Inhibition of the angiotensin converting enzyme by perindoprilat and release of nitric oxide.
Experiments were designed to investigate the mechanism underlying the endothelium-dependent relaxations to perindoprilat, a converting enzyme inhibitor, in canine coronary arteries previously exposed to bradykinin. Rings suspended in organ chambers were exposed to bradykinin for 3 min and washed extensively for 150 min. In rings previously exposed to the peptide, bradykinin induced relaxations which were augmented in the presence of perindoprilat; this response was not affected by indomethacin, but nitro-L-arginine induced a rightward shift of the relaxation to the peptide without affecting its maximal effect. In canine coronary arteries previously exposed to the peptide, perindoprilat caused endothelium-dependent relaxations (IC50 = 7.83), which had been observed previously at concentrations where the converting enzyme inhibitor did not augment the response to bradykinin. Carboxypeptidase B, but not aprotinin, impaired the relaxation to perindoprilat, suggesting a contribution of bradykinin. The relaxation to perindoprilat was not affected by the B1 antagonist Leu8-des-Arg9-bradykinin. However, the bradykinin B2 antagonist HOE-140 displayed a noncompetitive antagonism against the response to perindoprilat. The response to the converting enzyme inhibitor was not affected by indomethacin but was impaired significantly by nitro-L-arginine. The present findings suggest that in canine coronary arteries previously exposed to bradykinin, the relaxation to perindoprilat is mediated mainly by endothelium-derived nitric oxide. In addition, the response to perindoprilat may be due to factors other than just protection of bound bradykinin from degradation.
Desta
B
B
Center for Experimental Therapeutics, Baylor College of Medicine, Houston, Texas 77030, USA.
Vanhoutte
P M
PM
Boulanger
C M
CM
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D007611:Aprotinin / Q000494:pharmacology; D001920:Bradykinin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D043424:Carboxypeptidase B; D002268:Carboxypeptidases / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; C053500:perindoprilat; D009569:Nitric Oxide; D007611:Aprotinin; D002268:Carboxypeptidases; D043424:Carboxypeptidase B; D001920:Bradykinin