HYPERPOLARIZING FACTORS

There is now overwhelming evidence for factors, other than nitric oxid e (NO), that mediate endothelium-dependent vasodilation by hyperpolari zing the underlying smooth muscle via activation of Ca2+-activated Kchannels. Although the identity of endothelium-derived hyperpolarizing factor (EDHF) remains robe established, cytochrome P450 (CYP)-depende nt metabolites of arachidonic acid (AA), namely, the epoxides, fulfill several of the criteria required for consideration as putative mediat ors of endothelium-dependent. hyperpolarization. They are produced by the endothelium, released in response to vasoactive hormones, and elic it vasorelaxation via stimulation of Ca2+-activated K+ channels. Our s tudies in the rat indicate that, of the epoxides, 5,6-epoxyeicosatrien oic acid (5,6-EET) is the most likely mediator of NO-independent, but CYP-dependent coronary vasodilation in response to bradykinin. Studies in the rat kidney, however, support the existence of additional EDHFs as acetylcholine also exhibits NO-independent vasodilation that is un affected by CYP inhibitors in concentrations that attenuate responses to bradykinin. In some blood vessels, NO may tonically suppress the ex pression of CYP-dependent EDHF. In the event of impaired NO synthesis, therefore, a CYP-dependent vasodilator mechanism may serve as a backu p to a primary NO-dependent mechanism, although they may act in concer t. In other vessels, particularly microvessels, an EDHF may constitute the major vasodilator mechanism for hormones and other physiological stimuli. EDHFs appear to be important regulators of vascular tone; alt erations in this system can be demonstrated in hypertension and diabet es, conditions associated with altered endothelium-dependent vasodilat or responsiveness. (C) 1997 Elsevier Science Inc.