Oxygen-derived free radicals mediate endothelium-dependent contractions to acetylcholine in aortas from spontaneously hypertensive rats

1 Experiments were designed to investigate whether or not oxygen-derived free radicals mediate endothelium-dependent contractions to acetylcholine in the aorta of spontaneously hypertensive rat (SHR). 2 Isometric tension was measured in aortic rings taken from adult male SHR and Wistar-Kyoto rat (WKY) in the presence of N-G-nitro-L-arginine. 3 Endothelium-dependent contractions to acetylcholine were significantly greater in rings from SHR compared to WKY. Oxygen-derived free radicals. generated from xanthine plus xanthine oxidase, induced contractions that were larger in aortas from SHR than from WKY. Contractions to acetylcholine and free radicals were abolished by a selective TP-receptor antagonist. S 18886, and a preferential inhibitor of cyclo-oxygenase-1, valeryl salicylate, but not by a preferential inhibitor of cyclo-oxygenase-2. NS-398. 4 Allopurinol. deferoxamine and the combination of superoxide dismutase plus catalase inhibited the contractions to oxygen-derived free radicals but did not significantly affect those to acetylcholine. In contrast, diethyldithiocarbamic acid. an inhibitor of superoxide dismutase, or Tiron, a scavenger of superoxide anion, reduced endothelium-dependent contractions to acetylcholine in aortas from SHR. The effect of these two drugs was additive. 5 In SHR chronically treated with dimethylthiourea endothelium-dependent contractions to acetylcholine were decreased. and reduced further by acute in vitro exposure to deferoxamine or the combination of superoxide dismutase plus catalase. 6 These results suggest that in the SHR aorta acetylcholine-induced endothelium-dependent contractions involve endothelial superoxide anion production and the subsequent dismutation into hydroxyl radicals and/or hydrogen peroxide. The free radicals activate cyclo-oxygenase-1, most likely to produce endoperoxides, Activation of TP-receptors is required to observe endothelium-dependent contractions to acetylcholine or endothelium-independent contractions in response to free radical generation.