Vascular Protective Role of Endothelin B Receptors

内皮素 B 受体的血管保护作用

• 批准号: 7125509
• 负责人: Raouf A Khalil
• 金额: $ 34.18万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7125509
• 关键词: blood pressure; calcium flux; confocal scanning microscopy; cyclic AMP; cyclic GMP; dietary sodium; digital imaging; endothelin; enzyme activity; hormone receptor; immunofluorescence technique; inhibitor /antagonist; isozymes; kidney; laboratory rat; nitric oxide; nutrition related tag; prostacyclins; protein kinase C; protein structure function; urinalysis; vascular resistance; vascular smooth muscle; vasoconstriction; western blottings

DESCRIPTION (provided by applicant): High salt diet is often associated with increased vascular resistance and arterial pressure in salt-sensitive individuals. In normal individuals, however, high salt diet does not increase the arterial pressure significantly, suggesting possible vascular protective mechanisms. Endothelin-1 (ET-1) activates ETA and ETa receptors. Although the role of ETA receptors in vascular contraction and hypertension has been studied extensively, the importance of ETa receptors in modulating the vascular function and arterial pressure particularly during high salt diet is less clear. Preliminary data suggest that ET-1 production is enhanced during high sodium intake. Data also suggest that chronic blockade of ETa receptors results in a salt-sensitive form of hypertension; however, the vascular and cellular mechanisms involved are unclear. The overall objective of this proposal is to test the hypothesis that normally during high salt diet an increase in ET-1 production and enhancement of its ETA-mediated vascular contraction pathways are counterbalanced by enhanced ETa-mediated vascular relaxation pathways, thus preventing excessive increases in vascular resistance and arterial pressure. Accordingly, chronic blockade of Eta receptors during high salt diet will not only decrease vascular relaxation, but also enhance vascular reactivity leading to increased vascular resistance and salt-sensitive hypertension. The decreased vascular relaxation occurs as a result of inhibition of the endothelium-dependent nitric oxide-cGMP, prostacyclincAMP and/or hyperpolarizing factor pathway. The increased vascular reactivity occurs as a result of increased [Ca2+]i and protein kinase C activity in vascular smooth muscle. The increases in vascular reactivity, [Ca2+]i and PKC activity during chronic blockade of ETa receptors and high salt diet occur as a result of unbalanced stimulation of ETA receptors. To test this hypothesis chronically-instrumented rats on normal and high sodium diets and nontreated or treated with ETa and ETA receptor antagonists will be used. Integrated analysis will be used to investigate the relation between ETa-mediated vascular relaxation and ETA-mediated vascular contraction in isolated renal vessels, and the arterial pressure in vivo. These studies should help understand better the vascular protective mechanisms during high salt diet in normal individuals and the pathophysiological basis of the increased vascular resistance in salt-sensitive hypertension.

描述（由申请人提供）：高盐饮食通常与盐敏感个体的血管耐药性和动脉压增加有关。然而，在普通人中，高盐饮食不会显着增加动脉压，表明可能的血管保护机制。内皮素-1（ET-1）激活ETA和ETA受体。尽管已经对ETA受体在血管收缩和高血压中的作用进行了广泛的研究，但ETA受体在调节血管功能和动脉压的重要性，尤其是在高盐饮食期间，尚不清楚。初步数据表明，在高钠摄入量期间，ET-1产生增强。数据还表明，慢性阻断ETA受体会导致盐敏感的高血压形式。但是，涉及的血管和细胞机制尚不清楚。该提案的总体目的是检验以下假设：在高盐饮食中，ETA介导的血管收缩途径的增加和增强其ETA介导的血管收缩途径的增强是通过增强的ETA介导的血管松弛途径来抵消的，从而防止了血管耐药性和动脉压力的过度增加。因此，高盐饮食期间ETA受体的慢性阻断不仅会降低血管松弛，还可以增强血管反应性，从而导致血管耐药性增加和盐敏感性高血压。血管松弛降低是由于抑制内皮依赖性一氧化氮-CGMP，前列腺囊体和/或超极化因子途径而发生的。血管反应的增加是由于[Ca2+] I和血管平滑肌中蛋白激酶C活性增加而发生的。由于ETA受体的刺激不平衡，ETA受体的慢性阻断和高盐饮食期间的血管反应性增加，[Ca2+] I和PKC活性的增加。为了在正常和高钠饮食上测试该假设，长期对大鼠以及未经ETA和ETA受体拮抗剂进行治疗的大鼠。 综合分析将用于研究分离的肾血管中ETA介导的血管松弛与ETA介导的血管收缩之间的关系，并在体内进行动脉压。这些研究应有助于更好地理解正常个体高盐饮食期间的血管保护机制，以及盐敏感性高血压中血管耐药性增加的病理生理基础。