Na+, Ca2+, Arterial Contractility and Ouabain Hypertension

Na , Ca2 , 动脉收缩力 和 哇巴因 高血压

• 批准号: 7644870
• 负责人: MORDECAI P BLAUSTEIN
• 金额: $ 205.72万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7644870
• 关键词: Na+; Ca2+; Arterial; Contractility; Ouabain

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.

描述(由申请人提供)： 该计划基于盐依赖型高血压包括以下一系列事件的假设：由于摄入过多或肾脏排泄减少而导致的盐滞留，导致血浆内源性哇巴因(EO)水平升高。EO是一种肾上腺皮质激素，它选择性地抑制神经元、动脉肌细胞和内皮细胞中含有α2或α3亚单位的Na+泵。因此，在这些Na+泵所在的质膜-肌浆/内质网(PM-S/ER)连接处，局部细胞内Na+浓度升高。然后，通过钠/钙交换(NCX)，局部钙信号和钙储存 增强；然而，在慢性状态下，内皮依赖的血管扩张可能受到抑制。最终结果是血管收缩、外周血管阻力(PVR)和血压增加。这一假说将在大鼠和小鼠的分离小动脉和肌细胞上进行验证。这些研究旨在阐明急性和慢性小剂量哇巴因治疗的详细作用机制。哇巴因高血压(OH)大鼠模型、几个PM离子转运体和递质受体改变的转基因小鼠系，以及新型抗哇巴因药物和NCX阻滞剂将被使用。有4个 项目和2个核心。项目1将描述从哇巴因到PVR增加的途径中，完整动脉内平滑肌的几个关键步骤的生理学和药理学特征。项目2将集中在新鲜分离的心肌细胞中储存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中发生了变化。项目3将使用量子含量和钙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心肌细胞内钙信号的影响。 在肾脏直肠血管下行的内皮细胞和周细胞的功能，并将基于初步数据，将探索这些信号机制在OH的明显功能障碍。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。这一结果将阐明哇巴因改变钙稳态、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(S)。这将为抗高血压治疗的新靶点提供洞察力。

项目成果

Upregulation of Na+/Ca2+ exchanger and TRPC6 contributes to abnormal Ca2+ homeostasis in arterial smooth muscle cells from Milan hypertensive rats.

• DOI: 10.1152/ajpheart.00356.2010
• 发表时间: 2010-09
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: A. Zulian;Sergey G. Baryshnikov;Cristina I. Linde;J. Hamlyn;P. Ferrari;V. Golovina

Low-dose ouabain constricts small arteries from ouabain-hypertensive rats: implications for sustained elevation of vascular resistance.

低剂量哇巴因收缩哇巴因高血压大鼠的小动脉：对血管阻力持续升高的影响。

• DOI: 10.1152/ajpheart.00436.2009
• 发表时间: 2009
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Zhang,Jin;Hamlyn,JohnM;Karashima,Eiji;Raina,Hema;Mauban,JosephRH;Izuka,Michelle;Berra-Romani,Roberto;Zulian,Alessandra;Wier,WGil;Blaustein,MordecaiP
• 通讯作者: Blaustein,MordecaiP

Upregulation of Na+ and Ca2+ transporters in arterial smooth muscle from ouabain-induced hypertensive rats.

哇巴因诱导的高血压大鼠动脉平滑肌中 Na 和 Ca2 转运蛋白的上调。

• DOI: 10.1152/ajpheart.00784.2009
• 发表时间: 2010
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Pulina,MariaV;Zulian,Alessandra;Berra-Romani,Roberto;Beskina,Olga;Mazzocco-Spezzia,Amparo;Baryshnikov,SergeyG;Papparella,Italia;Hamlyn,JohnM;Blaustein,MordecaiP;Golovina,VeraA
• 通讯作者: Golovina,VeraA