Haemodynamic and humoral effects of oral perindopril, an angiotensin converting enzyme inhibitor, in man.

The tolerance to and dynamic effects of 1 week's oral treatment with the angiotensin converting enzyme inhibitor, perindopril, were assessed in a placebo controlled, parallel group study in 36 normotensive males. The daily dose of perindopril was 1, 2, 4, 8 or 16 mg. The drug was well tolerated and produced no change in routine haematology or serum biochemistry tests. Dose related inhibition of plasma angiotensin converting enzyme was observed. Perindopril 16 mg produced 90% inhibition 4 h after dosing and 60% after 24 h. A dose related rise in plasma renin activity followed doses of 4 mg and over. The renin remained above the normal range for 24 h. Perindopril caused a modest lowering of plasma aldosterone levels but had no effect on plasma adrenaline or noradrenaline levels. Standing diastolic blood pressure was lowered, particularly with 16 mg daily of perindopril but only a slight rise in heart rate occurred. Perindopril appears to be a well tolerated inhibitor of plasma angiotensin converting enzyme, with predictable effects on the renin angiotensin system and blood pressure. An appropriate dose range for further study would appear to be 4 to 16 mg daily.     

Different aortic reflection wave responses following long-term angiotensin-converting enzyme inhibition and beta-blocker in essential hypertension

1. In arterial hypertension, aortic wave reflections contribute to determining central systolic and pulse pressures. The present study assessed the central pressure alterations at the level of the common carotid artery following 1 month treatment with perindopril or atenolol and investigated during the 8 h following drug intake. 2. Twenty patients suffering from permanent hypertension were included after a 4 week run-in placebo period in a double-blind, randomized cross-over study comparing the angiotensin-converting enzyme (ACE) inhibitor perindopril with the beta-blocker atenolol during a 4 week treatment period. 3. Before and during the 8 h after drug intake, serial measurements included brachial artery systolic and diastolic blood pressures (SBP and DBP, respectively; mercury sphygmomanometer), carotid artery SBP and pulse pressure (PP; applanation tonometry), aortic pulse wave velocity (Complior; Colson, Les Lilas, France) and arterial wave reflections from the aorta (applanation tonometry; Sphygmocor; PWV Medical, Sydney, NSW, Australia). 4. Both treatments decreased brachial and carotid artery SBP, DBP and PP. Heart rate and pulse wave velocity decreased following atenolol (P < 0.001). Pulse wave velocity was reduced slightly following perindopril (NS). Arterial wave reflections were significantly (P < 0.001) decreased with perindopril in comparison with atenolol, but this effect on wave reflections was not associated with a larger decrease in carotid artery PP. 5. Thus, during chronic treatment, ACE inhibition and selective beta1-adrenoceptor blockade resulted in a similar decrease in brachial and carotid artery PP, but only atenolol reduced heart rate. Aortic pulse wave velocity was reduced with both drugs, but atenolol appeared more effective in improving aortic stiffness. Arterial wave reflections were decreased only following perindopril. 6. Central pulse pressure was improved following 1 month treatment with an ACE inhibitor or beta-adrenoceptor blockade following a decrease in arterial wave reflections with perindopril and a higher decrease in regional aortic stiffness with atenolol.     

Effects of an angiotensin converting enzyme inhibitor, ramipril, on intracranial circulation in healthy volunteers. off.

1. The effects of a single oral dose (10 mg) of ramipril on (a) systemic haemodynamics (arterial pressure, cardiac output), (b) carotid artery haemodynamics (blood flow and diameter, pulsed Doppler technique), (c) intracranial haemodynamics (middle cerebral artery mean blood velocity, transcranial Doppler technique), and (d) renin-angiotensin system (plasma converting enzyme and renin activities) have been investigated and compared with those of a placebo during the 24 h period following administration in a randomized, double-blind and cross-over study performed in six healthy volunteers. 2. Ramipril induced a strong and sustained inhibition of plasma converting enzyme activity (-96% at 4 h, -63% at 24 h) and an increase in plasma renin activity (+993% at 8 h). 3. As compared with placebo, ramipril did not significantly affect arterial blood pressure, heart rate, cardiac output and total peripheral resistance. 4. Ramipril significantly increased carotid blood flow (by 27% at 8 h) without significantly changing carotid artery diameter, indicating, given the unchanged arterial pressure, an arteriolar vasodilation in the carotid territory. 5. The middle cerebral artery mean blood flow velocity underwent spontaneous modifications during the placebo period but these changes were not affected by ramipril. This lack of influence of ramipril on intracranial haemodynamics suggests that the drug-induced arteriolar vasodilation and increase in carotid blood flow only concern the extracranial, musculo-cutaneous part of the carotid territory.     

A potent converting enzyme inhibitor CGS 13928C. Drug profile in normal volunteers

Summary The converting enzyme inhibitor CGS 13928C was evaluated in 15 healthy male volunteers. First the efficacy of a single oral dose of 0.5, 1, 2 or 5 mg in antagonizing the pressor response to exogenous angiotensin I was tested with continuous monitoring of the blood pressure and heart rate by an intraarterial catheter. CGS 13928C 1, 2 and 5 mg consistently reduced the response to angiotensin within 2 to 3 h and for a period exceeding the 4 h of monitoring. The 2 mg dose was hardly more effective than 1 mg and 5 mg did not further enhance the blockade. Subsequently, plasma renin and converting enzyme activity, angiotensin I, angiotensin II and aldosterone were measured serially before and up to 72 h following oral administration of either 1 mg (n=7) or 2 mg (n=8) CGS 13928C. As expected, plasma renin activity and angiotensin I rose, while plasma converting enzyme activity, angiotensin II and aldosterone fell following both doses of the drug. No side-effects occurred. In normal volunteers CGS 13928C is an effective and extremely potent, orally active converting enzyme inhibitor.     

Pharmacodynamics of converting enzyme inhibition: The cardiovascular, endocrine and autonomic effects of MK421 (enalapril) and MK521

1 Two new orally active inhibitors of angiotensin converting enzyme MK421 (enalapril maleate) and its lysine analogue MK521 were given to nine salt-replete normal subjects in a randomised placebo-controlled study.

2 Supine and erect blood pressure and heart rate were measured before (0) and 1, 2, 4, 6, 8, 12 and 24 h after drug administration. Plasma converting enzyme, renin, renin substrate and noradrenaline levels were measured at 0, 2, 4, 6, 8, 12 and 24 h with measurement of plasma drug levels from 4 h in addition. Blood pressure and heart rate responses to Valsalva's manoeuvre, isometric exercise and the cold pressor test were measured at 0, 6 and 24 h and to dynamic exercise at 6 and 24 h.

3 Both MK421 and MK521 significantly inhibited plasma converting enzyme activity, but the inhibition was more prolonged after MK521. Plasma drug concentrations were correspondingly higher after MK521 at the later time intervals. Significant decreases in supine and erect blood pressure without a reflex increase in heart rate were observed after active drug treatment and plasma renin activity was increased. Renin substrate was decreased significantly after MK421. Maximum changes in blood pressure, renin and renin substrate occurred 4-6 h after drug ingestion, corresponding to peak plasma drug levels and maximal inhibition of converting enzyme. Hormonal changes were also more prolonged after MK521. Plasma noradrenaline was unchanged. No significant effects of active drug treatment on any test of autonomic function were seen.

4 MK421 and MK521 are potent inhibitors of converting enzyme which decrease blood pressure in normal subjects without reflex tachycardia. Pharmacodynamic effects on blood pressure and renin occur in parallel with plasma drug levels and converting enzyme inhibition. These studies suggest that the hypotensive effect of MK421 and MK521 is due to inhibition of the renin-angiotensin system secondary to converting enzyme inhibition. Absence of tachycardia during converting enzyme inhibition is not due to alterations in autonomic reflexes.

     

Effect of a new angiotensin converting enzyme inhibitor MK 421 and its lysine analogue on the components of the renin system in healthy subjects.

1 MK 421 and its lysine analogue are two new inhibitors of angiotensin converting enzyme. Ten mg of both compounds were each given p.o. to 12 normotensive volunteers to determine their effect on the various components of the renin angiotensin aldosterone system. 2 Plasma converting enzyme activity decreased to very low levels within 3 to 4 h to recover only slowly over the next 72 h. Plasma angiotensin II and aldosterone also fell but returned to baseline within 24 h, whereas plasma renin activity rose reflecting the low angiotensin II levels. 3 There was a close correlation between both angiotensin II and aldosterone levels and the logarithm of plasma converting enzyme activity demonstrating that angiotensin II and aldosterone fell only when converting enzyme activity was reduced to very low levels. 4 Mean hourly urinary sodium excretion increased markedly 6 to 10 h post-drug, while blood pressure decreased slightly. Both drugs were well tolerated. 5 Thus 10 mg of MK 421 or its lysine analogue given orally are effective and long acting angiotensin converting enzyme inhibitors.     

A dose-response study of HOE 498, a new non-sulphydryl converting enzyme inhibitor, on blood pressure, pulse rate and the renin-angiotensin-aldosterone system in normal man.

The effect of different oral doses of HOE 498, a new non-sulphydryl containing converting enzyme inhibitor, was investigated in a double-blind, placebo-controlled study in normotensive volunteers. Dose-related reductions in serum converting enzyme activity, plasma angiotensin II and aldosterone were seen, greater at 4 h than at 12 h after drug ingestion. Converse dose-related increases in blood angiotensin I and plasma active renin concentration occurred. Falls of angiotensin II were as great with 20 mg as with 50 mg of HOE 498, although the effect was more prolonged with 50 mg. The reductions in concentrations of plasma angiotensin II and serum converting enzyme activity and the increases in plasma renin concentration were correlated with the concentration of HOE 498 - diacid in plasma. Dose-related falls in both supine and erect blood pressure were maximal 2-3.5 h after dosing. Pulse rate increased marginally but insignificantly in the supine; slightly and significantly in the upright position, concomitantly with the blood pressure reduction at all doses of active drug. We conclude that effects of single doses of HOE 498 on the renin-angiotensin system are maximal within 4 h, but are still apparent after 24 h. Thus it is likely that once daily administration will be adequate for treatment of high blood pressure in patients.     

CGS 13945: a new orally active angiotensin-converting enzyme inhibitor in normal volunteers

The new converting enzyme inhibitor CGS 13945 was evaluated in 14 male volunteers. The study consisted of two parts. First, the capacity of a single oral dose (10, 20, 50, 100, 250, or 500 mg) to inhibit the pressor response to exogenous angiotensin I was tested, with blood pressure and heart rate monitored continuously through an intra-arterial catheter. The 250-mg and particularly the 500-mg dose markedly reduced the pressor response to angiotensin I within 1/2 h and for a period exceeding 4 h. There was a close correlation between the pressor response to angiotensin I and plasma converting enzyme activity. In a second part, plasma renin and converting enzyme activity, angiotensin I and II, and plasma aldosterone were measured serially before and up to 48 h after oral administration of either 250 or 500 mg of CGS 13945 to six volunteers each. As expected, plasma renin activity and angiotensin I levels rose, while plasma converting enzyme activity and angiotensin II and aldosterone levels fell within 1/2 h. Twenty-four hours following administration of 500 mg CGS 13945, plasma converting enzyme had not quite returned to base line. No side effects were observed. CGS 13945 seems less potent than previously studied converting enzyme inhibitors, but equally effective and relatively long acting.     

Humoral and renal effects of MK-421 (enalapril) in hypertensive subjects

To assess the effect of MK-421 (enalapril) we treated six hospitalized hypertensive patients receiving constant sodium intake with incremental doses of this new angiotensin-converting enzyme blocking drug. After a few days of placebo treatment, MK-421 was given in single daily doses, starting with 1.25 mg and increasing until blood pressure was adequately controlled. On the lowest dose, converting enzyme activity was reduced by 50%, but angiotensin II and blood pressure did not change significantly. There were, however, significant increases in noradrenaline, renin, and aldosterone. With higher doses there was a more pronounced reduction in converting enzyme activity, while angiotensin II, aldosterone, and blood pressure all fell significantly. Renin levels rose, but noradrenaline and adrenaline were reduced. Orthostatic hypotension was not observed. With continued treatment, renal vasodilatation and enhanced natriuresis occurred together with a 1.2 kg decrement in body weight. Concurrently plasma volume rose, but renal blood flow remained unchanged. The data indicate that MK-421 effectively lowers blood pressure, and it does so by converting enzyme inhibition; sodium loss and a decrease in sympathetic activity are associated features. Since plasma volume increased despite enhanced natriuresis, the drug may act both at the arteriolar and at the venular level.     

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.     

Repeated administration of the converting enzyme inhibitor cilazapril to normal volunteers

Cilazapril 1.25 and 5.0 mg p.o. q.d. was administered in double-blind fashion to two groups of six normal volunteers on 8 consecutive days. Blood pressure, heart rate, and plasma converting enzyme activity were measured each day prior to drug administration and up to 72 h after the last dose. Plasma renin activity, blood angiotensin I, plasma angiotensin II, and aldosterone as well as plasma cilazaprilat levels were determined on the first and the last day of active treatment at times 0, 4, and 24 h. The drug was very well tolerated by all volunteers. At 4 h postdrug, plasma converting enzyme activity was reduced in dose-dependent fashion on the first and the eighth day; plasma cilazaprilat levels were also clearly dose dependent. Nevertheless, 24 h postdrug cilazaprilat levels were similar on the first and last day of drug administration, and plasma converting enzyme activity was also stable throughout the 8 days. The various components of the renin-angiotensin system responded in the usual fashion. These results provide strong evidence that cilazapril is a very potent and highly effective converting enzyme inhibitor. Doses well below 5 mg/day will probably suffice for therapeutic efficacy. These data also confirm the hypothesis formulated in the preceding article, i.e., that there is no accumulation of the drug with repeated administration despite its long pharmacological half-life (t1/2).     

RHC 3659: a new orally active angiotensin converting enzyme inhibitor in normal volunteers.

1 The new converting enzyme inhibitor RHC 3659 was tested in 15 male volunteers. The study consisted of two parts: first, the ability of a single oral dose (5, 10, 20, 40 or 80 mg) to inhibit the pressor response to exogenous angiotensin I was tested with blood pressure and heart rate monitored continuously through an intraarterial catheter. A dose-related shift to the right of the pressor response curve to angiotensin I was observed with a peak occurring within 0.5 to 1 h. The pressor response to angiotensin II was unaffected. 2 In the second part, plasma renin and converting enzyme activity, angiotensin II and aldosterone were measured serially before and up to 8 h after administration of a single oral dose of RHC 3659. As expected. plasma angiotensin II and aldosterone fell within 30 min while plasma renin activity increased. Plasma converting enzyme activity was suppressed at 0.5 h in a dose-related manner with levels still below 30% of control 4 h following 80 mg of the inhibitor. 3 However, in vitro the enzyme-inhibitor complex seemed quited fragile since during storage of the plasma samples at -20 degrees C, converting enzyme activity increased significantly already within days (P less than 0.001, n = 28) and continued to rise for more than 2 months. This fragility may explain the seemingly lower potency of RHC 3659 when compared to captopril. No side effects were observed.     

Captopril treatment: inter-dose variations in renin, angiotensins I and II, aldosterone and blood pressure.

1 The ability of captopril, 150 mg three times daily by mouth, to effect sustained reduction in plasma angiotensin II, with converse increases in circulating angiotensin I, and in active, inactive and total renin concentrations, has been assessed. 2 During prolonged treatment with captopril alone, and 12 h after the last dose of the drug, plasma angiotensin II remained approximately one-sixth of basal concentrations, while angiotensin I and renin concentrations were proportionately increased. However, further increases in angiotensin I, and in active, inactive and total renin concentrations, were seen 2 and 6 h after the morning dose of 150 mg captopril. 3 Inter-dose variations in plasma aldosterone and blood pressure were not closely related to concurrent variations in the renin-angiotensin system. 4 Arguments are presented for relying on measurements of plasma renin and angiotensin concentrations rather than of renin activity or aldosterone in assessing the effectiveness of converting enzyme inhibition.     

Pharmacodynamic, pharmacokinetic and humoral effects of oral zabicipril, an angiotensin converting enzyme inhibitor in normotensive man.

1. Zabicipril, S9650, a new angiotensin converting enzyme inhibitor, was administered to salt-replete, normotensive males in single doses of up to 10 mg. 2. The safety, tolerance and dose-response relationship with regard to inhibition of plasma ACE activity were characterised initially in an open, pilot, dose-finding study in 12 subjects and further explored in a double-blind, parallel group, placebo controlled study in another 30 subjects. 3. The drug was generally well tolerated and produced no change in routine haematology or serum biochemistry tests. 4. Dose related (0.03 to 10 mg) inhibition of plasma converting-enzyme was observed, with 2.5 mg of zabicipril producing over 90% inhibition at 4 h and 60% at 24 h. 5. There were no significant changes in blood pressure or heart rate in normotensive subjects over the dose range studied. 6. A dose related rise in plasma renin activity and angiotensin I was observed. No dose related reduction in plasma aldosterone was observed. 7. These initial studies suggest that zabicipril is a well tolerated inhibitor of converting enzyme with near maximal inhibitory effect occurring at a dose of 2.5 mg. Further exploration of the dose range after single and multiple doses is indicated.     

Effect on blood pressure and the renin-angiotensin system of repeated doses of the converting enzyme inhibitor CGS 14824A

Summary A new, orally active angiotensin converting enzyme (ACE) inhibitor, CGS 14824A, was evaluated in 12 healthy male volunteers. Two groups each of 6 volunteers were given 5 or 10 mg once daily p.o. for 8 days. Four hours after the first and the last morning doses, plasma angiotensin II, aldosterone and plasma converting enzyme activity had fallen, while blood angiotensin I and plasma renin activity had risen. Throughout the study, more than 90% inhibition of ACE was found immediately before giving either the 5 or 10 mg dose and 50% blockade was still present 72 h following the last dose. Based on the determination of ACE, there was no evidence of drug accumulation. No significant change in blood pressure or heart rate was observed during the course of the study. CGS 14824A was an effective, orally active, long-lasting and well tolerated converting enzyme inhibitor.     

Haemodynamic and pharmacological effects of the converting enzyme inhibitor CGS 14824A in normal volunteers

Summary The converting enzyme inhibitor CGS 14824A was evaluated in 15 healthy male volunteers. First, the efficacy of a single 5 or 10 mg oral dose in antagonizing the pressor response to exogenous angiotensin I was tested in 2 subjects. Blood pressure and heart rate were monitored continuously through an intra-arterial catheter. CGS 14824A 5 mg reduced the response to angiotensin I within 75 min to 50%, and 10 mg within 1 h to less than 25%, and for a period of more than 4 h. Subsequently, plasma renin and converting enzyme activity, plasma angiotensin I, angiotensin II and aldosterone were measured serially before and up to 72 h following oral administration of 2, 5, 10 or 20 mg CGS 14824A to groups of 5 volunteers. Plasma converting enzyme activity fell to well below 10% of baseline within 1 h after administration of 5 mg or more CGS 14824 A. Within 2 h following 2 mg p.o., a similarly low level was reached. Twenty four hours following the 20 mg dose, plasma converting enzyme activity was still below 10%. As expected, plasma renin activity and angiotensin I rose while angiotensin II and aldosterone fell following the 2 mg dose. This pattern of effects was enhanced by increasing the dose. Nonetheless, 24 h after the 20 mg dose, plasma angiotensin II and aldosterone had returned to their baseline levels. No side-effects occurred. Thus, in normal volunteers, CGS 14824A was an effective, potent and long acting converting enzyme inhibitor.     

The effect of enalapril on baroreceptor mediated reflex function in normotensive subjects.

The effects of enalapril, 20 mg orally, on the responses to baroreflex activation and deactivation by respectively phenylephrine and nitroglycerin were investigated in normotensive subjects on a normal sodium diet, with simultaneous measurement of plasma renin activity (PRA), converting enzyme activity (PCEA), aldosterone and catecholamines. Enalapril, 4 h after administration, lowered artificial blood pressure without modifying heart rate and plasma catecholamines. PCEA was abolished, PRA increased and plasma aldosterone decreased. Enalapril (a) displaced to the left the baroreflex set-point, (b) did not affect baroreflex sensitivity since the slopes of the RR-interval/systolic blood pressure regression lines remained unchanged during both activation and deactivation and (c) did not modify baroreflex efficacy since the maximal RR-interval responses as well as the overall RR-interval-time products to identical blood pressure variations were not modified. Thus, enalapril induced a resetting of the baroreflex, which probably accounts for the lack of reflex tachycardia observed during the drug-induced fall in blood pressure.     

Arterial vasodilating profile and biological effects of pinacidil in healthy volunteers.

1. The effects of pinacidil (25 mg, sustained release formulation) a) on systemic (arterial pressure, cardiac output) and regional (brachial and carotid arteries' diameters and flows) haemodynamics (pulsed Doppler techniques), b) on sympathetic (plasma noradrenaline) and renin-angiotensin (plasma renin activity) systems, and c) on atrial natriuretic factor have been investigated and compared with those of a placebo during the 12 h period following oral administration in a randomized, double-blind and cross-over study performed in six healthy volunteers. Simultaneously, the plasma levels of pinacidil and of its active metabolite, pinacidil N-oxide, were determined. 2. As compared with placebo, pinacidil decreased systemic vascular resistance and arterial blood pressure but cardiac output was not modified. 3. Pinacidil significantly increased brachial and carotid arteries' diameters (by 7 and 8% respectively) and flows (by 60 and 17% respectively) and decreased forearm vascular resistance (by 43%). Thus, pinacidil dilates both large and small arteries, increases large vessels' compliance and redistributes blood flow towards the muscular vascular bed. These effects peaked at 4 h and their duration at the brachial level was 8 h. 4. Pinacidil administration resulted in a stimulation of both sympathetic (increases in heart rate and plasma noradrenaline) and renin-angiotensin systems, and induced a transient increase in atrial natriuretic factor. 5. The duration of pinacidil haemodynamic effects at the brachial level is consistent with the pharmacokinetic data which show that pinacidil and pinacidil N-oxide plasma levels almost plateaued between 3 and 8, and 2 and 8 h respectively after oral administration of the sustained release formulation used.     

Effects of intravenous endralazine in essential hypertension.

The effects of endralazine, administered intravenously, on blood pressure, heart rate, forearm blood flow, plasma renin activity, aldosterone, adrenaline and noradrenaline were studied in five patients with essential hypertension. Endralazine reduced peripheral vascular resistance, resulting in decrease in mean arterial pressure from 141 to 116 mm Hg and increase in heart rate from 67 to 92 beats/min. Plasma renin activity, adrenaline and noradrenaline increased significantly after endralazine infusion. All effects observed are consistent with endralazine acting as a peripheral vasodilating drug.     

Effects of single doses of the converting enzyme inhibitor cilazapril in normal volunteers

The new converting enzyme inhibitor cilazapril, or RO 31-2848, was evaluated in 14 healthy male volunteers. In a pilot study in two subjects, the inhibiting capacity of single oral doses of 5 and 10 mg on the pressure and heart rate response to exogenous angiotensin I was assessed. Both doses reduced the blood pressure response to angiotensin I to 10% of control within 45 min and for the 4 h tested. In the main study, 12 volunteers each received two single oral doses of cilazapril at a 2-week interval, and plasma converting enzyme and renin activity, blood angiotensin I, plasma immunoreactive angiotensin II and aldosterone were measured serially. Single doses of 1.25, 2.5, 5, and 10 mg of cilazapril were tested in groups of six subjects each. All doses inhibited plasma converting enzyme activity by 90% for at least 8 h and induced the expected pattern of changes of the renin-angiotensin-aldosterone system. Only slight dose-dependent variations in the effect were observed. Basic heart rate and blood pressure were not altered by any of the doses, which all were well tolerated. These data suggest that cilazapril is a very potent and long-acting new converting enzyme inhibitor.