Endothelium-dependent relaxation to hydrogen peroxide in canine basilar artery: A potential new cerebral dilator mechanism

In prostglandin F(2 alpha)(PGF(2 alpha))-precontracted isolated canine basilar arterial rings, hydrogen peroxide (H(2)O(2)) produced endothelium-dependent relaxations at concentrations of from 4.4 x 10(-7) - similar to 4.4 x 10(-5) M. Removal of extracellular Ca(2+) ([Ca(2+)](o)) attenuated the relaxant effects of H(2)O(2). Complete inhibition of H(2)O(2) relaxant action was obtained after buffering intracellular Ca(2+) ([Ca(2+)](i)), in the endothelial cells, with 10 mu M 1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM). The H(2)O(2)-induced relaxations could be abolished completely by 1200 u/ml catalase and was suppressed significantly by 0.5 mu M atropine, 150 mu M N(G)-monomethyl-arginine (L-NMMA), 50 mu M N(G)-nitro-L-arginine methyl ester (L-NAME), 1 mu M Fe(2+), or 5 mu M methylene blue. These inhibitory effects of L-NMMA, L-NAME, or atropine could be reversed partly by 50 mu M L-arginine. The Fe(2+) inhibition of H(2)O(2)-stimulated relaxation was reduced significantly by either 1 mM deferoxamine (a Fe(2+) chelator) or 100 mu M dimethyl sulfoxide (DMSO, a (.)OH scavenger). Such relaxant effects of H(2)O(2) were enhanced, significantly, by an acetylcholinesterase antagonist, neostigmine. A variety of pharmacological antagonists (of diverse vasodilator agents) could not inhibit the relaxant action of H(2)O(2). Our observations suggest that at suitable pathophysiological concentrations, H(2)O(2) could induce release of an endothelium-derived relaxing factor (EDRF), probably nitric oxide (NO), from endothelial cells of the canine cerebral artery. The H(2)O(2) relaxant effects are clearly Ca(2+)-dependent, require formation of cyclic guanosine monophosphate (cGMP), and may be associated with release of endogenous acetylcholine (ACh). (C) 1998 Elsevier Science Inc.