The effects of long-term angiotensin-converting enzyme (ACE) inhibitor treatment with perindopril 2 mg/kg/day, by gavage, for 3 months on the mechanical function and structure of large arteries were studied in adult spontaneously hypertensive rats with established hypertension. Hemodynamic parameters, including instantaneous aortic blood flow and pressure, were recorded under anesthesia at the end of the treatment period. Systemic arterial compliance was calculated from aortic pressure and flow recordings; passive mechanical properties of the in situ localized carotid artery were measured. Histologic and morphologic parameters of the aortic media, including cross-sectional area and thickness, size, and density of smooth muscle nuclei and of elastin and collagen fibers, were measured using an automated image analysis system. ACE inhibitor treatment significantly decreased mean arterial pressure (−27%, p < 0.001) and total peripheral resistance (−30%, p < 0.05) while cardiac output was increased (29%, p < 0.05). Systemic arterial compliance and carotid compliance were both increased by treatment (63%, p < 0.05, and 83%, p < 0.05, respectively). Morphometric assessment of vascular structure showed that ACE inhibitor treatment significantly decreased medial cross-sectional area (−36%, p < 0.001) and thickness (−16%, p < 0.001) by affecting smooth muscle cell hypertrophy (nucleus size decreased by 26%, p < 0.05) without changes in smooth cell number. Collagen density was decreased by treatment (−42%, p < 0.05), whereas elastin density was not affected by treatment. It may be concluded that in the adult spontaneously hypertensive rat the decreases in both arterial pressure and arterial wall stiffness, induced by the ACE inhibitor, acted concomitantly to improve arterial wall function, and ACE-inhibitor treatment markedly affected arterial wall structure by reducing medial hypertrophy and collagen content.

Fifty adult male spontaneously hypertensive rats were randomly allocated to receive daily oral treatment with placebo, hydrochlorothiazide (HCTZ 10 mg/kg) and three different dosages of perindopril (S9490-30.1, 0.3 and 1 mg/kg) administered alone or in combination with HCTZ for two eight-day treatment periods separated by a therapeutic washout period of 13 days. Effect of order of treatment was evaluated in rats receiving perindopril plus HCTZ. Time course of changes in systolic blood pressure, heart rate, 24 h urine volume and urinary excretion of sodium, potassium and chloride were studied and compared for all groups. HCTZ alone and lower dosages of perindopril (0.1 mg/kg, 0.3 mg/kg) were ineffective in lowering elevated systolic blood pressure of the spontaneously hypertensive rat, and there were no significant intergroup differences in urine volume and electrolytes. However, antihypertensive efficacy of lower dosages of perindopril was significantly (P less than 0.01) enhanced when administered in combination with HCTZ. The combined treatment also induced significant (P less than 0.01) diuresis and urinary chloride excretion. No significant effect was seen in heart rate. The dose-effect relationship of the combination confirmed the existence of synergistic antihypertensive action between HCTZ and perindopril in the spontaneously hypertensive rat.

Vascular remodeling is central to the pathophysiology of hypertension and atherosclerosis. The effects of antihypertensive drugs on this process are important to consider from a mechanistic and a pathogenetic point of view in relation to vascular complications of hypertension, e.g., decrease in vascular reserves, shift in cerebral blood flow autoregulation and atherosclerosis development. There is now evidence that, in addition to several other growth factors, vasoactive peptides such as angiotensin II may act as vascular smooth muscle growth promoting substances. Based on these data, the effects of perindopril, a potent and long-lasting angiotensin-converting enzyme (ACE) inhibitor, on structural and mechanical properties of the arterial wall, have been studied in animal models of hypertension as well as in humans. Perindopril completely reversed aortic medial hypertrophy and arterial stiffening observed in renovascular hypertensive rats. Similar benefits were reported in mesenteric resistance vessels of spontaneously hypertensive rats. The effect of perindopril was totally in keeping with potent inhibition of vascular ACE and emphasized the potential role of angiotensin II as a vascular growth modulator. Clinical studies confirmed animal experiments; both suggest that increases in arterial compliance and distensibility following perindopril is likely to be related to drug-induced modification of the arterial wall, at least partially independently of blood pressure reduction. The increase in arterial compliance was associated with a selective decrease in pulse pressure, a finding that is important, not only for the arterial wall, but also for the structure and function of the hypertensive heart.

Hemodynamic and structural changes of the heart and large arterial vessels were studied in normotensive and spontaneously hypertensive rats following 12 weeks administration of converting enzyme inhibitor (perindopril, 2 mg/kg daily by gavage). In both strains, a significant blood pressure reduction was observed. In normotensive rats, the hemodynamic changes involved significant increase in systemic arterial compliance whereas slight changes in left ventricular weight and aortic medial thickness were observed. In hypertensive rats, the increase in compliance was relatively small, whereas there was a major reduction in medial thickness. Furthermore, the reduction of the media thickness was much more pronounced than that of the left ventricular hypertrophy. The present results suggest that the cardiac and arterial changes observed following long term converting enzyme inhibition do not strictly parallel the blood pressure changes in hypertensive rats. Dissociation between cardiac and arterial changes may be observed.

We studied changes in cortisol, aldosterone, progesterone, estrogens and cholesterol in cyclic female guinea-pigs and in animals under contraceptive, treated or not with an inhibitor of angiotensin converting enzyme (ACE) : perindopril. Perindopril decreased ACE by 80% without affecting steroid profiles.Peak value for plasma progesterone occurred at meta-estrus and diestrus. It disappeared under contraceptive treatment. The very low levels of estrogens in the female guinea pig remained unchanged in all cases. Plasma cortisol concentrations were higher at pro-estrus and estrus whereas plasma aldosterone concentrations remained constant during the estrous cycle and under contraceptive treatment. Furthermore, aldosterone did not change under perindopril treatment despite the decrease of the activity of ACE. The contraceptive treatment decreased plasma cholesterol levels. Under perindopril treatment, this drop was amplified. No change was detected in adrenal steroid concentrations, except for progesterone which decreased under contraceptive treatment.

Hemodynamic and structural changes of the heart and large arterial vessels were studied in normotensive and spontaneously hypertensive rats following 12-week administration of converting enzyme inhibitor (perindopril, 2 mg/kg daily by gavage). In both strains, a significant blood pressure reduction was observed. In normotensive rats, the hemodynamic changes involved significant increase in systemic arterial compliance, whereas slight changes in left ventricular weight and aortic medial thickness were observed. In hypertensive rats, the increase in compliance was relatively small, whereas there was a major reduction in medial thickness. The reduction of the media thickness was much more pronounced than that of the left ventricular hypertrophy. In both strains, the collagen density in the subendocardial layers of the left ventricle was significantly decreased in treated vs untreated groups. The isomyosine profile of the left ventricular muscle was also modified by ACE inhibition with an increase in the V1 form and a decrease in the V3 form. The present results suggest that the cardiac and arterial changes observed following long-term converting enzyme inhibition do not strictly parallel the blood pressure changes in hypertensive rats. Dissociation between cardiac and arterial changes may be observed.

Perindopril (P) is a prodrug whose active metabolite perindoprilat (PT) is an antihypertensive agent which acts by inhibition of angiotensin-converting enzyme (ACE). Anti-PT antiserum was produced in a rabbit immunized against PT that was covalently linked to bovine serum albumin. The radioligand is an iodinated (125I) derivative of PT-glycyltyrosinamide. Both the drug (PT) and the prodrug (P) are assayed in the same sample; PT is assayed as is and P is assayed after quantitative alkaline hydrolysis into PT. Certain data obtained from such assays suggest the occurrence in plasma and urine of a third immunoreactive component. A chromatographic fractionation of samples allowed us to isolate a new immunoreactive metabolite which was further identified as a glucuronide of PT (PT-G). Therefore, the whole assay was carried out as follows: biological samples were fractionated by stepwise chromatography on a anion-exchange resin (the first fraction contained P, the second contained PT, and the third contained PT-G); and RIA was performed on fractions 2 and 3 as is, and on fraction 1 after alkaline hydrolysis. Performances and assessments of this method are presented together with an example of a pharmacokinetic profile.

Perindopril, an angiotensin converting enzyme (ACE) inhibitor, is converted in vivo to its active diacid metabolite, perindoprilat and to a perindoprilat glucuronide. The pharmacokinetic parameters of perindopril, perindoprilat and perindoprilat glucuronide were evaluated after single administration to healthy volunteers (N = 12) of 8 mg of perindopril tert-butylamine salt by oral route (treatment A), by intravenous route (bolus in 5 min, treatment B) and of an equimolar dose of perindoprilat (6.1 mg) by intravenous route (infusion over 2 h, treatment C). The treatments were administered as a randomised 3-way cross-over design. Plasma samples were collected up to 96 h and urines up to 120 h. Perindopril is rapidly absorbed with an oral bioavailability of 95% and is mainly eliminated by metabolic processes. The formation of perindoprilat is slow and about 20% of the available parent drug is transformed into this metabolite. Elimination profile of perindoprilat is biphasic, with a rapid renal excretion of the free fraction and a long terminal half-life of the fraction bound to ACE. Perindoprilat glucuronide is mainly obtained from perindopril by a pre-systemic first pass metabolism.

The left coronary artery in rats was ligated for a period of 15 days to induce hypertrophy of the non-infarcted myocardium. Left ventricular performances were evaluated in the working heart model. In addition, cardiac hypertrophic indices and noradrenaline content were measured. Variables were determined in the absence or presence of the angiotensin-converting enzyme inhibitor, perindopril. A 35 and 60% decrease in the coronary and cardiac output, respectively, and a 57% decrease in the noradrenaline content of the non-infarcted left ventricular free wall were seen. Furthermore, a 15% increase in the heart/body weight ratio was observed in the infarcted group. After chronic treatment of the animals with perindopril (2 mg.kg-1 body weight, per os), coronary and cardiac output were impaired to a lesser extent: 8 and 35% respectively, with only a 15% decrease in the noradrenaline content of the non-infarcted left ventricular free wall. Furthermore, the increase in heart/body weight ratio was significantly less than in the nontreated infarct group (7%). We conclude that the beneficial effects of converting enzyme inhibition, during the development of myocardial infarction, on left ventricular performances are associated with a decrease in the hypertrophic indices and a normalization of sympathetic activity.

1. The metabolism of perindopril (non-thiol angiotensin-converting enzyme inhibitor) was studied in rat, dog and monkey after single oral and i.v. administration of 14C-perindopril, and in man after a single oral dose. 2. Six biotransformation products of perindopril from urine, faecal and plasma samples (bile only for rats) were identified. 3. The main route of biotransformation in all species is the hydrolysis of the carboxylic ethyl ester side-chain, with the formation of perindoprilate, the active metabolite. 4. A minor route of biotransformation led to the acyl glucuronides of perindopril and perindoprilate. 5. Internal dehydration of perindopril and perindoprilate into cyclic lactam structures occurs. This route of metabolism is of minor importance except in humans.

Food has been shown to reduce the bioavailability of the angiotensin-converting enzyme inhibitor captopril, but not the bioavailability of inhibitors administered as ester prodrugs. Perindopril is the ester pro-drug of the angiotensin-converting enzyme inhibitor perindoprilat. The influence of food on the pharmacokinetics of perindopril (4 mg administered orally) and the time course of angiotensin-converting enzyme inhibition in serum was studied in a randomized crossover short-term study of 12 healthy subjects. Food significantly decreased the relative availability of perindoprilat by 35% +/- 42%, the fractional urinary excretion of perindoprilat from 19% +/- 7% to 13% +/- 4% (p less than 0.05), and the partial metabolic clearance of perindopril to perindoprilat from 102 +/- 57 ml.min-1 to 72 +/- 32 ml.min-1 (p less than 0.05). These changes were associated with a significant decrease in the area under the percent angiotensin-converting enzyme inhibition-versus-time curve by 15% (p less than 0.05). Food did not alter the total amount of drug recovered in urine as perindopril and its metabolites, and it did not alter perindoprilat renal clearance. We concluded that food alters the conversion of perindopril to its active metabolite perindoprilat after single-dose administration of perindopril.

The effects of perindoprilat on renal hemodynamics and the elimination of water and electrolytes were studied acutely in the anesthetized dog. Two groups of animals were compared, one on normal sodium and water, the other on an acutely restricted sodium and water diet. In all cases, perindoprilat injected into renal artery (0.1 and 0.5 mg/kg) reduced blood pressure. In the animals on a low sodium diet, perindoprilat increased renal blood flow from 2.2 +/- 0.3 to 2.9 +/- 0.3 ml/min/g and decreased the filtration fraction; the decrease in renal vascular resistance predominated on the efferent arteriole of the glomerule (45% decrease), preferential site for the vasoconstrictor action of angiotensin II. In the animals on a normal sodium diet, renal blood flow was also increased from 4.1 +/- 0.6 to 5.1 +/- 0.6 ml/min/g but without the filtration fraction being affected. The renal vascular resistance was decreased at both pre- and post-glomerular levels (respectively, 50 and 25% decrease). After sodium and water restriction, but not in animals on a normal sodium diet, perindoprilat increased the fractional elimination of water and electrolytes. This salidiuresis might be accounted for by the hemodynamic effect of converting enzyme inhibitor and the decrease it elicits in filtration fraction, modifying sodium and water reabsorption in the proximal tubule.

The effects of renovascular hypertension and of its treatment with perindopril, a converting enzyme inhibitor, on the structure and function of large arteries were studied on 2 kidneys, 1 clip Goldblatt rats. One month after surgery, the animals rendered hypertensive (n = 24) and those who had had a blank operation (n = 24) were divided into two groups receiving either perindopril 1 mg/kg/day or distilled water during 4 week At the end of treatment haemodynamic values, including arterial pressure and instant blood flow at Doppler velocimetry, were measured in anaesthesized rats. The mechanical properties of the carotid artery were studied by in situ measurement of carotid compliance in response to imposed pressures. Finally, morphometric parameters of the thoracic aorta, including thickness of the media, density of elastin, collagen and nuclei and nuclear surface area, were studied by means of an automatized image analysis system. Hypertension was associated with a characteristic increase in aortic impedance (14,479 +/- 5,171 vs 9,022 +/- 4,071 dyn.sec/cm5; p less than 0.01) and a decrease in systemic arterial compliance (2.41 +/- 0.96 vs 3.92 +/- 1.15 x 10-3 ml/mmHg; p less than 0.05) and carotid compliance (6.31 +/- 1.85 vs 3.8 +/- 3.4 X 10-2 mm3/mmHg; p less than 0.05). Treatment with perindopril normalized the systolic and diastolic pressures and completely reversed the artery rigidity markers. Our morphometric analysis of the aortic wall enabled us to relate these functional changes to structural changes in vascular wall.(ABSTRACT TRUNCATED AT 250 WORDS)

This review of the pharmacological effects of perindopril is based on data from the literature and divided into three parts: (i) demonstration of the antihypertensive effect of the drug; (ii) characterization of its inhibitory effect on the angiotensin-converting enzyme, (iii) understanding of its mechanisms of action. The antihypertensive effect of perindopril has been demonstrated in spontaneously hypertensive rats or in artificially induced renovascular hypertension (1 clip-2 kidney, 1 clip-1 kidney). The intensity and duration of this effect is dose-dependent and is increased by stimulation of the renin-angiotensin system (renovascular hypertension, sodium depletion). The peripheral vascular resistance is decreased without corresponding increase in heart rate. The drug-induced vasodilatation predominates in the kidney bed and is associated, in dogs on low water and salt diet, with a rise in natriuresis. These effects are accompanied by inhibition of the angiotensin-converting enzyme. In vitro peridoprilate (the main active diacid of perindopril) is a potent (Cl50: 1.5 to 3.2 nM) competitive and relatively specific inhibitor of the angiotensin-converting enzyme. In vitro, perindopril competitively inhibits the pressive response to angiotensin I. In rats given an oral dose of 1 mg.kg-1 the activity of plasma converting enzyme is inhibited for 24 hours and even longer if they are sodium-deplete. In spontaneously hypertensive rats, the antihypertensive effect of perindopril lasts longer than its inhibitory effect on the plasma converting enzyme. This dissociation suggests that the angiotensin-converting enzyme is inhibited in tissues, as has been shown in various tissues including rat kidney and aorta.(ABSTRACT TRUNCATED AT 250 WORDS)