Cardiorenal protective effects of year-long antihypertensive therapy with an angiotensin-converting enzyme inhibitor or a calcium channel blocker in spontaneously hypertensive rats.

BACKGROUND: The objective of this study was to evaluate the effect of year-long antihypertensive therapy with a calcium channel blocker and an angiotensin-converting enzyme (ACE) inhibitor on cardiac and renal injury. METHODS: Male 15-week-old spontaneously hypertensive rats (SHR) were given either a normal diet and normal drinking water (n = 10), a diet containing 0.05% nitrendipine (n = 10), or drinking water containing 50 mg/L of quinapril (n = 10). After 12 months of antihypertensive treatment, cardiovascular organ injuries were evaluated. RESULTS: Tail-cuff blood pressure (BP) at 12 months was significantly lower in animals receiving nitrendipine or quinapril than in control animals (control, 231 +/- 2 mm Hg; nitrendipine, 194 +/- 3 mm Hg; quinapril, 191 +/- 3 mm Hg; P < .001). Furthermore, aortic thickness was reduced by nitrendipine (-19%, P < .001) or quinapril (-21%, P < .001), and cardiac ventricular weight was significantly reduced by quinapril (-18%, P < .001) but not by nitrendipine (-5%, P = not significant [NS]). Echocardiography at 12 months revealed that midwall fractional shortening was higher in the quinapril group than in the control or the nitrendipine groups (control, 9.3% +/- 0.5%; nitrendipine, 9.8% +/- 0.5%; quinapril, 10.6% +/- 0.6%; P < .05). Left ventricular hydroxyproline levels were lower in the nitrendipine group (-21%, P < .01) and the quinapril group (-36%, P < .001) than in the control animals. In control SHR, creatinine clearance began to decrease and proteinuria began to increase at 6 to 9 months. Quinapril but not nitrendipine attenuated these markers of renal impairment (creatinine clearance at 12 months: control, 4.7 +/- 0.4 mL/min/kg; nitrendipine, 5.0 +/- 0.4 mL/min/kg; quinapril, 6.1 +/- 0.4 mL/min/kg; P < .05). Histologically, the glomerular injury score was lower in the quinapril group than in the control or nitrendipine groups (control, 19 [range, 8 to 30]; nitrendipine, 18 [range, 9 to 32]; quinapril, 7 [range, 3 to 12]; P < .01). CONCLUSIONS: It is suggested that year-long antihypertensive therapy with an angiotensin-converting enzyme (ACE) inhibitor is superior to a calcium channel blocker in terms of cardiorenal protection in SHR.

ACE inhibitors improve nephrin expression in Zucker rats with glomerulosclerosis.

BACKGROUND: Podocyte injury is associated with many forms of human and experimental proteinuric glomerular disease. The aim of this study was to investigate the level of nephrin expression in a model of obesity and type II diabetes mellitus, the obese Zucker rat, as well as to investigate whether nephrin expression is influenced by treatment with quinapril or diltiazem, 2 drugs frequently used in type II diabetes mellitus. METHODS: Obese Zucker rats were treated with either quinapril or diltiazem at a dose of 10 mg/kg body weight per day and 100 mg/kg body weight per day, respectively, for 6 months. Real time reverse transcription-polymerase chain reaction (RT-PCR) and immunoperoxidase assays were used to assess and quantify nephrin gene expression and other markers of podocyte damage, such as desmin and synaptopodin protein. RESULTS: Quinapril treatment prevented the reduction of nephrin levels compared with the control group, while diltiazem treatment did not prevent the reduction. Similar results were obtained when other phenotypic markers, such as desmin, were assessed. Similarly, synaptodin showed this tendency, although it did not achieve statistically significant differences. CONCLUSION: The podocyte phenotypic changes assessed in a model of obesity and type II diabetes mellitus were corrected by an angiotensin-converting enzyme (ACE) inhibitor. These results could be associated with an improvement in the slit diaphragm, and therefore, in the maintenance of the filtration barrier. Diltiazem did not achieve similar results.

Effect of quinapril, quinapril-hydrochlorothiazide, and enalapril on the bone mass of hypertensive subjects: relationship with angiotensin converting enzyme polymorphisms.

BACKGROUND: Many alterations in extracellular metabolism of calcium have been associated to hypertension, but the number of studies relating this disease with osteoporosis is extremely low. This study clarifies the therapeutic effect of three treatments-quinapril, quinapril + hydrochlorothiazide (HCTZ), enalapril-on bone remodeling markers, bone mineral density (BMD) in hypertensive patients, and relationship with angiotensin converting enzyme (ACE) polymorphism. METHODS: This open, prospective study included 134 patients with low-to-moderate hypertension and stable BMD according to Joint National Committee criteria and 96 patients completed the study. After a washout period, patients were randomized to one of the three treatments, which they received for 1 year. Analyses of blood and urine samples and densitometric studies on lumbar spine were performed. RESULTS: Calcium and 25-hydroxyvitamin D levels increased (9.5 +/-0.3 and 9.6 +/-0.3 mg/dL, P =.01 and 46 +/-22 and 58 +/-22 nmol/L, P =.026, respectively) in the quinapril-treated group and calcium levels increased (9.4 +/-0.6 and 9.8 +/-0.4 mg/dL, P =.001) in the quinapril-HCTZ-treated group. The 1, 25-dihydroxyvitamin D levels, calciuria, and calcium/creatinine ratio decreased (64 +/-23 and 43 +/-16 nmol/L, P =.0001;209 +/-93 and 161 +/-93 mg/24 h, P =.0022;0.21 +/-0.09 and 0.17 +/-0.11, P =.04, respectively). In the enalapril-treated group 1, 25-dihydroxyvitamin D levels (61 +/-27 and 42 +/-19 nmol/L, P =.0022) decreased. Only women presented a statistical significance (1.064 +/-0.16 g/cm(2), P =.034) between ID+II polymorphism and BMD decrease, and between DD polymorphism with less BMD under baseline conditions and a BMD increase (1.070 +/-0.16 g/cm(2), P =.017) after ACE inhibitor treatment. CONCLUSIONS: The ACE inhibitors have a beneficial effect on BMD and calcium metabolism alterations in hypertensive subjects. Concerning BMD response, women presenting with the II+ID polymorphism had a poor response to antihypertensive drug treatment, whereas women with the DD polymorphism responded better. This is the first study demonstrating a relationship between ACE polymorphism and BMD response and antihypertensive ACE inhibitor treatment.

The influence of angiotensin-converting enzyme inhibitors on the aorta elastin metabolism in diet-induced hypercholesterolaemia in rabbits.

Aortic elastin turnover is significantly accelerated in atherosclerosis, partly because of activation of the renin-angiotensin-aldosterone system caused by hypercholesterolaemia. We postulated that angiotensin-converting enzyme inhibitors (ACE-I) prevent the aortic elastin loss in experimental hypercholesterolaemia. Two doses of ACE-I (captopril, enalapril and quinapril) were used: a dose equivalent to that applied to human subjects and a dose 10 times higher. We found that the increase in serum and aortic elastolytic activity in cholesterol-fed rabbits was prevented by high-dose captopril. The elastin content in aorta homogenates from cholesterol-fed rabbits was significantly decreased. The higher dose of captopril, but no other ACE-I, prevented this decrease in aortic elastin content. In cholesterol-fed rabbits the elastin-bound calcium content was significantly elevated. The higher doses of captopril and enalapril lowered the elastin-bound calcium content. In serum and aortic homogenates of cholesterol-fed rabbits, ACE activity was elevated by 15% and 77%, respectively. Both doses of captopril, enalapril and quinapril prevented this cholesterol-induced increase in serum and aortic ACE activity. We conclude that: 1) administration of captopril at doses 10 times higher than those used in humans prevents hypercholesterolaemia increased aortic elastin loss. 2) higher doses of captopril and enalapril prevent the hypercholesterolaemia-induced increase in aortic elastin-bound calcium.

Inhibition of arterial thrombogenesis by quinapril but not losartan.

The cardioprotective effect of angiotensin converting enzyme (ACE) inhibitors and angiotensin type I (AT1) receptor blockers may relate to their antithrombotic effect. We determined the differential effects of the ACE inhibitor quinapril and the AT1 receptor blocker losartan on arterial thrombus formation in the rat. Sprague-Dawley rats were fed regular chow or chow mixed with low-dose quinapril (0. 6 mg/kg/day), high-dose quinapril (1.2 mg/kg/day), or losartan (10 mg/kg/day) for 15 days. Abdominal aorta was exposed and wrapped with Whatman paper impregnated with 29% FeCl(3) (ferric chloride). Time to occlusive thrombus formation and weight of the thrombus were recorded. Aortic superoxide anion generation, platelet aggregation, plasma angiotensin II levels, and morphology of the thrombus were also examined. Both losartan and quinapril caused similar reductions in arterial pressure. Losartan did not affect the time to thrombus formation, whereas quinapril (both low and high doses) delayed the time to thrombus formation (P<.01 vs control). Weight of the thrombus was similar in all groups of rats. Platelet aggregation was inhibited by approximately 50 in both quinapril- and losartan-treated rats. The high-dose quinapril-treated rats showed markedly reduced vascular superoxide anion generation compared with the control rats (P<.05). Plasma angiotensin II levels were unaffected by quinapril treatment but were elevated 7-fold in losartan-treated rats (P <.001 vs. control rats). The thrombi in the control rats consisted of platelet aggregates, fibrin, and red blood cells. The intravascular platelet aggregates were much smaller in the quinapril-treated rats (P<.05 vs. control), but were similar in control and losartan-treated rats. In conclusion, quinapril but not losartan prolongs time to arterial thrombus formation and results in smaller platelet aggregates in the thrombus. Both quinapril and losartan decrease platelet aggregation, but only quinapril decreases superoxide anion generation. This effect on superoxide anion generation as well as mechanisms other than AT1 receptor blockade may underlie the salutary effect of quinapril on arterial thrombogenesis.

Chronic AT1 receptor blockade and angiotensin-converting enzyme (ACE) inhibition in (CHF 146) cardiomyopathic hamsters: effects on cardiac hypertrophy and survival.

OBJECTIVE: We have reported that angiotensin II AT1 receptors are upregulated and that there are no AT2 receptors in the ventricles of cardiomyopathic hamsters. Since the upregulation was present even when no histological lesions were detectable, these results suggested that angiotensin II plays a role in the genesis/maintenance of this pathology. A survival study was conducted to compare the effects of an angiotensin II AT1 receptor antagonist, losartan (L), to those of a placebo (P). Since the angiotensin-converting enzyme (ACE) inhibitor quinapril (Q) has been shown to have beneficial effects in this animal model, a Q group was included. METHODS: Male Syrian cardiomyopathic hamsters (CHF 146, n = 360) were orally administered P, low- (30 mg/kg/day) or high-dose (100 mg/kg/day) L, or Q (100 mg/kg/day), starting at day 50 of life. Inbred control hamsters (CHF 148, n = 180) were treated with P or L (100 mg/kg/day) as controls. Animals were sacrificed at intervals to evaluate cardiac hypertrophy. Kaplan-Meier analysis was performed to assess differences in survival. RESULTS: High-dose L had no effects on the survival of control hamsters. There was an unexpected dose-dependent decrease in the survival of cardiomyopathics treated with L (low-dose, P = 0.14; high-dose, P = 0.0015) compared to an increase with Q (P = 0.0003). Cardiac hypertrophy compared to P was increased with L but significantly decreased with Q in cardiomyopathics. CONCLUSIONS: In this model, losartan did not improve survival compared to placebo and quinapril and, if anything, increased mortality. Our results suggest that AT1 receptor antagonists and ACE inhibitors are not necessarily equivalent or interchangeable in terms of their effects on cardiac hypertrophy and survival in selected progressive heart failure models.

Platelet hyperactivity in hypertensive older patients is controlled by lowering blood pressure.

OBJECTIVE: Patients with hypertension tend to have a high prevalence of atherothrombotic accidents. Platelet hyperactivity is frequently associated with hypertension. Because the vascular disease associated with hypertension evolves over the years, we investigated platelet activity parameters in a population of older hypertensive patients with no other risk factors for cardiovascular disease. PARTICIPANTS: We studied 34 older, nonsmoking patients (mean age 74 +/- 5 years) with uncomplicated hypertension before and after the normalization of blood pressure (BP) was achieved with the angiotensin-converting enzyme inhibitor quinapril alone or in combination with the Ca2+ antagonist nifedipine. MEASUREMENTS: Platelet aggregation, P-selectin (CD62) expression on the platelet surface, serum levels of Interleukin-1beta (IL-1beta) and of Interleukin-6 (IL-6), as well as plasma levels of soluble P-selectin and Endothelin-1 (ET-1), were analyzed. RESULTS: All platelet hyperactivity parameters were reduced significantly with the normalization of BP at the end of antihypertensive drug treatment (systolic/diastolic: 186.2 +/- 2.7/103.4 +/- 1.1 mm Hg vs 135.0 +/- 1.3/85.9 +/- 1.9 mm Hg; P < .001). Those factors more strictly associated with endothelium injury, such as ET-1 and IL-6, did not show variations. A significant correlation (Spearman Rank test) was observed among all platelet function parameters and blood pressure values. CONCLUSIONS: This study demonstrated that even in a population of older hypertensive patients with no other risk factor for atherogenic disease, normalization of blood pressure induces a significant reduction of the parameters of enhanced platelet hyperactivity independent of the action exerted, at the platelet level, by the antihypertensive drugs.

Effects of antihypertensive therapy on factors mediating endothelium-dependent relaxation in rats treated chronically with L-NAME.

OBJECTIVES: To evaluate the relative participation of endothelium-derived factors mediating relaxation in response to acetylcholine in isolated mesenteric vascular beds from rats treated chronically with N(G)-nitro-L-arginine methylester (L-NAME); and to compare the consequences of prolonged treatment with either an angiotensin converting enzyme inhibitor or a calcium channel blocker on the components of acetylcholine-induced relaxation in this vascular preparation. MATERIALS AND METHODS: Male Sprague- Dawley rats were treated for 8 weeks with L-NAME (40 mg/kg per day), quinapril (10 mg/kg per day), diltiazem (100 mg/kg per day), L-NAME + quinapril and L-NAME + diltiazem. Systolic blood pressure was estimated by a tail-cuff plethysmograph. Relaxing responses to acetylcholine (10(-12) to 10(-8) mol) in mesenteric vascular beds precontracted with phenylephrine (10(-5) mol/l) were studied in the presence and absence of L-NAME (10(-5) mol/l), L-NAME + indomethacin (10(-5) mol/l) or L-NAME + indomethacin + potassium chloride (6 x 10(-5) mol/l). The area under the dose- response curve was used to calculate the approximate participation of nitric oxide, prostaglandins or endothelium-derived hyperpolarizing factor in the acetylcholine-induced relaxation. RESULTS: Chronic administration of L-NAME increased blood pressure levels and vascular responsiveness to phenylephrine. Treatments with either quinapril or diltiazem reduced blood pressure levels and attenuated the increased response to phenylephrine. Relaxing responses to acetylcholine were similar in all groups, independently of the treatment received. The calculated participation of endothelium-derived hyperpolarizing factor in the acetylcholine-induced relaxation was higher than that of nitric oxide and prostaglandins in all groups, but was higher in L-NAME-treated than in untreated rats. In contrast, the participation of both nitric oxide and prostaglandins was higher in control than in L-NAME-treated rats. Quinapril increased the participation of prostaglandins in L-NAME-treated rats. Diltiazem increased the participation of nitric oxide in L-NAME-treated rats. CONCLUSIONS: The administration of L-NAME in Sprague-Dawley rats increased the production of endothelium-derived hyperpolarizing factor as a compensatory mechanism to maintain acetylcholine-induced relaxation. Antihypertensive therapy with either quinapril or diltiazem produced a selective redistribution of the endothelial factors mediating acetylcholine-induced relaxation.

How should we treat hypertensive women with cardiac and renal impairment?

Arterial hypertension is the most common chronic medical condition requiring office visits to physicians and is a major contributing factor to the development of myocardial infarction and stroke. Its importance as a cardiovascular risk factor is at least as significant in women as in men; however, the ever-growing literature on hypertension shows surprisingly little data concerning sex differences. Large clinical trials of antihypertensive treatment have not clearly demonstrated gender differences in blood pressure response and outcome, but the majority of patients in these trials were men. Even so, some evidence indicates that white women treated for hypertension obtain less benefit than men. The pathophysiology of hypertension in men and women is similar in many aspects, but important gender differences are now emerging. Studies designed to clarify these differences are required, as a better knowledge of the underlying mechanisms will allow for a more precise stratification of risk and a more accurate approach to both nonpharmacologic and pharmacologic treatment.

Chronic ACE inhibition by quinapril modulates central vasopressinergic system.

OBJECTIVE: The role of the brain as a target for angiotensin converting enzyme (ACE) inhibitors in the treatment of heart failure and hypertension is unclear. To test the hypothesis that ACE inhibitors may modulate other central neuropeptide systems such as the central vasopressin system, we studied the effects of chronic treatment with the ACE inhibitor, quinapril, on ACE activity and on central vasopressin content in specific brain areas in rats. METHODS: 22 rats were chronically treated with quinapril (6 mg.kg-1 BW per gavage daily for 6 weeks; untreated controls, n = 14). ACE density in various brain regions was assessed by in vitro autoradiography using the specific ACE inhibitor, 125I-351A. Vasopressin content was determined in 19 brain areas (micropunch technique) known to be involved in cardiovascular regulation. RESULTS: Following chronic quinapril treatment ACE was significantly decreased in the thalamus (-38%), hypothalamus (-37%), hypophysis (-35%), cerebellum (-36%) choroid plexus (-20%), and locus coeruleus (-35%). Additionally, a marked reduction in serum ACE activity (-97%) was observed. Plasma levels of vasopressin were significantly decreased after quinapril treatment (0.97[s.e.m. 0.11] vs. 1.63[0.24] pg.ml-1 in controls, P < 0.05). Vasopressin content was significantly reduced in 9 of 19 specific brain areas. Regarding the hypothalamic vasopressin-producing nuclei, vasopressin was decreased in the paraventricular (292[197] vs. 2379[585] pg.mg-1 crotein in controls; P < 0.001) and supraoptic nuclei (13618[1979] vs. 24525[3894] pg.mg-1 protein; P < 0.05), but not in the suprachiasmatic nucleus. Vasopressin content was significantly reduced in brain areas connected by vasopressinergic fibres originating in the hypothalamic paraventricular nucleus: namely central gray, subcommissural organ, organum vasculosum laminae terminalis, dorsal raphe nucleus, and locus coerules. Vasopressin content was also significantly reduced in the median eminence (5887[1834] vs. 28321[4969] pg.mg-1 protein, P < 0.001), where the hormone is mainly concentrated in the hypothalamo-hypophysial tract. CONCLUSIONS: Autoradiographic studies in vitro indicate that orally administered quinapril suppresses central ACE activity after chronic treatment. ACE inhibition by quinapril strongly influences vasopressin content in important brain areas which are involved in central cardiovascular regulation. Therefore, central modulatory effects of ACE inhibitors may also contribute to overall therapeutic efficacy.

Preclinical toxicology studies with the angiotensin-converting enzyme inhibitor quinapril hydrochloride (Accupril).

Acute, subacute, and chronic toxicity studies, carcinogenicity bioassays, and reproductive and genetic toxicology studies were performed with quinapril, an ACE inhibitor used in the treatment of hypertension. Acute toxicity is minimal in rodents, and repeated dosing elicits gastric irritation, juxtaglomerular apparatus (JGA) hypertrophy and hyperplasia and tubular degenerative changes in the kidney, and reduced red cell parameters and heart weights in rodents and/or dogs. Other manifestations of toxicity, including hepatic lesions in dogs, reduced offspring weights in rats, marked sensitivity of the rabbit, and clastogenic effects at cytotoxic doses in the in vitro V79 chromosome aberration assay, have been reported with other drugs of this class.

Neointima formation in injured hamster carotid artery is effectively prevented by the combination G4120 and quinapril.

The prevention of neointima formation by the tissue selective angiotensin converting enzyme (ACE) inhibitor quinapril and by the combination quinapril/G4120 (a platelet alpha Ub beta 3 and smooth muscle cell alpha v beta 3 antagonist) was investigated in a hamster carotid artery injury model. Quinapril at 10 mg/kg/day reduced neointima formation by about 45%, 1 and 2 weeks after injury to the artery, i.e. significantly better than the non-tissue selective ACE inhibitor captopril at 100 mg/kg/day. Quinapril did not decrease the early smooth muscle cell (SMC) proliferation in the media, but in agreement with its inhibition of the carotid artery ACE activity by 62%, SMC proliferation was reduced by 70% in the newly forming intima. To improve the inhibition of early medial SMC proliferation, quinapril (10 mg/kg/day) was complemented with G4120 (100 micrograms/kg/h). This combined treatment reduced the proliferation of medial SMCs to about 50% throughout the first week following injury, whereas intima SMC proliferation was reduced by 70% throughout treatment. Accordingly, the drug combination reduced neointima formation more potently than each drug separately by 70%. The disruption of medial elastic laminae, observed in the control and G4120 treated group, was consistently reduced when G4120 was complemented with quinapril. Thus, the present study shows in a hamster model of carotid artery injury, that combining drugs that prevent SMC migration and proliferation via different modes of action can lead to the effective prevention of neointima formation.

Endothelium-dependent relaxation in resistance arteries from spontaneously hypertensive rats: effect of long-term treatment with perindopril, quinapril, hydralazine or amlodipine.

OBJECTIVE: To examine the effects of different types of antihypertensive treatment on endothelium-dependent relaxation in resistance arteries from spontaneously hypertensive rats (SHRs). DESIGN AND METHODS: Three-week-old SHRs were treated with the angiotensin converting enzyme (ACE) inhibitor perindopril (1 mg/kg/day) or quinapril (3 mg/kg/day) or the vasodilator hydralazine (50 mg/kg/day) or the calcium antagonist amlodipine (10 mg/kg/day). Control SHRs and Wistar-Kyoto (WKY) rats were treated with water. After 21 weeks rats were culled and mesenteric resistance arteries were mounted in a myograph. Relaxation responses to the endothelium-dependent vasodilators acetylcholine (ACh) and bradykinin were recorded before and after incubation with the nitric oxide synthase inhibitor NG-nitro-L-arginine (L-NOARG), as was the relaxation response to the nitric oxide donor sodium nitroprusside (SNP). RESULTS: All drugs prevented the rise in blood pressure found in the untreated SHRs. ACh-induced relaxation was significantly impaired in the untreated SHRs compared with the WKY rats. Treatment with either ACE inhibitor prevented the development of this impaired response. ACE inhibitor treatment significantly increased the relaxation response to bradykinin. Despite lowering blood pressure, hydralazine or amlodipine had no effect on ACh- or bradykinin-induced relaxation. Responses to SNP were not different between untreated SHRs and WKY rats and were not affected by drug treatment. CONCLUSION: Specific properties of certain antihypertensive drugs may play an important role in restoring endothelium-dependent relaxation in the small arteries that regulate peripheral resistance in the SHR.

Plasma digoxin immunoreactivity and arterial potassium relaxation after quinapril therapy in hypertensive rats.

Plasma digitalis-like substance and altered function of arterial Na+,K(+)-ATPase have both been linked with elevated blood pressure, but the influence of antihypertensive therapy on these factors remains unknown. Therefore, we treated spontaneously hypertensive rats and normotensive Wistar-Kyoto rats with the angiotensin-converting enzyme inhibitor quinapril for 10 weeks. The therapy markedly reduced blood pressure and plasma digoxin immunoreactivity, and it normalized the elevated plasma Na+:K+ ratio in the hypertensive animals. Relaxations of endothelium-denuded denervated arterial rings induced by return of potassium to the organ bath upon precontractions elicited by potassium-free solution were used to evaluate the function of vascular Na+,K(+)-ATPase. The rate of potassium relaxation was faster in quinapril-treated hypertensive rats and in both Wistar-Kyoto groups than in the hypertensive controls. Potassium relaxation was also effectively inhibited by the Na+,K(+)-ATPase inhibitor ouabain in all groups. In addition, arterial contractions to potassium chloride and relaxations to nitroprusside were examined. The contractions to lower concentrations of potassium chloride (20 mM) were enhanced in untreated hypertensive rats when compared with the other groups, although the maximal responses were corresponding in all groups. The time to reach base-line tension after washout of potassium chloride (125 mM) and the relaxations to nitroprusside did not differ in the study groups. In conclusion, the present results showed that long-term angiotensin-converting enzyme inhibition in parallel reduced plasma digoxin-like factor, enhanced arterial potassium relaxation (probably reflecting enhanced function of Na+,K(+)-ATPase) and normalized plasma Na+:K+ ratio in this type of genetic hypertension.

[Long-term treatment with quinapril in chronic aortic and mitral insufficiency]. / Langzeittherapie mit Quinapril bei chronischer Aorten- und Mitralinsuffizienz.

The effect on myocardial function and structure of long-term administration of quinapril (10-20 mg daily), an angiotensin-converting-enzyme (ACE) inhibitor, was investigated in 24 patients (18 men, 6 women; mean age 48 [20-65] years) with chronic isolated asymptomatic aortic or mitral regurgitation. Coronary heart disease had been excluded angiographically. After one year's treatment the regurgitation fraction, compared with the pretreatment value, had decreased by 27% in those patients with aortic regurgitation (AR) and 42% in those with mitral regurgitation (MR) (P = 0.0001). The mean left ventricular enddiastolic volume was reduced from 150 +/- 33 to 128 +/- 30 ml/m2 in patients with AR, from 146 +/- 26 to 109 +/- 24 ml/m2 in those with MR (P = 0.0001). The mean endsystolic volume fell from 55 +/- 27 to 44 +/- 28 ml/m2 in patients with AR and from 63 +/- 43 to 47 +/- 29 ml/m2 in those with MR (P = 0.002). The mean left ventricular ejection fraction at rest and on exercise rose slightly in patients with AR, remaining unchanged in those with MR. The left ventricular mass, as measured by echocardiography, was reduced by 35% in patients with AR, and the left ventricular hypertrophy, demonstrated in all patients, regressed. In patients with MR the left ventricular mass decreased by 15% and septal thickness became normal (borderline hypertrophy). These data indicate that, after one year's treatment with quinapril, left ventricular dilatation, mass and hypertrophy regressed and left ventricular function improved in patients with AR or MR.

Angiotensin-converting enzyme inhibition with quinapril (CI-906) and captopril in spontaneously hypertensive rats with suppressed renin-angiotensin system.

Renin- and nonrenin-mediated antihypertensive actions of angiotensin-converting enzyme (ACE) inhibitors were investigated in young spontaneously hypertensive rats (SHR). Renin was suppressed either by removal of 2/3 of the renal mass, deoxycorticosterone (DOC) treatment, or 1% of NaCl in drinking water. Blood pressure responses to the nonsulfhydryl ACE inhibitor quinapril (CI-906) and the sulfhydryl inhibitor captopril, given orally for 2 days each, were examined by the tail cuff method. The marked depressor responses observed in control SHR were attenuated by the different manipulations in a manner clearly related to suppression of plasma renin activity (PRA). The decrease in blood pressure falls and in PRA was smallest in partially nephrectomized SHR. The mineralocorticoid (DOC) administration or 1% NaCl reduced PRA and the responses to ACE inhibitors markedly, though not completely. In a further experiment, severe salt retention induced by DOC and NaCl in uninephrectomized SHR suppressed PRA to an unmeasurable level and prevented the depressor action of a large dose of captopril. The results suggest that in SHR the acute blood pressure-lowering effect of ACE inhibitors is completely dependent on the renin-angiotensin system. The experiments also show that this system clearly participates in the support of rapidly increasing blood pressure in young SHR.