Hydrogen peroxide relaxes porcine coronary arteries by stimulating BKCa channel activity
Hydrogen peroxide relaxes porcine coronary arteries by stimulating BKCa channel activity
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DOI：
10.1152/ajpheart.1998.275.4.h1283
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发表时间：
1998-10-01
影响因子：
4.8
通讯作者：
White, RE
中科院分区：
文献类型：
--
作者：
Barlow, RS;White, RE
多年来，人们已经知道中性粒细胞和巨噬细胞在对抗疾病时分泌H2O2，在这些条件下，在脉管系统内获得的水平可以达到几百微摩尔。由于H2O2对血管平滑肌的影响尚不完全清楚，本研究检测了H2O2对冠状动脉的细胞效应。在正常离子条件下，H2O2使前列腺素F-2 α或组胺预收缩的动脉松弛（EC50 = 252 +/- 22 μ M）。H2O2的作用与浓度有关，与内皮细胞无关。相比之下，H2O2不能使80 mM KCl收缩的动脉松弛，提示K+通道受累。单通道膜片钳记录显示，H2O2增加了大电导（119 pS）、Ca2+和电压激活的K+ (BKCa)通道的活性。这种反应被花生四烯酸模拟，并被二十碳三烯酸（一种脂氧合酶阻滞剂）抑制，表明白三烯参与其中。对完整动脉的进一步研究表明，二十碳三酸不仅阻断H2O2对血管的舒张反应，而且揭示了一种血管收缩效应，这种效应可以通过用吲哚美辛阻断环加氧酶活性而逆转。这些发现发现了一个新的效应分子——BKCa通道，它似乎介导H2O2的血管扩张作用，并表明一个单一的信号通路，花生四烯酸代谢，可以介导H2O2和其他活性氧的血管扩张和收缩作用。
It has been known for a number of years that neutrophils and macrophages secrete H2O2 while fighting disease, and the levels obtained within the vasculature under these conditions can reach several hundred micromolar. Because the effect of H2O2 on vascular smooth muscle is not fully understood, the present study examined the cellular effects of H2O2 on coronary arteries. Under normal ionic conditions, H2O2 relaxed arteries that were precontracted with prostaglandin F-2 alpha or histamine (EC50 = 252 +/- 22 mu M). The effect of H2O2 was concentration dependent and endothelium independent. In contrast, H2O2 did not relax arteries contracted with 80 mM KCl, suggesting involvement of K+ channels. Single-channel patch-clamp recordings revealed that H2O2 increased the activity of the large-conductance (119 pS), Ca2+- and voltage-activated K+ (BKCa) channel. This response was mimicked by arachidonic acid and inhibited by eicosatriynoic acid, a lipoxygenase blocker, suggesting involvement of leukotrienes. Further studies on intact arteries demonstrated that eicosatriynoic acid not only blocked the vasodilatory response to H2O2 but unmasked a vasoconstrictor effect that was reversed by blocking cyclooxygenase activity with indomethacin. These findings identify a novel effector molecule, the BKCa channel, which appears to mediate the vasodilatory effect of H2O2, and suggest that a single signaling pathway, arachidonic acid metabolism, can mediate the vasodilatory and vasoconstrictor effects of H2O2 and possibly other reactive oxygen species.