Mechanisms of hydrogen peroxide-induced contraction of rat aorta.
Mechanisms of hydrogen peroxide-induced contraction of rat aorta.
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DOI：
10.1016/s0014-2999(97)01576-8
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发表时间：
1998-03
影响因子：
5
通讯作者：
Z. Yang;T. Zheng;A. Zhang;B. T. Altura;B. M. Altura
中科院分区：
文献类型：
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作者：
Z. Yang;T. Zheng;A. Zhang;B. T. Altura;B. M. Altura
有人认为活性氧可能参与血管张力的调节。然而，潜在的机制仍有待阐明。本研究旨在研究过氧化氢（H2O2）（一种活性氧）对有内皮和无内皮的大鼠主动脉孤立环段的收缩作用。 H2O2 在 5×10−6 至 5×10−3M 的浓度下以浓度依赖性方式诱导离体大鼠主动脉环段的内皮依赖性收缩。 H2O2 诱导的裸露大鼠主动脉环的收缩比完整大鼠主动脉节段的收缩更强。 1200 u/ml过氧化氢酶完全抑制H2O2的收缩作用。 1.0 μM Fe2+ 或 10 μM proadifen（一种细胞色素 P450 单加氧酶抑制剂）的存在增强了 H2O2 对离体大鼠主动脉节段的收缩作用。 1 mM 去铁胺（Fe2+ 螯合剂）或 100 μM 二甲基亚砜（羟基自由基清除剂）显着减弱过氧化氢加 Fe2+ 或过氧化氢本身引起的血管收缩。去除细胞外 Ca2+([Ca2+]0)、添加 5 μM 维拉帕米、给予蛋白激酶 C 抑制剂（十字孢菌素）、蛋白酪氨酸磷酸化抑制剂（金雀异黄素）治疗或使用 5.0 μM 吲哚美辛可导致血管对 H2O2 的收缩反应显着减弱。药理学拮抗剂（例如毒蕈碱乙酰胆碱受体拮抗剂（阿托品）、组胺 H1 受体拮抗剂（苯海拉明）、组胺 H2 受体拮抗剂（西咪替丁）、α-肾上腺素受体拮抗剂（酚妥拉明）、β-肾上腺素受体拮抗剂（普萘洛尔）和 5-羟色胺受体拮抗剂（美西麦角））不抑制或减弱 H2O2 引起的收缩。原代主动脉平滑肌细胞暴露于H2O2（5×10−6至5×10−3M）中，20秒内细胞内Ca2+（[Ca2+]i）显着升高。 1.0 μM Fe2+ 的使用显着增强了平滑肌细胞中[Ca2+]i 的增量。 10 μM proadifen 处理未能改变过氧化氢诱导的平滑肌细胞 [Ca2+]i 增量。然而，5 μM 吲哚美辛的存在显着减弱了平滑肌细胞中 [Ca2+]i 的升高。目前的结果表明，在病理生理浓度下，H2O2 可以诱导大鼠主动脉节段的收缩，这是 Ca2+ 依赖性的。羟基自由基 (·OH )、环氧合酶产物、蛋白激酶 C 和蛋白酪氨酸磷酸化产物似乎在过氧化氢诱导的收缩中发挥一定作用。由细胞色素 P450 依赖性酶催化的代谢物（经过过氧化氢处理）似乎对大鼠主动脉段发挥血管舒张作用。最后，在过氧化氢治疗过程中，由细胞色素 P450 抑制剂（proadifen）产生的一些未鉴定的介质似乎在体外大鼠主动脉段血管平滑肌的收缩中发挥一定作用。
It has been suggested that reactive oxygen species may be involved in the regulation of vascular tone. However, the underlying mechanisms remain to be elucidated. The present studies were designed to investigate the contractile effects of hydrogen peroxide (H2O2), one of the reactive oxygen species, on isolated ring segments of rat aorta with and without endothelium. H2O2induced an endothelium-independent contraction in isolated rat aorta ring segments in a concentration-dependent manner at concentrations from 5×10−6to 5×10−3M. H2O2-induced contractions of denuded rat aorta rings were stronger than those on intact rat aorta segments. The contractile effects of H2O2were inhibited completely by 1200 u/ml catalase. The presence of 1.0 μM Fe2+or 10 μM proadifen, a cytochrome P450 monooxygenase inhibitor, potentiated the contractile effect of H2O2on isolated rat aorta segments. 1 mM deferoxamine (a Fe2+chelator) or 100 μM dimethyl sulfoxide (a hydroxyl radical scavenger) significantly attenuated the vessel contractions induced by hydrogen peroxide plus Fe2+or hydrogen peroxide itself. Removal of extracellular Ca2+([Ca2+]0), addition of 5 μM verapamil, administration of a protein kinase C inhibitor (staurosporine), treatment with an inhibitor of protein tyrosine phosphorylation (genistein) or employment of 5.0 μM indomethacin resulted in a significant attenuation of the contractile responses of the vessels to H2O2. Pharmacological antagonists (e.g. a muscarinic acetylcholine receptor antagonist (atropine), an antagonist of histamine H1receptors (diphenhydramine), an antagonist of histamine H2receptors (cimetidine), an α-adrenoceptor antagonist (phentolamine), a β-adrenoceptor antagonist (propranolol) and an antagonist of serotonin receptor (methysergide)) did not inhibit or attenuate the contractions induced by H2O2. Exposure of primary aortic smooth muscle cells to H2O2(5×10−6to 5×10−3M) produced significant rises of intracellular Ca2+([Ca2+]i) within 20 s. Employment of 1.0 μM Fe2+markedly enhanced the increment in [Ca2+]iin the smooth muscle cells. 10 μM proadifen treatment failed to alter the hydrogen peroxide-induced increment in [Ca2+]iof the smooth muscle cells. However, the presence of 5 μM indomethacin significantly attenuated the rise in [Ca2+]iin smooth muscle cells. The present results suggest that H2O2can induce contractions of rat aorta segments, at pathophysiological concentrations, which are Ca2+-dependent. Hydroxyl radicals (·OH ), cyclooxygenase products, protein kinase C and products of protein tyrosine phosphorylation appear to play some role in hydrogen peroxide-induced contractions. Metabolites catalyzed by cytochrome P450-dependent enzymes (upon treatment with hydrogen peroxide) appear to exert a vasodilator effect on rat aorta segments. Lastly, some unidentified mediators, produced by a cytochrome P450 inhibitor (proadifen), during hydrogen peroxide treatment, appear to play some role in contraction of vascular smooth muscle of rat aorta segments in vitro.