Effects of angiotensin I-converting enzyme inhibitor (SA-446) on renal function in dogs

The effects of an orally active inhibitor of angiotensin-converting enzyme (SA-446) on systemic arterial pressure, renal function and renin release were examined in anesthetized dogs. Intrarenal infusion of the larger dose of SA-446 (0.1 mg/min) caused an increase in RBF, urine flow and renin release and caused a fall in blood pressure. The smaller dose of SA-446 (0.02 mg/min) did not affect the blood pressure, but it increased the urine flow. However, the same dose of SA-446 in combination with probenecid caused a significant fall in blood pressure. The potentiation of SA-446 with probenecid may be explained by the elevation in plasma SA-446 concentration via the inhibition of its tubular secretion by probenecid.     

Effects of the new angiotensin-converting enzyme inhibitor imidapril on renal hemodynamics and function in anesthetized dogs.

The effects of a new angiotensin-converting enzyme (ACE) inhibitor, imidapril hydrochloride ((-)-(4S)-3-[(2S)-2- [[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino]propionyl]- 1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1) and of its active metabolite, 6366 A (CAS 89371-44-8) on renal function were studied in anesthetized dogs and compared to the effects of enalapril and its active metabolite, enalaprilat. Intravenous (i.v.) administration of 6366 A at 30 micrograms/kg strongly inhibited angiotensin I-induced renal vasoconstrictive and pressor responses. 6366 A promptly lowered blood pressure and renal vascular resistance, and caused clear increases in renal blood flow and glomerular filtration rate. It also increased urine volume and urinary excretion of sodium and chloride. These renal effects were also produced by intraduodenal (i.d.) administration of 2 mg/kg of imidapril. However, the effects of i.d. imidapril began later, developed gradually and reached a plateau after 2 to 3 h. Enalaprilat (30 micrograms/kg i.v.) and enalapril (2 mg/kg i.d.) had renal effects similar to 6366 A and imidapril. In conclusion, the ACE inhibitor imidapril has beneficial effects on renal function via its active metabolite, and the effects appear to be essentially identical to those of enalapril.     

Renal excretion of an angiotensin I converting enzyme inhibitor (SA-446) in dogs

Summary The renal excretory mechanism of an orally active inhibitor of angiotensin converting enzyme (SA-446) was examined in anesthetized dogs. Parenteral administration of this compound resulted in production of constant levels of about 2 mg/l in the plasma (P_SA) and the urine concentration was 726±200 mg/l, a level significantly higher than that in the plasma. Renal clearance of SA-446 (C_SA) was 2.24±0.34 ml/g·min and was significantly higher than GFR. The clearance ratio (C_SA/GFR) of over 1.0 was indicative of a net tubular secretion. Administration of probenecid resulted in a significant rise in P_SA and in a significant decrease in urinary excretion but with no change in the plasma protein binding ratio. C_SA decreased significantly from 2.24±0.34 to 0.71±0.14 ml/g·min. The inhibotory action of SA-446 (0.02 mg/kg, i.v.) on the pressor response to angiotensin I disappeared at about 50 min, this action being maintained for about 2 h in the probenecid pretreated dog.Since probenecid is a competitive inhibitor of organic anion secretory transport, our results show the net tubular secretion of SA-446, via organic anion transport systems. Prolongation of the action of SA-446, as induced by probenecid may be due to the increase of plasma concentration, by the inhibition of tubular secretion.     

Renal effects of perindoprilat, an angiotensin-converting enzyme inhibitor, in the anesthetized dog

The effects of perindoprilat on renal hemodynamics and the elimination of water and electrolytes were studied acutely in the anesthetized dog. Two groups of animals were compared, one on normal sodium and water, the other on an acutely restricted sodium and water diet. In all cases, perindoprilat injected into renal artery (0.1 and 0.5 mg/kg) reduced blood pressure. In the animals on a low sodium diet, perindoprilat increased renal blood flow from 2.2 +/- 0.3 to 2.9 +/- 0.3 ml/min/g and decreased the filtration fraction; the decrease in renal vascular resistance predominated on the efferent arteriole of the glomerule (45% decrease), preferential site for the vasoconstrictor action of angiotensin II. In the animals on a normal sodium diet, renal blood flow was also increased from 4.1 +/- 0.6 to 5.1 +/- 0.6 ml/min/g but without the filtration fraction being affected. The renal vascular resistance was decreased at both pre- and post-glomerular levels (respectively, 50 and 25% decrease). After sodium and water restriction, but not in animals on a normal sodium diet, perindoprilat increased the fractional elimination of water and electrolytes. This salidiuresis might be accounted for by the hemodynamic effect of converting enzyme inhibitor and the decrease it elicits in filtration fraction, modifying sodium and water reabsorption in the proximal tubule.     

Comparison of acute hemodynamic effects of MC-838, a new angiotensin-converting enzyme inhibitor, with captopril in anesthetized dogs

Effects of a new angiotensin-converting enzyme inhibitor, N-[3-(N-cyclohexanecarbonyl-D-alanylthio)-2-methylpropanoyl] -L-proline calcium (MC-838), on the systemic and coronary circulation were evaluated in anesthetized dogs, and the effects were compared with those of captopril. Administration of MC-838 (0.1, 0.3, 1.0 and 3.0 mg/kg, i.v.) produced a gradual and dose-dependent decline in aortic pressure associated with no marked changes in coronary blood flow, heart rate and LVdP/dt. Captopril (0.01, 0.03, 0.1 and 0.3 mg/kg, i.v.) also caused a dose-related decrease in aortic pressure, but the significant hypotension appeared more rapidly than that of MC-838. Both MC-838 and captopril inhibited selectively the pressor response to angiotensin I in a dose-related manner. The doses of MC-838 and captopril to lower mean aortic pressure by 10 mmHg from the pre-drug value were 2.8 mg/kg and 0.03 mg/kg, respectively; those of these drugs to cause 50% inhibition of angiotensin I-pressor response were 1.0 mg/kg and 0.04 mg/kg, respectively. When administration of MC-838 (3.0 mg/kg) was repeated three times at a 30 min-interval, the second and third injections caused no additional hypotension, while each of the repeated injections of captopril (0.3 mg/kg) produced significant hypotension. These results indicate that MC-838 inhibits angiotension I-conversion and decreases systemic blood pressure more slowly and persistently than captopril in anesthetized dogs.     

Effects of an angiotensin-converting enzyme (ACE) inhibitor, SA446, on tissue ACE activity in normotensive, spontaneously hypertensive, and renal hypertensive rats

Effects of an angiotensin-converting enzyme (ACE) inhibitor, SA446, on the renin-angiotensin system, particularly on tissue ACE activity, were studied in Wistar-Kyoto normotensive rats (WKY), spontaneously hypertensive rats (SHR), and two-kidney, one-clip renal hypertensive rats (RHR) by repeated oral administration for 7 days. SA446 (45 mg/kg/day p.o.) inhibited ACE activity in the lung, brain, kidney, heart, and whole blood throughout the administration period in WKY, but showed a slight hypotensive action and no inhibition of aorta ACE activity. On the other hand, SA446 had an apparent hypotensive action at the same dose in SHR and inhibited ACE activity significantly in the aorta as well as the kidney and whole blood during the administration period. Furthermore, enzyme activity in the aorta, kidney, heart, and whole blood was also inhibited at a hypotensive dose of SA446 (10 mg/kg/day p.o.) in RHR. The inhibition in whole blood and kidney was almost complete, and the inhibition in the aorta was greater on day 7 than on day 1. The maximum decrease of blood pressure was correlated with the maximum inhibition in aorta ACE activity, but not in brain, lung, or heart ACE activity. In addition, a good positive correlation was observed between the basal blood pressure and the basal aorta ACE activity in WKY, SHR, and RHR, although there was no correlation in the brain, lung, kidney, heart, or whole blood. These results suggest that the antihypertensive action of SA446 by repeated administration may be due to inhibition of arterial ACE activity in addition to inhibition of plasma and kidney ACE activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypotensive effect of SA446, an angiotensin converting enzyme inhibitor, in 2-kidney, 1-clip renal hypertensive and normotensive dogs

Hypotensive effects of SA446, an angiotensin converting enzyme (ACE) inhibitor, and effects on the renin-angiotensin system were evaluated in conscious normotensive and 2-kidney, 1-clip renal hypertensive dogs. SA446 (1 mg/kg, p.o.) remarkably inhibited the pressor response to angiotensin (Ang) I between 1 and 6 hr after the administration in normotensive dogs. SA446 significantly decreased blood pressure at 10 mg/kg, p.o., in normotensive dogs. During repeated administration of SA446 (100 mg/kg/day, p.o.) for 13 weeks, the blood pressure was lowered, and the pressor response to Ang I and plasma ACE activity were strongly inhibited. ACE activities in the aorta and kidney were also inhibited. Plasma renin activity and plasma Ang I concentration increased by repeated SA446 application, while plasma aldosterone concentration decreased. The hypotensive effect of SA446 (5 mg/kg, p.o.) was more potent in 2-kidney, 1-clip renal hypertensive dogs than in normotensive dogs. SA446 had longer inhibitory effects on the pressor response to Ang I and more potent hypotensive effects than captopril. The hypotension caused by SA446 appears to be associated mainly with an inhibition of ACE in plasma and also in the vascular wall.     

Effect of an angiotensin-converting enzyme inhibitor on blood pressure and erythropoiesis in rats

Positive correlation between systolic blood pressure and plasma renin substrate was demonstrated in Wistar-Kyoto rats when plasma renin substrate was reduced to within a range of 18 and 88% of control values with varying amounts of ramipril. When ramipril was given in amounts that had a maximum effect on systolic blood pressure, marked changes in erythropoietin, reticulocyte count and hematocrit % were observed. Consistent blood pressure-lowering effect was evident for several weeks after ramipril withdrawal. Furthermore, blood pressure obtained 3 days after the rats were taken off ramipril correlated positively with the hematocrit % measured while the rats were still on ramipril (r = 0.83; P less than 0.001). Mean blood volume of 17 rats receiving ramipril was similar to that of the 10 control rats. Plasma and renal renin substrate were highly and positively correlated (r = 0.86; P less than 0.001). Inasmuch as plasma renin substrate is rate-limiting for angiotensin I, it may reflect intrarenal AII and prove to be a useful clinical assessment of converting enzyme inhibition. The increased levels of renin, renin substrate and packed cell volume seen in rats fed Purina basal diet (10% fat) as compared with rats fed Purina lab chow (4.5% fat), support the working hypothesis that intrarenal angiotensin II controls both blood pressure and erythropoiesis.     

Cytochrome p450-dependent metabolites of arachidonic acid and renal function in the rat

1. The present study examined whether renal cytochrome P450 (CYP450)-derived eicosanoids influence the pressure-natriuretic and haemodynamic responses to elevated renal perfusion pressure (RPP) in the rat. 2. Natriuresis and diuresis, as well as changes in renal blood flow (RBF) and glomerular filtration rate (GFR) following step-wise elevations in RPP from 75 to 125 mmHg were compared in control rats and in rats treated with 12,12-dibromodecenoic acid (DBDD; 2.5 mg/kg per h; n = 5), an inhibitor of omega/omega-1 hydroxylase, or miconazole (1.3 mg/kg per h; n = 7), an inhibitor of epoxygenase. 3. In control rats, sodium excretion (U(Na)V) and urine volume (UV) increased five-fold when RPP was increased from 75 to 125 mmHg, while RBF and GFR increased two-fold when RPP increased from 75 to 100 mmHg, with no further increase between 100 and 125 mmHg, the autoregulatory range. 4. Miconazole, but not DBDD, altered the pressure-natriuresis relationship, exaggerating the increases in U(Na)V and UV three- to four-fold when RPP was increased from 100 to 125 mmHg. 5. In contrast, DBDD eliminated the autoregulatory response because it abolished the plateau in RBF and GFR when RPP was increased from 100 to 125 mmHg, whereas miconazole was without effect. 6. These results suggest that CYP450-dependent omega/omega-1 hydroxylase metabolites of arachidonic acid contribute to vascular responses, while epoxygenase metabolites contribute to renal tubular responses to alterations in RPP in the rat.     

Effects of sodium loading on antihypertensive responses to an angiotensin-converting enzyme inhibitor in spontaneously hypertensive and renal hypertensive rats

Sodium loading significantly attenuated the antihypertensive potency of an angiotensin-converting enzyme inhibitor, SA446, in 2-kidney, 1-clip renal hypertensive rats, but the potency of SA446 remained unchanged in spontaneously hypertensive rats. Basal levels of plasma renin activity of both types of hypertensive rats were suppressed by sodium loading. From these results, it appeared that a different mechanism was involved in the maintenance of hypertension in 2-kidney, 1-clip renal hypertensive rats and in spontaneously hypertensive rats. It also appeared that the mechanism of the antihypertensive action of angiotensin-converting enzyme inhibitors was not explainable only by the suppression of the plasma renin-angiotensin system.     

Effects of nifedipine on renin release and renal function in anesthetized dogs

The effects of nifedipine, classed as a calcium entry blocker, on urinary excretion and renin release were investigated in anesthetized dogs. Nifedipine was infused into one renal artery for three consecutive 10-min periods, at incremental rates of 0.3, 1, and 3 micrograms/min. Intrarenal infusion of nifedipine (3 micrograms/min) produced marked increases in urine flow rate (by 200%) and in urinary sodium (by 210%) and potassium (by 40%) excretion rates of the infused kidney without changes in mean systemic blood pressure, heart rate, glomerular filtration rate, and filtration fraction. Urinary osmolarity was slightly decreased by the drug, but this change was not statistically significant. There were no consistent changes in these parameters for the contralateral noninfused kidney. Renin secretion rate was increased to three times the preinfusion level during infusion of the highest nifedipine dose. The blood flow to the infused kidney was increased, and ipsilateral renal vascular resistance was simultaneously decreased upon nifedipine infusion. These results suggest that a nonhypotensive dose of nifedipine causes an increase in renin secretion and that this drug has a striking effect on the reabsorption of sodium and water by the renal tubules.     

Effects of intravenous S-9780, an angiotensin-converting enzyme inhibitor, in normotensive subjects

S-9780 is the active diacid metabolite of the new angiotensin-converting enzyme (ACE) inhibitor perindopril. In a double-blind, randomised, crossover study, the effects of 1, 2, and 4 mg of S-9780 administered intravenously (i.v.) were compared with placebo in eight normotensive subjects. All active doses caused immediate, maximal, and similar inhibition of plasma ACE with 40% inhibition persisting after 48 h. Plasma renin activity was elevated 4 and 8 h after dosing, but no effect on plasma aldosterone, adrenaline or noradrenaline levels was detected. Diastolic blood pressure was lowered by 4 mg of S-9780 until 24 h after dosing. Heart rate did not change. The pharmacokinetics of S-9780 fitted a three-compartment model with a terminal half-life (t1/2) of 31 h. Inhibition of plasma ACE was closely related to observed drug concentration, with 1.8 +/- 0.9 ng/ml (mean +/- S.D.) producing 50% inhibition of the enzyme. S-9780 caused predictable effects on the cardiovascular and renin angiotensin systems.     

Effect of angiotensin-converting enzyme inhibitor perindopril on interneurons in MPTP-treated mice.

We examined the effects of perindopril on the dopaminergic system in mice after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. The mice received four intraperitoneal injections of MPTP at 1-h intervals. Administration of perindopril showed dose-dependent neuroprotective effects against striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) depletion 3 days after MPTP treatment. Our immunohistochemical study showed that MPTP can severe damage in tyrosine hydroxylase (TH)-immunoreactive neurons after MPTP treatment. The administration of perindopril significantly attenuated MPTP-induced substantia nigra and striatal damage. The present study also showed that the immunoreactivity of parvalbumin (PV)- or neuronal nitric oxide synthase (nNOS)-positive cells in the substantia nigra was decreased 7 days after MPTP treatment, whereas no significant changes were observed in these cells of the striatum throughout the experiments. The administration of perindopril significantly attenuated MPTP-induced decrease of the PV- or nNOS-immunoreactivity in the nigral cells. In double-labeled immunostaining with anti-PV and anti-nNOS antibody, PV-immunoreactive cell bodies and fibers were not double-labeled for nNOS-immunoreactive cell bodies and fibers in both the striatum and substantia nigra after MPTP treatment. Furthermore, PV- or nNOS-immunoreactive cell bodies and fibers in both the striatum and substantia nigra were not double-labeled for TH-immunoreactive cell bodies and fibers. These results demonstrate that the ACE inhibitor perindopril has a dose-dependent protective effect against MPTP-induced striatal dopamine, DOPAC and HVA depletion in mice. The present study also demonstrates that perindopril is effective against MPTP-induced degeneration of the nigral neurons and interneurons. Furthermore, our immunohistochemical study suggests that PV-immunoreactive cells and nNOS-immunoreactive cells are different interneurons in both the striatum and substantia nigra. Thus, our results provide further evidence that the ACE inhibitor perindopril may offer a novel therapeutic strategy for Parkinson's disease (PD).     

Studies on mechanisms of antinephritic action of SA-446 an angiotensin I converting enzyme inhibitor (1). A comparison with actions of spironolactone, kallidinogenase and saralasin

The present study was made to clarify the mechanisms of the antinephritic action of SA-446, an angiotensin I converting enzyme inhibitor, on crescentic-type anti-GBM nephritis in rats as compared to the actions of spironolactone (an antialdosterone agent), kallidinogenase (a kallikrein agent) and saralasin (an angiotensin II antagonist). SA-446 (25 mg/kg/day, p.o.) had a tendency to reduce the urinary protein excretion and plasma urea nitrogen content. In addition, this drug remarkably inhibited not only glomerular histopathological changes (i.e., crescent formation, the adhesion of capillary walls to Bowman's capsule and fibrinoid necrosis) but also the elevation of blood pressure. Spironolactone (25 mg/kg/day, p.o.) and kallidinogenase (25 KU/day, i.m.) also showed beneficial effects on glomerular histopathological changes and hypertension, although both drugs were not as effective as SA-446. However, saralasin (72 micrograms/day, s.c.) caused a marked aggravating action on this nephritis. This nephritic model showed a marked low activity of plasma renin all through the 40 day experimental period. In this model, the urinary aldosterone excretion was increased, in spite of the decrease in plasma renin activity. SA-446 and kallidinogenase significantly inhibited the decrease in plasma renin activity and the increase in urinary aldosterone excretion. Spironolactone inhibited only the increase in the aldosterone excretion. However, saralasin decreased the plasma renin activity under the control level and strongly increased the urinary aldosterone excretion (about 1.8 times the control level on the 20th day). These results suggest that the antinephritic effect of SA-446 may be related to the antihypertensive action and the increase in renal blood flow through activation of the kallikrein-kinin and prostaglandins systems.     

Effect of perhexiline on atrioventricular nodal function of anesthetized dogs

We investigated the effects of perhexiline, a calcium-antagonistic vasodilator, on atrioventricular (AV) conduction in anesthetized open-chest dogs and in isolated, blood-perfused AV node preparations of the dog. Perhexiline, 3 mg/kg, prolonged the AV conduction time from 103.0 +/- 4.4 to 115.3 +/- 4.0 msec (p less than 0.05) in dogs with intact cardiac nerves. In dogs on which vagotomy and stellectomy had been performed, basal AV conduction time was 119.0 +/- 5.0 msec; 3 mg/kg of perhexiline barely prolonged it (121.0 +/- 7.0 msec). Thus, the negative dromotropic effect of perhexiline was abolished by denervation. The functional refractory period of the AV node was also lengthened with 3 mg/kg of perhexiline in the nerve-intact dogs (from 246.0 +/- 15.7) to 270.0 +/- 15.5 msec), but was scarcely affected by perhexiline in the cardiac denervated dogs (from 296.7 +/- 15.7 to 303.2 +/- 13.6 msec). Verapamil, 0.1-0.3 mg/kg, exerted a negative dromotropic effect in both innervated and denervated hearts. A direct inhibitory effect of perhexiline on AV conduction was observed in isolated blood-perfused AV node preparations, but it was much weaker when compared with that of verapamil.     

Effect of food on the bioavailability of lisinopril, a nonsulfhydryl angiotensin-converting enzyme inhibitor

A randomized, two-way, crossover study was performed on 18 normal volunteers to assess the influence of food on the bioavailability of lisinopril, (1-[N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline), a long-acting nonsulfhydryl angiotensin converting enzyme inhibitor. A single, 20-mg oral dose of lisinopril was administered to volunteers in the fasting state or following a standardized breakfast. Treatment periods were separated by 2-week intervals. No significant differences existed between fasting and fed regimens in the mean +/- SD area under the serum concentration-time curve (AUC0-120h; 1231 +/- 620 versus 1029 +/- 254 ng X h X ml-1), peak lisinopril serum concentration (86 +/- 48 versus 69 +/- 19 ng/mL), or time to peak lisinopril serum concentration (6.2 +/- 1.1 versus 6.8 +/- 1.0 h). Five-day urinary excretion of lisinopril was not altered by food (5.3 +/- 3.0 versus 5.1 +/- 2.0 mg). Based on the urinary data, the mean +/- SD bioavailability of lisinopril was not different following fasting or fed regimens (27 +/- 15 versus 26 +/- 10%). Unlike with captopril, food did not affect the bioavailability of lisinopril.     

Effect of angiotensin-converting enzyme inhibitor on collagenolytic enzyme activity in patients with acute myocardial infarction

Matrix metalloproteinases and their tissue inhibitors are key enzymes degrading myocardial collagen in acute myocardial infarction (AMI). The aim of the present study was to determine whether angiotensin-converting enzyme inhibitors (ACEI) influence collagenase-1 (MMP-1) and their tissue inhibitor (TIMP-1) activity in AMI patients. Plasma levels of MMP-1, TIMP-1 and MMP-1/TIMP-1 complex were measured in 24 patients (aged 58.4 +/- 13.9 years) with AMI. Thirteen patients received perindopril 4 mg/day (group A) and 11 did not (group B). Plasma samples collected on admission and at 0, 3, 6, 9, 12, 18, 24, 36 and 48 hours and on days 3, 4, 5, 7, 15 and 30 thereafter were analyzed by relevant ELISA kits. Ejection fraction (EF) was assessed by ventriculography and end-diastolic diameter (EDD) echo-study on days 6 and 30. Values of collagenolytic enzymes of group A compared with those in group B were on average lower by 34%, 18.3% and 40%, respectively. The difference in values between groups at 0 h, 3 h and 9 h was significant (p < 0.048). ANOVA repeated measurement analysis showed significance within subjects for MMP-1 alone (p < 0.043) and for MMP-1 and ACEI (p < 0.046), while for TIMP-1 and MMP-1/TIMP-1 complex significance was only p < 0.0009. Regarding EDD changes, patients in group A showed minimal or no changes (51.23 +/- 1.8 mm to 51.6 +/- 2.13 mm), their EF was 38.8% and infarct size was medium to large. In contrast, group B showed a trend to increase EDD (41 +/- 0.78 mm to 42.33 +/- 0.59 mm), their EF was 50.5% and infarct size was small to medium. In conclusion, early initiation of ACEI treatment reduces collagenolytic activity. This effect may be considered an alternative mechanism for beneficial effects on postinfarction remodeling.     

Essential hypertension: effect of an oral inhibitor of angiotensin-converting enzyme.

Captopril, a specific oral inhibitor of angiotensin-converting enzyme, was given to 18 unselected patients with moderate essential hypertension. Mean blood pressure fell by 14.5% at the maximum dose given, and this fall was significantly correlated with the initial plasma renin activity. The main fall in blood pressure occurred two hours after the first dose of captopril. These results suggest that captopril effectively lowers blood pressure in patients with essential hypertension and that the renin-angiotensin aldosterone system may maintain blood pressure in essential hypertension. This does not necessarily imply that the renin-angiotensin system is the cause of the high blood pressure.     

Antihypertensive activity of alacepril, an orally active angiotensin converting enzyme inhibitor, in renal hypertensive rats and dogs

Alacepril (1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine, DU-1219) showed a dose related and long lasting antihypertensive effect in renal hypertensive rats (two-kidney, one-clip), a typical renin dependent hypertensive model. The maximum hypotensive potency of alacepril (1-30 mg/kg) after single oral administration was slightly weaker than that of captopril (1-30 mg/kg). Judging from the AOC (area over the antihypertensive curve) value, the overall antihypertensive activity of alacepril was 3 times more potent than that of captopril on a weight basis. The long lasting antihypertensive effect of alacepril in renal hypertensive rats was also confirmed by once daily successive oral administration (1-2 mg/kg/d). In renal hypertensive dogs, alacepril (3 mg/kg) showed a stable and sustained hypotensive effect, and its duration of action was longer than that of captopril. Although alacepril did not possess a significant in vitro angiotensin converting enzyme (ACE) inhibitory activity, orally given alacepril (5.6-56.1 mg/kg) produced a potent and prolonged in vivo ACE inhibition which was estimated by suppression on angiotensin-I (310 ng/kg i.v.) induced pressor response in conscious normotensive rats. The prolonged in vivo ACE inhibitory activity of alacepril (5.6 mg/kg) was also observed in conscious normotensive dogs. These results suggest that the disposition and metabolism of orally given alacepril are responsible for the prolonged ACE inhibition and, concomitantly, for exerting the long lasting antihypertensive effect. Consequently, alacepril is a novel orally active ACE inhibitor having a potent and prolonged antihypertensive activity, and these properties suggest that alacepril is favorable for the treatment of hypertension.