Antihypertensive mechanism of action of the novel angiotensin converting enzyme inhibitor benazepril. Effect on isolated vascular preparations.
Benazepril (CGS 14824A HCl) is a new prodrug type angiotensin converting enzyme (ACE) inhibitor. The active form is considered to be benazeprilat, a diacid hydrolyzed compound. Benazepril and benazeprilat inhibited the contraction induced by exposure with angiotensin I, not angiotensin II, in the isolated rabbit aorta. The ACE inhibiting activity of benazeprilat was 1000 times more potent than that of benazepril in this experiment. Benazepril as well as benazeprilat and captopril exerted little influence on norepinephrine, serotonin and high K(+)-induced contraction or bradykinin-induced relaxation in isolated blood vessel preparations, thus angiotensin II synthesis inhibition seemed to be the main cause for its vasodilation. Benazepril, unlike benazeprilat or captopril showed considerable influence on prostaglandin (PG)-induced responses at higher concentrations. The vasocontraction induced by PGF2 alpha was competitively antagonized at 10(-5)-10(-4) mol/l, while vascular responses induced by PGE1, PGE2 or PGI2 was inhibited at 3 x 10(-4) mol/l of benazepril. Although these influences on PGs might not contribute much to its vasodilatory mechanism, the action seemed interesting in relation to cough induction, a known side effect of ACE inhibitors in the market. Benazepril has two asymmetric carbon atoms, thus four optical isomers are possible, SS (benazepril), SR (CGP 14'829A), RS (CGP 42'454A), RR (CGP 42'456A). The SS configuration was the most potent for antagonizing angiotensin I-induced vasocontraction, which seemed to be the best fitted for the ACE molecule.
Kuroda
K
K
Pre-Clinical Research Department, Ciba-Geigy Limited, Takarazuka, Japan.
Fukuda
Y
Y
Nakao
K
K
Inukai
T
T
D000527:Alprostadil / Q000494:pharmacology; D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents; D001552:Benzazepines / Q000494:pharmacology*; D001920:Bradykinin / Q000494:pharmacology; D015237:Dinoprost / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D011464:Epoprostenol / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001552:Benzazepines; D000804:Angiotensin II; D012701:Serotonin; D000803:Angiotensin I; D015237:Dinoprost; D011464:Epoprostenol; D000527:Alprostadil; D015232:Dinoprostone; D011188:Potassium; D001920:Bradykinin; C044946:benazepril; D009638:Norepinephrine