Inhibition of Nitric Oxide Synthase and Prospects For Therapy in Inflammatory Diseases

Abstract: Nitric oxide is synthesized enzymatically from arginine in numerous tissues and cell types by three_distinct isoforms of the enzyme nitric oxide synthase (NOS). Two of these isoforms are expressed in a constitutive manner (cNOS) predominantly in the vascular endothelium (eNOS, type III NOS) and in the nervous system (nNOS, type I NOS) and function in the maintenance of normal homeostasis. Under normal physiological conditions, these constitutive isoforms of NOS generate low levels of nitric oxide in response to increases in intracellular calcium concentrations. The expression of the third form (iNOS, type II NOS) is induced by endotoxin and/or inflammatory cytokines and generates high levels of nitric oxide over long periods of time. The excessive production of nitric oxide, generated either by iNOS or by the sustained activation of nNOS, elicits cellular cytotoxicity and tissue damage and is thought to contribute to the pathophysiology of human disease states. The development of selective inhibitors of iNOS and/or nNOS offers the potential of blocking the synthesis of a major injurious agent, nitric oxide, and ultimately reducing tissue damage during states of chronic inflammation or prolonged elevations in cytosolic calcium. In this review, the selective inhibition of the various isoforms of NOS is examined by structure activity relationships as unique targets for drug research and therapeutic intervention in a variety of disease states.