Evidence for involvement of both IKCa and SKCa channels in hyperpolarizing responses of the rat middle cerebral artery
Evidence for involvement of both IKCa and SKCa channels in hyperpolarizing responses of the rat middle cerebral artery
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DOI：
10.1161/01.str.0000217307.71231.43
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发表时间：
2006-05-01
期刊：
影响因子：
8.3
通讯作者：
Garland, CJ
中科院分区：
文献类型：
--
作者：
McNeish, AJ;Sandow, SL;Garland, CJ
背景和目的-大鼠大脑中动脉中内皮衍生的超极化因子反应可通过单独抑制 IKCa 通道来阻断，与需要同时阻断 IKCa 和 SKCa 的外周血管形成对比。由于 IKCa 和 SKCa 对外周动脉内皮依赖性超极化的贡献不同，具体取决于动脉收缩的水平，我们研究了 SKCa 在某些条件下可能对脑动脉中等效超极化做出贡献的可能性。 方法 - 将大鼠大脑中动脉（约 175 μm）安装在钢丝肌动描记器中。然后通过张力和膜电位的同时变化来评估 K-Ca 通道阻滞剂对蛋白酶激活受体 2 激动剂 SLIGRL (20 μmol/L) 的内皮依赖性反应的影响。这些数据与免疫组织化学显示的动脉 K-Ca 通道的分布相关。结果-SLIGRL 超极化和松弛的脑动脉经历不同水平的拉伸诱导张力。 IKCa（TRAM-34，1 μmol/L）或SKCa（apamin，50 nmol/L）的特异性抑制剂单独或组合不影响松弛。相比之下，相关的平滑肌超极化受到抑制，但只有与这些阻滞剂联合使用才能抑制。阻断一氧化氮合酶 (NOS) 或鸟苷酸环化酶会引起平滑肌去极化和收缩，单独使用 TRAM-34 即可消除 SLIGRL 的超极化和松弛，而 apamin 则没有效果。免疫标记显示内皮细胞内存在 SKCa 和 IKCa。结论 - 在缺乏 NO 的情况下，IKCa 支撑脑动脉内皮依赖性超极化和舒张。然而，当 NOS 活跃时，无论背景收缩的程度如何，SKCa 都会导致超极化。这些变化可能与血管疾病状态相关，在血管疾病状态下，NO 释放受到损害，并且 SKCa 表达水平可能发生改变。
Background and Purpose-Endothelium-derived hyperpolarizing factor responses in the rat middle cerebral artery are blocked by inhibiting IKCa channels alone, contrasting with peripheral vessels where block of both IKCa and SKCa is required. As the contribution of IKCa and SKCa to endothelium-dependent hyperpolarization differs in peripheral arteries, depending on the level of arterial constriction, we investigated the possibility that SKCa might contribute to equivalent hyperpolarization in cerebral arteries under certain conditions.Methods-Rat middle cerebral arteries (approximate to 175 mu m) were mounted in a wire myograph. The effect of K-Ca channel blockers on endothelium-dependent responses to the protease-activated receptor 2 agonist, SLIGRL (20 mu mol/L), were then assessed as simultaneous changes in tension and membrane potential. These data were correlated with the distribution of arterial K-Ca channels revealed with immunohistochemistry.Results-SLIGRL hyperpolarized and relaxed cerebral arteries undergoing variable levels of stretch-induced tone. The relaxation was unaffected by specific inhibitors of IKCa (TRAM-34, 1 mu mol/L) or SKCa (apamin, 50 nmol/L) alone or in combination. In contrast, the associated smooth-muscle hyperpolarization was inhibited, but only with these blockers in combination. Blocking nitric oxide synthase (NOS) or guanylyl cyclase evoked smooth-muscle depolarization and constriction, with both hyperpolarization and relaxation to SLIGRL being abolished by TRAM-34 alone, whereas apamin had no effect. Immunolabeling showed SKCa and IKCa within the endothelium.Conclusions-In the absence of NO, IKCa underpins endothelium-dependent hyperpolarization and relaxation in cerebral arteries. However, when NOS is active SKCa contributes to hyperpolarization, whatever the extent of background contraction. These changes may have relevance in vascular disease states where NO release is compromised and when the levels of SKCa expression may be altered.