Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.23.15 (renin)
35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Perindopril is a new angiotensin converting enzyme (ACE) inhibitor which is activated after hydrolysis in vivo to a diacid (S9780). Oral administration of perindopril (1-16 mg) to groups of 6 healthy males led to a long lasting and dose-elated inhibition of plasma ACE and rises in plasma renin activity with no evidence of accumulation of drug or effect. At higher doses there was a modest fall in blood pressure. S9780 given intravenously in doses of 1,2 or 4 mg caused an immediate inhibition of plasma ACE. The concentration of S9780 in plasma which led to 50% inhibition of plasma ACE was 1.55 +/- 1.14 ng/ml (mean +/- S.D.). Clinical trials with 2-8 mg once daily in essential hypertension are currently in progress.
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PMID:Perindopril, a new angiotensin converting enzyme inhibitor--clinical pharmacological studies in healthy subjects. 303 95

Systemic vasoconstriction due to stimulation of the sympathetic and renin-angiotensin-aldosterone systems is a hallmark of heart failure and this is accompanied by impaired endothelium-dependent relaxations at the level of large arteries. This study investigated, in a rat model of heart failure, whether such an endothelial dysfunction also exists at the level of the resistance artery, and whether this is associated with morphologic changes, as well as the effects of chronic treatment with the angiotensin-converting enzyme inhibitor perindopril (2 mg/kg/day). After 12 months, arterial pressure, left ventricular (LV) end diastolic pressure (LVEDP), and LV dP/dt were measured in anesthetized rats. Responses to acetylcholine and nitroprusside were determined in isolated and perfused mesenteric artery segments (diameter: 280 +/- 15 microns). After fixation, vessel diameter, media cross-sectional area, and media collagen and elastin densities were measured by image analysis. After 12 months, untreated rats showed signs of heart failure, i.e., reduced LV dP/dt, and increased LVEDP, heart weight/body weight, LV cavity circumference, and myocardial collagen density. In mesenteric vessels the endothelium-dependent vasodilator response to acetylcholine was impaired, whereas the response to the nitric oxide donor nitroprusside was unaffected. Heart failure did not affect vascular morphological parameters. Perindopril decreased blood pressure and LVEDP without any modification of LV dP/dt, and prevented cardiac remodeling. At the vascular level, perindopril improved the response to acetylcholine and reduced media cross-sectional area and collagen density without affecting internal vessel diameter or elastin density. Thus, heart failure decreases endothelium-dependent vasodilator response to acetylcholine without modification of vessel structure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vascular and myocardial protective effects of converting enzyme inhibition in experimental heart failure. 748 84

Quantitative autoradiography was used to determine the density and distribution of beta 1- and beta 2-adrenoceptors in the atrioventricular (AV) conducting system and surrounding myocardium of spontaneously hypertensive rats (SHR) after chronic infusion of perindopril (1 mg/kg/day) for 14 days by osmotic mini-pumps. Systolic blood pressure (SBP) was measured for a period of 4 weeks (2 weeks before and 2 weeks during perindopril infusion) in control and treated animals. Animals infused with vehicle (water) had a mean SBP of 248 mm Hg (measured on day 29); animals treated with perindopril had lower SBP (121 mm Hg, day 29). Perindopril treatment also prevented development of cardiac hypertrophy in SHR. beta-Adrenoceptor densities were measured in the AV node, His bundle, left and right bundle branches (LB, BB), interventricular and interatrial septa (IVS, IAS), mitral valve (MV), right papillary muscle, left and right ventricles (LV, RV), left and right atria (LA, RA), and apex. Perindopril produced no significant change in beta-adrenoceptors in any cardiac region examined. The results suggest that under experimental conditions in which perindopril treatment prevented cardiac hypertrophy and decreased SBP, there was no significant interaction between the renin-angiotensin system (RAS) and beta-adrenoceptor system in rat heart.
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PMID:Beta-adrenoceptor subtypes in the atrioventricular conducting system and myocardium of spontaneously hypertensive rats: effects of angiotensin-converting enzyme inhibition by perindopril. 752 49

Cardiovascular drugs have varying effects on hemodynamic, metabolic, and hormonal responses to exercise. To evaluate the effects of the novel angiotensin-converting enzyme (ACE) inhibitor, perindopril on these exercise-related responses, we studied 9 healthy volunteers in a double-blind, randomized, placebo-controlled trial. After a week of perindopril 4 mg orally daily or placebo therapy, volunteers performed a treadmill effort test; the sequence was repeated after a 1-week washout period. Perindopril caused a significant reduction in mean resting systolic and diastolic blood pressure (SBP, DBP) without increasing resting heart rate (HR); 15-min post-exercise SBP was also significantly reduced. There were no significant differences between the perindopril and placebo effort tests with respect to metabolic indexes studied (serum K+, plasma glucose, plasma free fatty acids) or plasma hormonal concentrations measured (ACTH and cortisol, norepinephrine (NE) and epinephrine (EPI), glucagon and insulin, growth hormone and prolactin, renin activity). In the perindopril arm of the study, however, there were modest but significant increases in mean serum K+ before exercise to immediately after exercise (0.4 +/- 0.1 mM, p < 0.01) and mean plasma glucose from before exercise to 5 min (0.6 +/- 0.2 mM, p < 0.01) and 15 min (0.5 +/- 0.2 mM, p < 0.05) after exercise. These data show that perindopril does not impair the hormonal changes associated with exercise in healthy subjects but induces a more consistent increase in blood K+ and glucose concentrations.
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PMID:Perindopril and physiologic responses to exercise. 752 76

1. The pharmacokinetics of perindopril and perindoprilat and the hormonal and haemodynamic responses following a single oral dose were studied in 12 Chinese and 10 Caucasian healthy, normotensive volunteers on two occasions. Perindopril was given on the first occasion as a 4 mg dose and then after at least 10 days as a weight-adjusted dose of 4 mg/70 kg. Plasma was sampled for assay of perindopril, perindoprilat, plasma renin activity (PRA), aldosterone, angiotensin I (AI) and ACE activity. Urine was collected for perindopril and perindoprilat assay. A radioimmunoassay technique was used to measure the prodrug and its active metabolite. 2. The time to maximum concentration (tmax) for perindopril was shorter for the Chinese group after the 4 mg dose (median 0.5, range 0.5-1.5 h vs median 1.0, 0.5-1.5 h P < 0.05) and also tended to be shorter after the weight-adjusted dose (median 0.5, range 0.5-1.0 h vs median 1.0, range 0.5-3.0 h). Cmax and AUC tended to be higher after the 4 mg dose in the Chinese group who had a lower body weight than the Caucasians. 3. The tmax of perindoprilat tended to be shorter for both doses and there was a tendency towards a higher Cmax after the 4 mg dose in the Chinese group but there was no statistically significant difference between the two groups. 4. There were no differences in the levels of PRA, plasma AI, plasma aldosterone or the degree of ACE-inhibition for either dose in the two ethnic groups. 5. Blood pressure was measured at intervals up to 24 h post-dose in both the supine and standing positions. Perindopril reduced blood pressure acutely with respect to the pre-dose level with good tolerability in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of the pharmacokinetics and pharmacodynamics of oral doses of perindopril in normotensive Chinese and Caucasian volunteers. 764 Jan 41

The mechanism of the blood pressure-lowering action of chronic administration of angiotensin-converting enzyme (ACE) inhibitors is still controversial. We investigated the effects of the ACE inhibitors, captopril and perindopril, on the renin-angiotensin system (RAS) in plasma and tissues (adrenal gland and kidney) in the rat. Captopril or perindopril was infused intraperitoneally into rats via a mini-osmotic pump for 6 days at a rate of 0.5 or 0.25 mg/kg/hr, respectively. Perindopril markedly increased plasma renin concentration (PRC) from 12.7 +/- 1.1 to 867 +/- 59 ng Ang I/ml/hr and significantly inhibited plasma angiotensin II (Ang II) from 17.5 +/- 3.5 to 7.8 +/- 0.6 pg/ml and plasma ACE activity from 31.6 +/- 1.7 to 1.7 +/- 0.3 U/liter. Captopril also increased PRC from 12.1 +/- 2.1 to 147 +/- 17 ng Ang I/ml/hr. However, it did not inhibit plasma Ang II (20.6 +/- 1.9 vs 22.0 +/- 2.1 pg/ml, N.S.) and increased plasma ACE activity from 35.9 +/- 1.8 to 65.0 +/- 4.8 U/liter. Perindopril increased kidney renin from 625.3 +/- 84.6 to 2152.3 +/- 233.4 micrograms/g/hr, while captopril produced a modest but insignificant rise in kidney renin (708.0 +/- 107.1 vs 1083.3 +/- 155.5 micrograms Ang I/g/hr, N.S.). On the other hand, both captopril and perindopril decreased adrenal Ang II significantly (from 21.1 +/- 2.7 to 9.2 +/- 0.5 pg/capsule and from 15.5 +/- 2.9 to 2.0 +/- 0.6 pg/capsule, respectively). Adrenal renin was not altered by either treatment. In spite of no inhibition of plasma Ang II, the pressor response to intravenous Ang I was still suppressed after captopril treatment. Both captopril and perindopril lowered the blood pressure of the rats significantly. Our results support the hypothesis that inhibition of tissue RAS is important for the hypotensive action of ACE inhibition.
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PMID:Role of the tissue renin-angiotensin system in the action of angiotensin-converting enzyme inhibitors. 770 Aug 88

We examined the dose-related effects of angiotensin-converting enzyme inhibitors on circulating and tissue levels of angiotensin and bradykinin peptides by administering perindopril or lisinopril to rats in drinking water for 7 days. A reduction in the ratio of plasma angiotensin II (Ang II) to Ang I was seen for 0.006 mg/kg per day perindopril, with an increase in plasma renin and Ang I at 0.017 mg/kg per day. Plasma Ang II levels did not decrease until 1.4 mg/kg per day perindopril, at which dose plasma Ang I levels reached a plateau of an approximate 25-fold increase. The effects of perindopril on Ang II and Ang I levels in heart, lung, aorta, and brown adipose tissue were parallel to those observed for plasma. By contrast, renal Ang I levels did not increase, and renal Ang II levels decreased by 40% at 0.017 mg/kg per day, the same threshold seen for the increase in plasma renin. Perindopril increased circulating bradykinin-(1-9) levels approximately eightfold, with a threshold dose of 0.052 mg/kg per day, and increased bradykinin-(1-9) levels in kidney, heart, and lung in parallel with the changes observed for plasma. By contrast, aortic and brown adipose tissue bradykinin-(1-9) and bradykinin-(1-7) levels increased severalfold for perindopril doses as low as 0.006 mg/kg per day. Lisinopril also increased aortic bradykinin-(1-9) and bradykinin-(1-7) levels at doses below the threshold for the decrease in the ratio of Ang II to Ang I. These data indicate that renal Ang II levels and vascular bradykinin-(1-9) levels respond to low doses of converting enzyme inhibitor and may be important mediators of the effects of these compounds. The parallel increases in bradykinin-(1-9) and bradykinin-(1-7) levels in aorta and brown adipose tissue, at inhibitor doses below the threshold for inhibition of Ang I conversion, may result from a mechanism different from inhibition of "classic" angiotensin-converting enzyme.
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PMID:Effects of converting enzyme inhibitors on angiotensin and bradykinin peptides. 814 13

When spontaneously hypertensive rats (SHR) treated at a young age with an inhibitor of angiotensin-converting enzyme (ACE) are withdrawn from treatment, their blood pressure (BP) remains below that of untreated rats. We examined the effects of ACE inhibitor treatment and its withdrawal on angiotensin-(1-7) [Ang-(1-7)], angiotensin II (Ang II) and angiotensin I (Ang I) in plasma, kidney, adrenal, heart, aorta, brown adipose tissue, lung, and brain of male SHR and normotensive Donryu rats. Rats were administered either vehicle or perindopril (3 mg/kg/day) from 6 to 10 weeks, from 6 to 20 weeks, and from 6 to 10 weeks, followed by perindopril withdrawal from 10 to 20 weeks. Angiotensin peptides and plasma levels of renin, angiotensinogen, ACE, and aldosterone were measured at 10 and 20 weeks of age. Perindopril reduced BP of both SHR and Donryu rats, although only SHR showed a reduction of BP of 19 mm Hg after perindopril withdrawal, associated with a reduction of 5% in heart weight/body weight ratio. Perindopril reduced the angiotensin II/angiotensin I ratio in all tissues by > 50%, with strain- and tissue-specific differences in the effects of perindopril on the levels of individual angiotensin peptides. None of the changes in Ang II levels persisted after perindopril withdrawal. In contrast to those of Donryu rats, plasma angiotensinogen levels of perindopril-withdrawn SHR were 14% lower than those of vehicle-treated SHR (p = 0.0356). Although the lower BP of perindopril-withdrawn SHR was not associated with an alteration in Ang II levels, the suppressed plasma angiotensinogen levels may have contributed to the lower BP of these rats. Alternatively, another action of perindopril, such as a change in cardiovascular structure, may have been responsible for the reduced BP of perindopril-withdrawn SHR.
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PMID:Converting enzyme inhibition and its withdrawal in spontaneously hypertensive rats. 858 85

In uninephrectomized rats on 1% NaCl solution to drink, aldosterone (0.75 micrograms/h subcutaneously for 8 weeks) raises blood pressure and causes marked interstitial and perivascular cardiac fibrosis, effects not seen in animals on a low salt intake. In extending these initial findings, we have shown that cardiac fibrosis (i) is not reversed by correction of mineralocorticoid-induced hypokalemia; (ii) appears not to involve the plasma or tissue renin-angiotensin systems, as fibrosis is largely unaffected by concurrent administration of Losartan or Perindopril; (iii) is independent of cardiac hypertrophy, in that it is equally seen in right and left ventricles, and in rats rendered hypertensive without cardiac hypertrophy by the administration of 9 alpha-fluorocortisol; (iv) is independent of elevated blood pressure, in that it is found in normotensive animals infused peripherally with aldosterone and intracerebroventricularly with the mineralocorticoid receptor (MR) antagonist RU28318; (v) is via classical MR, in that it is blocked by concurrent administration of the MR antagonist potassium canrenoate; and (vi) may or may not be a direct cardiac effect, inasmuch as data for in vivo effects on collagen formation by cardiac fibroblasts are conflicting. Although there is a high probability that the action of aldosterone to cause cardiac fibrosis in this experimental model is an effect via non-epithelial MR, the locus of aldosterone action remains to be established, as do the molecular mechanisms linking MR occupancy by aldosterone and collagen deposition. In addition, and in particular, the mechanisms underlying the crucial contribution of high salt intake in this model of mineralocorticoid excess await exploration.
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PMID:Mineralocorticoids, salt, hypertension: effects on the heart. 873 7

To assess the role of the renin-angiotensin system (RAS) in the renal alterations of the lyon hypertensive (LH) rat, the renal function of LH rats and of their normotensive (LN) controls was studied at different pressure levels after an early and chronic blockade of the RAS by perindopril (3 mg.kg-1.day-1 orally from 3 to 15 wk of age) and after an acute infusion of angiotensin II (ANG II, 10 or 50 ng.kg-1.min-1). Over the range of renal perfusion pressures studied (115-165 mmHg), control LH differed from LN rats by an increased preglomerular vasoconstriction and a blunted pressure-natriuresis curve. Perindopril fully prevented the development of hypertension in LH rats, suppressed their preglomerular vasoconstriction, and markedly improved their pressure-natriuresis. In perindopril-treated LH, ANG II produced a greater reduction in renal blood flow, glomerular filtration rate, and urinary sodium excretion that was not significantly modified by blockade of thromboxane A2-prostaglandin H2 receptors. These results indicate that the blood pressure level and the renal function of LH rats are closely dependent on an active RAS.
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PMID:In the Lyon hypertensive rat, renal function alterations are angiotensin II dependent. 877 Jan 33


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