Antihypertensive mechanism of alacepril: effect on norepinephrine-induced vasoconstrictive response in vitro and in vivo.
To investigate the antihypertensive mechanism of 1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine (alacepril, DU-1219) a novel orally active angiotensin converting enzyme inhibitor, we studied the inhibitory activity of alacepril and DU-1227 (desacetyl-alacepril, a metabolite of alacepril) on the norepinephrine (noradrenaline, NA)-induced vasoconstrictive and pressor response in vitro and in vivo, and compared with that of captopril. Alacepril and captopril (3 X 10(-4) mol/l) attenuated slightly the NA-induced contractile response in isolated rat thoracic aorta and mesenteric artery, however, DU-1227 (3 X 10(-4) mol/l) inhibited more strongly the response in main artery and peripheral vascular bed. Orally given alacepril (18.7 mg/kg) inhibited the NA-induced pressor response in conscious normotensive rats, and the activity was more potent and long-lasting than that of an equimolar dose of captopril (10 mg/kg). After oral administration in hypertensive rats challenged with NA, alacepril (1.87 to 18.7 mg/kg) showed a dose-related antihypertensive effect which was slower in onset and longer lasting than that of equimolar dose of captopril (1.0 to 10.0 mg/kg). Consequently, the reduced sensitivity of the sympathetic nervous system in peripheral vasculature might contribute partly to the antihypertensive mechanism of alacepril.
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000031:analogs & derivatives* / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D014661:Vasoconstriction / Q000187:drug effects*
D000959:Antihypertensive Agents; C048162:desacetyl-alacepril; D002216:Captopril; C046835:alacepril; D009638:Norepinephrine