REGULATION OF THE PROCESSING ENZYMES OF ANGIOTENSIN (1-7)

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Angiotensin I (Ang I) can be processed into a number of active fragments, of which Ang II remains the most widely studied. We have shown that Ang I can be processed directly into another unique product- Ang-(1-7)-which possesses important actions that include vasodilation, diuresis and natriuresis, stimulation of prostaglandins, potentiation of the vasodilator effects of bradykinin and the release of nitric oxide. These actions of Ang-(1-7) and the lack of vasoconstrictor, sodium and water retaining effects associated with Ang II argue that the production of Ang-(1-7) may counter-balance the actions of Ang II. In support of this hypothesis, we find that inhibition of Ang-(1-7) synthesis form Ang I results in a hypertensive response that is particularly revealed in animals that are salt depleted or under chronic blockade of the renin- angiotensin system (RAS). Moreover, we show that neutral endopeptidase or neprilysin (NEP) and angiotensin-converting enzyme (ACE) may be the predominant enzymes that generate and metabolize Ang-(1-7). The primary objective of this proposal will be to determine how activation of the RAS leads to variable expression of Ang-(1-7). The aims of this proposal are based on the hypothesis that regulation of NEP and ACE will influence the vascular levels of Ang (1-7) to oppose the actions of Ang II. We propose that under conditions such as low salt NEP is up- regulated to increase the generation of Ang-(1-7) while reciprocal changes in ACE also influence the peptide through a degradative process. Specific Aim 1 will establish the kinetic characterization of the processing of Ang I and Ang-(1-7) by ACE and NEP. Specific Aim 2 will explore the regulation of NEP and ACE under reduced salt intake in normotensive and hypertensive animals. Specific Aim 3 will investigate the mechanisms of the regulation of NEP and ACE in aortic endothelial cells. The proposed studies will provide a new understanding of the regulation of the biochemical processes that control expression of the components of the RAS.