Prolonged inhibition of local angiotensin-converting enzyme after single or repeated treatment with quinapril in spontaneously hypertensive rats.

Plasma and tissue angiotensin-converting enzyme (ACE) activities were measured in spontaneously hypertensive rats (SHR) after single or repeated oral (p.o.) treatment with a hypotensive dose (1 mg/kg) of quinapril and compared with those after administration of enalapril (1 mg/kg). The degree of ACE inhibition in response to quinapril varied in tissues; marked inhibition was observed in aorta, lung, and plasma by single treatment with quinapril, and inhibition in plasma and aorta caused by quinapril was more potent than that caused by enalapril. The prolonged ACE inhibition was observed in the aorta, a target organ, by repeated treatment with quinapril for 2 weeks. These results indicate that quinapril has a good pharmacokinetic profile, namely rapid absorption and easy penetration to the target organ. In addition, quinapril produced greater inhibition of cardiac ACE than did enalapril after either p.o. or intravenous (i.v.) administration, suggesting the beneficial effects of quinapril in treatment of congestive heart failure (CHF).     

Effects of SQ 14,225, an orally active inhibitor of angiotensin-converting enzyme on blood pressure, heart rate and plasma renin activity of conscious normotensive dogs.

Oral administration of SQ 14,225 (0.03--3 mg/kg) to conscious normotensive dogs caused inhibition of the pressor response to intravenously administered angiotensin I (AI), the duration of which was dose-dependent. All doses of 0.1 mg/kg or greater caused 85--95% inhibition 30 min after administration whereas 0.03 mg/kg produced only a 25% inhibition. Pressor responses to angiotensin II (AII) were not similarly inhibited. Blood pressure was moderately reduced in a dose-related manner and followed the same pattern as inhibition of the AI pressor responses. The maximum change occurred after 1.0 mg/kg with only a more rapid onset occurring after the 3.0 mg/kg dose. Heart rate was not appreciably changed. SQ 14,225 also increased plasma renin activity (PRA), the levels and duration of which were dose-related. These data indicate that SQ 14,225 is an orally effective, potent inhibitor of angiotensin I-converting enzyme (ACE) in dogs. It appears that in mongrel dogs, ACE inhibition results in a slight to moderate reduction in blood pressure and an increase in PRA.     

A pharmacodynamic study of SR 47436, a selective AT1 receptor antagonist, on blood pressure in conscious cynomolgus monkeys.

1. Conscious normotensive cynomolgus monkeys were chronically instrumented for the measurement of arterial blood pressure and heart rate to investigate the relationships between the plasma concentration, suppression of the pressor response to angiotensin II (AII), compensatory increase in plasma AII, and hypotensive effect obtained after a single oral dose of SR 47436, a potent and specific nonpeptide AT1 receptor antagonist. As blood sampling could influence the hypotensive effect of SR 47436 through activation of the renin angiotensin system (RAS), drug effects were studied in groups of animals with or without blood samplings. 2. SR 47436 at 10 mg kg-1 induced a hypotensive effect which was not greater following a second dose of 30 mg kg-1, indicating that a maximal hypotensive effect had already been obtained. 3. A single oral dose of SR 47436 (10 mg kg-1) caused a sustained hypotension and a marked inhibition of the AII-induced pressor response, lasting for up to 28 h. These effects of SR 47436 are consistent with good oral bioavailability and a slow elimination of the drug (t 1/2 approximately 20 h), and were accompanied by a sustained increase in plasma AII concentration. Taken together, both the hypotensive response and the compensatory increase in AII indicated that vascular and juxtaglomerular AII receptors were blocked. 4. Although a fair correlation between individual plasma drug concentrations and inhibition of AII-induced pressor response was observed, neither the hypotensive effect nor the compensatory increase in AII correlated with the plasma drug levels. 5. Basal arterial pressure and AII-induced pressor response were not affected by blood samplings. 6. These results suggest that SR 47436 is an effective and long lasting AT1 receptor antagonist with a potent hypotensive action in normotensive cynomolgus monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)     

Potassium homeostasis during angiotensin-converting enzyme inhibition with enalapril

The effect of angiotensin-converting enzyme (ACE) inhibition on renal and extrarenal potassium (K) regulation was examined. Six healthy men were studied in double-blinded crossover fashion on placebo or enalapril, 80 mg/day. On day 4, the subjects were given an intravenous infusion of KCl and on day 5 an oral dose of 10% NH4Cl. Treatment with enalapril decreased plasma aldosterone and increased plasma renin activity (PRA), epinephrine and norepinephrine, but did not affect serum glucose, plasma insulin or basal plasma K. Maximal increases in plasma K during K infusion or NH4Cl ingestion were similar during enalapril and placebo treatment. With enalapril treatment urinary K excretion was unchanged following K loading but moderately reduced following NH4Cl loading. We conclude that ACE inhibition does not acutely impair K homeostasis in men with normal renal function.     

Effects of perindopril on tissue angiotensin-converting enzyme activity demonstrated by quantitative in vitro autoradiography

Inhibition of plasma angiotensin II generation does not fully explain the chronic hypotensive effects of angiotensin-converting enzyme (ACE) inhibitors. Therefore, the pattern of tissue ACE inhibition in rats was studied after oral administration of perindopril, a new ACE inhibitor. Tissue ACE was measured by quantitative in vitro autoradiography using [125I]-351A as a radioligand and compared with plasma ACE and the pressor response to intravenous (i.v.) angiotensin I. Following oral perindopril (1 mg/kg), plasma ACE activity was acutely reduced, but recovered over 24 h. The peak concentration of plasma perindoprilic acid, the active diacid of perindopril, occurred at 1 h, and the drug was undetectable by 24 h. The pressor response to i.v. angiotensin I was inhibited by 95% at 4 h and had not fully recovered by 24 h. Four hours after oral administration of perindopril, ACE was markedly inhibited in the proximal tubules of the kidney (24% control), lung parenchyma (10%), and aortic wall (18%) (p less than 0.01). At 24 h, ACE in these tissues had only partially recovered (32-63%). ACE was also identified in vascular endothelium of organs, including the lung, kidney, and testis; in these sites, vascular ACE showed a pattern of inhibition similar to that of aortic ACE. In contrast, ACE in testicular seminiferous tubules was unaffected by perindopril. These results demonstrate a prolonged effect of ACE inhibitors on tissue ACE that may better explain the time course of these drugs than the changes in plasma ACE or plasma levels of the drug.     

Ceranapril (SQ 29,852), an orally active inhibitor of angiotensin converting enzyme (ACE).

Ceranapril (SQ 29,852) is a new inhibitor of angiotensin I (AI) converting enzyme (ACE) belonging to the hydroxylphosphonate class. The purpose of the present report is to present the in vivo pharmacology of ceranapril in conscious animal models. In conscious, normotensive rats, ceranapril administered i.v. (ED50 = 63 nmol/kg) or p.o. (ED50 = 530 nmol/kg) inhibited an AI pressor response with potency equal to that of captopril. However, in conscious dogs, ceranapril was a relatively poor inhibitor of the AI pressor response after both i.v. (ED50 = 300 nmol/kg) and p.o. (ED50 = 18 mumol/kg) administration; in monkeys ceranapril was a good inhibitor of the AI pressor response after i.v. (ED50 = 60 nmol/kg) but not p.o. (ED50 = 18 mumol/kg) administration. In rats, the duration of ceranapril's inhibition of an AI pressor response was longer than an equimolar dose of captopril. Similarly, in SHR, ceranapril's blood pressure lowering effect had a longer duration than that of captopril. Ceranapril's ACE inhibitory effects were longer lasting in anephric rats than in sham rats, suggesting a renal route of excretion for ceranapril. Ceranapril administration to conscious female dogs resulted in significant increases in renal plasma flow and GFR. In SHR, doses of 23 and 68 mumol/kg resulted in significant blood pressure lowering that lasted 24 h. Oral doses of 2.3, 6.8, 23, and 68 mumol/kg in two-kidney, one-clip hypertensive rats resulted in significant and dose-related falls in arterial pressure, which again persisted for 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of cimetidine on the pharmacokinetics and pharmacodynamics of enalapril in normal volunteers

The possible effects of cimetidine on the pharmacokinetics and pharmacodynamics of enalapril, a pro-drug requiring hepatic de-esterification to an active angiotensin-converting enzyme (ACE) inhibitor enalaprilat, were assessed in a randomized, crossover study. Cimetidine (400 mg) or placebo was administered orally every 12 h for 3 days and on the day of a single oral administration of enalapril maleate (10 mg) to seven healthy male subjects. Serum ACE, plasma renin activity (PRA), plasma aldosterone concentration (PAC), and alpha-human atrial natriuretic peptide (alpha-hANP) were measured before and 4 h after the enalapril dosing. There were no significant differences in any serum- and urine-derived kinetic parameters of enalapril and enalaprilat, nor in hemodynamics, PAC, or alpha-hANP between the two treatment trials. ACE decreased and PRA increased to a similar extent in the two trials. Serum enalaprilat concentration correlated significantly (p less than 0.001) with percentage of inhibition of ACE activity. The results suggest that the pharmacokinetics and pharmacodynamics of enalapril are unaffected by preadministration of cimetidine. Thus, cimetidine does not appear to alter hepatic esterase activity toward enalapril.     

Effects of an angiotensin-converting enzyme (ACE) inhibitor, SA446, on tissue ACE activity in normotensive, spontaneously hypertensive, and renal hypertensive rats

Effects of an angiotensin-converting enzyme (ACE) inhibitor, SA446, on the renin-angiotensin system, particularly on tissue ACE activity, were studied in Wistar-Kyoto normotensive rats (WKY), spontaneously hypertensive rats (SHR), and two-kidney, one-clip renal hypertensive rats (RHR) by repeated oral administration for 7 days. SA446 (45 mg/kg/day p.o.) inhibited ACE activity in the lung, brain, kidney, heart, and whole blood throughout the administration period in WKY, but showed a slight hypotensive action and no inhibition of aorta ACE activity. On the other hand, SA446 had an apparent hypotensive action at the same dose in SHR and inhibited ACE activity significantly in the aorta as well as the kidney and whole blood during the administration period. Furthermore, enzyme activity in the aorta, kidney, heart, and whole blood was also inhibited at a hypotensive dose of SA446 (10 mg/kg/day p.o.) in RHR. The inhibition in whole blood and kidney was almost complete, and the inhibition in the aorta was greater on day 7 than on day 1. The maximum decrease of blood pressure was correlated with the maximum inhibition in aorta ACE activity, but not in brain, lung, or heart ACE activity. In addition, a good positive correlation was observed between the basal blood pressure and the basal aorta ACE activity in WKY, SHR, and RHR, although there was no correlation in the brain, lung, kidney, heart, or whole blood. These results suggest that the antihypertensive action of SA446 by repeated administration may be due to inhibition of arterial ACE activity in addition to inhibition of plasma and kidney ACE activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intrarenal angiotensin converting enzyme inhibition in spontaneously hypertensive rats.

We examined the hypotensive effect of enalapril in relation to the local renin-angiotensin system of the kidney in spontaneously hypertensive rats (SHR). Oral administration of enalapril for 7 days decreased mean arterial blood pressure and renal tissue angiotensin II concentration without affecting plasma angiotensin II concentration in SHR. The enalapril treatment did not affect maximum binding of angiotensin II to renal tubules and glomeruli in SHR. In normotensive Wistar-Kyoto rats, no significant changes in mean arterial blood pressure, renal and plasma angiotensin levels were observed with enalapril treatment. Direct infusion of enalapril into the renal medullary interstitium decreased mean arterial blood pressure in association with the reduction of renal tissue angiotensin II concentration without changes in plasma angiotensin II concentration in SHR. These observations suggest that the inhibition of angiotensin conversion in the kidney is important for the hypotensive action of enalapril.     

A comparison of antihypertensive properties of captopril and enalapril after single and multiple oral administration in spontaneously hypertensive rats.

Oral dose of enalapril or captopril moderately reduced the blood pressure of the spontaneously hypertensive rats (SHR) but not those of normotensive rats. The single daily dose of captopril (30 mg/kg) produced antihypertensive response equivalent to enalapril (3 mg/kg). Chronic administration of these drugs for 2 weeks revealed that systolic blood pressure was reduced more by captopril than enalapril. We did not find differences in hypotensive activity between Enalapril IF and Renitec Merck as well as Captopril JZF Polfa and Capoten Squibb.     

Role of the alpha-adrenergic blocking effect in the acute hypotensive effect of beta-adrenergic blocking drugs with alpha-blocking activities in conscious SHR

Acute hypotensive effects and the mechanisms of three beta-adrenergic blocking drugs with alpha-blocking activity were studied in comparison with those of prazosin, propranolol and hydralazine in the conscious spontaneously hypertensive rat (SHR). Prazosin lowered the blood pressure dose-dependently and inhibited the pressor response to phenylephrine. Three beta-adrenergic blocking drugs with alpha-blocking activity, labetalol (30 mg/kg), arotinolol (100 mg/kg) and nipradilol (100 mg/kg) also lowered the blood pressure to the same extent as prazosin (0.3 mg/kg), but the inhibition of the pressor response to phenylephrine produced by them was disproportionately slight. Propranolol (100 mg/kg) did not lower the blood pressure. These results suggest that the acute hypotensive effects of three beta-adrenergic blocking drugs with alpha-blocking activity were attributable only partially to the alpha-adrenergic blocking effect; a mechanism or mechanisms other than the alpha-adrenergic blocking effect must be invoked to explain the acute hypotensive effect produced by lower doses of these drugs in the conscious SHR.     

Pharmacokinetics and pharmacodynamics of pentopril, a new angiotensin-converting-enzyme inhibitor in humans

In a single, ascending-dose tolerance study, nine healthy volunteers were given oral pentopril 50 to 750 mg (CGS 13945) in groups of three each. Disposition characteristics of pentopril and its active metabolite (CGS 13934) were determined using plasma concentration and urinary excretion data. The drug was absorbed rapidly following zero-order kinetics. The drug has an apparent volume of distribution of 0.83 L/kg and an oral clearance of about 0.79 L/hr/kg. Urinary excretions, calculated after 125- and 250-mg doses, showed a dose proportional urinary recovery of 21% (+/- 5%) for pentopril and 40% (+/- 5%) for CGS 13934. In the multiple-dose study of 125 mg orally q12h in six healthy subjects, the plasma concentrations for both drug and metabolite showed no appreciable accumulation of either compound, which was expected from their short pharmacokinetic half-lives (pentopril, less than 1 hr; CGS 13934, approximately 2 hr). In a separate pharmacodynamic study, drug and metabolite concentrations were evaluated against angiotensin-I (AI)-induced changes in blood pressure and plasma angiotensin-converting-enzyme (ACE) activity in healthy volunteers after single oral doses (range, 10-500 mg). The pharmacodynamic half-life for plasma ACE inhibition increased with the dose (10 mg, 1.5 hr; 500 mg, 9.8 hr). There was a close relationship between the plasma level of the metabolite and the inhibition of plasma ACE activity and AI-induced pressor response. A hyperbolic function adequately described the dependence of plasma ACE activity on plasma metabolite concentration with a concentration at half-maximal inhibition of 53 ng/mL.     

Acute and chronic effects of a novel dihydrobenzofuran analogue and enalapril on blood pressure and plasma and tissue angiotensin converting enzyme activity in the sodium deficient normotensive rat

1. Changes occurring in plasma and tissue angiotensin converting enzyme (ACE) activity have been examined in relation to blood pressure response following acute and chronic administration of N-[N-[[4-(2,3-dihydro-2-benzofuranyl)-1- (ethoxycarbonyl)]-butyl]-(s)-alanyl]-(s)-proline (BRL 36378) and enalapril in the sodium deficient normotensive rat. 2. Both BRL 36378 and enalapril produced a reduction in blood pressure which was evident at 2 and 24 h after acute administration, or at 24 h after chronic (21 days) administration. This was accompanied by inhibition of ACE activity in both plasma and tissues. 3. The magnitude of ACE inhibition was greater following enalapril administration than achieved after BRL 36378 treatment; this was reflected by the greater fall in blood pressure evoked by enalapril. 4. Removal of the respective ACE inhibitors revealed an apparent increase in total enzyme in the plasma of animals dosed chronically with BRL 36378 and enalapril. The onset of this increase in total enzyme was rapid, as it was apparent in plasma at 24 h after a single oral dose of BRL 36378 and enalapril. 5. The increase in total enzyme in plasma may be related to the degree of ACE inhibition, since the increase in total enzyme was of greater magnitude after 21 days treatment with enalapril than following corresponding dosing with BRL 36378. 6. No consistent effects on total enzyme were observed in tissues following acute and chronic administration with the ACE inhibitors. 7. Stimulation of drinking behaviour was observed throughout the periods of chronic (7 and 21 days) administration with both BRL 36378 and enalapril.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative hypotensive activity of REV 6207 and enalapril in the conscious furosemide-treated monkey

The cardiovascular effects of ascending doses (0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg i.v.) of two angiotensin l-converting enzyme (ACE) inhibitors, REV 6207 and enalapril, were assessed in conscious furosemide-treated (3 mg/kg s.c.) monkeys. Both ACE inhibitors produced a dose-related inhibition of the pressor response to angiotensin l (0.66 μ/kg i.v.) with concomitant decreases in mean arterial pressure and no change in heart rate. The calculated ED₅₀ values for REV 6207 (0.316 mg/kg) and enalapril (0.275 mg/kg) were similar and both abolished the pressor response to angiotensin l at a dose of 3 mg/kg. The results of the study show that REV 6207 is a potent nonsulfhydryl-containing ACE-inhibitor with blood-pressure-lowering activity comparable to enalapril in the conscious monkey with high renin activity.     

Effect of enalapril and quinapril on forearm vascular ACE in man

Objective: Different ACE inhibitors can be distinguished in vitro by their affinity for converting enzyme in vascular and other tissues. Quinapril appears to be amongst the more effective inhibitors of vascular tissue ACE in vitro. This study assesses the in vivo effect of single oral doses of quinapril and enalapril, in attenuating the vasoconstrictive action of angiotensin I (AI) (which we have previously shown depends on its conversion to angiotensin II (AII) by vascular ACE) in the forearm resistance vessels of man. Methods: The design was of randomized, open, placebo controlled, two way crossover type, Forearm blood flow (FABF) was measured simultaneously in both forearms by mercury in silastic strain gauge plethysmography. AI infusions were via a fine bore cannula in the left brachial artery with the right arm serving as a control. Results: Mean plasma ACE on placebo was 34.3 U · l⁻¹. Both quinapril and enalapril produced a similar degree of plasma ACE inhibition reducing concentrations to 2.8 U · l⁻¹ and 2.6 U · l⁻¹ respectively. Quinapril caused a significantly greater inhibition of AI induced vasoconstriction with a 30.0% reduction compared with 67.0% and 85.0% for enalapril and placebo respectively. Enalapril attenuated AI induced vasoconstriction to a greater degree than placebo but the difference was not significantly different. Conclusion: These results indicate that when quinapril and enalapril are administered as single 20 mg doses, each of which produces the same degree of plasma ACE inhibition and blood pressure reduction- quinapril inhibits vascular ACE to a greater degree than both enalapril and placebo.     

Correlation between the inhibition of renin-angiotensin system and antihypertensive effect of MK-421 and captopril in 2-kidney, 1-clip renal hypertensive rats after single and repeated oral administration of MK-421 or captopril

The angiotensin converting enzyme (ACE) activity in tissues and plasma renin activity (PRA) were measured in 2-kidney, 1-clip renal hypertensive rats (2K-RHR) and normotensive rats after a single and 3-weeks oral administrations of ACE inhibitors such as MK-421 and captopril. In the single dose study, MK-421 (1 and 3 mg/kg) and captopril (3 and 10 mg/kg) inhibited the ACE activities in kidney, aorta and plasma in a dose-dependent fashion. The inhibition of ACE activity in kidney or aorta was observed for a longer time than that in plasma. PRA took a time course reversal to that of plasma ACE activity. In the 3-weeks repeated dose study, the ACE activity in kidney and aorta was strongly inhibited after the administration of each ACE inhibitor, while there was no significant change in lung ACE activity at any time point examined. The plasma ACE activity markedly elevated after the administration of each agent. PRA significantly increased after the administration of either agent, while the plasma angiotensin II level was significantly inhibited. These results indicate that the inhibition of the ACE activity in blood vessel or kidney correlate well with the antihypertensive activity in 2K-RHR after a single and repeated administration of both ACE inhibitors, but not well with the inhibition of plasma ACE activity.     

A comparison of lisinopril with enalapril by monitoring plasma angiotensin II levels in humans

The present study was designed to examine and compare the acute effects of lisinopril (20 mg) and enalapril (10 mg) after a single oral administration on the inhibition of the renin-angiotensin system (RAS) in eight normal subjects. Serum concentration of lisinopril and enalaprilat, an active metabolite of enalapril, reached the respective maximal levels at 6 and 4 hr after administration of the drugs. At 24 hr, the serum concentration of lisinopril was higher than that of enalapril; thus the rate of disappearance of lisinopril was retarded, in comparison to that of enalapril. The reduction of serum angiotensin I converting enzyme (ACE) activity was consistent with the pattern of increase of concentration of the drugs in the serum. However, with these two drugs, the concentration of plasma ANG II was decreased in a similar manner, and it returned to the pretreatment level within 24 hr. Thus, there was no significant difference in ANG II levels throughout the 24 hr-study between the lisinopril and enalapril treatment. The results indicate that a single administration of 20 mg lisinopril and 10 mg enalapril show similar potency for lowering the circulating ANG II level, although lisinopril exerts a more sustained inhibition of serum ACE activity. The measurement of ANG II provides useful informations for evaluating the efficacy of ACE inhibitors for the inhibition of circulatory RAS.     

Antihypertensive and angiotensin converting enzyme inhibitory activities of a novel dihydrobenzofuran analogue

1. The biochemical and pharmacological profiles of the novel, orally active angiotensin converting enzyme (ACE) inhibitor, N-[N-[[4-(2, 3-dihydro-2-benzofuranyl)-1-(ethoxycarbonyl)]butyl]-(s)-alanyl]- (s)-proline (BRL 36378), have been compared with those of enalapril and captopril. 2. In the conscious sodium deficient spontaneously hypertensive rat, BRL 36378 and enalapril (0.3-10 mg/kg orally) produced comparable falls in blood pressure; at 3 mg/kg orally, captopril was less active than BRL 36378 and enalapril. 3. In the anaesthetised spontaneously hypertensive rat, enalapril was slightly more potent than BRL 36378 as an inhibitor of angiotensin I (AI) pressor responses whilst BRL 36378 was about twice as potent as captopril in this test (i.v. route used). BRL 36378 and enalapril were equipotent as potentiators of bradykinin depressor responses. 4. In the anaesthetised Wistar rat, the maximum inhibition of AI pressor responses by 0.1 microgram/kg i.v. BRL 36378 and captopril was achieved sooner than after the same dose of enalapril. The inhibitory effect of captopril subsided completely by 40-50 min but the maximum effects of BRL 36378 and enalapril persisted for at least 60 min. 5. In the conscious renal hypertensive cat, captopril was slightly more potent than BRL 36378 or enalapril as a blood pressure lowering agent, over 1-10 mg/kg orally. BRL 36378 was more potent than enalapril as an inhibitor of AI induced pressor responses in this model. Captopril possessed similar inhibitory activity to BRL 36378 although minor differences in time course were apparent.(ABSTRACT TRUNCATED AT 250 WORDS)     

ENALAPRIL DECREASES PLASMA NORADRENALINE LEVELS DURING THE COLD PRESSOR TEST IN HUMAN HYPERTENSIVES

1. The effects of the angiotensin-converting enzyme (ACE) inhibitor enalapril on the responses of blood pressure and plasma catecholamine levels to the cold pressor test in human hypertensives were examined. 2. Systolic and diastolic blood pressure decreased significantly after treatment with enalapril (5 mg/day for 4 weeks) as did the resting level of plasma noradrenaline. 3. The cold pressor test induced a rise in blood pressure and plasma noradrenaline levels. After 2 and 4 weeks enalapril treatment, the rises in the plasma noradrenaline level and systolic and diastolic pressure due to cold pressor test were reduced significantly. 4. These results suggest that ACE inhibition has a sympatho-inhibitory effect. One possible explanation is that enalapril reduces angiotensin II formation thus decreasing the activation of release-enhancing angiotensin II receptors on postganglionic sympathetic nerve endings.     

The haemodynamic and humoral effects of treatment for one month with the angiotensin converting enzyme inhibitor perindopril in salt replete hypertensive patients

Summary We have studied the effects of treatment for one month with perindopril, 4 or 8 mg once daily, in seven hypertensive patients. Blood pressure was lowered from 164/93 mm Hg to 145/84 mm Hg by 4 mg of perindopril and after one month remained at 142/82 mm Hg. Neither postural hypotension nor tachycardia occurred.Inhibition of plasma angiotensin converting enzyme (ACE) lasting for over 24 h was achieved and there was a significant increase in plasma renin activity (PRA).Maximum plasma concentrations of the active metabolite of perindopril, S-9780, were detected four h after oral administration.After treatment for one month there was evidence of reduced sensitivity of plasma ACE to the action of the inhibitor. The plasma concentration of S-9780 required to produce 50% inhibition of plasma ACE rose from 2.4 ng · ml^–1 following the first dose to 5.5 ng · ml^–1 after one month.