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Studies by the principal investigator (PI) demonstrated the existence of another angiotensin peptide, the heptapeptide angiotensin-(1-7), which possesses important properties as a vasodilator, diuretic and natriuretic factor via stimulation of the release of vasodilator prostaglandins, potentiation of the actions of bradykinin, and release of nitric oxide. The vasodepressor and antimitogenic effect of Ang-(1-7) suggest that it may act to oppose the actions of Ang II. In agreement with this interpretation, the applicant found that inhibition of Ang-(1-7) synthesis or neutralization of Ang-(1-7) activity with specific antibodies produces hypertensive responses more marked in animals with blockade of Ang II. The applicant proposes to show that Ang-(1-7) acts as a negative feedback stabilizer of Ang II in the regulation of arterial pressure and sodium excretion in three specific aims. Specific Aim 1 will determine the effect of inhibition of synthesis of Ang-(1-7) activity in normotensive and spontaneously hypertensive (SHR) rats receiving either a low or high salt diet. Specific Aim 2 will study the effect of these maneuvers in the isolated pressure controlled kidney to determine the role of local Ang-(1-7) in the preservation of electrolytes excretion. Specific Aim 3 will explore a new facet of the regulation of the function of Ang-(1-7) by characterizing mechanisms for the clearance of Ang-(1-7) from the circulation through: 1) the investigation of the role of ACE as the primary enzyme involved in the degradation of Ang-(1-7); and 2) the characterization of the receptor(s) that participate in the removal of the heptapeptide from cell surfaces. Hemodynamic studies will be complemented with measurements of angiotensins in the 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 effect 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.
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