VASODEPRESSOR MECHANISMS MEDIATED BY ANGIOTENSIN (1-7)

血管紧张素I(Ang I)被切割成许多活性片段， 哪个血管紧张素II(Ang II)仍然是研究最广泛的多肽。 然而，我们在1988年首次报道了另一种血管紧张素的存在。 肽-七肽血管紧张素-(1-7)，具有重要的 作为血管扩张剂、利尿剂和利尿剂的性能 刺激血管扩张剂前列腺素的释放，增强 缓激肽的作用，以及一氧化氮的释放。这个 血管紧张素-(1-7)的血管抑制和抗有丝分裂作用提示它 可以采取行动反对Ang II的行动。同意 解释，我们发现抑制Ang-(1-7)表明它 可以采取行动反对Ang II的行动。同意 解释，我们发现抑制Ang-(1-7)合成或 Ang-(1-7)活性与特异性抗体和 选择性受体拮抗剂产生更多高血压反应 在血管紧张素II活性被阻断或盐分耗竭的动物身上有标记。 这项提案的主要目标将是表明Ang-(1-7) 作为血管紧张素转换酶II的负反馈稳定剂 动脉压和钠排泄量。提出了四个具体目标 来实现这一目标。特定目标1将调查 血管紧张素-(1-7)抑制血管活性减弱的假说 对SHR和[MREN-2]27转基因高血压大鼠的高血压， 而盐耗竭进一步激活RAS暴露了Ang-(1- 7)介导的血管扩张机制。《特定目标2》将显示 局部产生的Ang-(1-7)作用于一种独特的受体来调节 肾压利钠利尿曲线。《特定目标3》将评估 血管紧张素-(1-7)对大鼠肠系膜血管的强烈扩张作用 微循环以评估多肽的旁分泌作用 确定导致血管降压剂丢失的机制 SHR和[MREN-2]27只高血压动物的活性。具体目标4将 探讨Ang-(1-7)功能调节的新方面 血管紧张素-(1-7)清除机制的表征 通过：1)--调查血管紧张素转换酶作为 参与Ang-(1-7)降解的主酶；和2)- 参与去除的受体(S)的特性 细胞表面的七肽。血液动力学研究是 补充测量血液、尿液中的血管紧张素和 尿液前列腺素和cGMP的组织及相关分析。这个 介导血流动力学和钠排泄作用的受体(S) Ang-(1-7)将通过对比 选择性和非选择性血管紧张素Ⅱ受体拮抗剂的作用。这个 拟议的研究可能会提供对生化反应的新理解 肾素-血管紧张素系统的生理学及其作用方式 依赖于抑制血管紧张素转换酶和血管紧张素Ⅱ受体的治疗 封锁。

Angiotensin I (Ang I) is cleaved into a number of active fragments, of which angiotensin II (ANG II) remains the most widely studied peptide. However, we first reported in 1988 the existence of another angiotensin peptide-the heptapeptide angiotensin-(1-7) which possesses important properties as a vasodilator, diuretic and natriuretic agent by stimulation of the release of vasodilator prostaglandins, potentiation of the actions of bradykinin, and release of nitric oxide. The vasodepressor and anti-mitogenic effects of Ang-(1-7) suggest that it may act to oppose the actions of Ang II. In agreement with this interpretation, we found that inhibition of Ang-(1-7) suggest that it may act to oppose the actions of Ang II. In agreement with this interpretation, we found that inhibition of Ang-(1-7) synthesis or neutralization of Ang-(1-7) activity with specific antibodies and selective receptor antagonists produces hypertensive responses more marked in animals with blockade of Ang II activity or salt depletion. The primary objective of this proposal will be to show that Ang-(1-7) acts as a negative feedback stabilizer of Ang II in the regulation of arterial pressure and sodium excretion. Four Specific Aims are proposed to accomplish this objective. Specific Aim 1 will investigate the hypothesis that blunted vasodepressor activity of Ang-(1-7) contributes to the hypertension of SHR and [mREN-2]27 transgenic hypertensive rats, whereas further activation of the RAS by salt depletion exposes Ang-(1- 7)-mediated vasodilator mechanisms. Specific Aim 2 will show whether Ang-(1-7) produced locally acts at a unique receptor to modulate the renal pressure natriuresis-diuresis curve. Specific Aim 3 will evaluate the potent vasodilator actions of Ang-(1-7) in the rat mesenteric microcirculation to assess the paracrine actions of the peptide and ascertain the mechanism that contributes to the loss of vasodepressor activity in SHR and [mRen-2]27 hypertensive animals. Specific Aim 4 will explore a new facet of the regulation of the function of Ang-(1-7) by characterizing the mechanisms for Ang-(1-7) clearance from the circulation through: 1)-the investigation of the role of ACE as the primary enzyme involved in Ang-(1-7) degradation; and 2)- the characterization of the receptor(s) that participates in the removal of the heptapeptide from cell surfaces. Hemodynamic studies are complemented with measurements of angiotensins in blood, urine and tissues and correlate assays in urine of prostaglandins and cGMP. The receptor(s) mediating the hemodynamic and sodium excretory actions of Ang-(1-7) will be characterized pharmacologically by contrasting the effects of both selective and non-selective Ang II antagonists. The proposed studies may provide a new understanding of the biochemical physiology of the renin angiotensin system and the mode of action of therapies that depend upon inhibition of ACE and Ang II receptor blockade.