Acidosis dilates brain parenchymal arterioles by conversion of calcium waves to sparks to activate BK channels.
Acidosis dilates brain parenchymal arterioles by conversion of calcium waves to sparks to activate BK channels.
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DOI：
10.1161/circresaha.111.258145
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发表时间：
2012-01-20
影响因子：
20.1
通讯作者：
Brayden JE
中科院分区：
文献类型：
--
作者：
Dabertrand F;Nelson MT;Brayden JE
酸中毒是脑循环中一种强有力的血管扩张信号。然而，这种反应发生的机制还不清楚，特别是在脑微循环中。扩张脑（软脑膜）动脉的一个重要机制是通过兰尼碱受体（RyR）通过局部Ca 2+信号（Ca 2+火花）激活大电导钙敏感性钾（BKCa）通道。然而，这一途径在脑微循环中的作用尚不清楚。本研究的目的是确定酸中毒扩张脑实质小动脉（PA）的机制，并阐明RyR和BKCa通道在这种反应中的作用。内径和血管平滑肌细胞（VSMC）的Ca 2+信号测定在孤立的加压小鼠PA，使用成像技术。在生理pH（7.4）下，VSMCs主要表现为RyR依赖的Ca ~（2+）波。在正常碳酸和高碳酸条件下，将外部pH从7.4降低至7.0均降低了Ca 2+波活性，并显著增加了Ca 2+火花活性。酸性pH引起的扩张的PA的抑制约60%的BKCa通道或RyR阻断剂，在一个非加性的方式。类似地，在BKCa通道敲除小鼠的小动脉中，对酸中毒的扩张反应降低了近60%。扩张诱导的酸性pH值不变的KATP通道或一氧化氮合酶的抑制剂。这些结果支持了新的概念，即酸化，通过转换Ca 2+波火花，导致激活BKCa通道，诱导脑实质小动脉扩张。
Acidosis is a powerful vasodilator signal in the brain circulation. However, the mechanisms by which this response occurs are not well understood, particularly in the cerebral microcirculation. One important mechanism to dilate cerebral (pial) arteries is by activation of large-conductance, calcium-sensitive potassium (BKCa) channels by local Ca2+ signals (Ca2+ sparks) through ryanodine receptors (RyRs). However, the role of this pathway in the brain microcirculation is not known. The objectives of this study were to determine the mechanism by which acidosis dilates brain parenchymal arterioles (PAs) and to elucidate the roles of RyRs and BKCa channels in this response. Internal diameter and vascular smooth muscle cell (VSMC) Ca2+ signals were measured in isolated pressurized murine PAs, using imaging techniques. In physiological pH (7.4), VSMCs exhibited primarily RyR-dependent Ca2+ waves. Reducing external pH from 7.4 to 7.0 in both normocapnic and hypercapnic conditions decreased Ca2+ wave activity, and dramatically increased Ca2+ spark activity. Acidic pH caused a dilation of PAs which was inhibited by about 60% by BKCa channel or RyR blockers, in a non-additive manner. Similarly, dilator responses to acidosis were reduced by nearly 60% in arterioles from BKCa channel knockout mice. Dilations induced by acidic pH were unaltered by inhibitors of KATP channels or nitric oxide synthase. These results support the novel concept that acidification, by converting Ca2+ waves to sparks, leads to the activation of BKCa channels to induce dilation of cerebral parenchymal arterioles.