Correlation between the inhibition of renin-angiotensin system and antihypertensive effect of MK-421 and captopril in 2-kidney, 1-clip renal hypertensive rats after single and repeated oral administration of MK-421 or captopril

The angiotensin converting enzyme (ACE) activity in tissues and plasma renin activity (PRA) were measured in 2-kidney, 1-clip renal hypertensive rats (2K-RHR) and normotensive rats after a single and 3-weeks oral administrations of ACE inhibitors such as MK-421 and captopril. In the single dose study, MK-421 (1 and 3 mg/kg) and captopril (3 and 10 mg/kg) inhibited the ACE activities in kidney, aorta and plasma in a dose-dependent fashion. The inhibition of ACE activity in kidney or aorta was observed for a longer time than that in plasma. PRA took a time course reversal to that of plasma ACE activity. In the 3-weeks repeated dose study, the ACE activity in kidney and aorta was strongly inhibited after the administration of each ACE inhibitor, while there was no significant change in lung ACE activity at any time point examined. The plasma ACE activity markedly elevated after the administration of each agent. PRA significantly increased after the administration of either agent, while the plasma angiotensin II level was significantly inhibited. These results indicate that the inhibition of the ACE activity in blood vessel or kidney correlate well with the antihypertensive activity in 2K-RHR after a single and repeated administration of both ACE inhibitors, but not well with the inhibition of plasma ACE activity.     

Comparison of acute cardiovascular effects of cadmium and captopril in relation to oxidant and angiotensin converting enzyme activity in rats

Cadmium (0.1, 0.32, 1.0 mg/kg i.v.) produced dose dependent hypertensive response in pentobarbitone anesthetized Sprague-Dawley (S-D) rats. The peak hypertensive effect was observed within 15 min of cadmium administration. This response gradually decreased over 1-h observation period. Heart rate did not change significantly. Serum malondialdehyde (MDA) levels increased with cadmium administration. The lower dose of cadmium (0.1 mg/kg i.v.) increased serum MDA to 0.14 +/- 0.02 nmol/mL as compared to 0.12 +/- 0.01 nmol/mL in the control group and was not statistically significant. However, mid (0.32 mg/kg i.v.) and high doses (1.0 mg/kg i.v.) raised serum MDA levels significantly (P < 0.01). Cadmium inhibited serum angiotensin converting enzyme (ACE) levels at all the three tested doses and was statistically significant (P < 0.01). Captopril (1.0, 3.2 mg/kg i.v.) produced a dose dependent mild hypotensive response. The peak effect was observed within 5 min. Cadmium produced inhibition of serum ACE levels, however, a dose response effect was not observed. Captopril (3.2 mg/kg i.v.) decreased serum ACE levels to 5.4 +/- 1.1 U/mL (control levels 10.7 +/- 1.4 U/mL). Serum MDA levels were decreased by captopril treatment. A correlation between serum ACE and MDA following higher dose of cadmium was found. These results indicate that acute administration of cadmium, an inorganic blocker of ACE and calcium channels cadmium produced hypertensive response while captopril produced mild hypotensive response in rats.     

EFFECTS OF LOW DOSE INFUSION OF ATRIAL NATRIURETIC FACTOR ON ACUTE INHIBITION OF ANGIOTENSIN CONVERTING ENZYME IN NORMAL MAN

1. We have studied the effects of low dose infusions of atrial natriuretic factor (human ANF (99-126), 1.95 pmol/min per kg) on angiotensin converting enzyme (ACE) inhibitor-induced haemodynamic and hormonal changes in healthy subjects. 2. ACE inhibitor (captopril 25 mg, administered orally) was given against a background infusion of physiological saline (placebo day) or ANF (experimental day). 3. Compared with the placebo observations, ANF enhanced the fall in plasma aldosterone concentrations induced by captopril (P less than 0.05). 4. The rise of plasma renin activity following administration of ACE inhibitor which was observed during placebo infusion was abolished by ANF (P less than 0.05). 5. The responses of systemic blood pressure and heart rate to the converting enzyme inhibition were not affected by the infusion of ANF. 6. These results suggest that variations in endogenous circulating ANF may influence, in part, the response of these hormonal levels during ACE inhibition.     

Effect of captopril and hydrochlorothiazide on the response to pressor agents in hypertensives

The effect on arterial pressure of incremental doses of norepinephrine (2 to 10 micrograms/min) and angiotensin II (50 to 800 ng/min) administered over 10 min periods was studied in sodium-replete hypertensive patients after crossover oral treatments with placebo, captopril 50 mg in a single dose, captopril 50 mg three times daily for one week and hydrochlorothiazide 50 mg daily for a week. Neither captopril nor hydrochlorothiazide affected the dose response to infusions of angiotensin II. In comparison to placebo responses, however, both single and multiple-dose captopril therapy, and hydrochlorothiazide attenuated the pressor responses to infusions of norepinephrine. Captopril significantly depressed angiotensin converting enzyme activity from pre-dose levels and angiotensin II infusions significantly elevated plasma aldosterone concentrations. These results confirm findings reported for single dose captopril in normotensive volunteers and indicate that attenuation of the vascular responsiveness to sympathetic stimulation may contribute to the antihypertensive effects of captopril and hydrochlorothiazide therapy.     

Comparison of Acute Cardiovascular Effects of Cadmium and Captopril in Relation to Oxidant and Angiotensin Converting Enzyme Activity in Rats

Abstract

Cadmium (0.1, 0.32, 1.0 mg/kg i.v.) produced dose dependent hypertensive response in pentobarbitone anesthetized Sprague-Dawley (S-D) rats. The peak hypertensive effect was observed within 15 min of cadmium administration. This response gradually decreased over 1-h observation period. Heart rate did not change significantly. Serum malondialdehyde (MDA) levels increased with cadmium administration. The lower dose of cadmium (0.1 mg/kg i.v.) increased serum MDA to 0.14 ± 0.02 nmol/mL as compared to 0.12 ± 0.01 nmol/mL in the control group and was not statistically significant. However, mid (0.32 mg/kg i.v.) and high doses (1.0 mg/kg i.v.) raised serum MDA levels significantly (P<0.01). Cadmium inhibited serum angiotensin converting enzyme (ACE) levels at all the three tested doses and was statistically significant (P<0.01). Captopril (1.0, 3.2 mg/kg i.v.) produced a dose dependent mild hypotensive response. The peak effect was observed within 5 min. Cadmium produced inhibition of serum ACE levels, however, a dose response effect was not observed. Captopril (3.2 mg/kg i.v.) decreased serum ACE levels to 5.4 ± 1.1 U/mL (control levels 10.7 ± 1.4 U/mL). Serum MDA levels were decreased by captopril treatment. A correlation between serum ACE and MDA following higher dose of cadmium was found. These results indicate that acute administration of cadmium, an inorganic blocker of ACE and calcium channels cadmium produced hypertensive response while captopril produced mild hypotensive response in rats.     

Effects of SQ 14,225, an orally active inhibitor of angiotensin-converting enzyme on blood pressure, heart rate and plasma renin activity of conscious normotensive dogs.

Oral administration of SQ 14,225 (0.03--3 mg/kg) to conscious normotensive dogs caused inhibition of the pressor response to intravenously administered angiotensin I (AI), the duration of which was dose-dependent. All doses of 0.1 mg/kg or greater caused 85--95% inhibition 30 min after administration whereas 0.03 mg/kg produced only a 25% inhibition. Pressor responses to angiotensin II (AII) were not similarly inhibited. Blood pressure was moderately reduced in a dose-related manner and followed the same pattern as inhibition of the AI pressor responses. The maximum change occurred after 1.0 mg/kg with only a more rapid onset occurring after the 3.0 mg/kg dose. Heart rate was not appreciably changed. SQ 14,225 also increased plasma renin activity (PRA), the levels and duration of which were dose-related. These data indicate that SQ 14,225 is an orally effective, potent inhibitor of angiotensin I-converting enzyme (ACE) in dogs. It appears that in mongrel dogs, ACE inhibition results in a slight to moderate reduction in blood pressure and an increase in PRA.     

The effects of captopril on rat aortic angiotensin-converting enzyme

Angiotensin -converting enzyme (ACE) activity was found to be present within the rat aorta using radioenzymatic techniques. Forty-two percent of the enzyme activity was localized within the tunica media. Using an equilibrium dialysis cell system that insured equal free captopril concentrations in both plasma and aorta, converting enzyme in both tissues was observed to possess similar dissociation constants for the inhibitor. Four daily intraperitoneal doses, but not a single dose, of captopril led to a persistent inhibition of aortic-converting enzyme 24 h after final drug administration. Plasma-converting enzyme activity was changed at this time. These results suggest that different pools of converting enzyme recover form captopril inhibition at different rates. The prolonged inhibition of aortic ACE is discussed in terms of drug accumulation within the vessel wall, and the effect of such accumulation on the persistent antihypertensive actions of captopril are also discussed.     

Effect of time and dose on angiotensin converting enzyme during captopril treatment in the rat

The effect of treatment time and dose of captopril with regard to angiotensin converting enzyme (ACE) in serum, lungs and kidneys of the rat were studied. Normotensive Wistar rats were treated with a constant dose of captopril (0.2 mg/ml) during various time periods. In a second study rats were treated with different captopril doses (6.25 micrograms, 12.5 micrograms, 25 micrograms, 50 micrograms, and 200 micrograms/ml water) during three weeks. Serum ACE activity and pulmonary and kidney plasma membrane ACE concentrations were measured in both studies. Captopril treatment resulted in a rapid decrease of ACE in pulmonary and kidney plasma membranes and a simultaneously increase of serum ACE activity during the first day of treatment. This was followed by increased membrane concentrations of ACE in the lungs and return to normal ACE concentrations in membranes of kidneys, presumably due to increased ACE biosynthesis. Serum ACE activity continued to increase during the whole study. Serum ACE activity increased in a dose dependent manner during treatment with different captopril doses. Increased plasma membrane ACE concentrations were not observed in the rats treated with captopril at doses below 200 micrograms/ml water.     

Angiotensin converting enzyme inhibitory activity of MK-0521 in vivo and antihypertensive effect of its single oral administration on blood pressure and effect on the renin-angiotensin system in 2-kidney Goldblatt hypertensive dogs

Angiotensin converting enzyme (ACE) inhibitory activity of MK-0521 in dogs and the effects of its single oral administration on blood pressure and the renin-angiotensin system in 2-kidney Goldblatt hypertensive dogs were compared with those of captopril and MK-421. MK-0521 at 0.001-0.1 mg/kg, i.v., or 0.01-1 mg/kg, p.o., attenuated the pressor effect of angiotensin I without affecting that of angiotensin II and augmented the depressor effect of bradykinin. The potency of MK-0521 to reduce the pressor effect of angiotensin I was 9.8 times that of captopril by intravenous administration, and by oral administration, it was 15.9-32.1 times that of captopril and approximately 3 times that of MK-421. When administered orally, the onset of action and the time to peak effectiveness were more rapid than those of MK-421, but slower than those of captopril. Duration of the action of MK-0521 was longer than that of captopril and equal or longer than that of MK-421. The inhibition of ACE was well correlated with serum MK-0521 levels. MK-0521 produced a dose-dependent antihypertensive effect in 2-kidney Goldblatt hypertensive dogs at over 0.3 mg/kg, p.o., without affecting the heart rate. The antihypertensive effect of MK-0521 was persistent and approximately 3 times more potent than that of captopril. MK-0521 inhibited the serum ACE activity and increased the plasma renin activity, while it had a tendency to decrease plasma aldosterone level. These changes were parallel to the time course of the antihypertensive effect. These results suggest that the main mechanism of the antihypertensive effect of MK-0521 is the suppression of angiotensin II production due to the inhibition of the ACE.     

Comparison of angiotensin-converting enzyme inhibitors in the rat in perfused hindlimbs and in vivo.

To investigate the role of local renin angiotensin systems in the functional responses to angiotensin I and II, the effects of angiotensin I and angiotensin II on resistance were measured in perfused hindlimbs of rats under normal conditions and during infusion of enalaprilate, lisinopril, zabiciprilate and captopril at two infusion rates. The angiotensin-converting enzyme (ACE) inhibitors significantly increased ED50 and decreased maximal resistance changes of angiotensin I dose dependently, without effects on angiotensin II responses. Captopril increased the ED50 of angiotensin I significantly more than did the other ACE inhibitors at a low infusion rate. The ACE inhibitors, except for lisinopril, increased the ED50 of angiotensin I pressor responses in vivo to the same extent, and were similarly potent to inhibit plasma ACE activity at 15 min after injection. The ratio of the doses of the ACE inhibitors used in vivo was the same as in perfused hindlimbs. These results suggest that, in the hindlimbs, angiotensin I causes ACE-dependent vasoconstriction. Captopril may be more effective to inhibit local ACE than the other ACE inhibitors investigated.     

ANGIOTENSIN II BLUNTS, WHILE AN ANGIOTENSIN-CONVERTING ENZYME INHIBITOR AUGMENTS, REFLEX SYMPATHETIC INHIBITION IN HUMANS*

1. The role of angiotensin (Ang)II in and the effects of angiotensin-converting enzyme (ACE) inhibitors on the regulation of sympathetic neural activity were examined in humans. 2. We measured baseline values of muscle sympathetic nerve activity (MSNA) and its reflex inhibition in 28 patients with essential hypertension with elevated plasma renin activity (PRA; > 1.0 ng/mL per h = 0.28 ng/L per s) before and after either acute or chronic oral administration of an ACE inhibitor or placebo and in 20 normotensive subjects before and after infusion of either AngII (5 ng/kg per min = 4.8 pmol/kg per min) or vehicle (5% dextrose). Muscle sympathetic nerve activity was recorded from the tibial nerve and its reflex inhibition was evaluated during pressor responses to bolus injection of phenylephrine (2 micrograms/kg, i.v.). 3. Blood pressure was significantly decreased (P < 0.01) after the acute oral administration of captopril (25 mg), accompanied by a slight increase in MSNA in patients with essential hypertension compared with control patients who received placebo administration. Reflex changes in MSNA were significantly augmented after oral administration of captopril (-4.1 +/- 0.5 vs -6.2 +/- 0.6%/mmHg, respectively; P < 0.01), with a significant reduction of plasma AngII, while they were not affected by placebo administration. 4. In contrast, acute AngII infusion was accompanied by decreases in both PRA and MSNA in normotensive subjects. Reflex changes in MSNA were significantly reduced after AngII infusion (-11.0 +/- 0.8 vs -7.4 +/- 1.0%/mmHg, respectively; P < 0.01) but not after vehicle alone. 5. Chronic ACE inhibition by 12 week oral imidapril administration (5-10 mg/day) significantly (P < 0.05) decreased baseline values of MSNA, which were accompanied by a significant (P < 0.05) increase in the reflex inhibition of MSNA, while plasma concentrations of noradrenaline were unaffected. 6. These results indicate that AngII blunts reflex inhibition of sympathetic neural activity and that inhibition of the renin-angiotensin system by an ACE inhibitor augments reflex regulation of sympathetic neural activity and reduces baseline values in patients with essential hypertension.     

Reactive hyperreninemia is a major determinant of plasma angiotensin II during ACE inhibition.

The new ACE inhibitor trandolapril was administered to normal volunteers at daily doses of 0.5, 2, and 8 mg for 10 days. Twenty-one volunteers, aged 21-30 years, were included in the study. To randomly selected groups of seven subjects, each dose was administered in a single-blind fashion. None of the doses induced a consistent fall in blood pressure. Angiotensin-converting enzyme activity (ACE) was measured in vitro using three different synthetic substrates (i.e., Hip-Gly-Gly, Z-Phe-His-Leu, or angiotensin I). Although the degree of ACE inhibition assessed with the three methods varied widely, all methods clearly indicated dose-dependent ACE inhibition. These in vitro results were confirmed by measuring ACE inhibition in vivo using the ratio of plasma angiotensin II (ANG II) to blood angiotensin I (ANG I). The dose-dependent ACE inhibition was paralleled by a dose-dependent rise in active renin and blood angiotensin I levels, most evident on day 10. In contrast, plasma ANG II levels on day 10 were not different whether the volunteers received 0.5 or 8 mg trandolapril. Thus, whereas increasing doses of this new ACE inhibitor progressively enhanced the blockade of ACE activity, this was not reflected by additional reductions of plasma ANG II levels. The progressive enhancement of ACE inhibition seemed to be offset by the accentuation of the compensatory rise in renin and ANG I, which was still partially converted to ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)     

RESPONSE OF PLASMA RENIN-ANGIOTENSIN SYSTEM TO A SINGLE CAPTOPRIL ADMINISTRATION IN PATIENTS RECEIVING LONG-TERM TREATMENT WITH CAPTOPRIL

1. The responses of angiotensin II (AII), AIII, aldosterone and plasma renin activity (PRA) to a single dose of captopril were investigated in hypertensive patients receiving long-term (more than 1 year) captopril therapy (CT patients) and compared with those of non-treated hypertensive patients (NT patients). 2. Baseline levels of AII and aldosterone were significantly lower in CT patients than in NT patients. AIII tended to be lower and PRA was slightly higher in CT than in NT patients, but these differences were not significant. 3. A single administration of captopril (50 mg orally) significantly decreased plasma levels of AII, AIII and aldosterone as well as blood pressure in both CT and NT patients. 4. These results demonstrate that chronically repeated administration of captopril to hypertensive patients effectively reduces the daily blood pressure and concomitantly the plasma AII level to acceptable levels in patients with no experience of ACE inhibition.     

Tissue levels, tissue angiotensin converting enzyme inhibition and antihypertensive effect of the novel antihypertensive agent alacepril in renal hypertensive rats

Tissue levels, tissue angiotensin I converting enzyme (ACE) inhibition and hypotension were examined 20 min, 1, 5 and 14 h after oral administration of 1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine (alacepril, DU-1219) (37.5 mg (92 mumol)/kg) or 1-[(S)-3-mercapto-2-methylpropanoyl]-L-proline (captopril) (20.0 mg (92 mumol)/kg) in renal hypertensive rats, using 14C-labeled compounds. Alacepril exerted a more gradual and more sustained antihypertensive effect than captopril. The maximal hypotension was observed 1 and 5 h after administration of captopril and alacepril, respectively. After administration of [14C]captopril, serum level reached the maximum at 20 min and then decreased rapidly. After administration of [14C]alacepril, serum level reached the maximum at 1 h and decreased more slowly than after [14C]captopril. Time course patterns of tissue levels were essentially in parallel with those of serum levels. Captopril exerted the maximal reduction of ACE activity in tissues 20 min after oral administration and thereafter, the reduction was diminished with time rapidly. [14C]Alacepril showed gradual reduction (the maximum at 1 h) and recovery of ACE activity relative to captopril. After oral administration of [14C]alacepril, tissue unbound fractions contained captopril and its derived metabolites while serum unbound fraction contained the intermediate metabolite desacetyl-alacepril (DU-1227) as well. Correlations between ACE inhibition and tissue levels and between changes in tissue ACE inhibition and in blood pressure with time after oral administration of the two agents were discussed. Furthermore, the direct comparison of alacepril and captopril was attempted by the difference in blood pressures and in ACE inhibitions induced after oral administration of the agents.     

Chronic Treatment with Quercetin does not Inhibit Angiotensin‐Converting Enzyme In Vivo or In Vitro

Abstract: The precise mechanisms explaining the anti‐hypertensive effects produced by quercetin are not fully known. Here, we tested the hypothesis that chronic quercetin treatment inhibits the angiotensin‐converting enzyme (ACE). We examined whether quercetin treatment for 14 days reduces in vivo responses to angiotensin I or enhances the responses to bradykinin in anaesthetised rats. We measured the changes in systemic arterial pressure induced by angiotensin I in doses of 0.03–10 μg/kg, by angiotensin II in doses of 0.01–3 μg/kg, and to bradykinin in doses of 0.03–10 μg/kg in anaesthetised rats pre‐treated with vehicle (controls), or daily quercetin 10 mg/kg intraperitoneally for 14 days, or a single i.v. dose of captopril 2 mg/kg. Plasma ACE activity was determined by a fluorometric method. Plasma quercetin concentrations were assessed by high performance liquid chromatography. Quercetin treatment induced no significant changes in the hypertensive responses to angiotensin I and angiotensin II, as well in the hypotensive responses to bradykinin (all p > 0.05). Conversely, as expected, a single dose of captopril inhibited the hypertensive responses to angiotensin I and potentiated the bradykinin responses (all p < 0.01), while no change was found in the vascular responses to angiotensin II (all p > 0.05). In addition, although we found significant amounts of quercetin in plasma samples (mean = 206 ng/mL), no significant differences were found in plasma ACE activity in rats treated with quercetin compared with those found in the control group (50 ± 6 his‐leu nmol/min/mL and 40 ± 7 his‐leu nmol/min/mL, respectively; p > 0.05). These findings provide strong evidence indicating that quercetin does not inhibit ACE in vivo or in vitro and indicate that other mechanisms are probably involved in the antihypertensive and protective cardiovascular effects associated with quercetin.     

Roles of peripheral and central angiotensin-converting enzyme (ACE) in hypovolemic thirst induced by compound 48/80 in rats

Subcutaneous (s.c.) injection of Hoe 498, an angiotensin converting enzyme (ACE) inhibitor, at the doses of 0.1, 0.5, 1.0 and 4.0 mg/kg produced a dose-related inhibition of compound 48/80-induced hypovolemic thirst in rats. A significant time-response relationship was observed between the pretreatment time of Hoe 498 at a dose of 4.0 mg/kg and the inhibition of compound 48/80-induced water intake. Nearly 90% of plasma ACE activity was inhibited by Hoe 498 at all doses used, and this inhibition at the dose of 4.0 mg/kg of Hoe 498 continued for more than 4 hr. Intracerebroventricular (i.c.v.) or s.c. injection of Hoe 498 in doses ranging from 0.5 to 20 micrograms comparably inhibited plasma ACE activity in a dose-dependent manner. The compound 48/80-induced water intake was significantly reduced by i.c.v. injection of Hoe 498 (20 micrograms) 30 min after compound 48/80 administration, but not reduced when the drug was given 15 min prior to injection of dipsogen. The inhibition of water intake by Hoe 498 seems to be dependent on the dose and time between administration of Hoe 498 and compound 48/80. The present data suggest that brain ACE is more involved in compound 48/80-induced water intake than peripheral systemic ACE.     

The effect of enalapril (MK421), an angiotensin converting enzyme inhibitor, on the conscious pregnant ewe and her foetus.

The effects of enalapril, an angiotensin converting enzyme (ACE) inhibitor, on maternal and foetal blood pressure, heart rate and components of the renin-angiotensin-aldosterone system were studied in 9 chronically-cannulated pregnant ewes and their foetuses. Six ewes received 1 mg kg-1 enalapril i.v. while 3 were given 2 mg kg-1. Although the initial fall in blood pressure was slightly greater in the higher dose group, there was substantial overlap of data. The pressor response to angiotensin I, assessing ACE activity, was abolished within 10 min of administration, and did not recover during 3 h of observation. Maternal systolic and diastolic pressures reached a nadir 90 min after administration (P less than 0.001, P less than 0.002 respectively). The maximum tachycardia was seen at 60 min (P less than 0.05). The foetuses of the ewes given 1 mg kg-1 enalapril showed no change in systolic or diastolic blood pressure or heart rate. Those of the ewes given the higher dose showed late-onset hypotension, coincident with the lowest maternal blood pressures. Maternal plasma renin concentration (PRC) had risen significantly by 30 min (P less than 0.02), reaching a maximum at approximately 90 min. Maternal plasma angiotensin II and aldosterone concentrations both fell initially (P less than 0.05) but were almost at basal levels by the end of the experiment. Foetal plasma renin, angiotensin II and aldosterone concentrations were unchanged throughout the experiment. Peak values of enaprilic acid, the active principle, were recorded in maternal plasma 65-90 min after administration of 1 mg kg-1, and 25-30 min after the administration of 2 mg kg-1. A trace amount of the active principle was recorded in the foetal plasma of one lamb, whose mother had been given the higher dose. None was recorded in the plasma from three other lambs. Maternal plasma ACE concentrations fell by an average of 84%; in 4 of the 6 ewes in which concentrations were measured they were undetectable after treatment. Foetal plasma ACE concentrations were unchanged throughout. Enalapril at 1 mg kg-1 thus exerts a depressor effect on the pregnant ewe which is probably related to its blockade of the renin-angiotensin system. Both direct measurement of the drug and foetal observation suggest that it does not cross the sheep placenta at this dose. This is consistent with its failure to cross the blood-brain barrier. Foetal effects were noted at 2 mg kg-1, and there was an unexpected foetal death in this group.     

The effect of the converting enzyme inhibitor HOE 498 on the renin angiotensin system of normal volunteers

Summary The converting enzyme inhibitor HOE 498 was evaluated in 12 normotensive male volunteers aged 21 to 26. The efficacy of single 5, 10 or 20 mg oral doses in blocking the pressor response to exogenous angiotensin I was tested in 3 of the subjects. All 3 doses of HOE 498 reduced the pressor response to exogenous angiotensin I to below 50% of control within 1,5 h following administration of the drug. Plasma renin and converting enzyme activity, blood angiotensin I, as well as plasma angiotensin II and aldosterone were measured serially before and up to 72 h following oral administration of a single dose of 2.5, 5, 10 or 20 mg of HOE 498 to groups of 5 volunteers each. As expected, blood angiotensin I levels and plasma renin activity rose while plasma converting enzyme activity, plasma angiotensin II and aldosterone concentration fell after administration of the drug. While the dose of 2.5 mg did not reduce plasma converting enzyme activity below 20% of control, the higher doses all resulted in plasma converting enzyme inhibition exceeding 90%. No side-effects were observed. It is concluded that in normal volunteers HOE 498 is an effective potent and long-acting converting enzyme inhibitor. Based on these preliminary findings it is expected that 5 mg HOE 948 will turn out to be adequate for therapeutic use.     

Inhibition of the acute effects of angiotensin II by the receptor antagonist irbesartan in normotensive men

Irbesartan (SR 47436, BMS 186295) is an imidazole derivative that specifically binds to the angiotensin type 1 receptor. The purpose of this study was to assess the inhibitory effect of irbesartan on the pressor action of exogenous angiotensin II in healthy subjects, to evaluate the dose dependency and duration of this inhibition, and to determine the effect of irbesartan on plasma components of the renin-angiotensin system. Forty-two healthy male volunteers maintained on ad libitum sodium intake were enrolled in a randomized, double-blind, placebo-controlled, parallel-design, dose-ranging study. On 2 study days 1 week apart, volunteers were given either a placebo or the active drug at one of the chosen doses (5, 25, 50, 75, 100, 150, or 300 mg). The pressor effects of an individually titrated test dose of exogenous angiotensin II as well as plasma levels of angiotensin II, active renin, aldosterone, and treatment drug were determined before and throughout the 24 h after drug administration. The inhibitory effect of irbesartan on the pressor response to angiotensin II was observed within 1 h after dosing, peaked between 2 and 4 h, and lasted more than 24 h for doses of 25 mg and more. The effect was clearly dose related. Two and 24 h after administration of irbesartan, 300 mg, the response of arterial blood pressure (systolic and diastolic) to a given dose of angiotensin II was reduced by approximately 100% and 60%, respectively. Plasma concentrations of angiotensin II and active renin increased markedly after irbesartan administration, whereas plasma concentrations of aldosterone decreased. No evidence was found that the high levels of circulating angiotensin II observed after irbesartan administration could override the inhibitory effect of irbesartan on any of the measured parameters up to 24 h after dose. In conclusion, irbesartan appears to be a well-tolerated, orally active, potent antagonist of the renin-angiotensin system in men.     

Vasopeptidase inhibition with omapatrilat improves cardiac geometry and survival in cardiomyopathic hamsters more than does ACE inhibition with captopril

Vasopeptidase inhibitors are single molecules that inhibit neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) simultaneously. Omapatrilat, the first in this new class of cardiovascular agents, potentiates vasodilatory and cardioprotective peptides and represses angiotensin II. This study compared the effects of omapatrilat with those of a pure ACE inhibitor on cardiac geometry and survival in animals with heart failure. BIO TO-2 cardiomyopathic hamsters (CMHs) in the early stages of dilated heart failure were treated with vehicle or maximal ACE inhibitory doses of captopril (750 micromol/kg/day) or omapatrilat (200 micromol/kg/day). Prolonged vasopeptidase inhibition increased median survival time after the start of treatment by 99 and 31% compared with vehicle and captopril, respectively (median survival times: 146, 221, and 290 days with vehicle, captopril, and omapatrilat, respectively; p < 0.001 for all comparisons). In similar CMHs, captopril or omapatrilat administered for 2 months significantly (p < 0.05) decreased heart weight, pulmonary congestion (lung weight), and left ventricular (LV) chamber volume compared with vehicle. Omapatrilat significantly increased LV mass-to-volume ratio compared with vehicle and captopril. Omapatrilat, but not captopril, significantly increased urinary atrial natriuretic peptide excretion, indicating NEP inhibition. Thus vasopeptidase inhibition with omapatrilat was more effective than ACE inhibition with captopril in preventing changes in LV geometry and premature mortality in hamsters with dilated heart failure.