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)

Experimental myocardial infarction is a model of cardiac overload due to amputation of part of the cardiac muscle. The development of cardiac failure depends on the size of the infarct and the time factor. This model of overload is associated with changes of the phenotype of the remaining healthy muscle and with peripheral vascular modifications partially dependent of the activation of pressor and/or deactivation of dilator systems. These changes are proportional to the size of the infarction at a given time after induction of the model. The degree of right ventricular hypertrophy and the decrease in blood pressure reflect the severity of infarction and the deterioration of the remaining myocardial function, affecting the haemodynamics both before and after the left ventricle. The increases in the 1/3 forms of isomyosins, the amount of subendocardial collagen, the biosynthesis, stocking and secretion of ANF are related to the infarct size and degree of overload. Similarly, the concentration of cyclic GMP is proportional to the infarct size. These parameters reflect ventricular overload, the increase of stress and energy deprivation of the remaining healthy muscle. The activation of peripheral pressor systems is also dependent on the infarct size reflects the effect of cardiac pump dysfunction on the kidney, liver, brain and endothelium. Large infarcts are associated with increased circulating renin and renal concentrations, with a decrease in angiotensinogen levels related to its consumption by the renin and to reduced hepatic synthesis and also with increased secretion and biosynthesis of vasopressin by the hypothalamus. In this model, Perindopril is beneficial by decreasing the cardiac load. It reduces the blood pressure, causes regression of bi-auricular and right ventricular hypertrophy. Changes in myosin isoenzyme configuration regress and subendocardial fibrosis and ANF concentrations are normalised. The effects of ACE inhibitors in this context, though very beneficial, are limited by the impossibility of normalising cardiac load and stress when the initial amputation of cardiac contractile mass exceeds 40%.
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PMID:[Experimental myocardial infarction in the rat. Effect of perindopril]. 166 27

The acute systemic and regional hemodynamic responses to a single oral dose (4 mg) of the angiotensin converting enzyme inhibitor perindopril were investigated in 10 patients with severe congestive heart failure. Perindopril produced significant and long-lasting decreases in systemic vascular resistance (-18%), right atrial pressure (-60%), and mean pulmonary capillary wedge pressure (-28%), whereas it significantly increased cardiac index (+ 12%). Brachial (+ 130%, pulsed Doppler technique) and renal (+ 34%) blood flows were also significantly increased whereas hepatic blood flow remained unchanged. Brachial flow/cardiac output and renal flow/cardiac output ratios increased significantly from 0.8 to 1.6 and from 13.2 to 16.5, respectively. The maximal decreases in forearm and renal (but not in systemic) vascular resistances were correlated with the basal plasma norepinephrine concentrations but not plasma epinephrine concentrations or plasma renin activity. We conclude that in severe heart failure (a) perindopril considerably improves systemic hemodynamics and exerts an inhomogeneous vasodilating effect, resulting in a redistribution of flows toward the forearm and renal territories, (b) norepinephrine is a major determinant of the arteriolar tone in these two vascular beds, and (c) the pulsed Doppler is a particularly suitable method to non-invasively detect and assess hemodynamic improvements in heart failure patients.
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PMID:Systemic and regional hemodynamic effects of perindopril in congestive heart failure. 169 80

The role of the renin angiotensin system (RAS) during pregnancy is not fully understood but numerous studies point to its importance in the homoeostasis of the fetal blood pressure and in the physiology of the fetal kidney near term. The aim of this study was to investigate the tissue distribution of angiotensin-converting enzyme (ACE) in the pregnant rabbit and its fetus and to assess the effect of Perindopril (PIL) a new ACE inhibitor on maternal and fetal tissue ACE activity. On day 28 of gestation, animals of the experimental groups were gavage-fed with 1 mg PIL or 10 mg PIL. ACE activity was assayed in tissue homogenates and serum with a radio-enzymatic method using (Gly-1-14C)-hippuryl-L-histidyl-leucine as specific substrate. In the kidney of control pregnant rabbit, decreasing values of ACE were found with a concentration gradient from the cortex to the inner papilla. ACE values in lung were comparable to those seen in kidney cortex. A significant effect of PIL was found with a percentage of inhibition of ACE activity in the renal cortex above 74% after 1 mg PIL and 88% after 10 mg PIL. In the control group, ACE activity was predominant in lung of fetuses. After maternal administration of 1 mg PIL, ACE activity fell significantly in fetal serum, placenta and fetal lung, but not in fetal kidney. Ten mg PIL produced a further significant decrease in ACE activity in fetal organs and serum. Plasma renin activity (PRA) was significantly stimulated after PIL administration in both mothers and fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tissue distribution of angiotensin converting enzyme and its inhibition by perindopril in pregnant rabbit and fetus. 196 31

During the development of hypertension in young spontaneously hypertensive rats (SHR) vascular resistance is increased, particularly in the renal circulation, and, to a lesser extent, in the splanchnic bed. Treatment with angiotensin converting enzyme inhibitors in young SHR reverses the renovascular abnormalities more effectively than simple vasodilators, suggesting that the resistance changes may depend on angiotensin II. Perindopril treatment during the development of hypertension causes a reduction in blood pressure as a result of a fall in total peripheral resistance, which persists long after treatment is stopped. These long-term effects can be prevented by replacing angiotensin during perindopril treatment. Not all organs share the long-term resistance changes following perindopril treatment, which are most marked in the renal, splanchnic, and cerebral circulations. The heterogeneous patterns of regional vascular resistance during the development and after prevention of hypertension with angiotensin converting enzyme inhibitors in SHR suggest that local factors, for example, angiotensin II related to the tissue renin-angiotensin system or local adrenergic activity, may be important in the genesis of high blood pressure in this genetic model.
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PMID:Angiotensin converting enzyme inhibitors, regional vascular hemodynamics, and the development and prevention of experimental genetic hypertension. 204 11

The pharmacodynamic effects and acceptability of perindopril (4 mg daily) and hydrochlorothiazide (25 mg daily) given alone or in combination for 1 month were investigated in a double-blind, placebo controlled, parallel group study. The pharmacokinetics of perindopril and its active metabolite perindoprilat and the time course of angiotensin converting enzyme inhibition were studied for 72 h following the last dose of treatment in the two appropriate groups. Similar decreases in blood pressure were seen 24 h after the last dose of perindopril or hydrochlorothiazide (11/7 mm Hg supine) given alone at these doses. The effect of these drugs given together was additive on diastolic blood pressure and synergistic on systolic blood pressure (24.5/12.6 mm Hg supine) taking into account the placebo response. The significant increase in plasma renin activity produced by perindopril alone was potentiated by concurrent administration of hydrochlorothiazide. The formation of perindoprilat was slightly reduced in the group also receiving hydrochlorothiazide and there was a very small reduction in ACE inhibition in this group. Perindopril, whether given alone or in combination with hydrochlorothiazide, was well tolerated and produced no clinically significant change in routine haematology or serum biochemistry. The additive or synergistic effects of perindopril and hydrochlorothiazide on blood pressure must be due to their complementary physiological actions and not to a pharmacokinetic interaction.
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PMID:The effect of perindopril and hydrochlorothiazide alone and in combination on blood pressure and on the renin-angiotensin system in hypertensive subjects. 207 13

The effects of specific active immunization against renin were compared with those of chronic angiotensin converting enzyme (ACE) inhibition. Male spontaneously hypertensive rats (SHR) were immunized (SHR-I) (n = 10) against pure murine renin (four injections of 30 micrograms/kg s.c.) or received (SHR-P) (n = 11) a converting enzyme inhibitor (perindopril, 2 mg/kg/day per os for 4 weeks). Sham-immunized SHR (SHR-S) (n = 12) and normotensive Wistar-Kyoto (WKY-S) (n = 12) rats served as controls. At 15 weeks of age, 24-hour average blood pressure was obtained in freely moving rats using intra-aortic pressure recording with computer analysis. Antirenin immunization induced high circulating titers of antibodies, a fall in plasma renin activity (-95%), and urinary excretion of mineralocorticoids. Perindopril abolished the pressor response to angiotensin I, whereas plasma ACE was only partly (-56%) decreased. It also increased plasma renin activity and did not alter the urinary excretion of steroids. Both immunization and perindopril allowed the blood pressure of SHR to return to the level of WKY-S rats and reduced the left ventricular weight. These decreases were associated with an elevated sympathetic nervous system activity as indicated by increases in the urinary excretion of catecholamines and their metabolites. It is conclude that, apart from an unaltered steroid synthesis, most of the cardiovascular effects of chronic ACE inhibition are similar to those of antirenin immunization, thus indicating that blockade of the circulating and renal renin-angiotensin system accounts for most of the effects of ACE inhibitors.
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PMID:Antirenin immunization versus angiotensin converting enzyme inhibition in rats. 219 42

Perindopril is a non-sulphydryl, pro-drug, ACE inhibitor. Following oral dosing, peak concentrations of the active moiety, perindoprilat, are achieved after 2-3 hours and perindoprilat is barely detectable by 24 hours. In contrast, maximal ACE inhibition is observed 4-6 hours after oral dosing and substantial inhibition persists beyond 24 hours. Inhibition of ACE is dose-dependent over the range 1-16 mg perindopril orally, and is mirrored by elevation of plasma renin activity and falls in aldosterone concentrations. Blood pressure reductions have been confirmed in normotensive and hypertensive subjects with maximal effect 6-10 hours after dosing and adequate antihypertensive activity at 24 hours. Blood pressure reductions are greater in the elderly than in young subjects due to pharmacokinetic differences. Dose reduction is required in elderly subjects and those with renal impairment. The antihypertensive efficacy of perindopril 4-8 mg once daily, is comparable to that of atenolol 50-100 mg once daily, captopril 25-50 mg twice daily or a hydrochlorothiazide/amiloride combination. Reduction in heart failure severity has also been reported. Perindopril appears to be a safe and effective agent for use in hypertension.
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PMID:Clinical pharmacology of perindopril. 228 58

Perindopril is an orally active non-thiol angiotensin-converting enzyme (ACE) inhibitor that is hydrolysed by esterases to a biologically active diacid metabolite. Perindopril decreases plasma concentrations of angiotensin II, increases plasma renin activity and reduces systolic and diastolic blood pressure in patients with essential hypertension. Most data support the hypothesis that the beneficial haemodynamic effects of perindopril are caused by ACE inhibition and the consequent reduction in angiotensin II, which either directly or indirectly results in dilatation of peripheral vessels and reduced vascular resistance. The marked blood pressure reduction after perindopril administration in hypertensive patients has not been accompanied by significant changes in heart rate. Furthermore, the lack of reflex tachycardia does not appear to be related to a reduction in baroreceptor sensitivity.
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PMID:Vascular haemodynamic effects of perindopril in essential hypertension. 240 92

Perindopril is an orally active, non-thiol angiotensin-converting enzyme (ACE) inhibitor, which in doses of 4 to 8mg is effective in the control of essential hypertension. As monotherapy it is as effective as once-daily atenolol and possibly more effective than twice-daily captopril. A synergistic response has been noted when perindopril is combined with a thiazide diuretic. Maximal pharmacodynamic effects (ACE inhibition, increase in plasma renin activity and angiotensin I, reduction in aldosterone and angiotensin II and blood pressure) are seen 4 to 6 hours after dosing, with substantial effects still present at 24 hours. Perindopril is a prodrug which requires de-esterification to perindoprilat for useful ACE inhibition. Maximal plasma perindoprilat concentrations are reached 2 to 6 hours after oral administration of perindopril, and 70% of the active metabolite is cleared by the kidneys. The other major metabolite of perindopril is an inactive glucuronide. Ageing is associated with increased serum perindoprilat concentrations, which are probably caused by a combination of enhanced conversion to the active metabolite and diminished renal clearance. Compensated cirrhosis does not appear to have an independent effect. There is little published experience of the use of perindopril in patients with cardiac failure or other cardiac disease, but preliminary evidence would support the general value of this class of agent as adjunctive therapy.
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PMID:Perindopril. A review of its pharmacokinetics and clinical pharmacology. 240 93

The novel prodrug-converting-enzyme (CE) inhibitor perindopril (S9490-3) diacid was found to be as potent as ramipril (Hoe498) diacid and more potent than enalapril (MK421) diacid and captopril against rat plasma CE in vitro (IC50 values were 3 X 10(-9), 2 X 10(-9), 1 X 10(-8), and 6 X 10(-8) mol/L, respectively). Four-week oral treatment with perindopril (0.1, 1, 3, and 10 mg/kg/day) in spontaneously hypertensive rats (SHRSP) lowered blood pressure (BP) dose-dependently with a threshold dose of 0.1 mg/kg/day and normalization of BP following doses between 1-3 mg/kg/day. Plasma CE was inhibited, angiogensinogen lowered, plasma renin concentration (PRC) and angiotensin I (ANGI) increased, all dose-dependently. CE was also inhibited in kidney, aortic wall, heart, lung, hypophysis, and brain cortex. Upon drug withdrawal, the BP depressant effect outlasted the effects on the plasma renin-angiotensin system (RAS) by more than a week. Perindopril, ramipril (both 1 mg/kg/day), and enalapril (30 mg/kg/day) showed equal antihypertensive actions in SHRSP, although their effects on parameters of the RAS in plasma were different. Our data reveal perindopril to be a potent antihypertensive drug. The findings are consistent with the view that the antihypertensive actions of CE inhibitors cannot be directly related to inhibition of the RAS in the plasma. Local interference with the RAS in tissue appears to be an additional factor involved.
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PMID:Antihypertensive action of the converting enzyme inhibitor perindopril (S9490-3) in spontaneously hypertensive rats: comparison with enalapril (MK421) and ramipril (Hoe498). 242 65


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