This proposal is based on the observation that the amino acid, arginine, causes both endothelium-dependent and endothelium-independent relaxation of the rat aorta. Detailed preliminary observations strongly suggest that smooth muscle can regulate its contractility by synthesizing nitric oxide via the l-arginine pathway. This pathway may participate in the regulation of smooth muscle homeostasis (tone and growth) as well as the interaction between smooth muscle and adjoining cells (endothelium and blood components). The application proposes to study in detail the nitric oxide pathway of rat aortic smooth muscle and to compare it to that of endothelium. The l-arginine pathway will be characterized by functional studies (organ chamber and bioassay studies), cultured cell studies, and biochemical measurements of arginine content and cGMP production. The possibility that calmodulin is involved will be investigated pharmacologically, and that several pools of arginine may give rise to nitric oxide will be determined by depletion studies. Also the role of cytokines will be investigated in modulating nitric oxide synthesis, relevant to their depressor role in shock, smooth muscle cell growth, and endothelial cell production of endothelin-1. Studies are relevant to the pathogenesis of vascular diseases in which contractility and growth rate is altered.
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