ramipril and Hypertension--Renovascular

Ramipril, a converting enzyme inhibitor, was first studied in rats with aortic stenosis, an experimental model of reno-vascular hypertension. In this study, ramipril has an antihypertrophic cardiac effect, independently to its hypotensive effect. The co-administration of Hoe 140, a specific antagonist of bradykinin receptors blocked totally the effect of ramipril on blood pressure, cardiac hypertrophy and on concentration of cGMP. These effects can therefore be explained by an accumulation of bradykinins. Furthermore, we investigated the preventing effects of ramipril on left ventricular hypertrophy, on growth of cardiac capillaries using SHR rats, treated in utero and during the 20 weeks following birth with two doses: a relatively high dose (1 mg/kg/day) and a low dose (0.01 mg/kg/day). Animals treated with a low dose of ramipril presented a high blood pressure similar to that observed in the control group. At the end of the treatment, the converting enzyme activity was inhibited in both groups. An increase in the growth of cardiac capillaries and of the cardiac concentration of glycogen and a decrease in the cardiac concentration of citric acid was observed in both groups. The ventricular weight decreased only in the high dose treatment group. This results demonstrated that early treatment with converting enzyme inhibitor even with a low dose which was unable to prevent the development of hypertension and of left ventricular hypertrophy. We could therefore draw a hypothesis of an accumulation of bradykinin due to the converting enzyme inhibitor which could explain in part this effect through an improvement of cardiac metabolism.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Bridged Bicyclo Compounds; Hypertension, Renovascular; Oligopeptides; Ramipril; Rats; Rats, Inbred SHR; Receptors, Bradykinin; Receptors, Neurotransmitter

In renal hypertensive rats with pressure overload left ventricular hypertrophy the angiotensin converting enzyme inhibitor ramipril, given in a high blood pressure lowering dose as well as in a low, non-antihypertensive dose, prevented and regressed left ventricular hypertrophy. These beneficial effects were abolished by coadministration of the specific bradykinin receptor antagonist (HOE 140) in the prevention--but not in the regression studies. Vascular function of rats with pressure overload left ventricular hypertrophy was impaired, whereas treated animals showed a reversal to normal. The angiotensin II subtype AT1 receptor antagonist, losartan, was barely active in the prevention, however markedly active in the regression of left ventricular hypertrophy. From these experimental studies in rats with pressure overload left ventricular hypertrophy and vascular dysfunction we conclude that inhibition of bradykinin degradation induced by ramipril may contribute to the antihypertrophic action during the prevention phase, whereas attenuation of angiotensin II formation may be more important during the regression period. In another model, the spontaneously hypertensive rat (SHR and stroke prone SHR)--a non-renal hypertensive model--cardiac left ventricular hypertrophy could be reduced by chronic high-dose ramipril treatment in prevention and regression studies, whereas the low dose regimen only reduced left ventricular hypertrophy in the regression experiments. In addition, both doses improved the myocardial capillary supply to the heart leading to improved function and metabolism. In comparison, vascular hypertrophy of the mesenteric artery could only be prevented by early-onset high dose treatment with the angiotensin converting enzyme inhibitor but not once hypertrophy has been established.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antihypertensive Agents; Bradykinin; Disease Models, Animal; Drug Evaluation; Hypertension, Renovascular; Hypertrophy, Left Ventricular; Ramipril; Rats; Rats, Inbred SHR

Topics: Aged, 80 and over; Angioplasty; Carbazoles; Carvedilol; Combined Modality Therapy; Diagnosis, Differential; Drug Therapy, Combination; Female; Humans; Hypertension; Hypertension, Renovascular; Life Style; Propanolamines; Ramipril; Renal Artery Obstruction; Stents; Weight Loss

We investigated the influence of myocardial collagen volume fraction (CVF, %) and hydroxyproline concentration (microg/mg) on rat papillary muscle function. Collagen excess was obtained in 10 rats with unilateral renal ischemia for 5 wk followed by 3-wk treatment with ramipril (20 mg. kg(-1). day(-1)) (RHTR rats; CVF = 3.83 +/- 0. 80, hydroxyproline = 3.79 +/- 0.50). Collagen degradation was induced by double infusion of oxidized glutathione (GSSG rats; CVF = 2.45 +/- 0.52, hydroxyproline = 2.85 +/- 0.18). Nine untreated rats were used as controls (CFV = 3.04 +/- 0.58, hydroxyproline = 3.21 +/- 0.30). Active stiffness (AS; g. cm(-2). %L(max)(-1)) and myocyte cross-sectional area (MA; micrometer(2)) were increased in the GSSG rats compared with controls [AS 5.86 vs. 3.96 (P < 0.05); MA 363 +/- 59 vs. 305 +/- 28 (P < 0.05)]. In GSSG and RHTR groups the passive tension-length curves were shifted downwards, indicating decreased passive stiffness, and upwards, indicating increased passive stiffness, respectively. Decreased collagen content induced by GSSG is related to myocyte hypertrophy, decreased passive stiffness, and increased AS, and increased collagen concentration causes myocardial diastolic dysfunction with no effect on systolic function.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Collagen; Elasticity; Glutathione Disulfide; Hydroxyproline; Hypertension, Renovascular; In Vitro Techniques; Ischemia; Male; Myocardial Contraction; Myocardium; Papillary Muscles; Ramipril; Rats; Rats, Wistar; Reference Values

Kinins have been shown to play an important role in the cardioprotective effect of ACE inhibitors (ACEi) during heart failure and ischemia-reperfusion. However, it is controversial as to whether kinins oppose the hypertensinogenic effect of deoxycorticosterone acetate plus salt (DOCA-salt) or aortic coarctation and whether they mediate both chronic antihypertensive and cardiac antihypertrophic effects of ACEi in hypertension. Using normal 129/SvEvTac mice and mice lacking the bradykinin B2 receptor gene (B2-KO), we investigated whether (1) the hypertensinogenic effect of DOCA-salt or aortic coarctation is enhanced in B2-KO mice and (2) the chronic antihypertensive and antihypertrophic effects of an ACEi (ramipril, 4 mg. kg-1. d-1) are mediated by B2 receptors in aortic coarctation (6 weeks)- and DOCA-salt (4 weeks)-induced hypertension. Before surgery, there was no difference between 129/SvEvTac and B2-KO mice in terms of blood pressure and heart weight, suggesting that kinins are not essential to maintaining normal blood pressure. DOCA-salt (volume expansion) or aortic coarctation (renin-dependent) induced similar hypertension and left ventricular hypertrophy (LVH) in 129/SvEvTac and B2-KO mice, suggesting that kinins do not play an essential role in the development of DOCA-salt- or aortic coarctation-induced hypertension. We found that B2 receptors mediate only the early (1 week) but not the late phase (4 weeks) of the chronic hypotensive effect of ACEi in DOCA-salt hypertension. On the other hand, chronic ACE inhibition prevented the development of hypertension and LVH in both 129/SvEvTac and B2-KO mice given DOCA-salt or subjected to aortic coarctation, suggesting that kinins do not participate in the chronic antihypertensive and antihypertrophic effects of ACEi in these 2 models of hypertension. Thus, in mice, kinins acting via B2 receptors do not participate in (1) maintenance of normal basal blood pressure, (2) establishment and maintenance of hypertension induced by DOCA-salt or aortic coarctation, and (3) chronic antihypertensive and cardiac antihypertrophic effects of ACEi in DOCA-salt and aortic coarctation hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aortic Coarctation; Blood Pressure; Desoxycorticosterone; Heart; Heart Rate; Hypertension; Hypertension, Renovascular; Kidney; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Nephrectomy; Organ Size; Ramipril; Receptor, Bradykinin B2; Receptors, Bradykinin; Sodium, Dietary

In renovascular hypertensive rats, low doses of angiotensin converting enzyme (ACE) inhibitors have been found to prevent myocardial hypertrophy independent of blood pressure level. This finding would suggest humoral rather than mechanical control of myocyte growth. The aim of this study was to examine the effect of nonantihypertensive doses of ACE inhibitor on myocardial hypertrophy and necrosis in hypertensive rats. Renovascular hypertension (RHT) was induced in four-week-old Wistar rats. Twenty-eight animals were treated for four weeks with three doses of ramipril (0.01, 0.1 or 1. 0 mg/kg/day, which are unable to lower blood pressure. Fourteen animals were not treated (RHT group). A sham operated, age/sex-matched group was used as control (n = 10). Myocardial histology was analysed in 3 microm thick sections of the ventricle stained with either haematoxylin-eosin, reticulin silver stain or Masson's trichrome. There was a significant correlation between systolic blood pressure and left ventricular to body weight ratio in both sets of animals: untreated plus controls and ramipril-treated rats. ACE inhibition prevented myocyte and perivascular necrosis and fibrosis in a dose-dependent manner. We conclude that myocardial hypertrophy in rats with renovascular hypertension is directly related to arterial pressure, and that this relationship is not affected by nonantihypertensive doses of ACE inhibitor. Myocardial necrosis/fibrosis and coronary artery damage induced by angiotensin II are prevented by ACE inhibitor in a dose-dependent manner, despite the presence of arterial hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiomegaly; Dose-Response Relationship, Drug; Hypertension, Renovascular; Hypertrophy, Left Ventricular; Male; Necrosis; Organ Size; Ramipril; Rats; Rats, Wistar

This study was done to investigate the mechanisms that underly the changes of renal renin gene expression upon hypoperfusion of one kidney. To this end the left renal arteries of male Sprague-Dawley rats were clipped with 0.2 mm silver clips and renal renin mRNA levels were assayed by RNase protection during the first ten days after clipping. Unilateral reduction of renal blood flow led to transient maximal fivefold increases of renin mRNA levels in the clipped kidneys and to sustained suppression of renin gene expression to 20% of the control value in the contralateral intact kidneys. Inhibition of prostaglandin (PG) formation by meclofenamate or EDRF synthesis by L-NAME markedly attenuated the increase of renin mRNA levels in response to clipping, and a combination of PG/EDRF inhibition almost abolished the increase of renin mRNA levels. Inhibition of PG/EDRF formation did not change the suppression of renin mRNA levels in the contralateral intact kidneys. Neither did renal denervation nor inhibition of macula densa function by furosemide prevent the suppression of renin gene expression in response to unilateral renal artery clipping. Only converting enzyme inhibition by ramipril and blockade of Ang II-AT1 receptors by losartan attenuated the decrease of renin mRNA levels in the contralaterals to clipped kidneys. These findings suggest that intact PG and EDRF synthesis represent stimulatory signals for renin gene expression that are required for the elevation of renin mRNA levels upon unilateral renal hypoperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arginine; Denervation; Disease Models, Animal; Furosemide; Gene Expression Regulation; Hypertension, Renovascular; Kidney; Male; Meclofenamic Acid; NG-Nitroarginine Methyl Ester; Nitric Oxide; Prostaglandin Antagonists; Ramipril; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger

Recent evidence suggests that tissue generation of angiotensins I and II depends on the level of the plasma components of the renin-angiotensin system and on tissue-specific processes. The present study was undertaken to clarify the possible relationship between plasma renin activity (PRA) and tissue angiotensin converting enzyme (ACE) activity in the heart, lung, kidney cortex and kidney medulla of Wistar-Kyoto rats. In the kidney cortex particular attention was focused on renal brush-border ACE.. Different experimental models known to have opposite effects on PRA were used: changes in salt intake, deoxycorticosterone acetate (DOCA) with or without salt supplements, and the Goldblatt two-kidney, one clip (2-K,1C) model. Two weeks after the start of the experiments the rats were killed, and PRA, and plasma and tissue ACE activity, were measured.. At the end of the study the blood pressure in the treated rats was not significantly different from control. As expected, the PRA were highest in the 2-K,1C and depleted-salt groups and lowest in the DOCA, DOCA-salt and high-salt groups. ACE responses were different in different types of tissue, with no relationship between PRA and plasma or tissue ACE activity. For example, DOCA treatment led to increased ACE activity in the heart and the kidney only if the rats were maintained on a high salt intake. DOCA or salt alone failed to have this effect. In the 2-K,1C model the unclipped kidneys did not show any significant variation in ACE activity, but the clipped kidneys exhibited increased ACE activity compared with sham-operated rats. This increase, coupled with increased renal renin secretion, could play a role in the acceleration of local angiotensin II formation, and could thus initiate and sustain the development of hypertension in this model.. The present results show that variations in ACE activity were organ-specific and were not linked either to hypertension or to changes in PRA.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Desoxycorticosterone; Hypertension, Renovascular; Kidney; Lung; Male; Microvilli; Myocardium; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Inbred WKY; Renin; Sodium Chloride

To examine the interrelation between renin mRNA levels, renin secretion, and blood pressure in rats, we clipped the left renal arteries of rats and measured renin mRNA levels in both kidneys, plasma renin activity, and blood pressure. One and 2 days after clipping, renin mRNA levels increased 3-fold and 4.3-fold in the stenosed kidney and were suppressed to 52% and 26% of controls in the intact kidneys; plasma renin activity increased from 8 to 16.5 and to 30.5 ng angiotensin I.h-1.mL-1 and systolic blood pressure rose from 114 to 123 and to 137 mm Hg. We found a strong correlation (P < .001) between plasma renin activity and renin mRNA levels in the clipped kidneys. We also found significant correlations (P < .05) between mRNA levels in the clipped and intact kidneys and between plasma renin activity and blood pressure for the individual animals. Treatment of normal rats with the converting enzyme inhibitor ramipril (5 mg/kg twice a day) for 2 days increased renin mRNA levels in both kidneys fourfold. In animals with unilateral clips, additional treatment with ramipril increased renin mRNA levels 6.4-fold in the stenosed and 3.3-fold in the intact kidneys. These findings suggest that endogenous angiotensin II exerts an inhibitory effect on renin mRNA expression in normal kidneys, clipped kidneys, and their contralaterals. Suppression of the renin gene in contralateral kidneys seems not to be directly mediated by the rise of plasma renin activity or by the rise of blood pressure in two-kidney, one clip rats.

Topics: Angiotensin II; Animals; Blood Pressure; Hypertension, Renovascular; Male; Ramipril; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger

The contribution of endogenous kinins to the chronic antihypertensive effect of angiotensin converting enzyme inhibitors was investigated in two-kidney, one clip hypertensive Wistar rats, using the new bradykinin B2-receptor antagonist HOE 140 (D-Arg, [Hyp3, Thi5, D-Tic7, Oic8]-bradykinin). In a first protocol, rats were pretreated orally with the angiotensin converting enzyme inhibitor ramipril (1 mg/kg per day), for 4 weeks. Acute blockade of bradykinin receptors by intravenous injections of HOE 140 at doses of 8.4 and 100 micrograms/kg, which inhibited the depressor responses to exogenous bradykinin, did not affect the antihypertensive effect of ramipril in these animals. Bradykinin receptors were then blocked chronically by subcutaneous infusion of HOE 140 (500 micrograms/kg per day) via osmotic minipumps for 6 weeks, while ramipril treatment was continued. HOE 140 partially reversed the antihypertensive effect of ramipril from 115.3 +/- 4.6 to 123.8 +/- 3.3 mm Hg (mean arterial blood pressure) after 3 weeks and to 121.3 +/- 2.9 mm Hg after 6 weeks. In contrast, in controls (ramipril plus subcutaneous vehicle infusion) mean arterial blood pressure decreased further from 112.0 +/- 6.0 to 110.3 +/- 4.9 mm Hg after 3 weeks and to 103.7 +/- 5.0 mm Hg after 6 weeks (p less than 0.05 and p less than 0.01, HOE 140 versus controls). Plasma catecholamines were not significantly different between the two groups at the end of the experiment, indicating that the partial reversal of the antihypertensive effect was not due to a bradykinin-like agonistic effect on catecholamine release.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antihypertensive Agents; Bradykinin; Bridged Bicyclo Compounds; Hypertension, Renovascular; Male; Oligopeptides; Ramipril; Rats; Rats, Inbred Strains; Receptors, Bradykinin; Receptors, Neurotransmitter; Time Factors

The contribution of endogenous bradykinin to the chronic antihypertensive actions of the ACE-inhibitor, ramipril, was investigated in 2-kidney 1 clip (2K1C) hypertensive kinin-deficient Brown Norway Katholieke rats (BN-K) and 2K1C hypertensive Wistar rats (WI) as well as in spontaneously hypertensive rats (SHR). Treatment with ramipril plus the BK B2-receptor antagonist HOE 140 for 6 weeks significantly attenuated the antihypertensive effects of the ACE-inhibitor in 2K1C hypertensive WI rats, but not in 2K1C hypertensive BN-K rats and in SHR. Our data support the hypothesis that potentiation of endogenous kinins contributes to the chronic antihypertensive actions of ACE-inhibitors in experimental renal hypertension. Whether this holds also true for other forms of hypertension remains to be answered.

Topics: Animals; Blood Pressure; Bradykinin; Heart Rate; Hypertension, Renovascular; Ramipril; Rats; Rats, Inbred BN; Rats, Inbred SHR; Rats, Wistar; Receptors, Bradykinin; Receptors, Neurotransmitter; Species Specificity

The possible role of vascular angiotensin converting enzyme (ACE) in the maintenance of one-kidney, one clip (1-K,1C) hypertensive rats was studied in comparison with age-matched, one-kidney (1-K) normotensive rats. Mean blood pressure was elevated after partial occlusion of the left renal artery with unilateral nephrectomy, and the high blood pressure persisted for at least 11 weeks, whereas no significant changes in mean blood pressure were observed in 1-K rats. Plasma and vascular renin activities and plasma ACE activity did not differ between the two groups of rats, both 5 and 11 weeks after operation. In contrast, ACE activity in lung and mesenteric arteries in 1-K,1C hypertensive rats was significantly elevated 11 weeks after operation, but not 5 weeks after operation, compared with the matched 1-K normotensive rats. In addition, the decreases in mean blood pressure induced by ACE inhibition were significantly greater in 1-K,1C rats than those in 1-K rats. These results indicate that the elevation of vascular ACE activity may play an important role in the maintenance of high blood pressure and may result in hypotension in response to ACE inhibitors in the chronic stage of 1-K,1C hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Vessels; Bridged Bicyclo Compounds; Hypertension, Renovascular; Lung; Male; Mesenteric Arteries; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Inbred Strains; Renin-Angiotensin System

The converting enzyme inhibitor, ramipril, 20 mg once daily, was given to 3 hypertensive patients with unilateral renovascular disease. At 1 month, 24 hours after the last dose of ramipril, blood pressure, plasma angiotensin II and converting enzyme activity remained low, and active renin and angiotensin I high. There was no tendency for converting enzyme inhibition to be overcome during 1 month of ramipril therapy. Ramipril caused slight increases in serum potassium and urea, no change in serum creatinine and no consistent changes in the renal vein renin ratio. Ramipril caused little change in renal plasma flow on the stenotic side, but filtration fraction was reduced in 2 patients. There was no serious deterioration in total or individual glomerular filtration rate during ramipril therapy. The drug was well tolerated and there were no serious side effects. Ramipril, given once daily, is likely to be effective in controlling hypertension with renal artery stenosis.

Topics: Adult; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Female; Glomerular Filtration Rate; Humans; Hypertension, Renovascular; Male; Middle Aged; Potassium; Ramipril; Renal Artery Obstruction; Renin-Angiotensin System

The cardiovascular and antihypertensive activities of the novel orally active non-sulfhydryl converting enzyme (CE) inhibitor 2-[N-[(S)-1-Ethoxycarbonyl-3-phenyl-propyl]-L-alanyl] -(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) were evaluated in several experimental preparations. The hemodynamic profile of Hoe 498 in anesthetized animals was characterized by a reduction in systemic blood pressure which was associated with a decrease in total peripheral and renal vascular resistance. These effects were enhanced upon sodium depletion. In conscious normotensive rats a single oral administration of Hoe 498 reduced systemic blood pressure for more than 5 h. The development of acute renovascular hypertension in anesthetized rats was prevented by oral pretreatment with Hoe 498. In conscious rats with renovascular hypertension (two-kidney, one clip) single oral doses of Hoe 498 induced a long lasting antihypertensive effect. Chronic oral treatment of spontaneously hypertensive rats with Hoe 498 lowered arterial blood pressure more effectively than enalapril. The threshold antihypertensive dose for Hoe 498 was 0.01 mg/kg/d, for enalapril 1 mg/kg/d. In conscious hypertensive dogs (two-kidney, two wrapped) Hoe 498 at a single oral dose of 10 mg/kg reduced systemic blood pressure for more than 6 h. Oral administration of Hoe 498 in a dose of 1 mg/kg/d for 5 d normalized systemic blood pressure in conscious hypertensive dogs. These findings demonstrate that in various models of experimental hypertension the novel orally active converting enzyme inhibitor Hoe 498 exerts marked cardiovascular and potent prolonged antihypertensive activities, which merit exploration with respect to possible therapeutic benefits.

Topics: Anesthesia; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Hemodynamics; Hypertension, Renovascular; Male; Ramipril; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Renal Circulation; Sulfhydryl Compounds