Influence of food on the pharmacokinetics of perindopril and the time course of angiotensin-converting enzyme inhibition in serum.

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.

Long-term effects of angiotensin-converting enzyme inhibition on the arterial wall of adult spontaneously hypertensive rats.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

S14080, a peripheral analgesic acting by release of an endogenous circulating opioid-like substance.

1. The oral administration of a benzothiazolinone derivative (benzoyl-6 dihydro-2,3 benzothiazole), S14080, caused dose-dependent antinociception in the rat paw pressure test, which represents a model of mechanical hyperalgesia. S14080 had no significant effect on the inflammatory oedema induced by carrageenin or on the tail flick test, nor did it possess a notable antipyretic effect. 2. Post-treatment with S14080 dose-dependently antagonized the hyperalgesia induced by prostaglandin E2, bradykinin, dopamine and by the hyperalgesic cytokines reported to be released by carrageenin (tumour necrosis factor alpha, interleukin-1 and interleukin-8). 3. The blockade of prostaglandin E2-induced paw hyperalgesia by oral pretreatment of the rats with S14080 was abolished by prior intraplantar administration of either naloxone or NorBNI which are non-specific and specific kappa opioid antagonists, respectively. 4. Adrenalectomy abolished the oral antinociceptive effect of S14080. 5. Five consecutive daily injections of S14080 did not produce tolerance such as that seen with the central antinociceptive action of morphine. 6. As with peripherally acting opiates, the antinociceptive activity of S14080 was abolished by the intraplantar injection of agents which inhibit either arginine synthetase (NG-monomethyl-L-arginine) or the activation of guanylate cyclase (methylene blue). 7. We conclude that S14080 is a new type of peripheral antinociceptive which, in rats, acts mainly by releasing an endogenous, opioid-like substance from the adrenal glands.

Remodeling of heart and arteries by chronic converting enzyme inhibition in spontaneously hypertensive rats.

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.

Pharmacokinetics of perindopril and its metabolites in healthy volunteers.

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.

Radioimmunoassay of a new angiotensin-converting enzyme inhibitor (perindopril) in human plasma and urine: advantages of coupling anion-exchange column chromatography with radioimmunoassay.

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.

Interaction between an angiotensin converting enzyme inhibitor, perindopril, and a thiazide diuretic in the spontaneously hypertensive rat.

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.

[Antihypertensive effect of perindopril. Experimental pharmacology]. / Effet antihypertenseur du perindopril. Pharmacologie expérimentale.

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)

[Effects of chronic inhibition of converting enzymes on the structure and function of the large arterial trunks in rats]. / Effets de l'inhibition chronique de l'enzyme de conversion sur la structure et la fonction des gros troncs artériels chez le rat.

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)

[Pharmacological approach to a treatment of senescence and cerebrovascular deficiencies related to hypoxia. Application to 5023 SE]. / Approche pharmacologique d'une thérapeutique de la sénescence et des déficits cérébro-vasculaires liés à l'hypoxie. Application au 5023 SE.

Duxil is a combination of almitrine and raubasine. Almitrine produces an increase of PaO2 in arterial blood, and this beneficial effect on hypoxemia is potentiated by that of raubasine on microcirculation. Pharmacological studies of Duxil in healthy animals and experimental models have demonstrated that the drug increases arterial oxygen supply, improves tissue oxygenation and is capable of correcting vascular and metabolic disorders due to hypoxia. After administration of Duxil to animals whose brain has been severely deprived of oxygen by experimental anoxia or ischaemia, the oxygen supply is sufficient for the brain cells to take up their preferential substrate (glucose) and to use it through the most energy-producing aerobic pathway. Thus, the energy stores (ATP or glycogen) of these cells are spared and above all, their structural integrity is preserved. Their functional activity may be maintained, and this would justify the use of Duxil in mental and behavioural disorders of cerebral senescence and cerebro-vascular diseases related to hypoxia.

Angiotensin converting enzyme inhibition and autoregulation of glomerular filtration.

The present study examines the influence of two angiotensin converting enzyme (ACE) inhibitors, perindopril and captopril, on renal plasma flow and on autoregulation of glomerular filtration in anaesthetized rats during reduction of renal perfusion pressure to 100, 90 and 80 mmHg. Groups 1 and 3 had a normal sodium intake (4 mmol/kg per day), while groups 2 and 4 were sodium depleted (0.5 mmol/kg per day) for 10 days. Renal perfusion pressure was measured before and after ACE inhibition in all groups. Groups 1 and 2 were given perindopril (0.3 mg/kg) and groups 3 and 4 were given captopril (3.0 mg/kg) intravenously. When renal perfusion pressure was reduced in group 1 following ACE inhibition with perindopril, the glomerular filtration rate remained unaltered. In group 3, captopril abolished autoregulation of the glomerular filtration rate, which decreased from 1.01 +/- 0.03 to 0.60 +/- 0.03 ml/min. Similarly, reduction in renal perfusion pressure was associated with an unaltered glomerular filtration rate in group 2, but in group 4 the glomerular filtration rate fell more significantly, from 0.89 +/- 0.06 to to 0.19 +/- 0.3 ml/min. Renal plasma flow decreased significantly in groups 1 and 3 during the renal perfusion pressure changes, both before and during ACE inhibition, but in groups 3 and 4 it remained relatively stable. These results indicate that ACE inhibition with captopril alters the normal autoregulation of the glomerular filtration rate, presumably by blocking the angiotensin II (Ang II) efferent arteriole vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular effects of S 9490-3, a new converting enzyme inhibitor: a computerized study in conscious spontaneously hypertensive rats.

The acute cardiovascular effects of S 9490-3, a new angiotensin converting enzyme (ACE) inhibitor, were studied by means of a computerized analysis of the intra-aortic blood pressure (BP), recorded continuously for 48 h in conscious, unrestrained, adult spontaneously hypertensive rats (SHR). The first 24-h recording period was used as a control. On the second day, the rats received a single intravenous (i.v.) injection of S 9490-3 (0.2 mg/kg) at 11 a.m. followed by another 2 mg/kg i.v. injection at 3 p.m. Cardiovascular activity was studied up to 8 a.m. the next day. No significant cardiovascular effects appeared after the 0.2 mg/kg dose, whereas the 2 mg/kg dose induced a rapid fall in systolic and diastolic BP, which remained significant for about 11 h. This BP decrease was not associated with any elevation in heart rate, but with a short lasting increase in dP/dt max. These results are in good agreement with those already obtained with S 9490-3 in various experimental conditions. They suggest that long-term recordings of intra-arterial BP in freely moving rats is of value in the study of drugs which act on the cardiovascular system.

Gas chromatography-mass spectrometry of perindopril and its active free metabolite, an angiotensin convertase inhibitor: choice of derivatives and ionization modes.

Perindopril, a perhydroindole compound and a novel class of angiotensin convertase inhibitor, after oral administration leads to an active metabolite by de-esterification of an ethyl ester. Routine biological measurements are currently done using a radioimmunological assay, but a mass fragmentographic method was developed using plasma spiked with the drugs, which were then derivatized to the isobutyl ester heptofluorobutyramide and assayed using ammonia negative chemical ionization. Levels of 100 pg/ml were assayed. However, isobutanol derivatization provoked partial transesterification of the ethyl ester of the parent drug into the diisobutyl ester derivative, which corresponds to the active metabolite. A second method of derivatization to stable trimethylsilyl esters preserved the original ethyl ester of the parent drug. Despite the lower ionization yields, the mass fragmentographic method was sensitive and accurate enough to work satisfactorily at the 2 ng/ml level in spiked plasma, which is the level found currently in patients.

Beneficial effect of perindopril, an angiotensin-converting enzyme inhibitor, on left ventricular performance and noradrenaline myocardial content during cardiac failure development in the rat.

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.

Antihypertensive effect of perindopril: experimental pharmacology.

This review of the pharmacological effects of perindopril based on data in the literature, consists of three approaches: i) demonstration of the antihypertensive effect; ii) characterization of converting enzyme inhibition; iii) understanding of the mechanisms of action. The antihypertensive effect of perindopril has been demonstrated in the spontaneously hypertensive rat and in renovascular hypertension (1 clip-2 kidney or 1 clip-1 kidney). Its intensity and duration are dose-dependent; they are increased in the presence of stimulation of the renin-angiotensin system (renovascular hypertension, sodium depletion). Peripheral vascular resistance is decreased, while cardiac output and heart rate are not increased. This vasodilatation is predominant in the renal vascular bed and is accompanied, in the salt and water restricted dog, by increased sodium excretion. These effects are accompanied by inhibition of the converting enzyme activity. In vitro, perindoprilat (the principal active diacid metabolite of perindopril) is a potent (IC50: 1.5 to 3.2 nM) and relatively specific competitive converting enzyme inhibitor. In vivo, perindopril competitively inhibits the pressor response to angiotensin I. Following a dose of 1 mg.kg-1, the plasma converting enzyme activity is significantly inhibited for 24 hours in the rat and for a longer period in the case of low-salt diet. In the spontaneously hypertensive rat, the antihypertensive effect of perindopril lasts longer than plasma converting enzyme inhibition. This dissociation of the pharmacological effects suggests a role of tissue converting enzyme inhibition, demonstrated in various tissues, including the rat kidney and aorta. Inhibition of the presynaptic effects of angiotensin II on the transmission of sympathetic impulses--demonstrated in pithed rats--and potentiation of the effects of bradykinin--observed in vitro and in vivo--may also be involved in the antihypertensive effect of perindopril.

Lack of effect of perindopril on plasma and adrenal corticosteroids in the guinea pig during the estrous cycle and under contraceptive treatment.

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.

Renal effects of perindoprilat, an angiotensin-converting enzyme inhibitor, in the anesthetized dog.

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.

Protective effect of angiotensin converting enzyme inhibitors (CEI): captopril and perindopril on vulnerability to ventricular fibrillation during myocardial ischemia and reperfusion in rat.

The purpose of the present study was to evaluate the effects of two CEI: captopril and perindopril on reperfusion arrhythmias and noradrenaline 3H (NA3H) release in the isolated rat heart on arrhythmias in pentobarbitone anaesthetized rats subject to left coronary artery ligation. In vitro, in control preparations, reperfusion after 10 min of local ischemia produced by coronary ligation was accompanied by a sudden release of NA3H in coronary flow and long lasting ventricular arrhythmias. Reperfusion arrhythmias were prevented by perfusion medium containing a high dose of CEI and CEI did not change the patterns of NA3H release. In vivo, mortality due to ventricular fibrillation was significantly reduced in rats pretreated with captopril or perindopril 15 min prior to coronary ligation. CEI reduced the severity of ventricular tachycardia (VT) and fibrillation (VF).

Vascular effects of perindopril: from experimental to clinical investigation.

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.

Angiotensin converting enzyme (ACE) inhibitors in experimental hypertension: influence on heart and arteries.

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.