Na+, Ca2+, Arterial Contractility & Quabain Hypertension

描述（由申请人提供）： 该计划基于盐依赖性高血压涉及以下事件序列的假设：由于过量摄入或肾脏排泄减少导致的盐潴留，导致血浆中内源性哇巴因（EO）水平升高。EO是一种肾上腺皮质激素，选择性地抑制神经元、动脉肌细胞和内皮细胞中α 2或α 3亚基的Na+泵。因此，局部细胞内Na+浓度上升质膜肌/内质网（PM-S/ER）连接，这些Na+泵位于。然后，通过Na/Ca交换（NCX），局部Ca 2+信号传导和Ca 2+储存被激活。 增强;然而，在慢性状态下，内皮依赖性血管舒张可能受到抑制。最终结果是血管收缩、外周血管阻力（PVR）和血压增加。这一假设将在大鼠和小鼠的分离小动脉和肌细胞上进行检验。这些研究旨在阐明急性和慢性低剂量哇巴因治疗的详细作用机制。将使用哇巴因-高血压（OH）大鼠模型、PM离子转运蛋白和递质受体改变的几种转基因小鼠系以及新型抗哇巴因药物和NCX阻断剂。有4 项目和2个核心。项目1将描述从哇巴因到PVR增加的通路中，完整动脉内平滑肌中几个关键步骤的生理学和药理学特征。项目2将集中于新鲜分离的心肌细胞中钙库操作的钙进入和储存机制，以及急性和慢性哇巴因对这些机制的影响，这些机制似乎在OH中发生了改变。项目3将采用量子含量和Ca 2+信号的新测量来表征小动脉中交感神经肌肉传递的细节，并将确定急性和慢性哇巴因治疗如何影响这些参数。项目4将阐明急性和慢性哇巴因治疗对细胞内Ca 2+信号的影响。 内皮细胞和周细胞功能的肾降直小血管，并根据初步数据，将探讨这些信号机制的OH明显功能障碍。这些项目将得到动物模型/分析化学/生物化学和成像/电生理学/关系数据库核心的支持。结果将阐明哇巴因改变Ca 2+稳态、增强交感神经肌肉传递、影响内皮反馈和诱发高血压的机制。这将为抗高血压治疗提供新的靶点。

DESCRIPTION (provided by applicant): This program is based on the hypothesis that salt-dependent hypertension involves the following sequence of events: Salt retention as a result of excessive intake or reduced renal excretion, leads to elevation of the endogenous ouabain (EO) level in plasma. EO, an adrenocortical hormone, selectively inhibits Na+ pumps with alpha2 or alpha3 subunits in neurons, artery myocytes and endothelial cells. Consequently, local intracellular Na+ concentrations rise at plasma membrane-sarco/endo-plasmic reticulum (PM-S/ER) junctions where these Na+ pumps are located. Then, via Na/Ca exchange (NCX), local Ca 2+signaling and Ca 2+storage are augmented; in the chronic state, however, endothelium-dependent vasodilation may be suppressed. The net result is an increase in vasoconstriction, peripheral vascular resistance (PVR) and blood pressure. This hypothesis will be tested on isolated small arteries and myocytes from rats and mice. The studies are designed to elucidate the detailed mechanism of action of acute and chronic low dose ouabain treatment. The ouabain-hypertensive (OH) rat model, several transgenic mouse lines with altered PM ion transporters and transmitter receptors, and novel anti-ouabain agents and NCX blockers will be used. There are 4 projects and 2 cores. Project 1 will characterize the physiology and pharmacology of several key steps in smooth muscle within intact arteries, in the pathway from ouabain to increased PVR. Project 2 will focus on store-operated Ca 2+ entry and storage mechanisms in freshly isolated myocytes, and the effects of acute and chronic ouabain on these mechanisms which appear to be altered in OH. Project 3 will employ novel measurements of quantal content and Ca 2+ signaling to characterize details of sympathetic neuromuscular transmission in small arteries, and will determine how acute and chronic ouabain treatment influences these parameters. Project 4 will elucidate the effects of acute and chronic ouabain treatment on Ca 2+signaling in endothelial cell and pericyte function in renal descending vasa recta and, based on preliminary data, will explore the apparent dysfunction of these signaling mechanisms in OH. The projects will be supported by animal model/analytic chemistry/biochemistry and imaging/electrophysiology/relational database cores. The results will elucidate the mechanism(s) by which ouabain alters Ca 2+ homeostasis, augments sympathetic neuromuscular transmission, influences endothelial feedback, and induces hypertension. This will provide insight into novel targets for anti-hypertensive therapy.