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.
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