Vascular Protective Role of Endothelin B Receptors

描述（由申请人提供）：高盐饮食通常与盐敏感个体血管阻力和动脉压升高有关。然而，在正常人中，高盐饮食不会显著增加动脉压，提示可能存在血管保护机制。内皮素-1 （ET-1）激活ETA和ETA受体。虽然ETA受体在血管收缩和高血压中的作用已被广泛研究，但ETA受体在高盐饮食中调节血管功能和动脉压的重要性尚不清楚。初步数据表明，高钠摄入会促进ET-1的产生。数据还表明，长期阻断ETa受体可导致盐敏感型高血压；然而，所涉及的血管和细胞机制尚不清楚。本提案的总体目标是验证高盐饮食中ET-1生成的增加及其介导的血管收缩途径的增强与eta介导的血管松弛途径的增强相抵消的假设，从而防止血管阻力和动脉压的过度增加。因此，高盐饮食对Eta受体的长期阻断不仅会降低血管舒张，还会增强血管反应性，导致血管阻力增加和盐敏感性高血压。血管舒张减弱是内皮依赖性一氧化氮- cgmp、前列腺环camp和/或超极化因子途径受到抑制的结果。血管反应性的增加是血管平滑肌中[Ca2+]i和蛋白激酶C活性增加的结果。在ETa受体的慢性阻断和高盐饮食中，血管反应性、[Ca2+]i和PKC活性的增加是由于ETa受体的不平衡刺激造成的。为了验证这一假设，将使用长期使用正常和高钠饮食的大鼠，以及未治疗或接受ETa和ETa受体拮抗剂治疗的大鼠。综合分析研究eta介导的离体肾血管舒张和血管收缩与体内动脉压的关系。这些研究将有助于更好地了解正常人高盐饮食对血管的保护机制，以及盐敏感性高血压患者血管阻力增加的病理生理基础。

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.