Yang Z, Zhang A, Altura B T, Altura B M
Department of Physiology, State University of New York, Health Science Center at Brooklyn, 11203, USA.
Gen Pharmacol. 1999 Oct;33(4):325-36. doi: 10.1016/s0306-3623(99)00019-1.
In phenylephrine-precontracted rings, H2O2 produced an endothelium-dependent relaxation at concentrations of 4.4 x 10(-7) to approximately 4.4 x 10(-5) M. Removal of extracellular Ca2+ ([Ca2+]0) markedly attenuated the relaxant effects of H2O2. Complete inhibition of the H2O2 relaxant action was obtained after buffering intracellular Ca2+ ([Ca2+]i) in endothelial cells, with 10 microM acetyl methyl ester of bis (o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM). These relaxant effects of H2O2 were nearly abolished by 15 x 10(-5)M N(G)-monomethyl-arginine (L-NMMA) or 5 x 10(-5) M N(G)-nitro-L-arginine (L-NAME) and were attenuated markedly by the presence of either 10(-6) M Fe2+, 10(-6) M Fe3+, or 5 x 10(-6) M methylene blue. These inhibitory effects of L-NMMA or L-NAME could be reversed partly by 5 x 10(-5) M L-arginine. These Fe(2+)- and Fe(3+)-induced inhibitions of H2O2-stimulated relaxation were reduced significantly by either 1.0 mM deferoxamine (a Fe2+ chelator) or 100 microM dimethyl sulfoxide (DMSO). In addition, 17-octadecynoic acid (2.5 microM) or proadifen (10 microM) (both antagonists of cytochrome P450 metabolism of fatty acids) markedly decreased the H2O2 relaxant effects. Proadifen (10 microM) produced concentration-dependent impairment of vasorelaxation to acetylcholine. A variety of amine antagonists and a cyclo-oxygenase inhibitor all fail to interfere with or attenuate the H2O2-induced relaxations. Our observations suggest that, at suitable pathophysiologic concentrations, H2O2 could induce release of an endothelium-derived relaxing factor, probably nitric oxide, from endothelial cells. The H2O2 relaxant effects are clearly Ca(2+)-dependent and require formation of cyclic guanosine monophosphate (cGMP). These vasorelaxing effects of H2O2 appear to be induced by H2O2 itself. Hydrogen peroxide may stimulate production of some unknown metabolites metabolized by cytochrome P450-dependent enzymes.
在去氧肾上腺素预收缩的血管环中，过氧化氢在浓度为4.4×10⁻⁷至约4.4×10⁻⁵ M时产生内皮依赖性舒张作用。去除细胞外Ca²⁺（[Ca²⁺]₀）显著减弱了过氧化氢的舒张作用。用10 μM双（邻氨基苯氧基）乙烷-N,N,N',N'-四乙酸乙酰甲酯（BAPTA-AM）缓冲内皮细胞内的Ca²⁺（[Ca²⁺]i）后，过氧化氢的舒张作用完全被抑制。15×10⁻⁵ M N(G)-单甲基精氨酸（L-NMMA）或5×10⁻⁵ M N(G)-硝基-L-精氨酸（L-NAME）几乎完全消除了过氧化氢的这些舒张作用，而10⁻⁶ M Fe²⁺、10⁻⁶ M Fe³⁺或5×10⁻⁶ M亚甲蓝的存在则显著减弱了其舒张作用。L-NMMA或L-NAME的这些抑制作用可被5×10⁻⁵ M L-精氨酸部分逆转。1.0 mM去铁胺（一种Fe²⁺螯合剂）或100 μM二甲基亚砜（DMSO）可显著降低Fe²⁺和Fe³⁺对过氧化氢刺激的舒张作用的抑制。此外，17-十八碳炔酸（2.5 μM）或丙胺卡因（10 μM）（两者均为脂肪酸细胞色素P450代谢的拮抗剂）显著降低了过氧化氢的舒张作用。丙胺卡因（10 μM）产生了对乙酰胆碱血管舒张的浓度依赖性损害。多种胺类拮抗剂和一种环氧化酶抑制剂均未能干扰或减弱过氧化氢诱导的舒张作用。我们的观察结果表明，在合适的病理生理浓度下，过氧化氢可诱导内皮细胞释放一种内皮源性舒张因子，可能是一氧化氮。过氧化氢的舒张作用明显依赖于Ca²⁺，并需要环磷酸鸟苷（cGMP）的形成。过氧化氢的这些血管舒张作用似乎是由过氧化氢本身诱导的。过氧化氢可能刺激细胞色素P450依赖性酶代谢的一些未知代谢产物的产生。
