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

Abstract

In prostglandin F 2α(PGF 2α)-precontracted isolated canine basilar arterial rings, hydrogen peroxide (H 2O 2) produced endothelium-dependent relaxations at concentrations of from 4.4 × 10 −7–∼4.4 × 10 −5 M. Removal of extracellular Ca 2+ ([Ca 2+] 0) attenuated the relaxant effects of H 2O 2. Complete inhibition of H 2O 2 relaxant action was obtained after buffering intracellular Ca 2+ ([Ca 2+] i), in the endothelial cells, with 10 μM 1,2-bis (2-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid (BAPTA-AM). The H 2O 2-induced relaxations could be abolished completely by 1200 u/ml catalase and was suppressed significantly by 0.5 μM atropine, 150 μM N G-monomethyl-arginine (L-NMMA), 50 μM N G-nitro-L-arginine methyl ester (L-NAME), 1 μM Fe 2+, or 5 μM methylene blue. These inhibitory effects of L-NMMA, L-NAME, or atropine could be reversed partly by 50 μM L-arginine. The Fe 2+ inhibition of H 2O 2-stimulated relaxation was reduced significantly by either 1 mM deferoxamine (a Fe 2+ chelator) or 100 μM dimethyl sulfoxide (DMSO, a •OH scavenger). Such relaxant effects of H 2O 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 2O 2. Our observations suggest that at suitable pathophysiological concentrations, H 2O 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 2O 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).