Mechanism of hydroxy radical-induced modulation of vascular tone

We investigated the effects of hydroxyl radicals ((OH)-O-.) generated by a (OH)-O-.-generating system (dihydroxyfumarate [DHF], adenosine diphosphate [ADP], and FeCl3) on isolated rabbit aorta suspended in Krebs-Ringer solution, The (OH)-O-.-generating system produced a concentration-dependent generation of (OH)-O-.. (OH)-O-. relaxed rabbit aorta and norepinephrine (NE)-precontracted aorta in a concentration-dependent manner. Mannitol completely prevented this relaxation. Relaxation was completely absent in preparations denuded of endothelium. The relaxant effect was reduced by 62% by an inhibitor of nitric oxide synthesis (N-G-monomethyl-L-arginine), by 58% by an inhibitor of guanylate cyclase (methylene blue), by 48% by an inhibitor of cyclooxygenase (indomethacin), and by 83% by an adenosine triphosphate (ATP)-sensitive K+ channel blocker (glyburide). The inhibition of (OH)-O-.-induced relaxation by a combination of indomethacin, methylene blue, and glyburide was not greater than by each of the individual agents. These results indicate that (OH)-O-. produces a relaxation of the aorta that is completely endothelium-dependent and is partly mediated by an endothelium-derived relaxing factor (nitric oxide), vasodilatory arachidonic acid metabolites, and an ATP-sensitive K+ channel. Copyright (C) 1996 Elsevier Science Inc.