The long-term objective of the proposed study is to improve our current understanding of the role of the angiotensin converting enzyme and locally formed angiotensin peptides in the regulation of regional vascular tone. While the role of pulmonary ACE in the formation of angiotensin II has been well established, less is known about the role ACE in the formation of angiotensin peptides from precursors in the peripheral vasculature and little is known about the role of des asp1 angiotensin I and angiotensin I(3-10) as precursors for the ACE dependent formation of angiotensin III and angiotensin IV in the regional circulation. In the proposed study, under constant flow conditions, we will investigate responses to the angiotensin peptides and study the role of ACE in mediating responses to des asp1 angiotensin I and angiotensin I(3-10), in the hindlimb vascular bed of the cat. Plasma concentrations of the angiotensin peptides will be determined and the role of Ang I(3- 10) as a substrate for ACE will be investigated. The receptors mediating responses to the angiotensin peptides will be characterized using newly developed nonpeptide angiotensin receptor agonists and antagonists. Pharmacologic probes will be used to determine the mechanism of action of the angiotensin peptides and the role of nitric oxide and cyclooxygenase products in mediating and modulating responses to angiotensin IV in the hindlimb vascular bed of the cat. These findings could have important clinical applications since it is known that plasma renin and angiotensin l levels are increased in a number of disease states.
