. The antihypertensive effects elicited by the methanolic extract of C. papaya were similar to those of enalapril, and the baroreflex sensitivity was normalised in treated spontaneously hypertensive rats. Plasma angiotensin converting enzyme activity and cardiac hypertrophy were also reduced to levels comparable to the enalapril-treated group. These results may be associated with the chemical composition of the methanolic extract of C. papaya, and are the first step into the development of a new phytotherapic product which could be used in the treatment of hypertension. Georg Thieme Verlag KG Stuttgart

  18. Does acute care for the elderly (ACE) unit decrease the incidence of falls?

    PubMed

    Abdalla, Ahmed; Adhaduk, Mehul; Haddad, Raad A; Alnimer, Yanal; Ríos-Bedoya, Carlos F; Bachuwa, Ghassan

    2017-11-11

    To determine whether acute care for the elderly (ACE) units decrease the incidence of patient falls compared to general medical and surgical (GMS) units, a non-concurrent prospective study included individuals aged 65 and older admitted to ACE or GMS units over a 2-year span was done. There were 7069 admissions corresponded to 28,401 patient-days. A total of 149 falls were reported for an overall incidence rate (IR) of 5.2 falls per 1000 patient-days, 95% CI, 4.4/1000-6.1/1000 patient-days. The falls IR ratio for patients in ACE unit compared to those in non-ACE units after adjusting for age, sex, prescribed psychotropics and hypnotics, and Morse Fall Score was 0.27/1000 patient-days; 95% CI, 0.13-0.54; p < 0.001. So, an estimated 73% reduction in patient falls between ACE unit and non-ACE units. Hospitals may consider investing in ACE units to decrease the risk of falls and the associated medical and financial costs. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Locally acting ACE-083 increases muscle volume in healthy volunteers.

    PubMed

    Glasser, Chad E; Gartner, Michael R; Wilson, Dawn; Miller, Barry; Sherman, Matthew L; Attie, Kenneth M

    2018-02-27

    ACE-083 is a locally acting follistatin-based therapeutic that binds myostatin and other muscle regulators and has been shown to increase muscle mass and force in neuromuscular disease mouse models. This first-in-human study examined these effects. In this phase 1, randomized, double-blind, placebo-controlled, dose-ranging study in healthy postmenopausal women, ACE-083 (50-200 mg) or placebo was administered unilaterally into rectus femoris (RF) or tibialis anterior (TA) muscles as 1 or 2 doses 3 weeks apart. Fifty-eight postmenopausal women were enrolled, 42 ACE-083 and 16 placebo. No serious adverse events (AE), dose-limiting toxicities, or discontinuations resulting from AEs occurred. Maximum (mean ± SD) increases in RF and TA muscle volume were 14.5% ± 4.5% and 8.9% ± 4.7%, respectively. No significant changes in mean muscle strength were observed. ACE-083 was well tolerated and resulted in significant targeted muscle growth. ACE-083 may have the potential to increase muscle mass in a wide range of neuromuscular disorders. Muscle Nerve, 2018. © 2018 The Authors Muscle & Nerve Published by Wiley Periodicals, Inc.

  20. The solar array is installed on ACE in SAEF-2

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Applied Physics Laboratory Engineer Cliff Willey (kneeling) and Engineering Assistant Jim Hutcheson from Johns Hopkins University install solar array panels on the Advanced Composition Explorer (ACE) in KSC's Spacecraft Assembly and Encapsulation Facility-II. Scheduled for launch on a Delta II rocket from Cape Canaveral Air Station on Aug. 25, ACE will study low-energy particles of solar origin and high-energy galactic particles for a better understanding of the formation and evolution of the solar system as well as the astrophysical processes involved. The ACE observatory will be placed into an orbit almost a million miles (1.5 million kilometers) away from the Earth, about 1/100 the distance from the Earth to the Sun. The collecting power of instrumentation aboard ACE is at least 100 times more sensitive than anything previously flown to collect similar data by NASA.

  1. 21 CFR 862.1090 - Angiotensin converting enzyme (A.C.E.) test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Angiotensin converting enzyme (A.C.E.) test system... Test Systems § 862.1090 Angiotensin converting enzyme (A.C.E.) test system. (a) Identification. An angiotensin converting enzyme (A.C.E.) test system is a device intended to measure the activity of angiotensin...

  2. ACE ID genotype and the muscle strength and size response to unilateral resistance training.

    PubMed

    Pescatello, Linda S; Kostek, Matthew A; Gordish-Dressman, Heather; Thompson, Paul D; Seip, Richard L; Price, Thomas B; Angelopoulos, Theodore J; Clarkson, Priscilla M; Gordon, Paul M; Moyna, Niall M; Visich, Paul S; Zoeller, Robert F; Devaney, Joseph M; Hoffman, Eric P

    2006-06-01

    To examine associations among the angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism and the response to a 12-wk (2 d.wk) unilateral, upper-arm resistance training (RT) program in the trained (T, nondominant) and untrained (UT, dominant) arms. Subjects were 631 (mean+/-SEM, 24.2+/-0.2 yr) white (80%) men (42%) and women (58%). The ACE ID genotype was in Hardy-Weinberg equilibrium with frequencies of 23.1, 46.1, and 30.8% for ACE II, ID, and DD, respectively (chi=1.688, P=0.430). Maximum voluntary contraction (MVC) and one-repetition maximum (1RM) assessed peak elbow flexor muscle strength. Magnetic resonance imaging measured biceps muscle cross-sectional area (CSA). Multiple variable and repeated-measures ANCOVA tested whether muscle strength and size differed at baseline and pre- to post-RT among T and UT and ACE ID genotype. Baseline muscle strength and size were greater in UT than T (P<0.001) and did not differ among ACE ID genotype in either arm (P >or= 0.05). In T, MVC increases were greater for ACE II/ID (22%) than DD (17%) (P<0.05), whereas 1RM (51%) and CSA (19%) gains were not different among ACE ID genotype pre- to post-RT (P >or= 0.05). In UT, MVC increased among ACE II/ID (7%) (P<0.001) but was similar among ACE DD (2%) pre- to post-RT (P >or= 0.05). In UT, 1RM (11%) and CSA (2%) increases were greater for ACE DD/ID than ACE II (1RM, 7%; CSA, -0.1%) (P<0.05). ACE ID genotype explained approximately 1% of the MVC response to RT in T and approximately 2% of MVC, 2% of 1RM, and 4% of CSA response in UT (P<0.05). ACE ID genotype is associated with the contralateral effects of unilateral RT, perhaps more so than with the muscle strength and size adaptations that result from RT.

  3. Wiseman in with ACE sample

    NASA Image and Video Library

    2014-05-30

    ISS040-E-006569 (2 June 2014) --- NASA astronaut Reid Wiseman, Expedition 40 flight engineer, performs an Advanced Colloids Experiment (ACE) sample 40-minute mixing activity in the Destiny laboratory of the International Space Station.

  4. Wiseman in with ACE sample

    NASA Image and Video Library

    2014-05-30

    ISS040-E-006567 (2 June 2014) --- NASA astronaut Reid Wiseman, Expedition 40 flight engineer, performs an Advanced Colloids Experiment (ACE) sample 40-minute mixing activity in the Destiny laboratory of the International Space Station.

  5. Improved ACE-FTS observations of carbon tetrachloride (CCl4)

    NASA Astrophysics Data System (ADS)

    Harrison, Jeremy; Chipperfield, Martyn; Boone, Chris; Bernath, Peter

    2016-04-01

    The Atmospheric Chemistry Experiment Fourier transform spectrometer (ACE-FTS), on board the SCISAT satellite, has been recording solar occultation spectra through the Earth's atmosphere since 2004 and continues to take measurements with only minor loss in performance. ACE-FTS time series are available for a range of chlorine 'source' gases, including CCl3F (CFC-11), CCl2F2 (CFC-12), CHF2Cl (HCFC-22), CH3Cl and CCl4. Recently there has been much community interest in carbon tetrachloride (CCl4), a substance regulated by the Montreal Protocol because it leads to the catalytic destruction of stratospheric ozone. Estimated sources and sinks of CCl4 remain inconsistent with observations of its abundance. Satellite observations of CCl4 in the stratosphere are particularly useful in validating stratospheric loss (photolysis) rates; in fact the atmospheric loss of CCl4 is essentially all due to photolysis in the stratosphere. However, the latest ACE-FTS v3.5 CCl4 retrieval is biased high by ˜ 20-30%. A new ACE-FTS retrieval scheme utilising new laboratory spectroscopic measurements of CCl4 and improved microwindow selection has recently been developed. This improves upon the v3.5 retrieval and resolves the issue of the high bias; this new scheme will form the basis for the upcoming v4 processing version of ACE-FTS data. This presentation will outline the improvements made in the retrieval, and a subset of data will be compared with modelled CCl4 distributions from SLIMCAT, a state-of-the-art three-dimensional chemical transport model. The use of ACE-FTS data to evaluate the modelled stratospheric loss rate of CCl4 will also be discussed. The evaluated model, which also includes a treatment of surface soil and ocean sinks, will then be used to quantify current uncertainties in the global budget of CCl4.

  6. ACE [Adult and Community Education] into the 21st Century: A Vision.

    ERIC Educational Resources Information Center

    Adult, Community, and Further Education Board, Melbourne (Australia).

    This document outlines a vision for adult and community education (ACE) in Victoria for the next 3 years and provides a broad map of how to reach that vision. A description of the context is followed by the ACE vision statement: ACE delivers accessible, quality, and timely learning in autonomous, community settings as a valued and essential…

  7. Adverse Childhood Experiences (ACEs) and Alcohol Abuse among South Carolina Adults.

    PubMed

    Crouch, Elizabeth; Radcliff, Elizabeth; Strompolis, Melissa; Wilson, Abygail

    2018-06-07

    Adverse childhood experiences (ACEs) have been associated with negative adult health outcomes, including alcohol misuse. The impact of ACEs on alcohol use may vary by gender, with ACEs impacting women more than men in coping with adulthood stressors. The objective of this study is to examine the gender-specific relationships between ACEs and self-reported binge drinking and heavy drinking in adulthood among South Carolina residents. This study analyzed a sample of 8492 respondents who completed the 2014 or 2015 South Carolina Behavioral Risk Factor Surveillance System (BRFSS) survey. Logistic regression was used to examine the impact of types and the number of ACEs on binge drinking and heaving drinking in adulthood. Thirty-seven percent of men and 22.8% of women survey respondents reported binge drinking and 12.2% of men and 4.1% of women reported heavy drinking. Almost all categories of ACE were associated with increased odds of reporting binge and heavy drinking; household mental illness had the greatest odds for men (aOR 1.31, 95% CI 1.30-1.33) and emotional abuse had the greatest odds for women (aOR 1.42, 95% CI 1.40-1.43). Men and women with four or more ACEs had greater odds of reporting binge and heavy drinking compared to their counterparts. Conclusions/Importance: Given the potential for negative outcomes associated with alcohol misuse and transmission of risky alcohol-related behaviors from parent to child, strategies that utilize a multigenerational approach could have a large impact on population health.

  8. ACE2 Therapy Using Adeno-associated Viral Vector Inhibits Liver Fibrosis in Mice

    PubMed Central

    Mak, Kai Y; Chin, Ruth; Cunningham, Sharon C; Habib, Miriam R; Torresi, Joseph; Sharland, Alexandra F; Alexander, Ian E; Angus, Peter W; Herath, Chandana B

    2015-01-01

    Angiotensin converting enzyme 2 (ACE2) which breaks down profibrotic peptide angiotensin II to antifibrotic peptide angiotensin-(1–7) is a potential therapeutic target in liver fibrosis. We therefore investigated the long-term therapeutic effect of recombinant ACE2 using a liver-specific adeno-associated viral genome 2 serotype 8 vector (rAAV2/8-ACE2) with a liver-specific promoter in three murine models of chronic liver disease, including carbon tetrachloride-induced toxic injury, bile duct ligation-induced cholestatic injury, and methionine- and choline-deficient diet-induced steatotic injury. A single injection of rAAV2/8-ACE2 was administered after liver disease has established. Hepatic fibrosis, gene and protein expression, and the mechanisms that rAAV2/8-ACE2 therapy associated reduction in liver fibrosis were analyzed. Compared with control group, rAAV2/8-ACE2 therapy produced rapid and sustained upregulation of hepatic ACE2, resulting in a profound reduction in fibrosis and profibrotic markers in all diseased models. These changes were accompanied by reduction in hepatic angiotensin II levels with concomitant increases in hepatic angiotensin-(1–7) levels, resulting in significant reductions of NADPH oxidase assembly, oxidative stress and ERK1/2 and p38 phosphorylation. Moreover, rAAV2/8-ACE2 therapy normalized increased intrahepatic vascular tone in fibrotic livers. We conclude that rAAV2/8-ACE2 is an effective liver-targeted, long-term therapy for liver fibrosis and its complications without producing unwanted systemic effects. PMID:25997428

  9. Unique Kinase Catalytic Mechanism of AceK with a Single Magnesium Ion

    PubMed Central

    Li, Quanjie; Zheng, Jimin; Tan, Hongwei; Li, Xichen; Chen, Guangju; Jia, Zongchao

    2013-01-01

    Isocitrate dehydrogenase kinase/phosphatase (AceK) is the founding member of the protein phosphorylation system in prokaryotes. Based on the novel and unique structural characteristics of AceK recently uncovered, we sought to understand its kinase reaction mechanism, along with other features involved in the phosphotransfer process. Herein we report density functional theory QM calculations of the mechanism of the phosphotransfer reaction catalysed by AceK. The transition states located by the QM calculations indicate that the phosphorylation reaction, catalysed by AceK, follows a dissociative mechanism with Asp457 serving as the catalytic base to accept the proton delivered by the substrate. Our results also revealed that AceK prefers a single Mg2+-containing active site in the phosphotransfer reaction. The catalytic roles of conserved residues in the active site are discussed. PMID:23977203

  10. ACE: A Collaborative School Consultation Program for Secondary School Teachers

    ERIC Educational Resources Information Center

    Couture, Caroline; Massé, Line

    2014-01-01

    This article presents a description of ACE (Accompagnement collaboratif des enseignants (Collaborative teacher accompaniment)), a new program designed to guide secondary school teachers in integrating students with behavioral problems in their classrooms. ACE proposes collaborative accompaniment inspired by behavioral and mental health…

  11. The ACE-DD genotype is associated with endothelial dysfunction in postmenopausal women.

    PubMed

    Méthot, Julie; Hamelin, Bettina A; Arsenault, Marie; Bogaty, Peter; Plante, Sylvain; Poirier, Paul

    2006-01-01

    To evaluate the effects of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D), the angiotensinogen M235T and the angiotensin II type 1 receptor A1166C polymorphisms, and hormone therapy used on endothelial function in postmenopausal women without manifestation of coronary artery disease. Sixty-four postmenopausal women (42 hormone therapy users and 22 hormone therapy nonusers) without clinical manifestation of coronary artery disease were evaluated using external vascular ultrasonography to measure endothelium-dependent (hyperemic response, flow-mediated dilatation) and -independent (nitroglycerin) dilatation. Genotypes were determined by polymerase chain reaction amplification. Women with the ACE-DD genotype displayed a lower flow-mediated dilatation compared to those with the ACE-II genotype (8.4% +/- 3.9% vs 12.6% +/- 5.4%, P = 0.04). Endothelial function was not associated with the angiotensinogen M235T and anglotensin II type 1 receptor A1166C polymorphisms. ACE polymorphism seems to modulate endothelial function among postmenopausal women without hormone therapy (8.2% +/- 5.1% vs 18.4% +/- 5.9% for the DD and the II genotype, respectively, P = 0.02). However, in hormone therapy users, flow-mediated dilatation was similar according to the ACE genotypes. Our findings suggest that ACE-I/D polymorphism is related to endothelial dysfunction in postmenopausal women. Furthermore, a potential interaction between estrogen users and ACE polymorphism on endothelial function may be present.

  12. Nyberg working with ACE in U.S. Laboratory

    NASA Image and Video Library

    2013-08-18

    ISS036-E-035770 (18 Aug. 2013) --- NASA astronaut Karen Nyberg, Expedition 36 flight engineer, works with new test samples for the Advanced Colloids Experiment, or ACE, housed in the Light Microscopy Module (LMM) inside the Fluids Integrated Rack of the International Space Station?s Destiny laboratory. Results from ACE will help researchers understand how to optimize stabilizers to extend the shelf life of products like laundry detergent, paint, ketchup and even salad dressing.

  13. Nyberg working with ACE in U.S. Laboratory

    NASA Image and Video Library

    2013-08-18

    ISS036-E-035767 (18 Aug. 2013) --- NASA astronaut Karen Nyberg, Expedition 36 flight engineer, works with new test samples for the Advanced Colloids Experiment, or ACE, housed in the Light Microscopy Module (LMM) inside the Fluids Integrated Rack of the International Space Station?s Destiny laboratory. Results from ACE will help researchers understand how to optimize stabilizers to extend the shelf life of products like laundry detergent, paint, ketchup and even salad dressing.

  14. Nyberg working with ACE in U.S. Laboratory

    NASA Image and Video Library

    2013-08-18

    ISS036-E-035780 (18 Aug. 2013) --- NASA astronaut Karen Nyberg, Expedition 36 flight engineer, works with new test samples for the Advanced Colloids Experiment, or ACE, housed in the Light Microscopy Module (LMM) inside the Fluids Integrated Rack of the International Space Station?s Destiny laboratory. Results from ACE will help researchers understand how to optimize stabilizers to extend the shelf life of products like laundry detergent, paint, ketchup and even salad dressing.

  15. Extension of the ACE solar panels is tested in SAEF-II

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Extension of the solar panels is tested on the Advanced Composition Explorer (ACE) spacecraft in KSC's Spacecraft Assembly and Encapsulation Facility-II (SAEF-II). Scheduled for launch on a Delta II rocket from Cape Canaveral Air Station on Aug. 25, ACE will study low-energy particles of solar origin and high-energy galactic particles. The collecting power of instruments aboard ACE is 10 to 1,000 times greater than anything previously flown to collect similar data by NASA.

  16. Advanced Collaborative Emissions Study (ACES)

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

    Greenbaum, Daniel; Costantini, Maria; Van Erp, Annemoon

    2013-12-31

    The objective of the Advanced Collaborative Emissions Study (ACES) was to determine before widespread commercial deployment whether or not the new, energy-efficient, heavy duty diesel engines (2007 and 2010 EPA Emissions Standards Compliant) may generate anticipated toxic emissions that could adversely affect the environment and human health. ACES was planned to take place in three phases. In Phase 1, extensive emissions characterization of four production-intent prototype engine and control systems designed to meet 2007 standards for nitrogen oxides (NOx) and particulate matter (PM) was conducted at an existing emissions characterization facility: Southwest Research Institute (SwRI). One of the tested enginesmore » was selected (at random, after careful comparison of results) for health testing in Phase 3. In Phase 2, extensive emission characterization of three production-intent prototype engine and control systems meeting the 2010 standards (including more advanced NOx controls to meet the more stringent 2010 NOx standards) was conducted at the same test facility. In Phase 3, one engine/aftertreatment system selected from Phase 1 was further characterized during health effects studies (at an existing inhalation toxicology laboratory: Lovelace Respiratory Research Institute, [LRRI]) to form the basis of the ACES safety assessment. The Department of Energy (DOE) award provided funding for emissions characterization in Phases 1 and 2 as well as exposure characterization in Phase 3. The main health analyses in Phase 3 were funded separately and are not reported here.« less

  17. ACE3 Draft Indicators: Biomonitoring

    EPA Pesticide Factsheets

    The page information was provided by EPA in conjunction with the opportunity for public comment on the draft indicators for ACE3, which ran from March 8 – April 21, 2011. The public comment period is now closed.

  18. ACE3 Draft Indicators: Health

    EPA Pesticide Factsheets

    The page information was provided by EPA in conjunction with the opportunity for public comment on the draft indicators for ACE3, which ran from March 8 – April 21, 2011. The public comment period is now closed.

  19. Selective imidazoline agonist moxonidine plus the ACE inhibitor ramipril in hypertensive patients with impaired insulin sensitivity: partners in a successful MARRIAGE?

    PubMed

    Rayner, Brian

    2004-03-01

    Hypertension in combination with clinically overt diabetes mellitus is recognized as a particularly powerful combination of risk factors that greatly increases cardiovascular vulnerability. There is also evidence that presumed pre-diabetic conditions such as insulin resistance, hyperinsulinaemia and compensatory hyperglycaemia may amplify overall cardiovascular risk in patients with hypertension, especially when encountered as part of the condition known as metabolic syndrome X (Reaven's syndrome). The long-term benefits of antihypertensive therapy may be compromised if these drugs exert adverse effects on metabolic parameters such as insulin sensitivity, or if they promote a transition from pre-diabetes to overt diabetes. Class differences in the effects of antihypertensives on metabolic indices may therefore be an important consideration when choosing treatment for patients who exhibit these characteristics. Experience from clinical trials suggests that drugs that target the renin-angiotensin system may have metabolic advantages over drugs such as beta-blockers and diuretics, but this conclusion has not been proved definitively. Moxonidine, which selectively targets imidazoline type-1 receptors in the sympathetic vasomotor centres of the rostral-ventrolateral medulla, is an effective antihypertensive and has been reported to exert favourable metabolic effects in preclinical and clinical studies. The MARRIAGE study (Moxonidine And Ramipril Regarding Insulin And Glucose Evaluation) will extend these preliminary observations by comparing the effects of moxonidine and the ACE inhibitor ramipril--and the combination of both drugs--on metabolic and haemodynamic parameters in patients with hypertension and impaired fasting glycaemia. A description is provided of the design and conduct of MARRIAGE.

  20. Economic evaluation of the Annual Cycle Energy System (ACES). Volume 1: Executive summary

    NASA Astrophysics Data System (ADS)

    1980-05-01

    Three different classes of building are investigated, namely: single family residence; multifamily residence; and commercial office building. For each building type in each geographic location, the economic evaluation of the annual cycle energy system (ACES) is based on a comparison of the present worth of the ACES to the present worth of a number of conventional systems. The results of this analysis indicate that the economic viability of the ACES is very sensitive to the assumed value of the property tax, maintenance cost, and fuel escalation rates, while it is relatively insensitive to the assumed values of other parameters. Fortunately, any conceivable change in the fuel escalation rates would tend to increase the viability of the ACES concept. An increase in the assumed value of the maintenance cost or property tax would tend to make the ACES concept less viable; a decrease in either would tend to make the ACES concept more viable.

  1. ACE and AGTR1 polymorphisms and left ventricular hypertrophy in endurance athletes.

    PubMed

    Di Mauro, Michele; Izzicupo, Pascal; Santarelli, Francesco; Falone, Stefano; Pennelli, Alfonso; Amicarelli, Fernanda; Calafiore, Antonio M; Di Baldassarre, Angela; Gallina, Sabina

    2010-05-01

    This study aimed to evaluate the role of angiotensin type 1 receptor gene (AGTR1) polymorphism (A1166C) in left ventricular hypertrophy (LVH) mediated by the angiotensin-converting enzyme (ACE) in endurance athletes. A group of 74 white, healthy male endurance athletes, aged between 25 and 40 yr, were enrolled in this study. All of them participated primarily in isotonic sports, training for at least >10 h x wk(-1), for at least 5 yr. The ACE genotype (insertion [I] or deletion [D] alleles) was ascertained by polymerase chain reaction (DD in 35, ID in 36, and II in 3). Group II was excluded from the analysis because of its small size. No difference was found between the two groups as regards age, blood pressure, HR, and echocardiographic data. The left ventricular mass index (LVMI) was significantly higher in group DD rather than in group ID (P = 0.029). The group DD showed a slightly higher prevalence of subjects with LVH (LVMI > 131 g x m(-2); 62.9%) than group ID (44.4%, P = 0.120). No association was found between ACE-DD and LVH (odds ratio (OR) = 2.12, 95% confidence interval = 0.82-5.46). Concerning the role of AGTR1 polymorphism, the highest LVMI was found in 15 athletes with ACE-DD and AGTR1-AC/CC genotypes (150 +/- 23 g x m(-2)); the lowest value of LVMI was found in the case of ACE-ID and AGTR1-AA (127 g x m(-2) +/- 18 g x m(-2)), whereas LVMI in subjects with ACE-DD + AGTR1-AA was similar to that in the ACE-ID + AGTR1-AC/CC group (134 +/- 18 g x m(-2) vs 133 +/- 20 g x m(-2), P = 0.880). The presence of ACE-DD + AGTR1 + AC/CC was strongly associated with LVH (OR = 4.6, P = 0.029). Moreover, subjects with LVH showed longer left ventricular isovolumetric relaxation time and higher end-systolic wall stress. The latter was strongly correlated to LVMI (r = 0.588), especially in the presence of ACE-DD + AGTR1 + AC/CC (r = 0.728). LVMI may be greater in the presence of ACE- DD and AGTR1-AC/CC polymorphisms.

  2. Frequency of APOE, MTHFR and ACE polymorphisms in the Zambian population

    PubMed Central

    2014-01-01

    Background Polymorphisms within the apolipoprotein-E (APOE), Methylenetetrahydrofolate reductase (MTHFR) and Angiotensin I-converting enzyme (ACE) genes has been associated with cardiovascular and cerebrovascular disorders, Alzheimer’s disease and other complex diseases in various populations. The aim of the study was to analyze the allelic and genotypic frequencies of APOE, MTHFR C677T and ACE I/D gene polymorphisms in the Zambian population. Results The allele frequencies of APOE polymorphism in the Zambian populations were 13.8%, 59.5% and 26.7% for the ε2, ε3 and ε4 alleles respectively. MTHFR C677T and ACE I/D allele frequencies were 8.6% and 13.8% for the T and D minor alleles respectively. The ε2ε2 genotype and TT genotype were absent in the Zambian population. The genetic distances between Zambian and other African and non-African major populations revealed an independent variability of these polymorphisms. Conclusion We found that the APOE ε3 allele and the I allele of the ACE were significantly high in our study population while there were low frequencies observed for the MTHFR 677 T and ACE D alleles. Our analysis of the APOE, MTHFR and ACE polymorphisms may provide valuable insight into the understanding of the disease risk in the Zambian population. PMID:24679048

  3. Fine-Mapping Angiotensin-Converting Enzyme Gene: Separate QTLs Identified for Hypertension and for ACE Activity

    PubMed Central

    Chung, Chia-Min; Wang, Ruey-Yun; Fann, Cathy S. J.; Chen, Jaw-Wen; Jong, Yuh-Shiun; Jou, Yuh-Shan; Yang, Hsin-Chou; Kang, Chih-Sen; Chen, Chien-Chung; Chang, Huan-Cheng; Pan, Wen-Harn

    2013-01-01

    Angiotensin-converting enzyme (ACE) has been implicated in multiple biological system, particularly cardiovascular diseases. However, findings associating ACE insertion/deletion polymorphism with hypertension or other related traits are inconsistent. Therefore, in a two-stage approach, we aimed to fine-map ACE in order to narrow-down the function-specific locations. We genotyped 31 single nucleotide polymorphisms (SNPs) of ACE from 1168 individuals from 305 young-onset (age ≤40) hypertension pedigrees, and found four linkage disequilibrium (LD) blocks. A tag-SNP, rs1800764 on LD block 2, upstream of and near the ACE promoter, was significantly associated with young-onset hypertension (p = 0.04). Tag-SNPs on all LD blocks were significantly associated with ACE activity (p-value: 10–16 to <10–33). The two regions most associated with ACE activity were found between exon13 and intron18 and between intron 20 and 3′UTR, as revealed by measured haplotype analysis. These two major QTLs of ACE activity and the moderate effect variant upstream of ACE promoter for young-onset hypertension were replicated by another independent association study with 842 subjects. PMID:23469169

  4. Effects of Sacubitril/Valsartan on Physical and Social Activity Limitations in Patients With Heart Failure: A Secondary Analysis of the PARADIGM-HF Trial.

    PubMed

    Chandra, Alvin; Lewis, Eldrin F; Claggett, Brian L; Desai, Akshay S; Packer, Milton; Zile, Michael R; Swedberg, Karl; Rouleau, Jean L; Shi, Victor C; Lefkowitz, Martin P; Katova, Tzvetana; McMurray, John J V; Solomon, Scott D

    2018-04-04

    Health-related quality of life (HRQL) of patients with heart failure is markedly reduced compared with that in patients with other chronic diseases, demonstrating substantial limitations in physical and social activities. In the Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, sacubitril/valsartan improved overall HRQL compared with enalapril, as determined by the Kansas City Cardiomyopathy Questionnaire (KCCQ). To examine the effects of sacubitril/valsartan on physical and social activities. The PARADIGM-HF trial was a randomized, double-blind, active treatment-controlled clinical trial performed from December 8, 2009, to March 31, 2014, in 8399 patients with New York Heart Association class II to IV disease and a left ventricular ejection fraction of 40% or less at 1043 centers in 38 countries. Data analysis was performed from August 1, 2017, to December 25, 2017. Sacubitril/valsartan, 200 mg twice daily, or enalapril, 10 mg twice daily. Patients completed HRQL assessments using the KCCQ at randomization, 4-month, 8-month, and annual visits. The effect of sacubitril/valsartan on components of the physical and social limitation sections of the KCCQ at 8 months and longitudinally and related biomarkers and clinical outcomes were studied. At baseline, 7618 of 8399 patients (90.7%) (mean [SD] age, 64 [11] years; 5987 [78.6%] male and 1631 [21.4%] female) completed the initial KCCQ assessment. Patients reported the greatest limitations at baseline in jogging and sexual relationships. Patients receiving sacubitril/valsartan had significantly better adjusted change scores in most physical and social activities at 8 months and during 36 months compared with those receiving enalapril. The largest improvement over enalapril was in household chores (adjusted change score difference, 2.35; 95% CI, 1.19-3.50; P < .001) and sexual relationships (adjusted change score difference

  5. Associations of centrally acting ACE inhibitors with cognitive decline and survival in Alzheimer's disease.

    PubMed

    Fazal, Karim; Perera, Gayan; Khondoker, Mizanur; Howard, Robert; Stewart, Robert

    2017-07-01

    Cognitive improvement has been reported in patients receiving centrally acting angiotensin-converting enzyme inhibitors (C-ACEIs). To compare cognitive decline and survival after diagnosis of Alzheimer's disease between people receiving C-ACEIs, non-centrally acting angiotensin-converting enzyme inhibitors (NC-ACEIs), and neither. Routine Mini-Mental State Examination (MMSE) scores were extracted in 5260 patients receiving acetylcholinesterase inhibitors and analysed against C-/NC-ACEI exposure at the time of Alzheimer's disease diagnosis. In the 9 months after Alzheimer's disease diagnosis, MMSE scores significantly increased by 0.72 and 0.19 points per year in patients on C-ACEIs and neither respectively, but deteriorated by 0.61 points per year in those on NC-ACEIs. There were no significant group differences in score trajectories from 9 to 36 months and no differences in survival. In people with Alzheimer's disease receiving acetylcholinesterase inhibitors, those also taking C-ACEIs had stronger initial improvement in cognitive function, but there was no evidence of longer-lasting influence on dementia progression. R.S. has received research funding from Pfizer, Lundbeck, Roche, Janssen and GlaxoSmithKline. © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.

  6. Comparison of Density Measurements on ACE and WIND

    NASA Astrophysics Data System (ADS)

    Fowler, G.; Russell, C. T.

    2001-12-01

    In studying the compression of the magnetosphere by the solar wind we have used data publically available on the CDA Web site and the ACE website. The solar wind velocities measured by these two spacecraft agree well but the densities do not. The density reported by WIND is on average only 75% of that reported by ACE. This ratio does not appear to be a constant, however. It seems to vary with the solar wind velocity.

  7. FIRE III ACE Data Sets

    Atmospheric Science Data Center

    2017-12-22

    ... in conjunction with the Surface Heat Budget of the Arctic Ocean (SHEBA) Experiment. The FIRE-ACE focused on all aspects of Arctic cloud ... Alaska with measurements extending well over the Arctic Ocean (ship and aircraft). Guide Documents:  FIRE Project ...

  8. 77 FR 48527 - National Customs Automation Program (NCAP) Test Concerning Automated Commercial Environment (ACE...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-14

    ... Program (NCAP) Test Concerning Automated Commercial Environment (ACE) Simplified Entry: Modification of... Automated Commercial Environment (ACE). The test's participant selection criteria are modified to reflect... (NCAP) test concerning Automated Commercial Environment (ACE) Simplified Entry functionality (Simplified...

  9. AceDRG: a stereochemical description generator for ligands

    PubMed Central

    Emsley, Paul; Gražulis, Saulius; Merkys, Andrius; Vaitkus, Antanas

    2017-01-01

    The program AceDRG is designed for the derivation of stereochemical information about small molecules. It uses local chemical and topological environment-based atom typing to derive and organize bond lengths and angles from a small-molecule database: the Crystallography Open Database (COD). Information about the hybridization states of atoms, whether they belong to small rings (up to seven-membered rings), ring aromaticity and nearest-neighbour information is encoded in the atom types. All atoms from the COD have been classified according to the generated atom types. All bonds and angles have also been classified according to the atom types and, in a certain sense, bond types. Derived data are tabulated in a machine-readable form that is freely available from CCP4. AceDRG can also generate stereochemical information, provided that the basic bonding pattern of a ligand is known. The basic bonding pattern is perceived from one of the computational chemistry file formats, including SMILES, mmCIF, SDF MOL and SYBYL MOL2 files. Using the bonding chemistry, atom types, and bond and angle tables generated from the COD, AceDRG derives the ‘ideal’ bond lengths, angles, plane groups, aromatic rings and chirality information, and writes them to an mmCIF file that can be used by the refinement program REFMAC5 and the model-building program Coot. Other refinement and model-building programs such as PHENIX and BUSTER can also use these files. AceDRG also generates one or more coordinate sets corresponding to the most favourable conformation(s) of a given ligand. AceDRG employs RDKit for chemistry perception and for initial conformation generation, as well as for the interpretation of SMILES strings, SDF MOL and SYBYL MOL2 files. PMID:28177307

  10. Prevalence of Concurrent Prescribing of ACE-Is and ARBs among Beneficiaries of Puerto Rico's Government-Sponsored Health Care Plan During 2012 and 2013.

    PubMed

    Figueroa-Ríos, Denise; Hernández-Muñoz, José J; García-Albarrán, Aileen; García-Rodríguez, Emily A; Méndez-Hernández, Glendaliz; Vélez-Rivera, Suzette M

    2017-06-01

    Cardiovascular conditions are the second cause of death in Puerto Rico. The individual use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) is considered the first-line therapy for the treatment of several cardiovascular-related medical conditions. However, the concurrent use of these 2 therapeutic classes of drugs is not supported by treatment guidelines. Studies have shown that their concurrent use represents a potential health risk. The research described in this paper aimed to determine the prevalence of the concurrent prescription of ACE-Is and ARBs, either separately or as a combination product, in a group of beneficiaries of the Puerto Rico Health Services Administration (ASES, by its initials in Spanish). A 2-year cross sectional study was conducted. All pharmacy claims from the years 2012 and 2013 were provided by ASES and subsequently evaluated by the investigators to identify those involving the prescription of an ACE-I, an ARB, or a combination of drugs belonging to both therapeutic classes. Each pharmacy claim was complemented with sociodemographic and clinical data. The final dataset was analyzed at the person-month level using frequency, cumulative frequency, percentage, and cumulative percentage. The final sample consisted of 361,841 beneficiaries. A total of 23,598 beneficiaries were excluded because of incomplete diagnostic information. Of the beneficiaries with complete information, 36,202 out of 338,243 (10.7%) had concurrent prescriptions for ACE-Is and ARBs during the study period. We excluded 1,124 beneficiaries who had a primary diagnosis of HF, resulting in a final pool of 35,078 beneficiaries (10.4%) who had prescriptions for combination products. An unacceptable pattern of ACE-I and ARB co-prescribing during the years 2012 and 2013 was observed in patients with diagnoses for which the combination is not clinically indicated.

  11. RNA interference targeting the ACE gene reduced blood pressure and improved myocardial remodelling in SHRs.

    PubMed

    He, Junhua; Bian, Yunfei; Gao, Fen; Li, Maolian; Qiu, Ling; Wu, Weidong; Zhou, Hua; Liu, Gaizhen; Xiao, Chuanshi

    2009-02-01

    The purpose of the present study was to investigate the effects on blood pressure and myocardial hypertrophy in SHRs (spontaneously hypertensive rats) of RNAi (RNA interference) targeting ACE (angiotensin-converting enzyme). SHRs were treated with normal saline as vehicle controls, with Ad5-EGFP as vector controls, and with recombinant adenoviral vectors Ad5-EGFP-ACE-shRNA, carrying shRNA (small hairpin RNA) for ACE as ACE-RNAi. WKY (Wistar-Kyoto) rats were used as normotensive controls treated with normal saline. The systolic blood pressure of the caudal artery was recorded. Serum levels of ACE and AngII (angiotensin II) were determined using ELISA. ACE mRNA and protein levels were determined in aorta, myocardium, kidney and lung. On day 32 of the experiment, the heart was pathologically examined. The ratios of heart weight/body weight and left ventricular weight/body weight were calculated. The serum concentration of ACE was lower in ACE-RNAi rats (16.37+/-3.90 ng/ml) compared with vehicle controls and vector controls (48.26+/-1.50 ng/ml and 46.67+/-2.82 ng/ml respectively; both P<0.05), but comparable between ACE-RNAi rats and WKY rats (14.88+/-3.15 ng/ml; P>0.05). The serum concentration of AngII was also significantly lower in ACE-RNAi rats (18.24+/-3.69 pg/ml) compared with vehicle controls and vector controls (46.21+/-5.06 pg/ml and 44.93+/-4.12 pg/ml respectively; both P<0.05), but comparable between ACE-RNAi rats and WKY rats (16.06+/-3.11 pg/ml; P>0.05). The expression of ACE mRNA and ACE protein were significantly reduced in the myocardium, aorta, kidney and lung in ACE-RNAi rats compared with that in vehicle controls and in vector controls (all P<0.05). ACE-RNAi treatment resulted in a reduction in systolic blood pressure by 22+/-3 mmHg and the ACE-RNAi-induced reduction lasted for more than 14 days. In contrast, blood pressure was continuously increased in the vehicle controls as well as in the vector controls. The ratios of heart weight/body weight

  12. Adverse Childhood Experiences (ACEs) questionnaire and Adult Attachment Interview (AAI): implications for parent child relationships.

    PubMed

    Murphy, Anne; Steele, Miriam; Dube, Shanta Rishi; Bate, Jordan; Bonuck, Karen; Meissner, Paul; Goldman, Hannah; Steele, Howard

    2014-02-01

    Although Adverse Childhood Experiences (ACEs) are linked to increased health problems and risk behaviors in adulthood, there are no studies on the association between ACEs and adults' states of mind regarding their early childhood attachments, loss, and trauma experiences. To validate the ACEs questions, we analyzed the association between ACEs and emotional support indicators and Adult Attachment Interview (AAI) classifications in terms of unresolved mourning regarding past loss or trauma and discordant states of mind in cannot classify (U/CC) interviews. Seventy-five urban women (41 clinical and 34 community) completed a questionnaire on ACEs, which included 10 categories of abuse, neglect, and household dysfunction, in addition to emotional support. Internal psychological processes or states of mind concerning attachment were assessed using the AAI. ACE responses were internally consistent (Cronbach's α=.88). In the clinical sample, 84% reported≥4 ACEs compared to 27% among the community sample. AAIs judged U/CC occurred in 76% of the clinical sample compared to 9% in the community sample. When ACEs were≥4, 65% of AAIs were classified U/CC. Absence of emotional support in the ACEs questionnaire was associated with 72% of AAIs being classified U/CC. As the number of ACEs and the lack of emotional support increases so too does the probability of AAIs being classified as U/CC. Findings provide rationale for including ACEs questions in pediatric screening protocols to identify and offer treatment reducing the intergenerational transmission of risk associated with problematic parenting. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. The effect of angiotensin-converting enzyme inhibition throughout a superovulation protocol in ewes.

    PubMed

    Pereira, Alécio Matos; de Souza Júnior, Antônio; Machado, Fernanda Brandão; Gonçalves, Gleisy Kelly Neves; Feitosa, Lauro César Soares; Reis, Adelina Martha; Santos, Robson Augusto Souza; Honorato-Sampaio, Kinulpe; Costa, Amilton Raposo

    2015-12-01

    Many studies identified new components of the renin–angiotensin system (RAS), such as Angiotensin-(1-7) [Ang-(1–7)] and Angiotensin-converting enzyme type 2 (ACE2), in mammalian ovaries.We previously showed Angiotensin-Converting Enzyme (ACE) inhibition, which increases the level of Ang-(1–7), stimulated ovarian estradiol output in ewe after estrous synchronization. Considering that Ang-(1–7) stimulates ovarian function and elevated estradiol before ovulation is associated with increased chance of achieving pregnancy, the present study investigated whether ACE inhibition throughout a superovulation protocol in ewe might improve ovulation outcome. At first, immunohistochemistry in ovaries of nonpregnant ewes revealed localization of Angiotensin II (Ang II), Ang-(1–7) and ACE2 in theca cells of antral follicles and in corpus luteum. Ang II and Ang-(1–7)were also detected in follicular fluid (FF) by Radioimmunoassay (RIA). Enalapril treatment throughout the superovulation protocol decreased 17β-estradiol (E2) output and raised progesterone:estradiol (P4:E2) ratio without a direct influence on ovulation and quality of embryos.

  14. Relationship of angiotensin I-converting enzyme (ACE) and bradykinin B2 receptor (BDKRB2) polymorphism with diabetic nephropathy.

    PubMed

    Zou, Honghong; Wu, Guoqing; Lv, Jinlei; Xu, Gaosi

    2017-06-01

    To determine whether ACE 2 I/D and BDKRB2 3 +9/-9 polymorphism causatively affect diabetic nephropathy progression RESULTS: STZ-induced metabolic disorder, as well as inflammatory responses, was significantly aggravated in ACE II-B2R 4 +9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp diabetic mice but not ACE II-B2R-9bp, indicating the genetic susceptibility of ACE DD or B2R+9bp to diabetic nephropathy. Furthermore, ACE II-B2R+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp rather than ACE II-B2R-9bp, worsened renal performance and enhanced pathological alterations induced by STZ. Markedly elevated monocyte chemoattractant protein-1(MCP-1), podocin, osteopontin (OPN), transforming growth factor-β1 (TGF-β1), and reduced nephrin, podocin were also detected both in diabetic mice and podocytes under hyperglycemic conditions in response to ACE II-B2R+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp, versus ACE II-B2R-9bp. In addition, high glucose-induced mitochondrial oxidative stress and cell apoptosis were observably increased in response to ACE II-B2R+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp but not ACE II-B2R-9bp. We provide first evidence indicating the causation between ACE DD or B2R+9bp genotype and the increased risk for diabetic nephropathy, broadening our horizon about the role of genetic modulators in this disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Early vs. late intervention of high fat/low dose streptozotocin treated C57Bl/6J mice with enalapril, α-lipoic acid, menhaden oil or their combination: effect on diabetic neuropathy related endpoints

    PubMed Central

    Yorek, Matthew S.; Obrosov, Alexander; Shevalye, Hanna; Coppey, Lawrence J.; Kardon, Randy H.; Yorek, Mark A.

    2017-01-01

    We have previously demonstrated that enalapril, α-lipoic acid and menhaden (fish) oil has potential as a treatment for diabetic peripheral neuropathy. In this study we sought to determine the efficacy of these treatments individually or in combination on multiple neuropathic endpoints in a high fat fed low dose streptozotocin treated mouse, a model of type 2 diabetes, following early or late intervention. Four or twelve weeks after the onset of hyperglycemia, diabetic mice were treated with enalapril, α-lipoic acid, menhaden oil or their combination for 12 weeks. Afterwards, endpoints including glucose tolerance, motor and sensory nerve conduction velocity, thermal nociception, and intraepidermal and cornea nerve fiber density was determined. Glucose clearance was impaired in diabetic mice and significantly improved only with combination treatment and early intervention. Diabetes caused steatosis, slowing of motor and sensory nerve conduction velocity, thermal hypoalgesia and reduction in intraepidermal and cornea nerve fiber density. Treating diabetic mice with enalapril, α-lipoic acid or menhaden oil partially protected diabetic mice from these deficits, whereas the combination of these three treatments was more efficacious following early or late intervention. These studies suggest that a combination therapy may be more effective for treating neural complications of type 2 diabetes. PMID:28025096

  16. Early vs. late intervention of high fat/low dose streptozotocin treated C57Bl/6J mice with enalapril, α-lipoic acid, menhaden oil or their combination: Effect on diabetic neuropathy related endpoints.

    PubMed

    Yorek, Matthew S; Obrosov, Alexander; Shevalye, Hanna; Coppey, Lawrence J; Kardon, Randy H; Yorek, Mark A

    2017-04-01

    We have previously demonstrated that enalapril, α-lipoic acid and menhaden (fish) oil has potential as a treatment for diabetic peripheral neuropathy. In this study we sought to determine the efficacy of these treatments individually or in combination on multiple neuropathic endpoints in a high fat fed low dose streptozotocin treated mouse, a model of type 2 diabetes, following early or late intervention. Four or twelve weeks after the onset of hyperglycemia, diabetic mice were treated with enalapril, α-lipoic acid, menhaden oil or their combination for 12 weeks. Afterwards, endpoints including glucose tolerance, motor and sensory nerve conduction velocity, thermal nociception, and intraepidermal and cornea nerve fiber density was determined. Glucose clearance was impaired in diabetic mice and significantly improved only with combination treatment and early intervention. Diabetes caused steatosis, slowing of motor and sensory nerve conduction velocity, thermal hypoalgesia and reduction in intraepidermal and cornea nerve fiber density. Treating diabetic mice with enalapril, α-lipoic acid or menhaden oil partially protected diabetic mice from these deficits, whereas the combination of these three treatments was more efficacious following early or late intervention. These studies suggest that a combination therapy may be more effective for treating neural complications of type 2 diabetes. Published by Elsevier Ltd.

  17. DNA methylation and genetic variation of the angiotensin converting enzyme (ACE) in depression.

    PubMed

    Lam, Dilys; Ancelin, Marie-Laure; Ritchie, Karen; Saffery, Richard; Ryan, Joanne

    2018-02-01

    Depression is one of the most prevalent psychiatric disorders, and in older persons is associated with high levels of comorbidity and under-treatment. Dysfunction of the hypothalamic-pituitary-adrenal (HPA) stress axis is consistently observed in the older population as well as depressed patients, with the angiotensin converting enzyme (ACE) a key regulator of the stress response. Epigenetic regulation of ACE may play an important role in HPA axis (dys)regulation. To investigate ACE promoter methylation as a biomarker of late-life depression, and its association with genetic variation and cortisol secretion. The longitudinal general population ESPRIT study is aimed at investigating psychiatric disorders in older persons (n=1863, average age=73). Depression was assessed using the Mini International Neuropsychiatric Interview according to DSM-IV criteria and the Centre for Epidemiologic Studies Depression Scale (CES-D). Genotype information for seven polymorphisms across the ACE gene was also available. Blood and saliva samples collected at baseline and used to extract DNA and measure cortisol, respectively. Sequenom MassARRAY was used to measure promoter DNA methylation of the ACE gene (n=552). There was no evidence of an association between ACE promoter methylation and depression. However, there was evidence that ACE genetic variants influenced methylation, and modified the association between depression and methylation (Δ at various sites; -2.05% to 1.74%; p=0.019 to 0.039). Multivariate analyses were adjusted for participants' lifestyle, health and medical history. Independent of depression status, ACE methylation was inversely correlated with cortisol levels (r=-0.336, p=0.042). This study provides evidence that associations between ACE methylation and depression are genotype-dependent, suggesting that the development of reliable depression biomarkers may need to consider methylation levels in combination with underlying genetic variation. ACE methylation may

  18. A Consolidation of ACE Research, 1990-2000. Review of Research.

    ERIC Educational Resources Information Center

    Golding, Barry; Davies, Merryn; Volkoff, Veronica

    The volume and scope of research into adult and community education (ACE) in Australia have increased significantly over the past decade. Studies designed to map, reevaluate, showcase, and promote ACE have been funded by Australia's federal and state governments and by bodies such as Adult Learning Australia. Practitioner-generated research has…

  19. Angiotensin converting enzyme (ACE) gene expression in experimentally induced liver cirrhosis in rats.

    PubMed

    Shahid, Syed Muhammad; Fatima, Syeda Nuzhat; Mahboob, Tabassum

    2013-09-01

    Angiotensin converting enzyme (ACE) is a key player of Renin Angiotensin System (RAS), involved in conversion of active product, angiotensin-II. Alterations in RAS have been implicated in the pathophysiology of various diseases involving heart, kidney, lung and liver. This study is designed to investigate the association of ACE gene expression in induction of liver cirrhosis in rats. Total 12 male albino Wistar rats were selected and divided in two groups. Control group received 0.9% NaCl, where as Test group received thioacidamide (TAA), dissolved in 0.9%NaCl, injected intraperitoneally at a dosage of 200mg/Kg of body weight, twice a week for 12 weeks. The rats were decapitated and blood sample was collected at the end of experimental period and used for liver functions, enzyme activity, antioxidant enzymes and lipid peroxidation estimations. Genomic DNA was isolated from excised tissue determine the ACE genotypes using specific primers. The ACE gene expression in liver tissue was assessed using the quantitative RT-PCR method. The activity of ALT, total and direct bilirubin, SOD and CAT levels were significantly high (p<0.05) and level of MDA was significantly low (p<0.05) in TAA treated rats as compared to control rats. The ACE gene expression after 12 weeks TAA treatment in cirrhotic rats was significantly increased (p<0.05) in comparison to controls. This study describes the importance of RAS in the development of hepatic fibrosis and the benefits of modulation of this system ACE gene expression. The finding of major up-regulation of ACE in the experimental rat liver provides further insight into the complexities of the RAS and its regulation in liver injury. The development of specific modulators of ACE activity and function, in future, will help determine the role of ACE and its genetic variants in the pathophysiology of liver disease.

  20. Up-Regulation of Angiotensin-Converting Enzyme (ACE) Enhances Cell Proliferation and Predicts Poor Prognosis in Laryngeal Cancer.

    PubMed

    Han, Chao-Dong; Ge, Wen-Sheng

    2016-11-01

    BACKGROUND The angiotensin-converting enzyme (ACE, CD143) gene plays a crucial role in the pathology of many cancers. Previous studies mostly focused on the gene polymorphism, but the other functions of ACE have rarely been reported. The purpose of this study was to investigate the expression of ACE and its biological function, as well as its prognostic value, in laryngeal cancer. MATERIAL AND METHODS The expression of ACE was detected by quantitative real-time polymerase chain reaction (qRT-PCR) analysis in 106 patients with laryngeal cancer and 85 healthy people. Then the cell proliferation was estimated after the cell lines Hep-2 were transfected with pGL3-ACE and empty vector, respectively. In addition, the relationship between ACE expression and clinicopathologic characteristics was analyzed. Finally, Kaplan-Meier analysis was used to evaluate the overall survival of patients with different ACE expression, while Cox regression analysis was conducted to reveal the prognostic value of ACE in laryngeal cancer. RESULTS Our results demonstrate that ACE is over-expressed in laryngeal cancer and thus promotes cell proliferation. The up-regulation of ACE was significantly influenced by tumor stage and lymph node metastasis. Patients with high ACE expression had a shorter overall survival compared with those with low ACE expression according to Kaplan-Meier analysis. The ACE gene was also found to be an important factor in the prognosis of laryngeal cancer. CONCLUSIONS Our study shows that the ACE gene was up-regulated, which promoted the cell proliferation, and it could be an independent prognostic marker in laryngeal cancer.

  1. ACE Insertion/Deletion Polymorphism and Diabetic Nephropathy: Clinical Implications of Genetic Information

    PubMed Central

    Ha, Sung-Kyu

    2014-01-01

    Approximately 20–40% of diabetic patients develop nephropathy which is the leading cause of ESRD in developed countries. The ACE I/D polymorphism is thought to be a marker for functional polymorphism which regulates circulating and tissue ACE activity. While the initial study found a protective effect of the II genotype on the development of nephropathy in IDDM patients, subsequent studies have addressed the role of ACE I/D polymorphism in the development and progression of diabetic nephropathy. RAAS blockers are the first line drugs for the treatment hypertension associated with diabetes and have been widely used in everyday clinical practice for the purpose of reducing proteinuria in patients with various renal diseases. However, the antiproteinuric effect of RAAS blockers is variable and the percentage of reducing proteinuria is in the range of 20–80%. The antiproteinuric effect of RAAS blockers may be related to a number of factors: the type or the dose of RAAS blockers, the duration of therapy, the level of sodium intake, and the type of patient's ACE I/D genotype. Besides the nongenetic factors, drug responses, can be influenced by ACE gene polymorphism. In this review, we discuss the relationship between ACE I/D polymorphism and diabetic nephropathy and therapeutic response of RAAS blockers. PMID:25587546

  2. The ACES mission: scientific objectives and present status

    NASA Astrophysics Data System (ADS)

    Cacciapuoti, L.; Dimarcq, N.; Salomon, C.

    2017-11-01

    "Atomic Clock Ensemble in Space" (ACES) is a mission in fundamental physics that will operate a new generation of atomic clocks in the microgravity environment of the International Space Station (ISS). The ACES clock signal will combine the medium term frequency stability of a space hydrogen maser (SHM) and the long term stability and accuracy of a frequency standard based on cold cesium atoms (PHARAO). Fractional frequency stability and accuracy of few parts in 1016 will be achieved. The on-board time base distributed on Earth via a microwave link (MWL) will be used to test fundamental laws of physics (Einstein's theories of Special and General Relativity, Standard Model Extension, string theories…) and to develop applications in time and frequency metrology, universal time scales, global positioning and navigation, geodesy and gravimetry. After a general overview on the mission concept and its scientific objectives, the present status of ACES instruments and sub-systems will be discussed.

  3. ACE Over Expression in Myelomonocytic Cells: Effect on a Mouse Model of Alzheimer's Disease

    PubMed Central

    Koronyo-Hamaoui, Maya; Shah, Kandarp; Koronyo, Yosef; Bernstein, Ellen; Giani, Jorge F.; Janjulia, Tea; Black, Keith L.; Shi, Peng D.; Gonzalez-Villalobos, Romer A.; Fuchs, Sebastien; Shen, Xiao Z.; Bernstein, Kenneth E.

    2014-01-01

    While it is well known that angiotensin converting enzyme (ACE) plays an important role in blood pressure control, ACE also has effects on renal function, hematopoiesis, reproduction, and aspects of the immune response. ACE 10/10 mice over express ACE in myelomonocytic cells. Macrophages from these mice have an increased polarization towards a pro-inflammatory phenotype that results in a very effective immune response to challenge by tumors or bacterial infection. In a mouse model of Alzheimer's disease (AD), the ACE 10/10 phenotype provides significant protection against AD pathology, including reduced inflammation, reduced burden of the neurotoxic amyloid-β protein and preserved cognitive function. Taken together, these studies show that increased myelomonocytic ACE expression in mice alters the immune response to better defend against many different types of pathologic insult, including the cognitive decline observed in an animal model of AD. PMID:24792094

  4. Effect of the NEP inhibitor SCH32615 on airway responses to intravenous substance P in guinea pigs.

    PubMed

    Shore, S A; Martins, M A; Drazen, J M

    1992-11-01

    We examined the effects of the selective neutral endopeptidase (NEP) inhibitor SCH32615 on airway responses to rapid intravenous infusions of substance P (SP) and neurokinin A (NKA) and on recovery of administered tachykinins from arterial blood in anesthetized mechanically ventilated guinea pigs. SCH32615, in doses that cause a marked increase in the magnitude of bronchoconstriction induced by infused NKA, had little effect on the changes in pulmonary conductance (GL) or dynamic compliance induced by SP. In animals in which SCH32615 (1 mg/kg) was administered in combination with the angiotensin-converting enzyme (ACE) inhibitor captopril (5.7 mg/kg), the dose of SP required to decrease GL by 50% was fourfold less than in animals that received captopril alone (P < 0.005). SP measured in arterial blood withdrawn within 45 s of intravenous administration of this tachykinin was not different in control and SCH32615-treated animals, whereas captopril caused an approximately threefold increase in SP concentrations (P < 0.005). When SCH32615 and captopril were administered together, significantly more SP was recovered than when captopril or SCH32615 was administered alone (P < 0.0005). Our results are consistent with the hypothesis that both NEP and ACE contribute to the degradation of intravenously infused SP. ACE degradation of SP is sufficient to limit SP-induced bronchoconstriction even in the presence of specific NEP inhibition.

  5. A Novel Splice-Site Mutation in Angiotensin I-Converting Enzyme (ACE) Gene, c.3691+1G>A (IVS25+1G>A), Causes a Dramatic Increase in Circulating ACE through Deletion of the Transmembrane Anchor

    PubMed Central

    Persu, Alexandre; Lambert, Michel; Deinum, Jaap; Cossu, Marta; de Visscher, Nathalie; Irenge, Leonid; Ambroise, Jerôme; Minon, Jean-Marc; Nesterovitch, Andrew B.; Churbanov, Alexander; Popova, Isolda A.; Danilov, Sergei M.; Danser, A. H. Jan; Gala, Jean-Luc

    2013-01-01

    Background Angiotensin-converting enzyme (ACE) (EC 4.15.1) metabolizes many biologically active peptides and plays a key role in blood pressure regulation and vascular remodeling. Elevated ACE levels are associated with different cardiovascular and respiratory diseases. Methods and Results Two Belgian families with a 8-16-fold increase in blood ACE level were incidentally identified. A novel heterozygous splice site mutation of intron 25 - IVS25+1G>A (c.3691+1G>A) - cosegregating with elevated plasma ACE was identified in both pedigrees. Messenger RNA analysis revealed that the mutation led to the retention of intron 25 and Premature Termination Codon generation. Subjects harboring the mutation were mostly normotensive, had no left ventricular hypertrophy or cardiovascular disease. The levels of renin-angiotensin-aldosterone system components in the mutated cases and wild-type controls were similar, both at baseline and after 50 mg captopril. Compared with non-affected members, quantification of ACE surface expression and shedding using flow cytometry assay of dendritic cells derived from peripheral blood monocytes of affected members, demonstrated a 50% decrease and 3-fold increase, respectively. Together with a dramatic increase in circulating ACE levels, these findings argue in favor of deletion of transmembrane anchor, leading to direct secretion of ACE out of cells. Conclusions We describe a novel mutation of the ACE gene associated with a major familial elevation of circulating ACE, without evidence of activation of the renin-angiotensin system, target organ damage or cardiovascular complications. These data are consistent with the hypothesis that membrane-bound ACE, rather than circulating ACE, is responsible for Angiotensin II generation and its cardiovascular consequences. PMID:23560051

  6. The Altus Cumulus Electrification Study (ACES): A UAV-based Investigation of Thunderstorms

    NASA Technical Reports Server (NTRS)

    Blakeslee, Richard; Arnold, James E. (Technical Monitor)

    2001-01-01

    The Altus Cumulus Electrification Study (ACES) is a NASA-sponsored and -led science investigation that utilizes an uninhabited aerial vehicle (UAV) to investigate thunderstorms in the vicinity of the NASA Kennedy Space Center, Florida. As part of NASA's UAV-based science demonstration program, ACES will provide a scientifically useful demonstration of the utility and promise of UAV platforms for Earth science and applications observations. ACES will employ the Altus 11 aircraft, built by General Atomics-Aeronautical Systems, Inc. By taking advantage of its slow flight speed (70 to 100 knots), long endurance, and high-altitude flight (up to 55,000 feet), the Altus will be flown near, and when possible, above (but never into) thunderstorms for long periods of time, allowing investigations to be conducted over entire storm life cycles. Key science objectives simultaneously addressed by ACES are to: (1) investigate lightning-storm relationships, (2) study storm electrical budgets, and (3) provide Lightning Imaging Sensor validation. The ACES payload, already developed and flown on Altus, includes electrical, magnetic, and optical sensors to remotely characterize the lightning activity and the electrical environment within and around thunderstorms. The ACES field campaign will be conducted during July 2002 with a goal of performing 8 to 10 UAV flights. Each flight will require about 4 to 5 hours on station at altitudes from 40,000 ft to 55,000 ft. The ACES team is comprised of scientists from the NASA Marshall Space Flight Center and NASA Goddard Space Flight Centers partnered with General Atomics and IDEA, LLC.

  7. Rediscovering ACE: Novel insights into the many roles of the angiotensin-converting enzyme

    PubMed Central

    Gonzalez-Villalobos, Romer A.; Shen, Xiao Z.; Bernstein, Ellen A.; Janjulia, Tea; Taylor, Brian; Giani, Jorge F.; Blackwell, Wendell-Lamar B.; Shah, Kandarp H.; Shi, Peng D.; Fuchs, Sebastien; Bernstein, Kenneth E.

    2013-01-01

    Angiotensin converting enzyme (ACE) is best known for the catalytic conversion of angiotensin I to angiotensin II. However, the use of gene-targeting techniques has led to mouse models highlighting many other biochemical properties and actions of this enzyme. This review discusses recent studies examining the functional significance of ACE tissue-specific expression and the presence in ACE of two independent catalytic sites with distinct substrates and biological effects. It is these features which explain why ACE makes important contributions to many different physiological processes including renal development, blood pressure control, inflammation and immunity. PMID:23686164

  8. Validity of the T-ACE in pregnancy in predicting child outcome and risk drinking.

    PubMed

    Chiodo, Lisa M; Sokol, Robert J; Delaney-Black, Virginia; Janisse, James; Hannigan, John H

    2010-01-01

    Preventing fetal alcohol spectrum disorders (FASDs) requires detection of in-pregnancy maternal risk drinking. The widely used T-ACE screen has been applied in various ways, although the impact of those different uses on effectiveness is uncertain. We examined relations among different T-ACE scoring criteria, maternal drinking, and child outcome. Self-reported across-pregnancy maternal drinking was assessed in 75 African-American women. The different T-ACE criteria used varied the level of drinking that defined tolerance (two or three drinks) and the total T-ACE score cut-points (two or three). Receiver operator curves and regression analysis assessed the significance of relations. Increasing the total T-ACE score cut-point to 3 almost doubled specificity in detecting risk drinking whereas maintaining adequate sensitivity, equivalent to that in the original report, and identified substantially more neurobehavioral deficits in children. Redefining tolerance at three drinks did not improve T-ACE effectiveness in predicting outcomes. This study is among the first to show the ability of an in-pregnancy T-ACE assessment to predict child neurodevelopmental outcome. In addition, increasing the total T-ACE score criterion (from 2 to 3) improved identification of non-drinking mothers and unaffected children with little loss in detection of drinkers and affected children. Efficient in-pregnancy screens for risk drinking afford greater opportunities for intervention that could prevent/limit FASDs. Published by Elsevier Inc.

  9. Acute lead exposure increases arterial pressure: role of the renin-angiotensin system.

    PubMed

    Simões, Maylla Ronacher; Ribeiro Júnior, Rogério F; Vescovi, Marcos Vinícius A; de Jesus, Honério C; Padilha, Alessandra S; Stefanon, Ivanita; Vassallo, Dalton V; Salaices, Mercedes; Fioresi, Mirian

    2011-04-11

    Chronic lead exposure causes hypertension and cardiovascular disease. Our purpose was to evaluate the effects of acute exposure to lead on arterial pressure and elucidate the early mechanisms involved in the development of lead-induced hypertension. Wistar rats were treated with lead acetate (i.v. bolus dose of 320 µg/Kg), and systolic arterial pressure, diastolic arterial pressure and heart rate were measured during 120 min. An increase in arterial pressure was found, and potential roles of the renin-angiotensin system, Na(+),K(+)-ATPase and the autonomic reflexes in this change in the increase of arterial pressure found were evaluated. In anesthetized rats, lead exposure: 1) produced blood lead levels of 37±1.7 µg/dL, which is below the reference blood concentration (60 µg/dL); 2) increased systolic arterial pressure (Ct: 109±3 mmHg vs Pb: 120±4 mmHg); 3) increased ACE activity (27% compared to Ct) and Na(+),K(+)-ATPase activity (125% compared to Ct); and 4) did not change the protein expression of the α1-subunit of Na(+),K(+)-ATPase, AT(1) and AT(2). Pre-treatment with an AT(1) receptor blocker (losartan, 10 mg/Kg) or an ACE inhibitor (enalapril, 5 mg/Kg) blocked the lead-induced increase of arterial pressure. However, a ganglionic blockade (hexamethonium, 20 mg/Kg) did not prevent lead's hypertensive effect. Acute exposure to lead below the reference blood concentration increases systolic arterial pressure by increasing angiotensin II levels due to ACE activation. These findings offer further evidence that acute exposure to lead can trigger early mechanisms of hypertension development and might be an environmental risk factor for cardiovascular disease.

  10. Effects of the lercanidipine-enalapril combination vs. the corresponding monotherapies on home blood pressure in hypertension: evidence from a large database.

    PubMed

    Mancia, Giuseppe; Omboni, Stefano; Chazova, Irina; Coca, Antonio; Girerd, Xavier; Haller, Hermann; Parati, Gianfranco; Pauletto, Paolo; Pupek-Musialik, Danuta; Svyshchenko, Yevgeniya

    2016-01-01

    To compare a combination of a dihydropyridine calcium-channel blocker with an angiotensin converting enzyme inhibitor vs. monotherapy with one or the other drug and placebo for their effects on home blood pressure (HBP). After a 2-week placebo wash-out, patients with an elevated office blood pressure (BP) (diastolic 100-109 and systolic <180 mmHg) and HBP (diastolic ≥85 mmHg) were randomized double-blind to a 10-week treatment with placebo, lercanidipine, 10 or 20 mg daily, enalapril, 10 or 20 mg daily, or the four possible combinations. In addition to office BP, HBP was self-measured via a validated semiautomatic device twice in the morning and twice in the evening during the 7 days before randomization and at the end of treatment. Baseline and treatment HBP values were separately averaged for each day, morning, evening or the whole monitoring period, excluding the first day. Day-by-day HBP variability was defined as the SD or the variation coefficient of the daily BP averages. Eight hundred and fifty-four patients with valid HBP recordings at baseline and at the end of treatment were analyzed (intention-to-treat population). From the baseline value (147.0±11.6 mmHg) systolic/diastolic HBP showed a small reduction (average baseline-adjusted change: -1.8/-1.6 mmHg) with placebo, a more marked significant fall with monotherapies (-8.8/-5.9 mmHg, P < 0.001/<0.001 vs. placebo) and even more with combination treatment (11.6/-7.6 mmHg, P < 0.001/ < 0.001 vs. placebo and P < 0.01/ < 0.05 vs. monotherapy). A similar pattern was observed for each of the days of the BP self-monitoring period as well as for either morning or evening values, although the difference between mono and combination treatment appeared to be consistently significant for the morning values only. Day-by-day systolic BP-SD was unaffected by placebo and slightly reduced by drug treatments, with no, however, significant changes in SBP-variation coefficient. Baseline and end of

  11. CD36/Sirtuin 1 Axis Impairment Contributes to Hepatic Steatosis in ACE2-Deficient Mice

    PubMed Central

    Qadri, Fatimunnisa; Penninger, Josef M.; Santos, Robson Augusto S.; Bader, Michael

    2016-01-01

    Background and Aims. Angiotensin converting enzyme 2 (ACE2) is an important component of the renin-angiotensin system. Since angiotensin peptides have been shown to be involved in hepatic steatosis, we aimed to evaluate the hepatic lipid profile in ACE2-deficient (ACE2−/y) mice. Methods. Male C57BL/6 and ACE2−/y mice were analyzed at the age of 3 and 6 months for alterations in the lipid profiles of plasma, faeces, and liver and for hepatic steatosis. Results. ACE2−/y mice showed lower body weight and white adipose tissue at all ages investigated. Moreover, these mice had lower levels of cholesterol, triglycerides, and nonesterified fatty acids in plasma. Strikingly, ACE2−/y mice showed high deposition of lipids in the liver. Expression of CD36, a protein involved in the uptake of triglycerides in liver, was increased in ACE2−/y mice. Concurrently, these mice exhibited an increase in hepatic oxidative stress, evidenced by increased lipid peroxidation and expression of uncoupling protein 2, and downregulation of sirtuin 1. ACE2−/y mice also showed impairments in glucose metabolism and insulin signaling in the liver. Conclusions. Deletion of ACE2 causes CD36/sirtuin 1 axis impairment and thereby interferes with lipid homeostasis, leading to lipodystrophy and steatosis. PMID:28101297

  12. ACE2 activity was increased in atherosclerotic plaque by losartan: Possible relation to anti-atherosclerosis.

    PubMed

    Zhang, Yue Hui; Hao, Qing Qing; Wang, Xiao Yu; Chen, Xu; Wang, Nan; Zhu, Li; Li, Shu Ying; Yu, Qing Tao; Dong, Bo

    2015-06-01

    Angiotensin-converting enzyme 2 (ACE2) is a new member of the renin-angiotensin system (RAS) and it has been proposed that ACE2 is a potential therapeutic target for the control of cardiovascular disease. The effect of losartan on the ACE2 activity in atherosclerosis was studied. Atherosclerosis was induced in New Zealand white rabbits by high-cholesterol diet for 3 months. An Angiotensin II (Ang II) receptor blocker (losartan, 25 mg/kg/d) was given for 3 months. ACE2 activity was measured by fluorescence assay and the extent of atherosclerosis was evaluated by H&E and Oil Red O staining. In addition, the effect of losartan on ACE2 activity in smooth muscle cells (SMCs) in vitro was also evaluated. Losartan increased ACE2 activity in atherosclerosis in vivo and SMCs in vitro. Losartan inhibited atherosclerotic evolution. Addition of losartan blocked Ang II-induced down-regulation of ACE2 activity, and blockade of extracellular signal-regulated kinase (ERK1/2) with PD98059 prevented Ang II-induced down-regulation of ACE2 activity. The results showed that ACE2 activity was regulated in atherosclerotic plaque by losartan, which may play an important role in treatment of atherosclerosis. The mechanism involves Ang II-AT1R-mediated mitogen-activated protein kinases, MAPKs (MAPKs) signaling pathway. © The Author(s) 2014.

  13. Amelioration of carcinogenesis and tumor growth in the rat liver by combination of vitamin K2 and angiotensin-converting enzyme inhibitor via anti-angiogenic activities.

    PubMed

    Yoshiji, Hitoshi; Kuriyama, Shigeki; Noguchi, Ryuichi; Yoshii, Junichi; Ikenaka, Yasuhide; Yanase, Koji; Namisaki, Tadashi; Kitade, Mitsuteru; Yamazaki, Masaharu; Akahane, Takemi; Asada, Kiyoshi; Tsujimoto, Tatsuhito; Uemura, Masahito; Fukui, Hiroshi

    2006-01-01

    Recent studies have revealed that angiogenesis plays a pivotal role in carcinogenesis and tumor growth. We previously reported that the clinically used vitamin K(2) (VK) and angiotensin-converting enzyme inhibitor (ACE-I) exerted potent anti-angiogenic activities. The aim of our current study was to examine the combination effect of VK and ACE-I on hepatocarcinogenesis induced by diethyl-nitrosamine, and orthotopic hepatocellular carcinoma (HCC) growth in rats. When used individually, both VK and ACE-I at clinically comparable low doses exerted significant inhibitory effects on tumor development in the liver. A combination treatment of VK and ACE-I showed a more potent suppressive effect against hepatocarcinogenesis. Neovascularization increased during hepatocarcinogenesis, and VK and ACE-I significantly attenuated angiogenesis in the tumor. In orthotopic HCC transplantation, VK and ACE-I also showed marked suppressive effects against HCC development similar to those against hepatocarcinogenesis. In both experiments, the suppressive effects of VK and ACE-I against angiogenesis were similar in magnitude to their inhibitory effects against hepatocarcinogenesis and orthotopic HCC development. In the orthotopic model, VK and ACE-I treatment resulted in a marked increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. Since both VK and ACE-I are widely used in clinical practice without serious side effects, this combination therapy may be an effective new therapeutic strategy against hepatocarcinogenesis and HCC growth in the future.

  14. Application of plug-plug technique to ACE experiments for discovery of peptides binding to a larger target protein: a model study of calmodulin-binding fragments selected from a digested mixture of reduced BSA.

    PubMed

    Saito, Kazuki; Nakato, Mamiko; Mizuguchi, Takaaki; Wada, Shinji; Uchimura, Hiromasa; Kataoka, Hiroshi; Yokoyama, Shigeyuki; Hirota, Hiroshi; Kiso, Yoshiaki

    2014-03-01

    To discover peptide ligands that bind to a target protein with a higher molecular mass, a concise screening methodology has been established, by applying a "plug-plug" technique to ACE experiments. Exploratory experiments using three mixed peptides, mastoparan-X, β-endorphin, and oxytocin, as candidates for calmodulin-binding ligands, revealed that the technique not only reduces the consumption of the protein sample, but also increases the flexibility of the experimental conditions, by allowing the use of MS detection in the ACE experiments. With the plug-plug technique, the ACE-MS screening methodology successfully selected calmodulin-binding peptides from a random library with diverse constituents, such as protease digests of BSA. Three peptides with Kd values between 8-147 μM for calmodulin were obtained from a Glu-C endoprotease digest of reduced BSA, although the digest showed more than 70 peaks in its ACE-MS electropherogram. The method established here will be quite useful for the screening of peptide ligands, which have only low affinities due to their flexible chain structures but could potentially provide primary information for designing inhibitors against the target protein. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Adverse childhood experiences (ACEs) and later-life depression: perceived social support as a potential protective factor.

    PubMed

    Cheong, E Von; Sinnott, Carol; Dahly, Darren; Kearney, Patricia M

    2017-09-01

    To investigate associations between adverse childhood experiences (ACEs) and later-life depressive symptoms; and to explore whether perceived social support (PSS) moderates these. We analysed baseline data from the Mitchelstown (Ireland) 2010-2011 cohort of 2047 men and women aged 50-69 years. Self-reported measures included ACEs (Centre for Disease Control ACE questionnaire), PSS (Oslo Social Support Scale) and depressive symptoms (CES-D). The primary exposure was self-report of at least one ACE. We also investigated the effects of ACE exposure by ACE scores and ACE subtypes abuse, neglect and household dysfunction. Associations between each of these exposures and depressive symptoms were estimated using logistic regression, adjusted for socio-demographic factors. We tested whether the estimated associations varied across levels of PSS (poor, moderate and strong). 23.7% of participants reported at least one ACE (95% CI 21.9% to 25.6%). ACE exposures (overall, subtype or ACE scores) were associated with a higher odds of depressive symptoms, but only among individuals with poor PSS. Exposure to any ACE (vs none) was associated with almost three times the odds of depressive symptoms (adjusted OR 2.85; 95% CI 1.64 to 4.95) among individuals reporting poor PSS, while among those reporting moderate and strong PSS, the adjusted ORs were 2.21 (95% CI 1.52 to 3.22) and 1.39 (95% CI 0.85 to 2.29), respectively. This pattern of results was similar when exposures were based on ACE subtype and ACE scores, though the interaction was clearly strongest among those reporting abuse. ACEs are common among older adults in Ireland and are associated with higher odds of later-life depressive symptoms, particularly among those with poor PSS. Interventions that enhance social support, or possibly perceptions of social support, may help reduce the burden of depression in older populations with ACE exposure, particularly in those reporting abuse. © Article author(s) (or their employer

  16. Remarks on KERMA Factors in ACE files

    NASA Astrophysics Data System (ADS)

    Konno, C.; Ochiai, K.; Takakura, K.; Sato, S.

    2014-04-01

    Some neutron KERMA factors in ACE files are negative and extremely large if nuclear data libraries do not keep energy-balance. The status of neutron KERMA factors in the official ACE file of ENDF/B-VII.1 is examined. As a result, it is found out that neutron KERMA factors of nuclei more than 200 in ENDF/B-VII.1 have some problems. Effects of the inadequate KERMA factor are also investigated, which are large for neutron heat while those are small for total (neutron + gamma) heat. Users who use only neutron KERMA factors should check if the factors are adequate or not before they use the factors.

  17. Angiotensin I-converting-enzyme-inhibitory and antibacterial peptides from Lactobacillus helveticus PR4 proteinase-hydrolyzed caseins of milk from six species.

    PubMed

    Minervini, F; Algaron, F; Rizzello, C G; Fox, P F; Monnet, V; Gobbetti, M

    2003-09-01

    Sodium caseinates prepared from bovine, sheep, goat, pig, buffalo or human milk were hydrolyzed by a partially purified proteinase of Lactobacillus helveticus PR4. Peptides in each hydrolysate were fractionated by reversed-phase fast-protein liquid chromatography. The fractions which showed the highest angiotensin I-converting-enzyme (ACE)-inhibitory or antibacterial activity were sequenced by mass spectrum and Edman degradation analyses. Various ACE-inhibitory peptides were found in the hydrolysates: the bovine alpha(S1)-casein (alpha(S1)-CN) 24-47 fragment (f24-47), f169-193, and beta-CN f58-76; ovine alpha(S1)-CN f1-6 and alpha(S2)-CN f182-185 and f186-188; caprine beta-CN f58-65 and alpha(S2)-CN f182-187; buffalo beta-CN f58-66; and a mixture of three tripeptides originating from human beta-CN. A mixture of peptides with a C-terminal sequence, Pro-Gly-Pro, was found in the most active fraction of the pig sodium caseinate hydrolysate. The highest ACE-inhibitory activity of some peptides corresponded to the concentration of the ACE inhibitor (S)-N-(1-[ethoxycarbonyl]-3-phenylpropyl)-ala-pro maleate (enalapril) of 49.253 micro g/ml (100 micro mol/liter). Several of the above sequences had features in common with other ACE-inhibitory peptides reported in the literature. The 50% inhibitory concentration (IC(50)) of some of the crude peptide fractions was very low (16 to 100 micro g/ml). Some identified peptides were chemically synthesized, and the ACE-inhibitory activity and IC(50)s were confirmed. An antibacterial peptide corresponding to beta-CN f184-210 was identified in human sodium caseinate hydrolysate. It showed a very large spectrum of inhibition against gram-positive and -negative bacteria, including species of potential clinical interest, such as Enterococcus faecium, Bacillus megaterium, Escherichia coli, Listeria innocua, Salmonella spp., Yersinia enterocolitica, and Staphylococcus aureus. The MIC for E. coli F19 was ca. 50 micro g/ml. Once generated

  18. Angiotensin I-Converting-Enzyme-Inhibitory and Antibacterial Peptides from Lactobacillus helveticus PR4 Proteinase-Hydrolyzed Caseins of Milk from Six Species

    PubMed Central

    Minervini, F.; Algaron, F.; Rizzello, C. G.; Fox, P. F.; Monnet, V.; Gobbetti, M.

    2003-01-01

    Sodium caseinates prepared from bovine, sheep, goat, pig, buffalo or human milk were hydrolyzed by a partially purified proteinase of Lactobacillus helveticus PR4. Peptides in each hydrolysate were fractionated by reversed-phase fast-protein liquid chromatography. The fractions which showed the highest angiotensin I-converting-enzyme (ACE)-inhibitory or antibacterial activity were sequenced by mass spectrum and Edman degradation analyses. Various ACE-inhibitory peptides were found in the hydrolysates: the bovine αS1-casein (αS1-CN) 24-47 fragment (f24-47), f169-193, and β-CN f58-76; ovine αS1-CN f1-6 and αS2-CN f182-185 and f186-188; caprine β-CN f58-65 and αS2-CN f182-187; buffalo β-CN f58-66; and a mixture of three tripeptides originating from human β-CN. A mixture of peptides with a C-terminal sequence, Pro-Gly-Pro, was found in the most active fraction of the pig sodium caseinate hydrolysate. The highest ACE-inhibitory activity of some peptides corresponded to the concentration of the ACE inhibitor (S)-N-(1-[ethoxycarbonyl]-3-phenylpropyl)-ala-pro maleate (enalapril) of 49.253 μg/ml (100 μmol/liter). Several of the above sequences had features in common with other ACE-inhibitory peptides reported in the literature. The 50% inhibitory concentration (IC50) of some of the crude peptide fractions was very low (16 to 100 μg/ml). Some identified peptides were chemically synthesized, and the ACE-inhibitory activity and IC50s were confirmed. An antibacterial peptide corresponding to β-CN f184-210 was identified in human sodium caseinate hydrolysate. It showed a very large spectrum of inhibition against gram-positive and -negative bacteria, including species of potential clinical interest, such as Enterococcus faecium, Bacillus megaterium, Escherichia coli, Listeria innocua, Salmonella spp., Yersinia enterocolitica, and Staphylococcus aureus. The MIC for E. coli F19 was ca. 50 μg/ml. Once generated, the bioactive peptides were resistant to further

  19. Angiotensin-converting enzyme inhibition improves cardiac fatty acid metabolism in patients with congestive heart failure.

    PubMed

    Yamauchi, S; Takeishi, Y; Minamihaba, O; Arimoto, T; Hirono, O; Takahashi, H; Miyamoto, T; Nitobe, J; Nozaki, N; Tachibana, H; Watanabe, T; Fukui, A; Kubota, I

    2003-08-01

    This study aimed to examine whether angiotensin-converting enzyme (ACE) inhibition improved cardiac fatty acid metabolism in patients with congestive heart failure (CHF). Myocardial 123I-beta-methyl-iodophenylpentadecanoic acid (123I-BMIPP) imaging was performed in 25 patients with CHF and in 10 control subjects. Myocardial 123I-BMIPP images were obtained 30 min and 4 h after tracer injection. The heart-to-mediastinum (H/M) ratio of 123I-BMIPP uptake and the washout rate of 123I-BMIPP from the myocardium were calculated. Patients were given enalapril for 6 months, and 123I-BMIPP imaging was repeated. H/M ratios on early and delayed images were lower in CHF patients than in normal controls (P<0.01). The washout rate of 123I-BMIPP from the myocardium was faster in CHF patients than in controls (P<0.01). As the severity of the New York Heart Association (NYHA) functional class increased, the H/M ratio decreased and the washout rate increased. The washout rate of 123I-BMIPP was inversely correlated with left ventricular fractional shortening (R=-0.62, P<0.01). ACE inhibition with enalapril increased the H/M ratio on delayed images (P<0.05) and reduced the washout rate of 123I-BMIPP (P<0.05) in CHF patients. These data suggest that: (1) angiotensin II-mediated intracellular signalling activation may be a possible mechanism for the decreased myocardial uptake and enhanced washout of 123I-BMIPP in heart failure patients; and (2) the improvement in fatty acid metabolism by ACE inhibition may represent a new mechanism for the beneficial effect of this therapy in heart failure.

  20. ACE ID genotype affects blood creatine kinase response to eccentric exercise.

    PubMed

    Yamin, Chen; Amir, Offer; Sagiv, Moran; Attias, Eric; Meckel, Yoav; Eynon, Nir; Sagiv, Michael; Amir, Ruthie E

    2007-12-01

    Unaccustomed exercise may cause muscle breakdown with marked increase in serum creatine kinase (CK) activity. The skeletal muscle renin-angiotensin system (RAS) plays an important role in exercise metabolism and tissue injury. A functional insertion (I)/deletion (D) polymorphism in the angiotensin I-converting enzyme (ACE) gene (rs4646994) has been associated with ACE activity. We hypothesized that ACE ID genotype may contribute to the wide variability in individuals' CK response to a given exercise. Young individuals performed maximal eccentric contractions of the elbow flexor muscles. Pre- and postexercise CK activity was determined. ACE genotype was significantly associated with postexercise CK increase and peak CK activity. Individuals harboring one or more of the I allele had a greater increase and higher peak CK values than individuals with the DD genotype. This response was dose-dependent (mean +/- SE U/L: II, 8,882 +/- 2,362; ID, 4,454 +/- 1,105; DD, 2,937 +/- 753, ANOVA, P = 0.02; P = 0.009 for linear trend). Multivariate stepwise regression analysis, which included age, sex, body mass index, and genotype subtypes, revealed that ACE genotype was the most powerful independent determinant of peak CK activity (adjusted odds ratio 1.3, 95% confidence interval 1.03-1.64, P = 0.02). In conclusion, we indicate a positive association of the ACE ID genotype with CK response to strenuous exercise. We suggest that the II genotype imposes increased risk for developing muscle damage, whereas the DD genotype may have protective effects. These findings support the role of local RAS in the regulation of exertional muscle injury.

  1. Potential Expanded Indications for Neprilysin Inhibitors

    PubMed Central

    Riddell, Elizabeth; Vader, Justin M.

    2017-01-01

    Purpose of review The goal of this article is to review potential expanded indications for neprilysin inhibitors. This article reviews the rationale and design for ongoing and future trials of sacubitril/valsartan in cardiovascular and non-cardiovascular disease. Recent findings Randomized trial data are lacking for use of sacubitril/valsartan in acute heart failure and advanced heart failure. Mechanistic data from animal studies suggest a role for neprilysin inhibition in the treatment of post-myocardial infarction systolic dysfunction and heart failure with preserved ejection fraction. Beyond the cardiovascular system, renal and neurological function may be impacted by neprilysin inhibition. Forthcoming randomized trials will address the clinical impact of sacubitril/valsartan on these conditions. Summary Neprolysin inhibition with sacubitril/valsartan offers a new therapeutic strategy with a broad range of potential therapeutic actions. In PARADIGM-HF, the combination of neprolysin and RAAS inhibition was proven to be superior to enalapril for patients with stable NYHA class II–III heart failure and reduced left ventricular ejection fraction. Preliminary data suggests it may also have a role in other cardiovascular and non-cardiovascular disease. Several ongoing and planned studies will determine the extent of its benefit for these other indications. PMID:28281174

  2. Impact of Modified System of Objectified Judgement Analysis (SOJA) methodology on prescribing costs of ACE inhibitors.

    PubMed

    Alabbadi, Ibrahim; Crealey, Grainne; Scott, Michael; Baird, Simon; Trouton, Tom; Mairs, Jill; McElnay, James

    2006-01-01

    System of Objectified Judgement Analysis (SOJA) is a structured approach to the selection of drugs for formulary inclusion. How- ever, while SOJA is a very important advance in drug selection for formulary purposes, it is hospital based and can only be applied to one indication at a time. In SOJA, cost has been given a primary role in the selection process as it has been included as a selection criterion from the start. Cost may therefore drive the selection of a particular drug product at the expense of other basic criteria such as safety or efficacy. The aims of this study were to use a modified SOJA approach in the selection of ACE inhibitors (ACEIs) for use in a joint formulary that bridges primary and secondary care within a health board in Northern Ireland, and to investigate the potential impact of the joint formulary on prescribing costs of ACEIs in that health board. The modified SOJA approach involved four phases in sequence: an evidence-based pharmacotherapeutic evaluation of all available ACEI drug entities, a separate safety/risk assessment analysis of products containing agents that exceeded the pharmacotherapeutic threshold, a budget-impact analysis and, finally, the selection of product lines. A comprehensive literature review and expert panel judgement informed the selection of criteria (and their relative weighting) for the pharmacotherapeutic evaluation. The resultant criteria/scoring system was circulated (in questionnaire format) to prescribers and stakeholders for comment. Based on statistical analysis of the latter survey results, the final scoring system was developed. Drug entities that exceeded the evidence threshold were sequentially entered into the second and third phases of the process. Five drug entities (11 currently available in the UK) exceeded the evidence threshold and 22 of 26 submitted product lines containing these drug entities satisfied the safety/risk assessment criteria. Three product lines, each containing a different

  3. Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model

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

    Dhawale, Vaibhav Shrirang; Amara, Venkateswara Rao

    Angiotensin-I converting enzyme (ACE) is positively correlated to asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and is highly expressed in lungs. ACE2, the counteracting enzyme of ACE, was proven to be protective in pulmonary, cardiovascular diseases. In the present study we checked the effect of ACE2 activation in animal model of asthma. Asthma was induced in male wistar rats by sensitization and challenge with ovalbumin and then treated with ACE2 activator, diminazene aceturate (DIZE) for 2 weeks. 48 h after last allergen challenge, animals were anesthetized, blood, BALF, femoral bone marrow lavage were collected for leucocytemore » count; trachea for measuring airway responsiveness to carbachol; lungs and heart were isolated for histological studies and western blotting. In our animal model, the characteristic features of asthma such as altered airway responsiveness to carbachol, eosinophilia and neutrophilia were observed. Western blotting revealed the increased pulmonary expression of ACE1, IL-1β, IL-4, NF-κB, BCL2, p-AKT, p-p38 and decreased expression of ACE2 and IκB. DIZE treatment prevented these alterations. Intraalveolar interstitial thickening, inflammatory cell infiltration, interstitial fibrosis, oxidative stress and right ventricular hypertrophy in asthma control animals were also reversed by DIZE treatment. Activation of ACE2 by DIZE conferred protection against asthma as evident from biochemical, functional, histological and molecular parameters. To the best of our knowledge, we report for the first time that activation of ACE2 by DIZE prevents asthma progression by altering AKT, p38, NF-κB and other inflammatory markers. - Highlights: • Diminazene aceturate (DIZE), an ACE2 activator prevents ovalbumin-induced asthma. • DIZE acted by upregulating ACE2, downregulating ACE1, MAPKs, markers of inflammation, apoptosis. • DIZE reduced airway inflammation, fibrosis, right ventricular

  4. Egg ovotransferrin-derived ACE inhibitory peptide IRW increases ACE2 but decreases proinflammatory genes expression in mesenteric artery of spontaneously hypertensive rats.

    PubMed

    Majumder, Kaustav; Liang, Guanxiang; Chen, Yanhong; Guan, LeLuo; Davidge, Sandra T; Wu, Jianping

    2015-09-01

    Egg ovotransferrin-derived angiotensin converting enzyme (ACE) inhibitory peptide IRW was previously shown to reduce blood pressure in spontaneously hypertensive rats through reduced vascular inflammation and increased nitric oxide-mediated vasorelaxation. The main objective of the present study was to investigate the molecular mechanism of this peptide through transcriptome analysis by RNAseq technique. Total RNA was extracted from kidney and mesenteric arteries; the RNAseq libraries (from untreated and IRW-treated groups) were constructed and subjected to sequence using HiSeq 2000 system (Illumina) system. A total of 12 764 and 13 352 genes were detected in kidney and mesenteric arteries, respectively. The differentially expressed (DE) genes between untreated and IRW-treated groups were identified and the functional analysis through ingenuity pathway analysis revealed a greater role of DE genes identified from mesenteric arteries than that of kidney in modulating various cardiovascular functions. Subsequent qPCR analysis further confirmed that IRW significantly increased the expression of ACE-2, ABCB-1, IRF-8, and CDH-1 while significantly decreased the expression ICAM-1 and VCAM-1 in mesenteric arteries. Our research showed for the first time that ACE inhibitory peptide IRW could contribute to its antihypertensive activity through increased ACE2 and decreased proinflammatory genes expression. © 2015 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Zebrafish aussicht mutant embryos exhibit widespread overexpression of ace (fgf8) and coincident defects in CNS development.

    PubMed

    Heisenberg, C P; Brennan, C; Wilson, S W

    1999-05-01

    During the development of the zebrafish nervous system both noi, a zebrafish pax2 homolog, and ace, a zebrafish fgf8 homolog, are required for development of the midbrain and cerebellum. Here we describe a dominant mutation, aussicht (aus), in which the expression of noi and ace is upregulated. In aus mutant embryos, ace is upregulated at many sites in the embryo, while noi expression is only upregulated in regions of the forebrain and midbrain which also express ace. Subsequent to the alterations in noi and ace expression, aus mutants exhibit defects in the differentiation of the forebrain, midbrain and eyes. Within the forebrain, the formation of the anterior and postoptic commissures is delayed and the expression of markers within the pretectal area is reduced. Within the midbrain, En and wnt1 expression is expanded. In heterozygous aus embryos, there is ectopic outgrowth of neural retina in the temporal half of the eyes, whereas in putative homozygous aus embryos, the ventral retina is reduced and the pigmented retinal epithelium is expanded towards the midline. The observation that aus mutant embryos exhibit widespread upregulation of ace raised the possibility that aus might represent an allele of the ace gene itself. However, by crossing carriers for both aus and ace, we were able to generate homozygous ace mutant embryos that also exhibited the aus phenotype. This indicated that aus is not tightly linked to ace and is unlikely to be a mutation directly affecting the ace locus. However, increased Ace activity may underly many aspects of the aus phenotype and we show that the upregulation of noi in the forebrain of aus mutants is partially dependent upon functional Ace activity. Conversely, increased ace expression in the forebrain of aus mutants is not dependent upon functional Noi activity. We conclude that aus represents a mutation involving a locus normally required for the regulation of ace expression during embryogenesis.

  6. ACE genotype, phenotype and all-cause mortality in different cohorts of patients with type 1 diabetes.

    PubMed

    Færch, Louise H; Sejling, Anne-Sophie; Lajer, Maria; Tarnow, Lise; Thorsteinsson, Birger; Pedersen-Bjergaard, Ulrik

    2015-06-01

    Carrying the D-allele of the angiotensin-converting enzyme (ACE) I/D polymorphism and high ACE activity are prognostic factors in diabetic nephropathy, which predicts mortality in type 1 diabetes. We studied the association between the ACE D-allele and ACE phenotype and long-term all-cause mortality in three single-institution outpatient cohorts. Genotype-based analyses were performed in 269 patients from Hillerød Hospital (HIH) (follow-up: 12 years) and in 439 patients with diabetic nephropathy and 437 patients with persistent normoalbuminuria from the Steno Diabetes Center (SDC) (follow-up: 9.5 years). Patients not on renin-angiotensin system (RAS)-blocking treatment were included in analyses of serum ACE activity (HIH: n = 208) and plasma ACE concentration (SDC: n=269). In the HIH cohort, carrying a D-allele was associated with excess mortality (hazard ratio (HR) = 4.0 (95% confidence interval (CI) 1.0-16)), but not in the SDC cohorts. At HIH, serum ACE activity was associated with excess mortality (HR=1.04 (95% CI 1.0-1.1 per unit increase)), but in the SDC cohort plasma ACE concentration was not. In unselected patients with type 1 diabetes, carrying the ACE D-allele and high spontaneous serum ACE activity were associated with 12-year excess mortality. These findings could not be reproduced in two other cohorts with persistent normoalbuminuria or diabetic nephropathy. © The Author(s) 2013.

  7. ACE2 and vasoactive peptides: novel players in cardiovascular/renal remodeling and hypertension.

    PubMed

    Mendoza-Torres, Evelyn; Oyarzún, Alejandra; Mondaca-Ruff, David; Azocar, Andrés; Castro, Pablo F; Jalil, Jorge E; Chiong, Mario; Lavandero, Sergio; Ocaranza, María Paz

    2015-08-01

    The renin-angiotensin system (RAS) is a key component of cardiovascular physiology and homeostasis due to its influence on the regulation of electrolyte balance, blood pressure, vascular tone and cardiovascular remodeling. Deregulation of this system contributes significantly to the pathophysiology of cardiovascular and renal diseases. Numerous studies have generated new perspectives about a noncanonical and protective RAS pathway that counteracts the proliferative and hypertensive effects of the classical angiotensin-converting enzyme (ACE)/angiotensin (Ang) II/angiotensin type 1 receptor (AT1R) axis. The key components of this pathway are ACE2 and its products, Ang-(1-7) and Ang-(1-9). These two vasoactive peptides act through the Mas receptor (MasR) and AT2R, respectively. The ACE2/Ang-(1-7)/MasR and ACE2/Ang-(1-9)/AT2R axes have opposite effects to those of the ACE/Ang II/AT1R axis, such as decreased proliferation and cardiovascular remodeling, increased production of nitric oxide and vasodilation. A novel peptide from the noncanonical pathway, alamandine, was recently identified in rats, mice and humans. This heptapeptide is generated by catalytic action of ACE2 on Ang A or through a decarboxylation reaction on Ang-(1-7). Alamandine produces the same effects as Ang-(1-7), such as vasodilation and prevention of fibrosis, by interacting with Mas-related GPCR, member D (MrgD). In this article, we review the key roles of ACE2 and the vasoactive peptides Ang-(1-7), Ang-(1-9) and alamandine as counter-regulators of the ACE-Ang II axis as well as the biological properties that allow them to regulate blood pressure and cardiovascular and renal remodeling. © The Author(s), 2015.

  8. Communications, Navigation, and Surveillance Models in ACES: Design Implementation and Capabilities

    NASA Technical Reports Server (NTRS)

    Kubat, Greg; Vandrei, Don; Satapathy, Goutam; Kumar, Anil; Khanna, Manu

    2006-01-01

    Presentation objectives include: a) Overview of the ACES/CNS System Models Design and Integration; b) Configuration Capabilities available for Models and Simulations using ACES with CNS Modeling; c) Descriptions of recently added, Enhanced CNS Simulation Capabilities; and d) General Concepts Ideas that Utilize CNS Modeling to Enhance Concept Evaluations.

  9. SIGACE Code for Generating High-Temperature ACE Files; Validation and Benchmarking

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

    Sharma, Amit R.; Ganesan, S.; Trkov, A.

    2005-05-24

    A code named SIGACE has been developed as a tool for MCNP users within the scope of a research contract awarded by the Nuclear Data Section of the International Atomic Energy Agency (IAEA) (Ref: 302-F4-IND-11566 B5-IND-29641). A new recipe has been evolved for generating high-temperature ACE files for use with the MCNP code. Under this scheme the low-temperature ACE file is first converted to an ENDF formatted file using the ACELST code and then Doppler broadened, essentially limited to the data in the resolved resonance region, to any desired higher temperature using SIGMA1. The SIGACE code then generates a high-temperaturemore » ACE file for use with the MCNP code. A thinning routine has also been introduced in the SIGACE code for reducing the size of the ACE files. The SIGACE code and the recipe for generating ACE files at higher temperatures has been applied to the SEFOR fast reactor benchmark problem (sodium-cooled fast reactor benchmark described in ENDF-202/BNL-19302, 1974 document). The calculated Doppler coefficient is in good agreement with the experimental value. A similar calculation using ACE files generated directly with the NJOY system also agrees with our SIGACE computed results. The SIGACE code and the recipe is further applied to study the numerical benchmark configuration of selected idealized PWR pin cell configurations with five different fuel enrichments as reported by Mosteller and Eisenhart. The SIGACE code that has been tested with several FENDL/MC files will be available, free of cost, upon request, from the Nuclear Data Section of the IAEA.« less

  10. ACE3 Draft Indicators: Special Features

    EPA Pesticide Factsheets

    The page information was provided by EPA in conjunction with the opportunity for public comment on the draft indicators for ACE3, which ran from March 8 – April 21, 2011. The public comment period is now closed.

  11. MSCs with ACE II gene affect apoptosis pathway of acute lung injury induced by bleomycin.

    PubMed

    Zhang, Xiaomiao; Gao, Fengying; Li, Qian; Dong, Zhixia; Sun, Bo; Hou, Lili; Li, Zhuozhe; Liu, Zhenwei

    2015-02-01

    The aim of this study was to evaluate the effect and related mechanisms of Mesenchymal stem cells (MSCs) and Angiotensin converting enzyme II (ACE II) on acute lung injury (ALI). MSCs were separated from umbilical cord cells, and the changes of phenotype before and after ACE II silence were observed using Flow Cytometer. ALI model was induced by 10 mg/mL bleomycin in 60 Balb/c mice, and the rest 8 mice were regarded as the baseline group. The mice were randomly divided into four groups (n = 15): control, ACE II, stem, and stem + ACE II. The apoptotic index (AI) was calculated using TUNEL, and the detection of protein and mRNA of Bax, Bak and p53, Bcl-2, Grp78, CHOP and Caspase 12 were used by western-blot and RT-PCR, respectively. The umbilical cord cells differentiated into stable MSCs about 14 days, and ACE II transfection reached a peak at the 5th day after transfection. ACE II silence did not affect the phenotype of MSCs. All the proteins and mRNAs expression except Bcl-2 in the stem and stem + ACE II were significantly lower than those in control from 8 h (p < 0.05, p < 0.01), while Bcl-2 exhibited an opposite trend. Stem + ACE II performed a better effect than single stem in most indexes, including AI (p < 0.05, p < 0.01). The co-administration of MSCs and ACE II can significantly suppress apoptosis in ALI mice, and may be an effective clinical treatment for ALI.

  12. United States Air Force in Southeast Asia 1965-1973. Aces and Aerial Victories

    DTIC Science & Technology

    1976-01-01

    UNITED STATES IN SOUTHEAST ACES and AERIAL VICTORIES The United States Air Force in SoutheastAsia 1965*19?3 by R Frank Fuirefl William H...TYPE 3. DATES COVERED 00-00-1976 to 00-00-1976 4. TITLE AND SUBTITLE United States Air Force in Southeast Asia 1965-1973. Aces and Aerial... aces and aerial victories, 1965-1973. Includes index and glossary. 1. Vietnamese Conflict, 1961-1975-Aerial operations, American. 2. Viet- namese

  13. Advanced Crew Escape Suits (ACES): Particle Impact Test

    NASA Technical Reports Server (NTRS)

    Rosales, Keisa R.; Stoltzfus, Joel M.

    2009-01-01

    NASA Johnson Space Center (JSC) requested NASA JSC White Sands Test Facility to assist in determining the effects of impaired anodization on aluminum parts in advanced crew escape suits (ACES). Initial investigation indicated poor anodization could lead to an increased risk of particle impact ignition, and a lack of data was prevalent for particle impact of bare (unanodized) aluminum; therefore, particle impact tests were performed. A total of 179 subsonic and 60 supersonic tests were performed with no ignition of the aluminum targets. Based on the resulting test data, WSTF found no increased particle impact hazard was present in the ACES equipment.

  14. ACE-FTS on SCISAT: 10th year on-orbit anniversary

    NASA Astrophysics Data System (ADS)

    Lachance, Richard L.; Buijs, Henry L.; Soucy, Marc-André

    2013-09-01

    The Atmospheric Chemistry Experiment (ACE) is a mission on-board the Canadian Space Agency's (CSA) SCISAT-1. ACE is composed of a suite of instruments consisting of an infrared Fourier Transform Spectrometer (FTS) coupled with an auxiliary imager monitoring aerosols based on the extinction of solar radiation using two filtered detectors (visible and near infrared). A suntracker is also included to provide fine pointing during occultation. A second instrument, MAESTRO, is a spectrophotometer covering the near ultra-violet to the near infrared. In combination, the instrument payload covers the spectral range from 0.25 to 13.3 μm. The ACE mission came about from a need to better understand the chemical and dynamical processes that control the distribution of ozone in the upper troposphere and stratosphere, with particular emphasis on the Arctic region. Measurement of the vertical distribution of molecular species in these portions of the atmosphere permits elucidation of the key chemical and dynamical processes. The ACE-FTS measures the vertical distributions of trace gases as well as polar stratospheric clouds, aerosols, and temperature by a solar occultation technique from low earth orbit. By measuring solar radiation at high spectral resolution as it passes through different layers of the atmosphere, the absorption thus measured provides information on vertical profiles of atmospheric constituents, temperature, and pressure. Detailed and sensitive vertical distribution of trace gases help to better understand the chemical processes not only for ozone formation and destruction but also for other dynamic processes in the atmosphere. The ACE/SCISAT-1 satellite was successfully launched by NASA on August 12, 2003, and has been successfully operating since, now celebrating its 10th year on-orbit anniversary. This paper presents a summary of the heritage and development history of the ACE-FTS instrument. Design challenges and solutions are related. The actual on

  15. The Role of Plasminogen Activator Inhibitor-1 and Angiotensin-Converting Enzyme Gene Polymorphisms in Bronchopulmonary Dysplasia

    PubMed Central

    Atac, Fatma Belgin; Ozkiraz, Servet; Dilmen, Ugur; Gulcan, Hande; Tarcan, Aylin; Ozbek, Namik

    2010-01-01

    Background: Bronchopulmonary dysplasia (BPD) is a multifactorial disease of preterm infants that is characterized by airway injury, inflammation, and parencymal remodeling. Activation of the coagulation cascade leads to intraalveolar fibrin deposition in many inflammatory pulmonary disorders. Increased fibrin formation or decreased fibrinolysis may cause extravascular fibrin deposition. Extravascular fibrin deposits in septae and alveoli due to the altered fibrin turnover are the pathological hallmarks of BPD, which strongly indicate the importance of the imbalance in the competing activities of coagulation and fibrinolysis. Objective: We investigated the predictive value of variations in plasminogen activator inhibitor-1 (PAI-1) and angiotensin-converting enzyme (ACE) genes as molecular determinants for BPD in neonates. Methods: The study group comprised 98 preterm infants with BPD and a control group including 94 preterm infants without BPD. Restriction fragment size analyses were performed by visualizing digested polymerase chain reaction products for ACE and PAI-1 genotypes. Results: No significant associations were found between ACE, PAI-1 gene polymorphisms, and BPD phenotype in our population. Conclusions: The two gene polymorphisms (PAI-1 and ACE) had no role in the development of BPD in our study. Further studies with other genes are required for the identification of molecular predisposing factors for BPD that may help in the development of new treatments. PMID:20818980

  16. Advanced Colloids Experiment (ACE-T1)

    NASA Technical Reports Server (NTRS)

    Meyer, William V.; Sicker, Ron; Brown, Dan; Eustace, John

    2015-01-01

    Increment 45 - 46 Science Symposium presentation of Advanced Colloids Experiment (ACE-T1) to RPO. The purpose of this event is for Principal Investigators to present their science objectives, testing approach, and measurement methods to agency scientists, managers, and other investigators.

  17. Advanced Colloids Experiment (ACE-H-2)

    NASA Technical Reports Server (NTRS)

    Meyer, William V.; Sicker, Ron; Chmiel, Alan J.; Eustace, John; LaBarbera, Melissa

    2015-01-01

    Increment 43 - 44 Science Symposium presentation of Advanced Colloids Experiment (ACE-H-2) to RPO. The purpose of this event is for Principal Investigators to present their science objectives, testing approach, and measurement methods to agency scientists, managers, and other investigators.

  18. Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced Upper Airway Angioedema.

    PubMed

    Sinert, Richard; Levy, Phillip; Bernstein, Jonathan A; Body, Richard; Sivilotti, Marco L A; Moellman, Joseph; Schranz, Jennifer; Baptista, Jovanna; Kimura, Alan; Nothaft, Wolfram

    Upper airway angioedema is a rare, unpredictable, and at times life-threatening adverse effect of angiotensin-converting enzyme inhibitors (ACE-Is) with no existing effective pharmacologic treatment. Icatibant is a bradykinin B2 receptor antagonist that may be beneficial in patients with ACE-I-induced angioedema. We aimed to evaluate the efficacy of icatibant in subjects with ACE-I-induced angioedema. At 31 centers in 4 countries, adults on ACE-Is who presented within 12 hours of the onset of at least moderately severe angioedema were randomized 1:1 to icatibant 30 mg or placebo administered subcutaneously. The primary efficacy end point was time to meeting discharge criteria after study drug administration, based on the severity of airway symptoms assessed hourly by a blinded physician using clinical ratings across 4 domains. A total of 121 subjects were randomized (icatibant, n = 61; placebo, n = 60); 118 received treatment a median of 7.8 hours from symptom onset. We observed no difference in time to meeting discharge criteria between groups (median, 4.0 hours in each group; P = .63). There also was no difference in time to onset of symptom relief (median, icatibant, 2.0 hours; placebo, 1.6 hours; P = .57) or any other secondary end point. Similar findings were noted in prespecified and post hoc subgroup analyses stratified by symptom severity, time interval to treatment, age, and other clinical covariates. No new safety signals were detected. Icatibant was no more efficacious than placebo in at least moderately severe ACE-I-induced angioedema of the upper airway. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Real-time Kp predictions from ACE real time solar wind

    NASA Astrophysics Data System (ADS)

    Detman, Thomas; Joselyn, Joann

    1999-06-01

    The Advanced Composition Explorer (ACE) spacecraft provides nearly continuous monitoring of solar wind plasma, magnetic fields, and energetic particles from the Sun-Earth L1 Lagrange point upstream of Earth in the solar wind. The Space Environment Center (SEC) in Boulder receives ACE telemetry from a group of international network of tracking stations. One-minute, and 1-hour averages of solar wind speed, density, temperature, and magnetic field components are posted on SEC's World Wide Web page within 3 to 5 minutes after they are measured. The ACE Real Time Solar Wind (RTSW) can be used to provide real-time warnings and short term forecasts of geomagnetic storms based on the (traditional) Kp index. Here, we use historical data to evaluate the performance of the first real-time Kp prediction algorithm to become operational.

  20. Effect of ACE-inhibition on coronary microvascular function and symptoms in normotensive women with microvascular angina: A randomized placebo-controlled trial

    PubMed Central

    Suhrs, Elena; Raft, Kristoffer Flintholm; Høst, Nis; Prescott, Eva

    2018-01-01

    Objective Studies have suggested a beneficial effect of angiotensin-converting enzyme (ACE) inhibition. To explore whether the ACE inhibitor ramipril has a direct effect on the microvasculature beyond the blood pressure (BP) lowering effect, we investigated whether ramipril improved coronary microvascular function in normotensive women with coronary microvascular dysfunction (CMD). Methods We included 63 normotensive women with angina, no epicardial stenosis>50% and CMD defined as a coronary flow velocity reserve (CFVR)<2.2 assessed by adenosine stress-echocardiography in a randomized double-blinded, superiority trial with 1:1 allocation to placebo or ramipril (maximum dose 10 mg depending on blood pressure) for 24±6 weeks. Primary outcome was CFVR. Secondary outcomes were left ventricular systolic and diastolic function and symptoms evaluated by Seattle Angina Questionnaire (clinicaltrials.gov, NCT02525081). Results Follow-up was available on 55 patients. BP remained unchanged during treatment in both groups. CFVR improved in both the ramipril (p = 0.004) and placebo group (p = 0.026) with no difference between groups (p = 0.63). Symptoms improved in both groups with no significant between-group differences. No changes were detected in parameters of systolic and diastolic function. No serious adverse reactions were reported. Conclusions In normotensive women with angina and CMD, treatment with ramipril had no significant effect on CFVR or symptoms compared with placebo. The effect of ACE inhibition previously reported may be mediated by blood pressure reduction. PMID:29883497

  1. ACES: An Enabling Technology for Next Generation Space Transportation

    NASA Astrophysics Data System (ADS)

    Crocker, Andrew M.; Wuerl, Adam M.; Andrews, Jason E.; Andrews, Dana G.

    2004-02-01

    Andrews Space has developed the ``Alchemist'' Air Collection and Enrichment System (ACES), a dual-mode propulsion system that enables safe, economical launch systems that take off and land horizontally. Alchemist generates liquid oxygen through separation of atmospheric air using the refrigeration capacity of liquid hydrogen. The key benefit of Alchemist is that it minimizes vehicle takeoff weight. All internal and NASA-funded activities have shown that ACES, previously proposed for hypersonic combined cycle RLVs, is a higher payoff, lower-risk technology if LOX generation is performed while the vehicle cruises subsonically. Andrews Space has developed the Alchemist concept from a small system study to viable Next Generation launch system technology, conducting not only feasibility studies but also related hardware tests, and it has planned a detailed risk reduction program which employs an experienced, proven contractor team. Andrews also has participated in preliminary studies of an evolvable Next Generation vehicle architecture-enabled by Alchemist ACES-which could meet civil, military, and commercial space requirements within two decades.

  2. Assessing Cost-Effectiveness in Obesity (ACE-Obesity): an overview of the ACE approach, economic methods and cost results

    PubMed Central

    2009-01-01

    Background The aim of the ACE-Obesity study was to determine the economic credentials of interventions which aim to prevent unhealthy weight gain in children and adolescents. We have reported elsewhere on the modelled effectiveness of 13 obesity prevention interventions in children. In this paper, we report on the cost results and associated methods together with the innovative approach to priority setting that underpins the ACE-Obesity study. Methods The Assessing Cost Effectiveness (ACE) approach combines technical rigour with 'due process' to facilitate evidence-based policy analysis. Technical rigour was achieved through use of standardised evaluation methods, a research team that assembles best available evidence and extensive uncertainty analysis. Cost estimates were based on pathway analysis, with resource usage estimated for the interventions and their 'current practice' comparator, as well as associated cost offsets. Due process was achieved through involvement of stakeholders, consensus decisions informed by briefing papers and 2nd stage filter analysis that captures broader factors that influence policy judgements in addition to cost-effectiveness results. The 2nd stage filters agreed by stakeholders were 'equity', 'strength of the evidence', 'feasibility of implementation', 'acceptability to stakeholders', 'sustainability' and 'potential for side-effects'. Results The intervention costs varied considerably, both in absolute terms (from cost saving [6 interventions] to in excess of AUD50m per annum) and when expressed as a 'cost per child' estimate (from ACE

  3. The Altus Cumulus Electrification Study (ACES): A UAV-Based Science Demonstration

    NASA Technical Reports Server (NTRS)

    Blakeslee, R. J.; Croskey, C. L.; Desch, M. D.; Farrell, W. M.; Goldberg, R. A.; Houser, J. G.; Kim, H. S.; Mach, D. M.; Mitchell, J. D.; Stoneburner, J. C.

    2003-01-01

    The Altus Cumulus Electrification Study (ACES) is an unmanned aerial vehicle (UAV)- based project that investigated thunderstorms in the vicinity of the Florida Everglades in August 2002. ACES was conducted to investigate storm electrical activity and its relationship to storm morphology, and to validate satellite-based lightning measurements. In addition, as part of the NASA sponsored UAV-based science demonstration program, this project provided a scientifically useful demonstration of the utility and promise of UAV platforms for Earth science and applications observations. ACES employed the Altus II aircraft, built by General Atomics - Aeronautical Systems, Inc. Key science objectives simultaneously addressed by ACES are to: (1) investigate lightning-storm relationships, (2) study storm electrical budgets, and provide Lightning Imaging Sensor validation. The ACES payload included electrical, magnetic, and optical sensors to remotely characterize the lightning activity and the electrical environment within and around thunderstorms. ACES contributed important electrical and optical measurements not available from other sources. Also, the high altitude vantage point of the UAV observing platform (up to 55,000 feet) provided cloud-top perspective. By taking advantage of its slow flight speed (70 to 100 knots), long endurance, and high altitude flight, the Altus was flown near, and when possible, over (but never into) thunderstorms for long periods of time that allowed investigations to be conducted over entire storm life cycles. An innovative real time weather system was used to identify and vector the aircraft to selected thunderstorms and safely fly around these storms, while, at the same time monitor the weather near our base of operations. In addition, concurrent ground-based observations that included radar (Miami and Key West WSRBD, NASA NPOL), satellite imagery, and lightning (NALDN and Los Alamos EDOT) enable the UAV measurements to be more completely

  4. PAPR reduction in FBMC using an ACE-based linear programming optimization

    NASA Astrophysics Data System (ADS)

    van der Neut, Nuan; Maharaj, Bodhaswar TJ; de Lange, Frederick; González, Gustavo J.; Gregorio, Fernando; Cousseau, Juan

    2014-12-01

    This paper presents four novel techniques for peak-to-average power ratio (PAPR) reduction in filter bank multicarrier (FBMC) modulation systems. The approach extends on current PAPR reduction active constellation extension (ACE) methods, as used in orthogonal frequency division multiplexing (OFDM), to an FBMC implementation as the main contribution. The four techniques introduced can be split up into two: linear programming optimization ACE-based techniques and smart gradient-project (SGP) ACE techniques. The linear programming (LP)-based techniques compensate for the symbol overlaps by utilizing a frame-based approach and provide a theoretical upper bound on achievable performance for the overlapping ACE techniques. The overlapping ACE techniques on the other hand can handle symbol by symbol processing. Furthermore, as a result of FBMC properties, the proposed techniques do not require side information transmission. The PAPR performance of the techniques is shown to match, or in some cases improve, on current PAPR techniques for FBMC. Initial analysis of the computational complexity of the SGP techniques indicates that the complexity issues with PAPR reduction in FBMC implementations can be addressed. The out-of-band interference introduced by the techniques is investigated. As a result, it is shown that the interference can be compensated for, whilst still maintaining decent PAPR performance. Additional results are also provided by means of a study of the PAPR reduction of the proposed techniques at a fixed clipping probability. The bit error rate (BER) degradation is investigated to ensure that the trade-off in terms of BER degradation is not too severe. As illustrated by exhaustive simulations, the SGP ACE-based technique proposed are ideal candidates for practical implementation in systems employing the low-complexity polyphase implementation of FBMC modulators. The methods are shown to offer significant PAPR reduction and increase the feasibility of FBMC as

  5. The two-component system GrvRS (EtaRS) regulates ace expression in Enterococcus faecalis OG1RF.

    PubMed

    Roh, Jung Hyeob; Singh, Kavindra V; La Rosa, Sabina Leanti; Cohen, Ana Luisa V; Murray, Barbara E

    2015-01-01

    Expression of ace (adhesin to collagen of Enterococcus faecalis), encoding a virulence factor in endocarditis and urinary tract infection models, has been shown to increase under certain conditions, such as in the presence of serum, bile salts, urine, and collagen and at 46 °C. However, the mechanism of ace/Ace regulation under different conditions is still unknown. In this study, we identified a two-component regulatory system GrvRS as the main regulator of ace expression under these stress conditions. Using Northern hybridization and β-galactosidase assays of an ace promoter-lacZ fusion, we found transcription of ace to be virtually absent in a grvR deletion mutant under the conditions that increase ace expression in wild-type OG1RF and in the complemented strain. Moreover, a grvR mutant revealed decreased collagen binding and biofilm formation as well as attenuation in a murine urinary tract infection model. Here we show that GrvR plays a major role in control of ace expression and E. faecalis virulence. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  6. Assessment of the relationship between ACE I/D gene polymorphism and renal allograft survival.

    PubMed

    Yang, Chun-Hua; Lu, Yi; Chen, Xue-Xia; Xian, Wen-Feng; Tu, Wei-Feng; Li, Hong-Yan

    2015-12-01

    The relationship between the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and renal allograft survival after renal transplantation from the published reports are still debatable. This study was performed to evaluate the relationship between the ACE I/D gene polymorphism and renal allograft survival after renal transplantation using meta-analysis. Eligible studies were identified from PubMed and Cochrane Library on 1 November 2014, and eligible studies were recruited and synthesized using a meta-analysis methodology. Twelve investigations were included in this meta-analysis for the assessment of the relationship between the ACE I/D gene polymorphism and renal allograft survival. In this meta-analysis, the ACE I/D gene polymorphism was not associated with renal allograft survival after renal transplantation for overall populations, Caucasians, Brazilians and Africans. Interestingly, the ACE D allele and DD genotype were associated with renal allograft survival after renal transplantation in the Asian population. ACE D allele and DD genotype were associated with renal allograft survival after renal transplantation in the Asian population. However, more studies should be performed to confirm this association. © The Author(s) 2015.

  7. Rationale and design of the comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial.

    PubMed

    Velazquez, Eric J; Morrow, David A; DeVore, Adam D; Ambrosy, Andrew P; Duffy, Carol I; McCague, Kevin; Hernandez, Adrian F; Rocha, Ricardo A; Braunwald, Eugene

    2018-04-01

    The objective is to assess the safety, tolerability, and efficacy of sacubitril/valsartan compared with enalapril in patients with heart failure (HF) with a reduced ejection fraction (EF) stabilized during hospitalization for acute decompensated HF. Sacubitril/valsartan, a first-in-class angiotensin receptor-neprilysin inhibitor, improves survival among ambulatory HF patients with a reduced EF. However, there is very limited experience with the in-hospital initiation of sacubitril/valsartan in patients who have been stabilized following hospitalization for acute decompensated HF. PIONEER-HF is a 12-week, prospective, multicenter, double-blind, randomized controlled trial enrolling a planned 882 patients at more than 100 participating sites in the United States. Medically stable patients >18 years of age with an EF <40% and an amino terminal-pro b-type natriuretic peptide >1600 pg/mL or b-type natriuretic peptide >400 pg/mL are eligible for participation no earlier than 24 hours and up to 10 days from initial presentation while still hospitalized. Patients are randomly assigned 1:1 to in-hospital initiation of sacubitril/valsartan titrated to 97/103 mg by mouth twice daily versus enalapril titrated to 10 mg by mouth twice daily for 8 weeks. All patients receive open-label treatment with sacubitril/valsartan for the remaining 4 weeks of the study. The primary efficacy end point is the time-averaged proportional change in amino terminal-pro b-type natriuretic peptide from baseline through weeks 4 and 8. Secondary and exploratory end points include serum and urinary biomarkers as well as clinical outcomes. Safety end points include the incidence of angioedema, hypotension, renal insufficiency, and hyperkalemia. The PIONEER-HF trial will inform clinical practice by providing evidence on the safety, tolerability, and efficacy of in-hospital initiation of sacubitril/valsartan among patients who have been stabilized following an admission for acute decompensated HF with a

  8. Associations of centrally acting ACE inhibitors with cognitive decline and survival in Alzheimer’s disease

    PubMed Central

    Fazal, Karim; Khondoker, Mizanur; Howard, Robert; Stewart, Robert

    2017-01-01

    Background Cognitive improvement has been reported in patients receiving centrally acting angiotensin-converting enzyme inhibitors (C-ACEIs). Aims To compare cognitive decline and survival after diagnosis of Alzheimer’s disease between people receiving C-ACEIs, non-centrally acting angiotensin-converting enzyme inhibitors (NC-ACEIs), and neither. Method Routine Mini-Mental State Examination (MMSE) scores were extracted in 5260 patients receiving acetylcholinesterase inhibitors and analysed against C-/NC-ACEI exposure at the time of Alzheimer’s disease diagnosis. Results In the 9 months after Alzheimer’s disease diagnosis, MMSE scores significantly increased by 0.72 and 0.19 points per year in patients on C-ACEIs and neither respectively, but deteriorated by 0.61 points per year in those on NC-ACEIs. There were no significant group differences in score trajectories from 9 to 36 months and no differences in survival. Conclusions In people with Alzheimer’s disease receiving acetylcholinesterase inhibitors, those also taking C-ACEIs had stronger initial improvement in cognitive function, but there was no evidence of longer-lasting influence on dementia progression. Declaration of interest R.S. has received research funding from Pfizer, Lundbeck, Roche, Janssen and GlaxoSmithKline. Copyright and usage © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license. PMID:28713585

  9. Exercise-induced changes in insulin action are associated with ACE gene polymorphisms in older adults.

    PubMed

    Dengel, Donald R; Brown, Michael D; Ferrell, Robert E; Reynolds, Thomas H; Supiano, Mark A

    2002-10-29

    We evaluated the association between insulin resistance and the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) gene polymorphism in a group of older hypertensive subjects (63 +/- 1 yr, n = 35) before and after a 6-mo aerobic exercise program (AEX). Insulin sensitivity index (S(I)), assessed by the frequently sampled intravenous glucose tolerance test, was significantly (P = 0.0001) increased following AEX. In addition, there was a significant (P = 0.001) interaction between AEX and ACE genotype. S(I) increased significantly (P < 0.05) more in those with the II (2.5 +/- 0.8 microU x 10(-4) x min(-1) x ml(-1)) ACE genotype compared with both the DD and ID (0.7 +/- 0.1 and 0.7 +/- 0.2 microU x 10(-4) x min(-1) x ml(-1), respectively) ACE genotypes. Similarly, there was a significant (P = 0.036) decrease in the acute insulin response to glucose (AIR(G)) and a significant (P = 0.05) interaction between AEX and ACE genotype. AIR(G) decreased significantly (P < 0.05) more in those with the II (-17.6 +/- 5.6 mU/ml) ACE genotype compared with both the DD and ID (-1.4 +/- 6.2 and -3.6 +/- 2.5 mU/ml) ACE genotypes. In conclusion, we demonstrated that those older hypertensives with the ACE II genotype have the greatest improvement in insulin action following AEX.

  10. The effect of peptidase inhibitors on bradykinin-induced bronchoconstriction in guinea-pigs in vivo.

    PubMed Central

    Ichinose, M.; Barnes, P. J.

    1990-01-01

    1. Bradykinin (BK) instilled directly into the airway lumen caused bronchoconstriction in anaesthetized, mechanically ventilated guinea-pigs in the presence of propranolol (1 mg kg-1 i.v.). The geometric mean dose of BK required to produce 100% increase in airway opening pressure (PD100) was 22.9 nmol (95% c.i. 11.7-44.6 nmol). 2. The dose-response curve for the effect of instilled BK was significantly shifted to the left by the angiotensin converting enzyme (ACE) inhibitor, captopril (5 and 50 nmol instillation, PD100 = 3.0, 95% c.i. 0.98-8.9, and 2.0 nmol, 95% c.i. 0.65-6.2 nmol, respectively). 3. The neutral endopeptidase (NEP) inhibitor, phosphoramidon (5 and 50 nmol instillation) also shifted the dose-response curve for the effect of instilled BK; the PD100 values = 2.2 (95% c.i. 0.40-11.7) and 1.8 nmol (95% c.i. 0.87-3.5 nmol), respectively. 4. After pretreatment with captopril (50 nmol) and phosphoramidon (50 nmol) in combination, the dose-response curve for the effect of instilled BK (PD100 = 1.1 nmol, 95% c.i. 0.37-3.2 nmol) was similar to that obtained in the presence of each inhibitor used alone. 5. The kinase I inhibitor, DL-2-mercaptomethyl-3-guanidinoethylthiopropionic acid (50 nmol instillation) failed to alter the dose-response curve to instilled BK (PD100 = 14.6 nmol, 95% c.i. 6.7-32.0 nmol). 6. These data suggest that both ACE and NEP degrade BK in the airway lumen, but that kininase I is not involved. PMID:2282470

  11. Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria.

    PubMed

    Riera, Marta; Anguiano, Lidia; Clotet, Sergi; Roca-Ho, Heleia; Rebull, Marta; Pascual, Julio; Soler, Maria Jose

    2016-03-15

    Circulating and renal activity of angiotensin-converting enzyme 2 (ACE2) is increased in non-obese diabetic (NOD) mice. Because paricalcitol has been reported to protect against diabetic nephropathy, we investigated the role of paricalcitol in modulating ACE2 in these mice. In addition, renal ADAM17, a metalloprotease implied in ACE2 shedding, was assessed. NOD female and non-diabetic control mice were studied for 21 days after diabetes onset and divided into various treatment groups. Diabetic animals received either vehicle; 0.4 or 0.8 μg/kg paricalcitol, aliskiren, or a combination of paricalcitol and aliskiren. We then studied the effect of paricalcitol on ACE2 expression in proximal tubular epithelial cells. Paricalcitol alone or in combination with aliskiren resulted in significantly reduced circulating ACE2 activity in NOD mice but there were no changes in urinary albumin excretion. Serum renin activity was significantly decreased in mice that received aliskiren but no effect was found when paricalcitol was used alone. Renal content of ADAM17 was significantly decreased in animals that received a high dose of paricalcitol. Renal and circulating oxidative stress (quantified by plasma H2O2 levels and immunolocalization of nitrotyrosine) were reduced in high-dose paricalcitol-treated mice compared with non-treated diabetic mice. In culture, paricalcitol incubation resulted in a significant increase in ACE2 expression compared with nontreated cells. In NOD mice with type 1 diabetes, paricalcitol modulates ACE2 activity, ADAM17, and oxidative stress renal content independently from the glycemic profile and urinary albumin excretion. In tubular cells, paricalcitol may modulate ACE2 by blocking its shedding. In the early stage of diabetic nephropathy, paricalcitol treatment counterbalances the effect of diabetes on circulating ACE2 activity. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard

  12. Correlations between ACE single nucleotide polymorphisms and prognosis of patients with septic shock.

    PubMed

    Dou, Xin-Man; Cheng, Hui-Juan; Meng, Ling; Zhou, Lin-Lin; Ke, Yi-Hong; Liu, Li-Ping; Li, Yu-Min

    2017-04-30

    The aim of the present study is to investigate association between septic shock (SS) and angiotensin I-converting enzyme ( ACE ) single nucleotide polymorphisms (SNPs). From October 2009 to December 2016, 238 SS patients and 242 healthy individuals were selected for our study. ACE activity was detected, ACE rs4291 and rs4646994 polymorphisms were detected using PCR-restriction fragment length polymorphism (PCR-RFLP). The Kaplan-Meier survival curve was employed to evaluate the association between ACE SNPs and patients' survival and univariate and multivariate analyses to estimate risk factors for SS. ACE activity in the case group was increased in comparison with the control group. Allele and genotype frequencies of rs4291 and rs4646994 were different between the case and control groups. The TT genotype frequency of the rs4291 polymorphisms and the DD genotype of the rs4646994 polymorphisms of the case group were higher than those in the control group. The AT and TT genotypes indicated a significant elevation of ACE activity than the AA genotype, while a significant decline was found in the DI and II genotypes in comparison with the DI genotype. Patients with TT or DD genotypes had increased fatality rate within 7 and 30 days when compared with those with non-TT or non-DD genotypes. Lower sepsis-related organ failure assessment (SOFA) scores, rs4291, serum ACE and rs4646994 were all considered as risky factors for SS patients. The study demonstrates that TT genotype of rs4291 or DD genotype of rs4646994 may be indicative of a higher risk of SS and a poorer prognosis in SS patients. © 2017 The Author(s).

  13. Tailoring health-related messages for young adults with adverse childhood experiences (ACEs).

    PubMed

    Karatekin, Canan; Ahluwalia, Rohini; Desir, Michelle

    2018-06-01

    The goal was to identify factors that might affect likelihood of seeking health-related interventions for young adults with adverse childhood experiences (ACEs). We tested whether ACEs were associated with (1) regulatory focus (tendency toward promoting good outcomes versus preventing bad outcomes), and (2) patient activation (the intention to take active charge of one's health). We further tested whether promotion and prevention and patient activation were associated with each other and with health. Students at a public university (N = 321) completed online questionnaires assessing ACEs, regulatory focus, patient activation, and health. Greater childhood adversity showed small but significant associations with being a less activated patient and being less focused on promoting good outcomes. In contrast, greater childhood adversity had a much stronger association with focusing on preventing negative outcomes. Students with a more significant mental health history were more likely to have been exposed to childhood adversity, to be less activated patients, and to focus more on prevention. Results suggest that using a prevention focus may be effective in health messages aimed to reach individuals with high levels of ACEs. Furthermore, individuals with high levels of ACEs may benefit from interventions aimed at increasing patient activation. Copyright © 2018 Elsevier Ltd. All rights reserved.

  14. The evolving landscape of RAAS inhibition: from ACE inhibitors to ARBs, to DRIs and beyond.

    PubMed

    Epstein, Benjamin J; Leonard, Paul T; Shah, Niren K

    2012-06-01

    Chronic renin-angiotensin-aldosterone system (RAAS) activation has far-reaching effects on cardiometabolic risk and is a substantial contributor to cardiovascular (CV) disease and renal dysfunction. The vascular effects of sustained RAAS activation are associated with hemodynamic imbalances, as well as inflammatory stimulation and prothrombotic processes that lead to fibrosis, endothelial dysfunction and cellular remodeling. RAAS inhibition therapies, which include the use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and more recently, direct renin inhibitors, have been used in clinical practice for more than 30 years. Our understanding of how these drugs work, alone and in combination, has contributed to an expanding landscape of treatment options and established RAAS inhibition as essential for reducing the risk of CV and renal disease. This perspective provides a historical overview of how RAAS inhibitors have evolved to their present-day status and will discuss recently discovered functions for components of this complicated and powerful regulatory system.

  15. The carboxypeptidase angiotensin converting enzyme (ACE) shapes the MHC class I peptide repertoire

    PubMed Central

    Shen, Xiao Z.; Billet, Sandrine; Lin, Chentao; Okwan-Duodu, Derick; Chen, Xu; Lukacher, Aron E.; Bernstein, Kenneth E.

    2011-01-01

    The surface presentation of peptides by major histocompatibility complex (MHC) class I molecules is critical to CD8+ T cell mediated adaptive immune responses. Aminopeptidases are implicated in the editing of peptides for MHC class I loading, but C-terminal editing is thought due to proteasome cleavage. By comparing genetically deficient, wild-type and over-expressing mice, we now identify the dipeptidase angiotensin-converting enzyme (ACE) as playing a physiologic role in peptide processing for MHC class I. ACE edits the C-termini of proteasome-produced class I peptides. The lack of ACE exposes novel antigens but also abrogates some self-antigens. ACE has major effects on surface MHC class I expression in a haplotype-dependent manner. We propose a revised model of MHC class I peptide processing by introducing carboxypeptidase activity. PMID:21964607

  16. The angiotensin converting enzyme inhibitor, captopril, prevents the hyperactivity and impulsivity of neurokinin-1 receptor gene 'knockout' mice: sex differences and implications for the treatment of attention deficit hyperactivity disorder.

    PubMed

    Porter, Ashley J; Pillidge, Katharine; Grabowska, Ewelina M; Stanford, S Clare

    2015-04-01

    Mice lacking functional neurokinin-1 receptors (NK1R-/-) display behavioural abnormalities resembling attention deficit hyperactivity disorder (ADHD): locomotor hyperactivity, impulsivity and inattentiveness. The preferred ligand for NK1R, substance P, is metabolised by angiotensin converting enzyme (ACE), which forms part of the brain renin angiotensin system (BRAS). In view of evidence that the BRAS modulates locomotor activity and cognitive performance, we tested the effects of drugs that target the BRAS on these behaviours in NK1R-/- and wildtype mice. We first tested the effects of the ACE inhibitor, captopril, on locomotor activity. Because there are well-established sex differences in both ADHD and ACE activity, we compared the effects of captopril in both male and female mice. Locomotor hyperactivity was evident in male NK1R-/- mice, only, and this was abolished by treatment with captopril. By contrast, male wildtypes and females of both genotypes were unaffected by ACE inhibition. We then investigated the effects of angiotensin AT1 (losartan) and AT2 (PD 123319) receptor antagonists on the locomotor activity of male NK1R-/- and wildtype mice. Both antagonists increased the locomotor activity of NK1R-/- mice, but neither affected the wildtypes. Finally, we tested the effects of captopril on the performance of male NK1R-/- and wildtype mice in the 5-choice serial reaction-time task (5-CSRTT) and found that ACE inhibition prevented the impulsivity of NK1R-/- mice. These results indicate that certain behaviours, disrupted in ADHD, are influenced by an interaction between the BRAS and NK1R, and suggest that ACE inhibitors could provide a novel treatment for this disorder. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  17. Beneficial role of D allele in controlling ACE levels: a study among Brahmins of north India.

    PubMed

    Kumari, Shobha; Sharma, Nidhi; Thakur, Sunil; Mondal, Prakash R; Saraswathy, Kallur N

    2016-06-01

    India being a country with vast diversity is expected to have different dietary and life style patterns which in turn may lead to population-specific environmental risk factors. Further, the interaction of these risk factors with the genetic makeup of population makes it either susceptible or resistant to cardiovascular disease. One such candidate gene is angiotensin converting enzyme (ACE) for various cardiovascular mechanisms. ACE is the key enzyme of the renin angiotensin aldosterone system pathway which maintains homeostasis blood pressure in the body and any variation in the levels is reported to be associated with various complex diseases. The DD genotype is found to increase ACE levels, which is associated with cardiovascular diseases and decrease in ACE levels are associated with kidney diseases. The aim of this study was to understand the distribution of ACE I/D polymorphism and ACE levels among Brahmins of National Capital Region (NCR) north India, with respect to age and sex ratio distribution. In this study, 136 subjects of which 50 males and 86 females, who were unrelated up to first cousin, aged 25 to70 years were studied. ACE gene was found to be polymorphic with high frequency of heterozygote (ID) followed by II and DD genotypes. The studied population was found to be in Hardy-Weinberg equilibrium with respect to ACE I/D polymorphism (P = 0.55). I allele frequency was found to be higher (0.560) than the D allele (0.44). The median level of ACE was found to be 65.96 ng/mL (48.12-86.24) which is towards lower side of the normal range. ACE levels were found to be increased among individual having either of the homozygotes that is II or DD and higher frequency of heterozygote (ID) is indicative of advantage in the population by maintaining lower ACE levels. The limitation of the present study is low sample size, however, the merit is that the subjects belonged to a Mendalian population with a common gene pool.

  18. Variation in the ACE, PPARGC1A and PPARA genes in Lithuanian football players.

    PubMed

    Gineviciene, Valentina; Jakaitiene, Audrone; Tubelis, Linas; Kucinskas, Vaidutis

    2014-01-01

    The aim of this study was to determine the impact of ACE (I/D), PPARGC1A (G/A) and PPARA (G/C) polymorphisms on footballers performance among 199 Lithuanian professional footballers and 167 sedentary, healthy men (controls). Genotyping was performed using polymerase chain reaction and restriction fragment length polymorphism methods on DNA from leucocytes. Results revealed that the angiotensin-1-coverting enzyme gene (ACE) genotype distribution was significantly different between total football players group (II 23.6%, ID 46.7% and DD 29.6%) and the controls (II 24.6%, ID 29.9% and DD 45.5%; P=0.002). Although investigating PPARGC1A (G/A) and PPARA (G/C) polymorphisms no significant results were obtained in the total football players group, however, significant differences were determined between forwards and controls [PPARGC1A: GG 54.6%, GA 29.5%, AA 15.9% vs. GG 49.7%, GA 44.3% and AA 6.0% (P = 0.044); PPARA: GG 52.3%, GC 40.9%, CC 6.8% vs. GG 72.4%, GC 24.6% and CC 3.0% (P = 0.034)]. In the whole cohort, the odds ratio of the genotype [ACE ID + PPARA GG] being a footballer was 1.69 (95% CI 1.04-2.74), and of [ACE ID + PPARGC1A GG] 1.93 (95% CI 1.10-3.37) and of [ACE II + PPARA GC] 2.83 (95% CI 1.02-7.91) compared to controls. It was revealed that ACE ID genotype together with PPARA GG and PPARGC1A GG as well as ACE II genotype with PPARA GC is probably the 'preferable genotype' for footballers. Summing up, the present study suggests that the ACE, PPARGC1A and PPARA polymorphisms genotypes are associated, separately and in combination, with Lithuanian footballers' performance.

  19. Identification of an ACE-Inhibitory Peptide from Walnut Protein and Its Evaluation of the Inhibitory Mechanism.

    PubMed

    Wang, Cong; Tu, Maolin; Wu, Di; Chen, Hui; Chen, Cheng; Wang, Zhenyu; Jiang, Lianzhou

    2018-04-11

    In the present study, a novel angiotensin I-converting enzyme inhibitory (ACE inhibitory) peptide, EPNGLLLPQY, derived from walnut seed storage protein, fragment residues 80-89, was identified by ultra-high performance liquid chromatography electrospray ionization quadrupole time of flight mass spectrometry (UPLC-ESI-Q-TOF-MS/MS) from walnut protein hydrolysate. The IC 50 value of the peptide was 233.178 μM, which was determined by the high performance liquid chromatography method by measuring the amount of hippuric acid (HA) generated from the ACE decomposition substrate (hippuryl-l-histidyl-l-leucine (HHL) to assess the ACE activity. Enzyme inhibitory kinetics of the peptide against ACE were also conducted, by which the inhibitory mechanism of ACE-inhibitory peptide was confirmed. Moreover, molecular docking was simulated by Discovery Studio 2017 R2 software to provide the potential mechanisms underlying the ACE-inhibitory activity of EPNGLLLPQY.

  20. Association of Angiotensin-Converting Enzyme (ACE) Gene Polymorphism with Inflammation and Cellular Cytotoxicity in Vitiligo Patients.

    PubMed

    Rashed, Laila; Abdel Hay, Rania; Mahmoud, Rania; Hasan, Nermeen; Zahra, Amr; Fayez, Salwa

    2015-01-01

    Vitiligo is a disorder with profound heterogeneity in its aetio-pathophysiology. Angiotensin converting enzyme (ACE) plays an important role in the physiology of the vasculature, blood pressure and inflammation. An insertion/deletion (I/D) polymorphism of the ACE gene was reported be associated with the development of vitiligo. Our aim was to evaluate the ACE I/D polymorphism in vitiligo patients and controls. Our second aim was to find a possible association between ACE gene polymorphism and inflammatory mediators (as interleukin (IL)-6) and/or cellular cytotoxicity induced by serum nitrite (as a breakdown product of the cytotoxic nitric oxide) in vitiligo patients. This case-control study included 74 vitiligo patients and 75 apparently healthy controls. The distribution of ACE gene I/D genotype was investigated using PCR. Serum ACE, IL-6 and nitrite were measured by colorimetric method, ELISA and Griess assay respectively. The ACE allele frequency was significantly different between vitiligo patients and healthy controls (P = 0.026). However there was no significant difference between the ACE genotyping frequency in both groups (P = 0.115). There were statistically significant higher VIDA score (P = 0.007), and serum IL-6 (P < 0.001) in patients with the DD genotype when compared to other genotypes. Serum nitrite in patients with the DD genotype was significantly higher (P = 0.007) when compared to patients with II genotype. Serum levels of ACE, IL-6 and nitrite in vitiligo patients were statistically significantly higher than those in controls. As a conclusion, ACE gene polymorphism might grant susceptibility to develop vitiligo. Serum IL-6 and nitrite levels might have an important role in the pathogenesis of vitiligo. Targeting these two factors might have an implication in the treatment of some resistant cases.