Increased expression of Ca2+-sensitive K+ channels in the cerebral microcirculation of genetically hypertensive rats -: Evidence for their protection against cerebral vasospasm
Increased expression of Ca2+-sensitive K+ channels in the cerebral microcirculation of genetically hypertensive rats -: Evidence for their protection against cerebral vasospasm
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DOI：
10.1161/01.res.82.6.729
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发表时间：
1998-04-06
影响因子：
20.1
通讯作者：
Rusch, NJ
中科院分区：
文献类型：
--
作者：
Liu, YP;Hudetz, AG;Rusch, NJ
Ca 2+敏感性K+通道（K-Ca通道）在缓冲压力引起的脑小动脉收缩中起关键作用。在高血压动物的血管平滑肌细胞中，有报道称通过该通道的电流被放大，这意味着K-Ca通道的表达或性质可能受到体内血压水平的调节。在这项研究中，我们通过比较正常血压和遗传性高血压大鼠脑阻力动脉中K-Ca通道的性质、表达水平和生理作用，研究了这一假设及其功能相关性，全细胞膜片钳实验显示，自发性高血压大鼠（SHR）生理膜电位下的伊比利亚毒素敏感性K-Ca通道电流密度是Wistar大鼠的4.7倍。京都（WKY）大鼠脑血管平滑肌细胞（n=18和21，分别），然而，额外的单通道分析在分离的补丁显示类似水平的单位电导，电压，和钙离子敏感性的K-Ca通道从WKY和SHR膜。与此相反，使用针对K-Ca通道α-亚基的抗体的Western分析显示，与WKY大鼠相比，SHR脑血管膜中相应的125-kD免疫反应性信号增加了4.1倍。在SHR和WKY大鼠软脑膜小动脉中评估了这种增强的K-Ca通道表达的功能影响，通过原位颅窗活体显微镜进行监测。用伊比利亚毒素（0.1 ~ 100 nmol/L）对SHR和WKY大鼠软脑膜小动脉进行性药理学阻断，呈剂量依赖性收缩（n=6 ~ 8）。高血压大鼠脑血管平滑肌细胞膜上K-Ca通道的表达增加，这一动态平衡机制可能对慢性高血压时脑动脉静息张力的调节起重要作用。在特定的心血管病理过程中，不同类型的K+通道的过表达可以为血管扩张剂治疗提供新的疾病特异性膜靶点的上调。
The Ca2+-sensitive K+ channel (K-Ca channel) plays a key role in buffering pressure-induced constriction of small cerebral arteries. An amplified current through this channel has been reported in vascular smooth muscle cells obtained from hypertensive animals, implying that the expression or properties of K-Ca channels may be regulated by in vivo blood pressure levels. In this study, we investigated this hypothesis and its functional relevance by comparing the properties, expression levels, and physiological role of K-Ca channels in cerebral resistance arteries from normotensive and genetically hypertensive rats, Whole-cell patch-clamp experiments revealed a 4.7-fold higher density of iberiotoxin-sensitive K-Ca channel current at physiological membrane potentials in spontaneously hypertensive rat (SHR) compared with Wistar-Kyoto (WKY) rat cerebrovascular smooth muscle cells (n=18 and 21, respectively), However, additional single-channel analysis in detached patches showed similar levels of unitary conductance, voltage, and Ca2+ sensitivity in K-Ca channels from WKY and from SHR membranes. In contrast, Western analysis using an antibody directed against the K-Ca channel alpha-subunit revealed a 4.1-fold increase in the corresponding 125-kD immunoreactive signal in cerebrovascular membranes from SHR compared with WKY rats, The functional impact of this enhanced K-Ca channel expression was assessed in SHR and WKY rat pial arterioles, which were monitored by intravital microscopy through in situ cranial windows. Progressive pharmacological block of K-Ca channels by iberiotoxin (0.1 to 100 nmol/L) dose-dependently constricted pial arterioles from SHR and WKY rats (n=6 to 8). The arterioles in SHR constricted 2- to 4-fold more intensely, and vasospasm occurred in some vessels, These data provide the first direct evidence that elevated levels of in situ blood pressure induce K-Ca channel expression in cerebrovascular smooth muscle membranes, This homeostatic mechanism may critically regulate the resting tone of cerebral arterioles during chronic hypertension, Furthermore, the overexpression of distinct K+ channel types during specific cardiovascular pathologies may provide for the upregulation of novel disease-specific membrane targets for vasodilator therapies.