Yang Di, Félétou Michel, Boulanger Chantal M, Wu Heng-Fang, Levens Nigel, Zhang Ji-Nan, Vanhoutte Paul M
Jiangsu Province Hospital, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, P.R. China.
Br J Pharmacol. 2002 May;136(1):104-10. doi: 10.1038/sj.bjp.0704669.
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). Isometric tension was measured in aortic rings taken from adult male SHR and Wistar-Kyoto rat (WKY) in the presence of NG-nitro-L-arginine. 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. 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. 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. 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.
设计实验以研究氧衍生的自由基是否介导自发性高血压大鼠（SHR）主动脉中对乙酰胆碱的内皮依赖性收缩。在存在NG-硝基-L-精氨酸的情况下，测量取自成年雄性SHR和Wistar-Kyoto大鼠（WKY）的主动脉环的等长张力。与WKY相比，SHR的主动脉环中对乙酰胆碱的内皮依赖性收缩明显更大。黄嘌呤加黄嘌呤氧化酶产生的氧衍生自由基诱导的收缩在SHR主动脉中比WKY主动脉中更大。对乙酰胆碱和自由基的收缩被选择性TP受体拮抗剂S 18886和环氧化酶-1的优先抑制剂戊酰水杨酸消除，但未被环氧化酶-2的优先抑制剂NS-398消除。别嘌呤醇、去铁胺以及超氧化物歧化酶加过氧化氢酶的组合抑制了对氧衍生自由基的收缩，但对乙酰胆碱的收缩没有显著影响。相比之下，超氧化物歧化酶抑制剂二乙氨基二硫代甲酸或超氧阴离子清除剂Tiron减少了SHR主动脉中对乙酰胆碱的内皮依赖性收缩。这两种药物的作用是相加的。在用二甲基硫脲长期治疗的SHR中，对乙酰胆碱的内皮依赖性收缩减少，并且在急性体外暴露于去铁胺或超氧化物歧化酶加过氧化氢酶的组合后进一步降低。这些结果表明，在SHR主动脉中，乙酰胆碱诱导的内皮依赖性收缩涉及内皮超氧阴离子的产生以及随后歧化为羟基自由基和/或过氧化氢。自由基激活环氧化酶-1，最有可能产生内过氧化物。需要激活TP受体才能观察到对乙酰胆碱的内皮依赖性收缩或对自由基产生的内皮非依赖性收缩。
