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.     

The potentiation of cardiodepressant and hypotensive effects of bradykinin by enalapril and captopril both in vitro and in vivo.

1. Bradykinin (cumulative concentrations of 0.007-0.09 micrograms ml-1) produced a dose-related, but statistically insignificant depression of the isometric contraction of the isolated, spontaneously beating atria of the guinea-pig. The same concentrations of bradykinin did not change the atrial rate, but a tendency to a slight decrease was observed. 2. Enalapril (4.06 or 13.54 mumol l-1), produced a dose-related potentiation of the effect of the highest concentration of bradykinin on the isometric contraction. 3. Captopril (equimolar concentrations) also potentiated the effect of the highest concentration of bradykinin on the isometric contraction. This effect of captopril was not dose-related. 4. Both enalapril and captopril did not change the effect of bradykinin on the heart rate. 5. Bradykinin induced dose-related hypotensive responses in anaesthetized cats (0.03-1.0 microgram/kg b.w., i.v.) with a tendency towards bradycardia. 6. Enalapril (0.3 and 1.0 mg/kg b.w., i.v.) significantly potentiated bradykinin-induced hypotension and bradycardia. However, the potentiating effect of enalapril was not dose-dependent. 7. Captopril (0.1, 0.3 and 1.0 mg/kg b.w., i.v.) significantly potentiated bradykinin-induced hypotension and bradycardia. Also, the potentiating effect of captopril was not dose-dependent. 8. The failure of ACE inhibitors to potentiate the cardiodepressant and hypotensive effects of bradykinin in a dose-dependent manner is explained with some other mechanism(s) independent of ACE inhibition.     

Acute effects of cadmium on the renin angiotensin system in rats.

The effect of cadmium acetate (1 mg/kg i.p.) on the renin angiotensin system was examined in male Sprague-Dawley rats. Blood pressure, plasma renin activity (PRA) and serum angiotensin converting enzyme (ACE) levels were determined in the rats. Cadmium acetate produced a hypertensive response which was not associated with elevated PRA. However, ACE levels in the serum were significantly decreased in the cadmium-treated group as compared with normal controls (P less than 0.01).     

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.     

Some in vitro and in vivo studies of a new angiotensin I-converting enzyme inhibitor [[S-(R*), S*]-1-[(3-acetylthio)-3-benzoyl-2-methylpropionyl]-L-proline] (CL 242,817) in comparison with captopril

Some in vitro and in vivo properties of CL 242,817, a new angiotensin l-converting enzyme (ACE) inhibitor, were studied and compared to those of captopril. In vitro CL 242,817 effectively inhibited rabbit lung ACE (IC50 54.9 nM), angiotensin l (Al)-induced contractions (IC50 0.82 μM), and potentiated bradykinin (BK)-induced contractions (EC50 0.383μM) of the guinea pig ileum. In these systems, CL 242,817 was approximately 3.5, 27, and 96 times less effective than captopril, respectively. In vivo, equimolar oral doses of CL 242,817 (8.36 mg/kg) and captopril (5 mg/kg) were equieffective in inhibiting the pressor responses to intravenously (i.v.) administered angiotensin l (Al) in normotensive rats and dogs. Similar equimolar oral doses of CL 242,817 and captopril were also equieffective in potentiating the depressor responses to i.v. administered BK in the rat. In the anesthetized dog 30 min after dosing, captopril (0.5 mg/kg i.v.) produced significantly greater potentiation of the BK response than a similar dose of CL 242,817. A single 1 mg/kg i.v. dose of Cl 242,817 or captopril effectively lowered mean arterial blood pressure of the aortic-coarcted hypertensive rat (AHR) and markedly inhibited serum ACE activity after 1 hr. Serum from AHR treated with CL 242,817 or captopril exhibited an apparent loss in ACE inhibition upon cold storage. However, the loss of inhibition of ACE activity was faster with captopril than with CL 242,817. Kinetic studies indicate that CL 242,817 is a pure competive inhibitor of ACE with an estimated Ki of 24.3 nM.     

Captopril potentiates the vasodepressor action of Met-enkephalin in the anaesthetized rat

The transient vasodepressor action of Met-enkephalin (10-80 micrograms kg-1, i.v.) in anaesthetized rats was significantly potentiated by the angiotensin-converting enzyme inhibitor, captopril (2 mg kg-1, i.v.); at this dose, it failed to modify the transient vasodepressor action of the non-specific vasodilator, nitroprusside (2.5, 5.0, 10 micrograms kg-1, i.v.). Captopril (2 mg kg-1, i.v.) caused a slow, progressive fall in the blood pressure of anaesthetized spontaneously hypertensive (SH) rats when compared to vehicle-treated controls. Pretreatment with naloxone (1.5 mg kg-1, i.v.) 30 min earlier failed to alter significantly the hypotensive action of captopril in anaesthetized SH rats. It was concluded that although captopril potentiated the vasodepressor action of Met-enkephalin in anaesthetized normotensive rats, potentiation of endogenous opioids does not appear to be involved in the hypotensive action of captopril in anaesthetized SH rats.     

Captopril does not potentiate hypotension and algesia by substance P

Captopril (1-5 mg/kg, i.v.) did not affect the vasodepressor responses to substance P (1-30 micrograms/kg, i.v.) in anaesthetized rats. Substance P (100 micrograms/kg, s.c.) produced significant algesia in mice; this was not potentiated by the smaller doses of captopril (1-2 mg/kg, i.p.), but was instead antagonized by the high dose (5 mg/kg, i.p.). It is concluded that captopril does not have any influence on substance P degradation in vivo since the pharmacological actions of the undecapeptide are not enhanced after captopril treatment.     

Synergistic effect on reduction in blood pressure with coadministration of the renin inhibitor, CP-80,794, and the angiotensin converting enzyme inhibitor, captopril.

The effects of coadministration of a renin inhibitor, CP-80,794, and an angiotensin converting enzyme inhibitor, captopril, on blood pressure of sodium-depleted guinea pigs was studied. Dose-response curves for CP-80,794 (0.3-3.0 mg/kg i.v.) and captopril (0.03-1.0 mg/kg i.v.) were obtained either alone or in the presence of a submaximal dose of the other inhibitor. The hypotensive response calculated for each compound individually was subtracted from the combined dose response. The results showed that statistically significant synergy with captopril and CP-80,794 occurred when the area rather than the peak drop or duration of change in blood pressure was measured. The degree of the synergy indicated that to achieve the same reduction in blood pressure, the dose of each drug, below the high end of its response range, could be decreased approximately sixfold when administered in combination. It was determined that the plasma pharmacokinetics of CP-80,794 were not altered during coadministration, as plasma concentrations of CP-80,794 were similar in the presence and absence of 0.1 mg/kg i.v. of captopril. These results indicate that by inhibiting sequential enzymes in the renin-angiotensin system, synergistic effects can be produced. The relative safety of each inhibitor could be improved by large reductions in dose when used concurrently.     

MECHANISMS OF CAPTOPRIL-INDUCED POTENTIATION OF THE DEPRESSOR RESPONSES TO ARACHIDONIC ACID IN RATS

The mechanisms underlying potentiation by captopril of the depressor responses to arachidonic acid were studied in chloralose-anaesthetized rats. Captopril, in a dose (0.5 mg/kg, i.v.) which inhibited the pressor responses to angiotensin I (0.03-1 microgram/kg, i.v.), enhanced the depressor responses to bradykinin (3-300 micrograms/kg, i.v.) and potentiated the hypotensive action of arachidonic acid (3 mg/kg, intravenously). This phenomenon was observed not only when captopril and arachidonic acid were administered intravenously, but also when these compounds were injected directly into the aortic arch. The enhancement of arachidonic acid-induced hypotension by captopril was not significantly affected by pretreatment with a low dose of aprotinin (3 mg/kg, i.v.), but was abolished by bilateral nephrectomy or by pretreatment with a higher dose of aprotinin (6 mg/kg, i.v.). It is suggested that captopril augments the depressor responses to arachidonic acid by inhibiting angiotensin converting enzyme. This results in accumulation of bradykinin which in turn increases release of vasodilator prostaglandins, originating most probably, from the kidneys. The possibility that blockade of angiotensin II formation by captopril may leave the vasodilator action of prostaglandin unopposed cannot be excluded.     

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.     

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.     

Antihypertensive activity of alacepril in spontaneously hypertensive rats and deoxycorticosterone acetate-salt hypertensive rats and dogs

Antihypertensive activity of alacepril (1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine, DU-1219), an orally active angiotensin converting enzyme (ACE) inhibitor, was investigated in hypertensive models with normal or low plasma renin activity (PRA). After single oral administration in spontaneously hypertensive rats (SHR), alacepril (1-30 mg/kg) showed a dose related antihypertensive effect with a gradual onset and long lasting action. The maximum hypotensive effect was about 3 times more potent than that of captopril (3-100 mg/kg) on a weight basis. When comparing the AOC (area over the antihypertensive curve) values, the overall antihypertensive activity of alacepril was 8 times stronger than that of captopril. In deoxycorticosterone acetate-salt (DOCA-salt) hypertensive rats, alacepril (10-100 mg/kg) produced a significant and sustained hypotensive effect. The maximum hypotensive potency and the overall antihypertensive activity of alacepril were remarkably stronger than those of captopril (30, 100 mg/kg). During once daily successive oral administration for 10 days in SHR, alacepril (3-10 mg/kg/d) reduced dose relatedly the daily starting blood pressure. In DOCA-salt hypertensive rats and dogs, alacepril (30 mg/kg/d) produced a significant antihypertensive effect, while captopril (30 mg/kg/d) did not reduce daily starting blood pressure. Therefore, it may be expected that alacepril is a more effective antihypertensive agent than captopril in various hypertensions of different etiology.     

Comparative hypotensive activity of REV 6207 and enalapril in the conscious furosemide-treated monkey

The cardiovascular effects of ascending doses (0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg i.v.) of two angiotensin l-converting enzyme (ACE) inhibitors, REV 6207 and enalapril, were assessed in conscious furosemide-treated (3 mg/kg s.c.) monkeys. Both ACE inhibitors produced a dose-related inhibition of the pressor response to angiotensin l (0.66 μ/kg i.v.) with concomitant decreases in mean arterial pressure and no change in heart rate. The calculated ED₅₀ values for REV 6207 (0.316 mg/kg) and enalapril (0.275 mg/kg) were similar and both abolished the pressor response to angiotensin l at a dose of 3 mg/kg. The results of the study show that REV 6207 is a potent nonsulfhydryl-containing ACE-inhibitor with blood-pressure-lowering activity comparable to enalapril in the conscious monkey with high renin activity.     

Prolonged inhibition of local angiotensin-converting enzyme after single or repeated treatment with quinapril in spontaneously hypertensive rats.

Plasma and tissue angiotensin-converting enzyme (ACE) activities were measured in spontaneously hypertensive rats (SHR) after single or repeated oral (p.o.) treatment with a hypotensive dose (1 mg/kg) of quinapril and compared with those after administration of enalapril (1 mg/kg). The degree of ACE inhibition in response to quinapril varied in tissues; marked inhibition was observed in aorta, lung, and plasma by single treatment with quinapril, and inhibition in plasma and aorta caused by quinapril was more potent than that caused by enalapril. The prolonged ACE inhibition was observed in the aorta, a target organ, by repeated treatment with quinapril for 2 weeks. These results indicate that quinapril has a good pharmacokinetic profile, namely rapid absorption and easy penetration to the target organ. In addition, quinapril produced greater inhibition of cardiac ACE than did enalapril after either p.o. or intravenous (i.v.) administration, suggesting the beneficial effects of quinapril in treatment of congestive heart failure (CHF).     

Antihypertensive and angiotensin converting enzyme inhibitory activities of a novel dihydrobenzofuran analogue

1. The biochemical and pharmacological profiles of the novel, orally active angiotensin converting enzyme (ACE) inhibitor, N-[N-[[4-(2, 3-dihydro-2-benzofuranyl)-1-(ethoxycarbonyl)]butyl]-(s)-alanyl]- (s)-proline (BRL 36378), have been compared with those of enalapril and captopril. 2. In the conscious sodium deficient spontaneously hypertensive rat, BRL 36378 and enalapril (0.3-10 mg/kg orally) produced comparable falls in blood pressure; at 3 mg/kg orally, captopril was less active than BRL 36378 and enalapril. 3. In the anaesthetised spontaneously hypertensive rat, enalapril was slightly more potent than BRL 36378 as an inhibitor of angiotensin I (AI) pressor responses whilst BRL 36378 was about twice as potent as captopril in this test (i.v. route used). BRL 36378 and enalapril were equipotent as potentiators of bradykinin depressor responses. 4. In the anaesthetised Wistar rat, the maximum inhibition of AI pressor responses by 0.1 microgram/kg i.v. BRL 36378 and captopril was achieved sooner than after the same dose of enalapril. The inhibitory effect of captopril subsided completely by 40-50 min but the maximum effects of BRL 36378 and enalapril persisted for at least 60 min. 5. In the conscious renal hypertensive cat, captopril was slightly more potent than BRL 36378 or enalapril as a blood pressure lowering agent, over 1-10 mg/kg orally. BRL 36378 was more potent than enalapril as an inhibitor of AI induced pressor responses in this model. Captopril possessed similar inhibitory activity to BRL 36378 although minor differences in time course were apparent.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prolonged effects of p-chlorophenylalanine on the blood pressure of conscious normotensive and DOCA/saline hypertensive rats.

1. In deoxycorticosterone acetate (DOCA) saline hypertensive rats a single dose of p-chlorophenylalanine methylester (PCPAME) (400 mg/kg i.p.) produced a significant fall in blood pressure (20-43 mmHg) which lasted for at least 8 days and was accompanied by a parallel depletion of brain stem 5-hydroxytryptamine (5-ht) but not of noradrenaline (NA). 2. In normotensive rats single doses of PCPAME (200 and 400 mg/kg i.p.) produced a significant hypotension (15-20 mmHg) after a latent period of 5 days. An initial pressor response (12 mmHg) was observed at the higher dose level only on day 3. 3. The hypotensive response to PCPAME (200 mg/kg i.p.) in normotensive rats was not modified by pretreatment with 5,6-dihydroxytryptamine (5,6-DHT; 50 mug i.c.v.) or 6-hydroxydopa (6-ohda; 3 X 250 mug intracerebroventricularly). 4. It is concluded that the hypotensive response to PCPAME in normotensive rats in independent of brain stem depletion of 5-HT and is probably not mediated by the formation of a false transmitter substance acting via central noradrenergic inhibitory pathways. The mechanism involved in the antihypertensive response to PCPAME in DOVA/saline hypertensive rats has yet to be defined.     

Reversal of bradykinin-induced reflex tachycardia to bradycardia by captopril; evidence for prostacyclin involvement

In conscious male New Zealand rabbits, bradykinin caused dose-dependent (0.03-1 microgram/kg i.v.) hypotension and reflex tachycardia. After inhibition of angiotensin converting enzyme (ACE, also known as kininase II) with captopril (1 mg/kg i.v.), the hypotensive effect of bradykinin was enhanced in magnitude and duration but the normally observed tachycardia was reversed to bradycardia. In rabbits treated with indomethacin to inhibit cyclooxygenase and then given captopril, the bradycardia to bradykinin reverted to tachycardia whereas the magnitude of the initial hypotensive effect was unchanged. However, inhibition of thromboxane synthetase with SQ 80,338 (1-[3-phenyl-2-propenyl]-1H-imidazole) was without effect on either bradykinin-induced hypotension or bradycardia in captopril treated rabbits. Infusion of nicotine to inhibit prostacyclin synthetase completely reversed the bradycardia induced by bradykinin in captopril-treated rabbits, an effect unrelated to ganglion blockade by nicotine since mecamylamine had no effect on the actions of bradykinin. beta-Adrenoceptor blockade with nadolol did not modify the bradycardia caused by bradykinin in captopril-treated rabbits whereas atropine methylnitrate caused a marked reduction. Captopril had no inhibitory effect on reflex tachycardia caused by nitroglycerin or acetylcholine and only reduced that caused by eledoisin. Hypotension and bradycardia resulted from giving rabbits prostacyclin (100 microgram/kg i.v.). These results suggest that the bradycardia observed in conscious rabbits to bradykinin after captopril treatment is the result of an increase in circulating bradykinin due to ACE (kininase II) inhibition leading to a vago-vagal reflex induced by the synthesis of prostaglandins, probably prostacyclin.     

HYPOTENSIVE EFFECTS OF CAPTOPRIL ADMINISTERED CENTRALLY IN INTACT CONSCIOUS SPONTANEOUSLY HYPERTENSIVE RATS AND PERIPHERALLY IN ANEPHRIC ANAESTHETIZED SPONTANEOUSLY HYPERTENSIVE RATS

1. The hypotensive response to captopril in anaesthetized spontaneously hypertensive rats (SHR) is not modified by bilateral nephrectomy performed 1 or 24 h previously. 2. Intracerebroventricular injection (i.c.v.) of captopril (2 mg kg^?1) significantly lowered blood pressure of conscious SHR over a 7-h period of observation but there was no significant blood pressure response to i.c.v. vehicle, or to intravenous captopril (2 mg kg^?1) in SHR. 3. There was no significant blood pressure response to captopril (2 mg kg”') i.c.v. in the normotensive Wistar Kyoto controls (NT-WK). 4. These results indicate that captopril can lower the blood pressure of SHR by mechanisms independent of the kidneys or the circulating renin-angiotensin system. 5. The hypotensive effect of central captopril in SHR but not in the NT-WK suggests biochemical differences between the brains of the two rat strains.     

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.     

DO ANGIOTENSIN CONVERTING ENZYME INHIBITORS LIMIT MYOCARDIAL INFARCT SIZE?

1. Effects of captopril, ramiprilat and Hoe 140, a specific bradykinin receptor antagonist, on infarct size were assessed in a rabbit model of myocardial infarction. 2. Rabbits were untreated or pretreated with 0.5 mg/kg of captopril, 0.05 mg/kg of ramiprilat or 20 nmol/kg of Hoe 140 before 30 min coronary artery occlusion and 72 h reperfusion. 3. Captopril and ramiprilat treatment reduced systemic blood pressure by about 10 mmHg without alteration of heart rate, and the dose of Hoe 140 almost completely blocked hypotensive response to intravenous injection of bradykinin (100 ng/kg). 4. Infarct size expressed as percentage of area at risk was 44.5 ± 3.3% in the control group, 41.9 ± 1.6% in the captopril group, 51.8 ± 2.7% in the ramiprilat group and 46.7 ± 2.2% in the Hoe 140 group. All percentages were not significantly different. 5. These data suggest that angiotensin converting enzymes (ACE), with or without sulfhydryl groups do not limit myocardial infarct size and that endogenous bradykinin in ischaemic myocardium does not play a major protective role against ischaemic myocardial necrosis.