NITRIC-OXIDE ATTENUATES THE RELEASE OF ENDOTHELIUM-DERIVED HYPERPOLARIZING FACTOR

Background The contribution of the endothelium-derived hyperpolarizing factor (EDHF), proposed to be a cytochrome P450-derived metabolite of arachidonic acid, to endothelium-dependent dilatation under physiolog ical conditions has yet to be established, because its effect can be d etected only after inhibition of NO synthase and cyclooxygenase. The p ossibility that NO exerts a feedback inhibition on EDHF formation was studied in isolated perfused arterial segments. Methods and Results Un der combined blockade of NO synthase and cyclooxygenase, the EDHF-medi ated vasodilatation elicited by receptor-dependent agonists in rabbit carotid and porcine coronary arteries was significantly attenuated by the NO donors C87-3786 and CAS 1609. The endothelium-independent dilat ation elicited by isoproterenol was not altered by either NO donor. In N-G-nitro-L-arginine-treated carotid artery segments, C87-3786 signif icantly attenuated the acetylcholine-induced increase in 6-keto-prosta glandin F-1 alpha release, which was taken as an index of arachidonic acid liberation. In parallel experiments using cultured human endothel ial cells, C87-3786 attenuated the Ca2+ response to bradykinin. The re lease of EDHF from a luminally perfused porcine coronary artery was de tected by recording the membrane potential of downstream-situated cult ured rat aortic smooth muscle cells. The NO donor C87-3786 had no effe ct on the hyperpolarization elicited by preformed EDHF but markedly in hibited its release from bradykinin-stimulated donor segments. Conclus ions These findings indicate that under physiological conditions, the production of EDHF is damped by NO. Therefore, it follows that when NO synthesis is impaired, alleviation of this intrinsic inhibition may, at least in part, maintain endothelial vasodilator function.