Drug discoveries and molecular biology techniques are increasing our understanding of the role of the renin angiotensin system (RAS) in the genesis of arterial hypertension. The proposed research capitalizes on this theme by exploring the mechanisms for and role of raised levels of angiotensin-(1-7) [Ang-(1-7)] in the plasma of spontaneously hypertensive rats (SHR) but not normal rats (WKY), which may reveal the role of Ang-(1- 7) in the regulation of arterial pressure. This amino terminal angiotensin (Ang) fragment, an endogenous component of the RAS in both periphery and brain, stimulates vasopressin release and prostaglandin (PG) synthesis by acting on a type 2 Ang receptor that is not linked to mobilization of intracellular Ca2+. This novel hormone is cleaved from Ang I by tissue specific endopeptidases. The role of Ang-(1-7) will be evaluated by interrelated experiments employing cellular biology, biochemical and physiological techniques. We will ascertain the endogenous distribution and enzymatic mechanisms that account for increased production of Ang-(1-7) in SHR. The hydrolysis of Ang I will be studied, both in vivo and in vitro, before and after application of specific inhibitors of ACE, prolyl endopeptidase and neutral endopeptidases 24.11 and 24.15. Ang peptides will be quantitated by high pressure liquid chromatography combined with radioimmunoassay. Other experiments will evaluate whether the potent capacity of Ang-(1-7) to release PGs is a mechanism of its potential participation in hypertension. Plasma and organ PGs will be measured during manipulations that either augment or inhibit formation of Ang-(1-7). Pilot studies showed that ACE causes exaggerated formation of Ang-(1-7) but no fall in plasma Ang II levels. Thus, the possibility that the antihypertensive effect of chronic ACE inhibitor treatment is related to an Ang-(1-7) mediated increase in PG production will be explored by measurements of autacoids after blockade of Ang-(1-7) production. The original studies done by our group suggest that studies of Ang-(1-7) will provide a body of knowledge vital to the understanding of the tissue functions of the angiotensin system. The selective functions of Ang-(1-7) and the abnormal expression of the hormone in SHR constitute a unique model with which we can unravel the importance of Ang peptides in the pathogenesis of hypertension.
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