ENDOTHELIUM-DERIVED HYPERPOLARIZING FACTOR(S) AND THE POTENTIATION OFKININS BY CONVERTING-ENZYME INHIBITORS

Inhibitors of angiotensin converting-enzyme (ACE) enhance the endothel ium-dependent relaxation to bradykinin and cause the accumulation of k inins in the vascular wall. Bradykinin elicits the production of vasod ilator prostanoids and nitric oxide by endothelial cells. However, the re is an additional component to the dilator actions of bradykinin, wh ich is mediated by a diffusible endothelium-derived hyperpolarizing fa ctor (EDHF). The knowledge gathered on the nature of EDHF and its mech anism of action are reviewed briefly. EDHF causes hyperpolarization an d relaxation of arterial smooth muscle by activating K+-channel, the n ature of which varies between species. During the inhibition of both c yclooxygenase and nitric oxide synthase, concentration-response relati onships of the hyperpolarization and relaxation elicited by bradykinin overlap in canine coronary arteries. Both effects are enhanced equall y by the ACE inhibitor perindoprilat. They are inhibited by membrane d epolarization that is obtained by raising the extracellular concentrat ions of potassium ions. Likewise, in the human coronary artery, the hy perpolarization elicited by bradykinin, which is also mediated by EDHF , is augmented in the presence of perindoprilat and prevented by potas sium-induced depolarization. In this blood vessel, contrary to the can ine coronary artery, the EDHF-mediated responses occur at concentratio ns comparable to those initiating the nitric oxide-dependent component . Therefore, the increased production of EDHF, which is induced by kin ins, may contribute to the cardiovascular effects of perindoprilat, to gether with an enhanced production of nitric oxide and vasodilator pro stanoids.