Endothelium-derived hyperpolarizing factor in coronary microcirculation: responses to arachidonic acid

In coronary resistance vessels, endothelium-derived hyperpolarizing factor (EDHF) plays an important role in endothelium-dependent vasodilation. EDHF has been proposed to be formed through cytochrome P-450 monooxygenase metab olism of arachidonic acid (AA). Our hypothesis was that AA-induced coronary microvascular dilation is mediated in part through a cytochrome P-450 path way. The canine coronary microcirculation was studied in vivo (beating hear t preparation) and in vitro (isolated microvessels). Nitric oxide synthase (NOS) (N-omega-nitro-L-arginine, 100 muM) and cyclooxygenase (indomethacin, 10 muM) or cytochrome P-450 (clotrimazole, 2 muM) inhibition did not alter AA-induced dilation. However, when a Ca2+-activated K+ channel channel or cytochrome P-450 antagonist was used in combination with NOS and cyclooxyge nase inhibitors, AA-induced dilation was attenuated. We also show a negativ e feedback by NO on NOS-cyclooxygenase-resistant AA-induced dilation. We co nclude that AA-induced dilation is attenuated by cytochrome P-450 inhibitor s, but only when combined with inhibitors of cyclooxygenase and NOS. Theref ore, redundant pathways appear to mediate the AA response in the canine cor onary microcirculation.