RENOVASCULAR CA2+ CHANNEL EXPRESSION IN HYPERTENSION

描述(来自应用程序的逐字)：此项目的目标是 首次提供L类钙离子的疾病特异性表达谱 自发性高血压大鼠肾血管平滑肌细胞膜上的通道。初步结果 用Western方法显示成孔α1c的表达增加 成人肾动脉肌膜L型钙通道亚基的研究 SHR与血压正常的WKY大鼠比较。这一更改与一个 增强离体肾动脉钙依赖性静息张力。看起来， 然而，Alpha1c亚单位在肾血管肌肉中并没有上调 4周龄高血压前期SHR的细胞膜。这些发现提供了第一个 直接证据表明，体内全身血压升高可能会导致 肾动脉平滑肌L型钙通道的疾病特异群 可以深刻影响动脉直径的肌肉。在这方面，肾脏 患有高血压的人的血液循环也会出现升高 血管阻力对L型钙通道的阻断敏感 拦截者。这种反应被认为代表了一种关键的保护机制 预防肾小球高血压和损伤。根据我们早期的发现， 这个为期3年的新项目将开始比较亚单位组成， L型钙通道在肾血管中的调节和生理作用 4周龄至12周龄SHR和年龄匹配的WKY的平滑肌膜： (A)检查离体肾动脉的钙通道功能；(B)测量 膜片钳肾血管平滑肌细胞钙电流密度，(C) 使用核糖核酸酶保护试验、免疫印迹和免疫沉淀 确定导致疾病特异性的分子机制的方法 L型钙通道亚单位在升压过程中的表达 应用同样的实验方法检测L型钙离子通道 当成年自发性高血压患者的全身血压降低时，变化是正常的 大鼠口服降压药。值得注意的是，唯一的 高血压病患者肾循环中钙离子通道的变化 提供了一个重要的诊断工具来预测易感性 压力引起的肾脏疾病，以及旨在 改变这种钙离子通道可能会提供一种新的方法来减少肾脏 全身性高血压期间的损伤。

DESCRIPTION (Verbatim from the application): The goal of this project is to provide the first profile of the disease-specific expression of L-type Ca2+ channels in renovascular smooth muscle membranes of the SHR. Early results using Western methods show an increased expression of pore-forming alpha1c subunit of the L-type Ca2+ channel in renal arterial muscle membranes of adult SHR compared to normotensive WKY rats. This alteration was associated with an enhanced Ca2+-dependent resting tone in isolated renal arteries. It appears, however, that the alpha1c subunit is not upregulated in renovascular muscle membrane of 4 week old prehypertensive SHR. These findings provide the first direct evidence that elevated systemic blood pressure in vivo may induce a disease-specific population of L-type Ca2+ channels in renal arterial smooth muscle that can profoundly affect arterial diameter. In this regard, the renal circulation of humans with essential hypertension also develops an elevated vascular resistance, which is sensitive to block by L-type Ca2+ channel blockers. This response is thought to represent a critical protective mechanism to prevent glomerular hypertension and injury. Based on our early findings, this new 3-year project will begin to compare the subunit composition, regulation, and physiological role of L-type Ca2+ channels in renovascular smooth muscle membranes between 4 and 12 week-old SHR and age-matched WKY by: (a) examining Ca2+ channel function in isolated renal arteries, (b) measuring Ca2+ current density in patch-clamped renovascular smooth muscle cells, (c) using ribonuclease protection assays, Western blots, and immunoprecipitation methods to define the molecular mechanisms that induce the disease-specific expression of L-type Ca2+ channel subunits during pressure elevation, and (d) apply these same experimental approaches to examine if L-type Ca2+ channel changes are normalized when systemic blood pressure is lowered in adult SHR rats by oral antihypertensive drugs. Notably, the identification of a unique Ca2+ channel profile in the renal circulation during essential hypertension may provide an important diagnostic tool for predicting susceptibility to pressure-induced renal disease, and new gene or drug therapies designed to alter this Ca2+ channel profile may provide a novel approach to reduce renal injury during systemic hypertension.