RENOVASCULAR CA2+ CHANNEL EXPRESSION IN HYPERTENSION

描述（来自应用程序的逐字）：该项目的目标是 提供了L型Ca 2+的疾病特异性表达的第一个概况， SHR肾血管平滑肌膜中的通道。早期结果 使用Western方法显示， 成人肾动脉肌膜L型钙通道亚单位的研究 SHR与血压正常的WKY大鼠比较。这种变化与一种 在离体肾动脉中增强钙依赖性静息张力。看来， 然而，alpha 1c亚单位在肾血管肌中没有上调， 4周龄高血压前期SHR的膜。这些发现提供了第一 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型钙通道疾病特异性分布 可以深刻影响动脉直径的肌肉。在这方面，肾 患有原发性高血压的人的循环也发展为升高的 血管阻力，对L-型Ca 2+通道阻断敏感 阻滞剂。这种反应被认为是一种重要的保护机制 防止肾小球高血压和损伤。根据我们早期的发现， 这个新的3年项目将开始比较亚单位组成， L型钙通道在肾血管内皮细胞中的生理作用 4 - 12周龄SHR和年龄匹配的WKY之间平滑肌膜： (a)检查分离的肾动脉中的Ca 2+通道功能，（B）测量 膜片钳肾血管平滑肌细胞中的Ca 2+电流密度，（c） 使用核糖核酸酶保护试验、蛋白质印迹和免疫沉淀 方法来确定诱导疾病特异性的分子机制， 在压力升高过程中L型Ca 2+通道亚基的表达，和（d） 应用这些相同的实验方法来检测L型Ca 2+通道是否 当成年SHR的全身血压降低时，变化正常化 大鼠口服降压药。值得注意的是， 原发性高血压时肾循环钙通道的变化可能 提供了一个重要的诊断工具，用于预测 压力引起的肾病，以及新的基因或药物治疗， 改变这种Ca 2+通道分布可以提供一种新的方法来降低肾功能， 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.