Endothelium-derived hyperpolarizing factor - Identification and mechanismsof action in human subcutaneous resistance arteries

Backgroand-Both a vascular endothelial cytochrome P450 (CYP450) product of arachidonic acid metabolism and the potassium ion (K+) have been identified as endothelium-derived hyperpolarizing factors (EDHFs) in animal vascular tissues. We studied the relative importance of EDHF, nitric oxide (NO), and prostacyclin (PGI(2)) as vasodilators in human subcutaneous arteries. We a lso examined the mechanisms underlying the vasodilator action of EDHF to el ucidate its identity. Methods and Results-Subcutaneous resistance arteries were obtained from 41 healthy volunteers. The contribution of EDHF to the vasodilation induced by acetylcholine was assessed by inhibiting production of NO, PGI(2), and mem brane hyperpolarization. The mechanisms underlying the relaxation evoked by K+ and EDHF were elucidated. EDHF was found to account for approximate to 80% of acetylcholine-mediated vasorelaxation. Its action was insensitive to the combination of barium and ouabain, whereas barium and ouabain reversed K+-mediated vasorelaxation. EDHF-mediated vasorelaxation, however, was sen sitive to the phospholipase A(2) inhibitor oleyloxyethyl phosphorylcholine and the CYP450 inhibitor ketoconazole. Conclusions-EDHF is the major contributor to endothelium-dependent vasorela xation in human subcutaneous resistance arteries. A product of phospholipas e A(2)/CYP450-dependent metabolism of arachidonic acid and not Kt is the Li kely identity of EDHF in human subcutaneous resistance arteries.