NITRIC OXIDE SYNTHASE--ENZYMOLOGY AND METABOLIC ROLE

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DESCRIPTION: Nitric oxide synthase catalyzes the conversion of arginine to citrulline and NO. NO activates soluble guanylyl cyclase, and thereby increases cellular cGMP content. Since cGMP is a vasorelaxant, NO generation has profound physiologic and pathophysiologic function in maintaining normal blood pressure. The hypotension resulting from shock and other conditions may be attributed to overproduction of NO. Since NO is generated by three isoforms of NOS which may be differentially activated, the applicant proposes to develop mechanism-based, isoform- specific inhibitors of NOS. Four interactive but independent aims are presented. Aim 1 concerns a better understanding of the chemistry of arginine conversion to OH-arginine. Aim 2 will investigate the arginine/citrulline binding site(s) in the three NOS isoforms. Aim 3 will be to design and synthesise heme-binding arginine and citrulline derivatives. Aim 4 will develop covalently reactive, non-metabolizable inhibitory arginine and citrulline derivatives. The overall rationale for developing isoform specific inhibitors is to provide experimental as well as therapeutic tools which may alleviate hypotensive complications which accompany cytokine-induced and endotoxemic shock.