Previous exposure to bradykinin unmasks an endothelium-dependent relaxation to the converting enzyme inhibitor trandolaprilat in isolated canine coronary arteries

Abstract

Experiments were designed to investigate the mechanism underlying the endothelium-dependent relaxation to trandolaprilat, 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 repeatedly for 150 min. Trandolaprilat caused relaxations [IC50(- log M)8.59] in rings with endothelium previously exposed to bradykinin. This response was observed already at concentrations where trandolaprilat did not augment relaxations to bradykinin. When the rings were exposed to acetylcholine or to Des-Arg9-bradykinin (B1 agonist) trandolaprilat caused only a minimal response. Carboxypeptidase B but not aprotinin impaired the relaxation to trandolaprilat, suggesting a contribution of bradykinin. After exposure to [3H]-bradykinin, no detectable amounts of the peptide were released by trandolaprilat or found in the preparations. The relaxation to trandolaprilat was not affected by the B1 antagonist Leu8-des-Arg9- bradykinin. HOE-140, a B2 antagonist impaired the maximal response to trandolaprilat, while exhibiting competitive antagonism against bradykinin (pA2 9.00). The maximal relaxation to trandolaprilat was impaired in the presence of nitro-L-arginine and methylene blue. The potency, but not the maximal effect of bradykinin was reduced by these inhibitors. Exogenous bradykinin, but not trandolaprilat, caused an endothelium-dependent hyperpolarization. At equipotent submaximal concentrations, bradykinin released both nitric oxide and endothelium-derived hyperpolarizing factor although trandolaprilat stimulated the production of nitric oxide only. These findings suggest that acute endothelium-dependent relaxations to trandolaprilat in preparations previously exposed to bradykinin are mediated by nitric oxide and may be due partially to protection of bound bradykinin but also to some other unresolved mechanism(s) as well.