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PubMed1998

Protective effect of the angiotensin-converting enzyme inhibitor perindopril on diabetic glomerulopathy in streptozotocin-induced diabetic rats.

OBJECTIVES: To evaluate the protective effect of the angiotensin-converting enzyme inhibitor perindopril on diabetic glomerulopathy in rats with experimentally induced diabetes and explore its possible mechanisms. METHODS: Ninety-two adult male Wistar rats were randomly allocated into diabetes mellitus (DM), diabetes mellitus + perindopril (DMP) and control (C) groups. According to the duration of diabetes or observation (1, 3, 6 months), each group was randomly subdivided into DM1, DM3, DM6; DMP1, DMP3, DMP6; and C1, C3, C6 groups. Diabetes was induced by intraperitoneal injection of streptozotocin. The rats in the DMP groups received perindopril 1 mg.kg-1.d-1, through gastric intubation. Urinary protein excretion rate was determined by the method of Coomassie brilliant blue. Plasma renin activity, renal tissue renin activity, and plasma and renal tissue angiotensin II concentration were assayed by radioimmunoassay (RIA). Renal tissue total RNA was extracted by the Chomezymskis AGPC method. Renal angiotensinogen mRNA expression level was assessed by slot blot hybridization using a full length rat angiotensinogen cDNA probe labelled with 32P-dCTP and a random primer. RESULTS: There was increased activity of the renin angiotensin system in diabetic rats. Perindopril decreased proteinuria and delayed the progression of glomerular basement membrane thickening. However, it did not reduce the expansion of the mesangial matrix (P < 0.05). Renin activity increased and angiotensin II concentration decreased significantly in both plasma and renal tissue in diabetes + perindopril groups (P < 0.05). CONCLUSIONS: Perindopril may help prevent the progression of diabetic glomerulopathy, and the inhibition of renin angiotensin system activity may be a mechanism for this action.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Comparative efficacy of perindopril and enalapril once daily using 24-hour ambulatory blood pressure monitoring.

ACE inhibitors are important therapeutic agents in controlling hypertension, correcting some of its pathophysiological derangement and improving its prognosis. While there are many such agents, there may be some important differences between them. This placebo run-in, double blind, crossover study, using 24-hour ambulatory blood pressure monitoring, compares the efficacy of perindopril 4-8 mg and enalapril 10-20 mg as once daily antihypertensive agents on 32 patients. For diastolic blood pressure (DBP), perindopril had a placebo-corrected peak (P) reduction of blood pressure (BP) of -6.4 +/- 1.3 mmHg vs its placebo-corrected trough (T) of -5.2 +/- 1.7 mmHg. Enalapril had a reduction in DBP of -8.5 +/- 1.3 mmHg (P) and -5.7 +/- 1.7 mmHg (T). For systolic blood pressure (SBP), perindopril had a reduction of -7.5 +/- 1.6 mmHg (P) vs -7.3 +/- 2.2 mmHg (T) compared to enalapril with -10.8 +/- 1.6 mmHg (P) vs -8.3 +/- 2.3 mmHg (T). Placebo-corrected trough-to-peak ratio (SBP/DBP) for perindopril was 0.97/0.81 vs 0.77/0.67 for enalapril. There was no difference noted in 24-hour mean BP, area under the curve or post-dose casual BP measurements. Both perindopril and enalapril were well tolerated and the two treatment groups had similar safety profiles. Perindopril thus had a predictable and sustained blood pressure effect giving a 24-hour cover for the patient without excessive peak effect or poor trough effect.

Adult↗
PubMed2001

The angiotensin-I-converting enzyme inhibitor perindopril suppresses tumor growth and angiogenesis: possible role of the vascular endothelial growth factor.

Angiotensin-I converting enzyme (ACE) inhibitor is used widely as an antihypertensive agent, and it has been suggested recently that it decreases the risk of cancer (A. F. Lever et al., Lancet, 352: 179-184, 1998). In this study, we examined the effect of several ACE inhibitors and angiotensin-II type 1 receptor (AT(1)-R) antagonists on tumor development and angiogenesis in a murine hepatocellular carcinoma model. Among ACE inhibitors, perindopril appeared to be a potent inhibitor of tumor development and angiogenesis, whereas AT(1)-R antagonists did not exert such an inhibitory effect. The inhibitory effect of perindopril was achieved even on established tumors. The level of the potent angiogenic factor, vascular endothelial growth factor (VEGF), in the tumor was significantly suppressed by perindopril. In vitro studies showed that perindopril-derived active form, perindoprilat, suppressed the endothelial cell tubule formation. Perindoprilat treatment also significantly inhibited VEGF mRNA expression in BNL-HCC cells in vitro. These results showed that the ACE inhibitor perindopril inhibited tumor development and angiogenesis independent from AT(1)-R blockage, and that VEGF alternation may be involved in the mechanism of this inhibitory effect. Because perindopril is widely used in clinical practice, it may represent an effective new strategy for anticancer therapy.

Angiotensin Receptor Antagonists↗
PubMed1999

[Greater reduction of urinary albumin excretion in hypertensive patients with perindopril than nifedipine].

OBJECTIVE: To examine the effect of perindopril and nifedipine on renal function in patients with essential hypertension (EH). METHODS: 52 cases with EH were divided randomly into two groups: perindopril group (4mg qd, n = 26); nifedipine group (10 mg tid, n = 26). Treatment period lasted for 24 weeks. Parameters of renal function were measured before and after treatment. RESULTS: (1) After treatment, the arterial pressure decreased in a similar way in the two groups, urinary albumin excretion was significantly less after treatment in the perindopril group [urinary albumin excretion/24 h (mg/24 h): 66.7 +/- 25.9 vs 104.5 +/- 41.8, P < 0.01; urine protein/24h (g/L): 0.17 +/- 0.039 vs 0.24 +/- 0.064, P < 0.01], GFR (ml/min) was higher in the perindopril group after treatment (125.5 +/- 15.2 vs 112.2 +/- 13.2, P < 0.05). No significant changes were observed with nifedipine (P < 0.05). (2) No significant correlation between the decrement of urinary albumin excretion and of SBP, DBP was found in both groups (P > 0.05). CONCLUSION: It is shown that perindopril, but not nifedipine, is able to reduce urinary excretion of albumin in patients with essential hypertension independently of its effective antihypertensive property. It is probable that the positive effect of perindopril on microalbuminuria is attributable to modification in intrarenal hemodynamics or to change in glomerular permeability.

Adult↗
PubMed2004

[Effect of perindopril on renal interstitial fibrosis of hypertension in rats].

OBJECTIVE: To explore the effect of perindopril on renal interstitial fibrosis of spontaneously hypertensive rats and on the expression of transforming growth factor-beta1. METHODS: Spontaneously hypertensive rats at the age of 9 weeks were randomly assigned to 2 groups: Spontaneously hypertensive rats (SHR, vehicle once daily, n = 10) and Treament-SHR (T-SHR, perindopril, 4 mg/(kg x d), per day PO, n = 10). Wistar-Kyoto rats (WKY, n = 7) were served as controls. After 10 weeks of treatment, the serum concentration of TGF-beta1, collagen type I, III and TGF-beta1 in the renal interstitum and renal mRNA levels of TGF-beta1 were detected. RESULTS: There were no significant differences in the serum TGF-beta1 levels among the 3 groups (P > 0.05). Immunohistochemical studies revealed a significant interstitial accumulation of collagens I, III and TGF-beta1 in SHR compared with those in WKY (P < 0.01 or P < 0.05). These changes in SHR were significantly ameliorated by the administration of perindopril (P < 0.01 or P < 0.05). In SHR, renal TGF-beta1 mRNA expression was increased significantly compared with that in WKY (P < 0.01), but perindopril decreased it to the normal levels of WKY (P > 0.05). The increased expression of TGF-beta1 was blocked by perindopril. The expressions of collagens I and III in renal interstitum significantly correlated with the accumulation of TGF-beta1 in the renal (r = 0. 734, r = 0.762, respectively; P < 0.01). CONCLUSION: The tubulointerstitial fibrosis of spontaneously hypertensive rats is mediated by an increased level of TGF-beta1 in the renal tissue, and perindopril may decrease the expression of TGF-beta1 to ameliorate the tubulointerstitial fibrosis.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

[Use of the ACE inhibitor perindopril in patients with chronic obstructive lung diseases, complicated by cor pulmonale].

The purpose of the study was to evaluate hemodynamic effects and safety of the ACE inhibitor perindopril in treatment of secondary pulmonary hypertension (PH) in patients with chronic obstructive bronchitis (COB). The subjects were 42 patients with COB and secondary PH (functional class (FC) III-IV), whose treatment included 4-week administration of perindopril. Studied were hemodynamic parameters and day profile of blood pressure (24-hour monitoring). Treatment of these patients with perindopril resulted in improvement of PH, positive changes in the right heart, and normalization of blood pressure day profile. Both course treatment and prolonged administration of perindopril were effective in COB patients with clinical manifestations of FC III and IV PH. Long outpatient administration of perindopril in individual doses led to good clinical results and significant positive hemodynamic changes. According to the authors, the ACE inhibitor perindopril may be recommended for correction of hemodynamic disturbances in cases of chronic cor pulmonale in patients with chronic obstructive lung diseases.

Adult↗
PubMed2006

[Effects of perindopril on left ventricular remodeling and myocardial osteopontin expression in rats with myocardial infarction].

OBJECTIVE: To observe the effects of perindopril on left ventricular remodeling and myocardial osteopontin expression in rats with myocardial infarction (MI). METHODS: Male adult SD rats were randomly divided into sham-operation group, MI-saline group and MI-perindopril group, and in the latter two groups, ligation of the left anterior descending artery was performed to establish rat models of myocardial infarction and perindopril (2 mg/kg daily) or saline was administered since the next day of MI. Four weeks later, the left ventricular diameter (LVEDD and LVESD) and left ventricular ejection fraction were estimated with echocardiography, and the left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and -/+dp/dt(max) was obtained via hemodynamic measurement, with also evaluation of the cardiac myocyte diameter and interstitial fibrosis infiltration with histological methods. Western blotting was performed to detect the expression level of myocardium osteopontin protein. RESULTS: Compared with the sham-operation group, all MI rats developed significant systolic and diastolic dysfunction, as indicated by decreased LVEF, LVSP and -/+dp/dt(max), as well as increased LVEDP. MI rats showed significantly dilated left ventricles and higher ventricular weight/body weight ratio, significantly increased cardiomyocyte diameter and marked interstitial fibrosis in the non-infarction area. Perindopril treatment partially prevented cardiac dysfunction and left ventricular remodeling as indicated by the above indices. No osteopontin was detected in the myocardium of sham-operation rats, and in MI rats, high level of osteopontin expression, as detected in MI-saline group, was significantly inhibited by perindopril treatment. CONCLUSION: Perindopril treatment can significantly inhibit left ventricular remodeling and myocardium osteopontin expression in rats with MI.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

[The hemostasis parameters and ACE gene polymorphism in patients with essential hypertension treated with perindopril].

PURPOSE: 1. The assessment in haemostasis system, fibrinogen, tissue plasminogen activator (t-PA) and its inhibitor type-1, von Willebrand factor and beta-thromboglobulin (beta-TG) levels and the changes in renin-angiotensin system (RAS), by determined angiotensin converting enzyme I (ACE) activity, in patients with essential hypertension (in relation to left ventricular hypertrophy) in comparison with normotension subjects. 2. The analysis of changes in haemostasis and RAS during treatment with perindopril in relation to left ventricular hypertrophy (group LVH+ and LVH-). 3. The assessment of haemostasis parameters levels and ACE activity in effect of treatment with perindopril in relation to ACE gene I/D polymorphism. MATERIAL AND METHODS: The study involved 78 male divided on two groups: cases and controls. The cases contained 44 male outpatients (25-38 years old) with untreated essential hypertension without clinical feature of coronary heart disease and 34 age- and gender- matched healthy controls. CONCLUSION: 1. Untreated essential hypertension predisposes to the procoagulant state characterised by increased Fb level and suppressed of fibrinolysis. These changes not depend on ACE gene I/D polymorphism. The left ventricular hypertrophy not intensificates the procoagulant state. 2. The treatment with perindopril decreases blood pressure effectively independent of ACE gene I/D genotype and left ventricular hypertrophy. Perindopril impairs RAS activity, most in patients with ACE gene II genotype. The treatment with perindopril is only partially effective in alleviating the procoagulant state, by reducing fibrinogen level in II homozygotes due to its more potent inhibitory action on the RAS in this group. The treatment makes fibrinolysis better mainly to high t-PA levels, independently of ACE gene I/D polymorphism. 3. Left ventricular hypertrophy not differentiates the response on treatment in relation to haemostasis parameters and RAS, however there was a slight decrease in ACE activity in patients with left ventricular hypertrophy. 4. The changes in haemostasis system and ACE activity, observed during treatment, suggest the appearance of positive relation between haemostasis and RAS. Probably the antithrombotic act of perindopril is more pronounced in II genotype group.

Adult↗
PubMed1991

Hemodynamic and humoral interactions between perindopril and indomethacin in essential hypertensive subjects.

To evaluate whether perindopril, a carboxyl-containing new angiotensin-converting enzyme (ACE) inhibitor, exerts its antihypertensive action through the stimulation of prostaglandin synthesis, 10 uncomplicated essential hypertensive patients randomly received indomethacin (50 mg b.i.d.) or the corresponding placebo for 1 week and the reverse treatment after 2 weeks. Perindopril alone tended to reduce serum and urinary thromboxane B2 (TxB2) and to raise urinary 6-ketoPGF1 alpha and PGE2 and inhibited serum ACE activity 24 h post dosing by about 85%. Indomethacin, which significantly inhibited serum TxB2 and urinary TxB2, 6-ketoPGF1 alpha, and PGE2 without interfering with the inhibitory effect of perindopril on ACE, significantly reduced the antihypertensive action of perindopril alone by about 30%, but decreased though not significantly that of perindopril plus placebo. Although the size of the study limits the interpretation, these findings suggest that the stimulation of prostaglandin synthesis plays only a minor role in the antihypertensive action of perindopril.

Adult↗
PubMed1991

[Perindopril and chronic heart failure].

Haemodynamic studies performed in patients with cardiac failure have shown that perindopril decreases right and left ventricular filling pressures, systemic blood pressure and peripheral resistances, slightly reduces the heart rate and increases cardiac output. Flammang showed that these haemodynamic changes are sustained after 12 months' treatment. A randomised double blind multicenter trial versus placebo was carried out over 3 months following a 15 days pre-inclusion period in 125 patients with NYHA Stage II and III cardiac failure stabilised by digitalis and diuretic therapy. Perindopril was administered at a dosage of 2 or 4 mg according to initial systolic blood pressure and efficacy was evaluated at 1 and 3 months according to the NYHA classification, a score of clinical severity, the duration of two exercise stress tests on a bicycle ergometer or treadmill and the cardiothoracic ratio. There were no cases of cardiac decompensation (NYHA Stage IV) in the group of perindopril whilst 3 cases were observed in the placebo group. Significant improvements in the clinical scores and effort capacity were observed in the perindopril group. The duration of exercise on the treadmill was 778 seconds with perindopril compared to 544 seconds in the placebo group. Systolic blood pressure did not change and there was a slight decrease in standing diastolic pressures. No significant increases in blood urea or creatinine levels were observed. To study the effects on blood pressure, a major factor in the management of a patient with cardiac failure, McFadyen compared the changes in blood pressure after a single dose of perindopril, enalapril, captopril and placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1989

[First intention treatment of arterial hypertension. Effectiveness and safety of perindopril].

Inhibitors of the angiotensin conversion enzyme (ICE) represent an effective and well tolerated therapeutic class, for the treatment of arterial hypertension. The antihypertensive efficacy or perindopril, an ICE active in one single daily dose, is at least equal to that of reference antihypertensive drugs administered at usual doses. The possibility of occurrence of some side-effects while using ICE, has resulted in a particular attention in evaluating the safety of perindopril. First, the renal function was monitored. During essential hypertension, no significant variation of the creatininemia was observed with long-term administration of the drug (12 months). In elderly hypertensive patients or patients with chronic renal insufficiency, the glomerular filtration is also preserved, except during rare occurrences of decreased creatinine clearance, especially after adjunction of hydrochlorothiazide. A discrete elevation of the kaliemia without clinical significance is observed when perindopril is used as a single drug. Reports of symptomatic hypotension with perindopril are rare (0.2%), even in situations of water and sodium depletion. Among other side-effects of ICE, cough, more recent, was thoroughly investigated. Its frequency was determined during a double blind trial comparing perindopril (1.2%) with captopril (2.4%). It was also evaluated during a long-term study concerning 632 hypertensive patients (391 patients treated in 1 year); its incidence is the 2.9 p. cent and it resulted in discontinuation of the treatment in 8 cases. In this study, 36 patients interrupted the treatment prematurily because of an adverse reaction (5.7%). Finally no harmful drug interaction was reported. The favorable tolerance profile of perindopril is combined with a beneficial effect on the functional and structural modifications of the heart and large vessels related to hypertension.

Antihypertensive Agents↗
PubMed1989

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.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Chronic low-dose treatment with perindopril improves cardiac function in stroke-prone spontaneously hypertensive rats by potentiation of endogenous bradykinin.

We investigated the effect of chronic angiotensin-covering enzyme (ACE) inhibitor treatment on functional and biochemical cardiac parameters in stroke-prone spontaneously hypertensive rats (SHRsp). Animals were treated prenatally and, subsequently, up to the age of 20 weeks with the ACE inhibitor perindopril (0.01 and 1 mg/kg per day). The contribution of endogenous bradykinin potentiation to the actions of the ACE inhibitor was assessed by co-treatment with the bradykinin B2-receptor antagonist, icatibant (500 micrograms/kg/day s.c.), from 6 to 20 weeks of age and by measurement of myocardial prostacyclin and cyclic guanosine monophosphate (GMP) concentrations. Chronic high-dose treatment with perindopril attenuated the development of hypertension and left ventricular hypertrophy while low-dose perindopril treatment had no effect on these parameters. However, low-dose perindopril improved cardiac function of isolated perfused hearts as demonstrated by an increasing left ventricular pressure and dp/dtmax without change in heart rate. Low-dose perindopril further reduced lactate concentrations and the enzymatic activities of lactate dehydrogenase and creatine kinase in the coronary venous effluent and increased tissue concentrations of glycogen, adenosine triphosphate, and creatine kinase in the myocardium. Concomitant chronic bradykinin receptor blockade abolished all ACE inhibitor-induced effects on cardiac function and metabolism. Cardiac prostacylin concentrations were 3-fold elevated in perindopril-treated animals when compared to vehicle-treated controls, while cardiac cyclic GMP concentrations remained unchanged. Our data demonstrate that chronic ACE inhibitor treatment can improve cardiac function and metabolism independently of the antihypertensive and antihypertrophic drug actions by potentiation of endogenous bradykinin.

Analysis of Variance↗
PubMed1995

Effect of perindopril in pacing-induced canine models of acute and chronic heart failure.

OBJECTIVE: To examine the effects of perindopril, a nonsulfhydryl-containing angiotensin-converting enzyme inhibitor, on total vascular capacitance and hemodynamics in acute and chronic dog models of heart failure. METHODS: Acute heart failure was induced in anesthetized, splenectomized dogs by a volume load (dextran 70, 20 mL/kg) during rapid right ventricular pacing (RRVP) at 250 beats/min. Pretreatment with perindopril (0.3 mg/kg daily for six days, n = 7) was compared with no treatment (n = 7). Total vascular capacitance and compliance were measured from plots of mean circulatory filling pressure during acetylcholine-induced circulatory arrests at different blood volumes. Chronic heart failure was induced by continuous RRVP in splenectomized dogs treated with perindopril (0.3 mg/kg daily, n = 8), which were compared with untreated dogs (n = 8). Hemodynamics and total vascular capacitance and compliance were measured at baseline and after 33 days of RRVP. RESULTS: Perindopril treatment did not significantly modify the increased pulmonary capillary wedge and mean circulatory filling pressures, reduced total vascular compliance or total vascular capacitance associated with the volume load and acute RRVP. During chronic RRVP, perindopril reduced weight gain and the development of ascites, reduced right atrial pressure (6.3 +/- 1.3 versus 10.3 +/- 1.2 mmHg), mean circulatory filling pressure (9.3 +/- 1.0 versus 14.7 +/- 1.2 mmHg), stressed blood volume (22 +/- 3 versus 33 +/- 4 mL/kg) and central blood volume (10 +/- 1 versus 14 +/- 1 mL/kg) while increasing cardiac output (122 +/- 9 versus 98 +/- 7 mL/kg). However, the reduction in total vascular capacitance was not attenuated and pulmonary capillary wedge pressure was not lowered significantly (18.5 +/- 1.5 versus 21.4 +/- 1.3 mmHg). CONCLUSION: Perindopril failed to modify hemodynamics in the pacing-induced canine model of acute heart failure but had beneficial effects in the model of chronic heart failure.

Acute Disease↗
PubMed1995

The effects of perindopril on vascular smooth muscle polyploidy in stroke-prone spontaneously hypertensive rats.

OBJECTIVE: To quantify vascular smooth muscle polyploidy and growth kinetics in aortic cells from stroke-prone spontaneously hypertensive rats (SHRSP) and from normotensive Wistar-Kyoto (WKY) rats, and to examine the effects of treatment with the angiotensin converting enzyme (ACE) inhibitor perindopril on these parameters. DESIGN: The following experimental groups were used: young (age < 20 weeks) and old (age > 20 weeks) untreated WKY rats and untreated SHRSP; SHRSP treated with perindopril, and age- and sex-matched control SHRSP; and SHRSP treated with hydralazine and hydrochlorothiazide and age- and sex-matched control SHRSP. The effects of treatment of the SHRSP with perindopril for 30 days on vascular smooth muscle polyploidy and growth kinetics were measured and compared with the effects of equivalent antihypertensive doses of hydralazine and hydrochlorothiazide. METHODS: Vascular smooth muscle polyploidy was measured using flow-cytometry DNA analysis of freshly harvested cells. Growth curves were performed on cultured aortic cells. Plasma renin activity was measured by an antibody-trapping method, plasma angiotensin II (Ang II) by radioimmunoassay and plasma ACE activity by a colorimetric method. Cardiac hypertrophy was evaluated by measuring the heart weight:body weight and left ventricle + septum weight:body weight ratios. RESULTS: The SHRSP had markedly and significantly elevated G2 + M phase of the cell cycle. Treatment with perindopril resulted in a significant reduction in polyploidy in the SHRSP, whereas treatment with hydralazine and hydrochlorothiazide had no effect on the percentage of cells in the G2 + M phase of the cell cycle. The regression of polyploidy after treatment with perindopril was associated with a significant reduction in the concentration of Ang II and ACE activity, and with a significant regression of cardiac hypertrophy. Increased mitogenesis of cultured vascular smooth muscle cells from the SHRSP was not altered by treatment with perindopril. CONCLUSIONS: ACE inhibition reduces vascular smooth muscle polyploidy in large conduit arteries. This type of vascular protection is mediated by the reduced Ang II and possibly by increased kinins level, rather than by the hypotensive effect alone.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Effects of perindopril on hypertension and stroke prevention in experimental animals.

BACKGROUND: Among the antihypertensive agents available for the treatment of hypertension, only angiotensin-converting enzyme (ACE) inhibitors have been shown to modify cardiovascular changes in structure and function. OBJECTIVE: To study the effect of perindopril treatment on hypertension and stroke prevention in two genetic models of hypertensive rats. DESIGN: Adult (15 weeks old) spontaneously hypertensive rats (SHR) were treated with perindopril to determine the dose- and duration-dependent effects of treatment on systolic blood pressure, and the effect of withdrawal of this treatment on blood pressure and survival. In stroke-prone SHR, treatment was initiated in young animals (six weeks), and dose- and duration-dependent effects of perindopril treatment on stroke prevention were assessed. RESULTS: In adult SHR, perindopril caused a dose-dependent lowering of blood pressure. Blood pressure was controlled for a 24 h period with a single daily dose. The magnitude of rebound hypertension after withdrawal of treatment was negatively correlated with duration of treatment. After 12 weeks of treatment, the blood pressure of treated SHR remained normotensive without further treatment, and the life span of treated SHR was also extended. Treatment of young, stroke-prone SHR with perindopril prevented stroke in these animals during the treatment period. After withdrawal of treatment, survival of the rats was increased in animals given a longer treatment period (24 weeks versus eight or 12 weeks). CONCLUSION: Treatment with the ACE inhibitor perindopril is effective in the prevention of hypertension and stroke in experimental animals.

Analysis of Variance↗
PubMed1995

An equivalence study of the safety and efficacy of a fixed-dose combination of perindopril with indapamide versus fixed-dose combinations of captopril with hydrochlorothiazide and enalapril with hydrochlorothiazide in the treatment of hypertension.

OBJECTIVE: The aim of this multicenter, randomly allocated, double-blind, parallel-group study was to evaluate the equivalence of three fixed-dose combination drugs in mild to moderate hypertension: perindopril + indapamide (4 + 1.25 mg), captopril + hydrochlorothiazide (50 + 25 mg) and enalapril + hydrochlorothiazide (20 + 12.5 mg). PATIENTS AND METHODS: After a single-blind, 4-week, placebo run-in phase, 527 patients (mean +/- SD age 54.5 +/- 1.2 years) with a supine diastolic blood pressure of 101.2-101.7 mmHg were randomly assigned to one of the three treatments for 8 weeks. The main evaluation criteria were diastolic blood pressure and serum potassium concentration. Equivalence was assessed on an intention-to-treat basis, using Schuirmann's method, which involves performing two one-tailed statistical tests on the data. Thirty-five patients were withdrawn from the study but there were no differences between groups in the reasons for withdrawal. RESULTS: Diastolic blood pressure decreased by between 13.1 and 14.2 mmHg in the three groups. The 90% confidence intervals for the differences between perindopril + indapamide and the other treatments were -1.1, +1.7 mmHg for captopril + hydrochlorothiazide and -0.4, +2.6 mmHg for enalapril + hydrochlorothiazide. Schuirmann's test was highly statistically significant (P<0.001 for perindopril + indapamide versus captopril + hydrochlorothiazide; P<0.002 for perindopril + indapamide versus enalapril + hydrochlorothiazide), so that the two one-sided hypotheses that the treatments were not equivalent were rejected at the nominal level of alpha = 0.05. Similarly, the safety of the treatments was equivalent in terms of serum potassium. The 90% confidence intervals of the differences between perindopril + indapamide and the other treatments were -8.7, -1.6% for captopril + hydrochlorothiazide (P = 0.004) and -1.5, +2.7% for enalapril + hydrochlorothiazide (P<0.001). CONCLUSIONS: We conclude that the safety and efficacy of perindopril + indapamide, captopril + hydrochlorothiazide and enalapril + hydrochlorothiazide were equivalent after 8 weeks of treatment in patients with mild to moderate hypertension.

Adolescent↗
PubMed1993

The effect of haemodialysis on the pharmacokinetics of perindoprilat after long-term perindopril.

We have studied the pharmacokinetics of perindoprilat, the active metabolite of perindopril, in 7 hypertensive patients undergoing haemodialysis after short-term and long-term (1 month) perindopril. We also measured angiotensin-converting enzyme activity. Each subject took 2 mg of perindopril after a 4-hour haemodialysis. Serial blood samples were obtained each hour during dialysis and between dialysis (7 samples over 44 h). Perindoprilat steady state was reached within 5 haemodialysis sessions. There was a high degree of angiotensin converting enzyme inhibition after the first dose. Administration for 1 month did not modify the time to peak perindoprilat concentration but significantly increased the mean maximal concentration: 10.2 versus 26.8 ng.ml-1. The mean accumulation ratio was 3.5. The mean reduction in perindoprilat concentration after dialysis was greater than 50%. Perindoprilat haemodialysis clearance was 62 ml.min-1 after the first administration and 72 ml.min-1 after 1 month. Tolerance of perindopril was good throughout the study. Treatment can be begun with 2 mg of perindopril after haemodialysis in hypertensive patients undergoing haemodialysis.

Adult↗