Combined Use of Nitric Oxide and Nitric Oxide Synthase Inhibitors as a Possible Therapeutic Approach

Abstract

Since the discovery in 1987 that endothelium-derived relaxant factor (EDRF) is identical to the gaseous mediator nitric oxide (NO), we have learned that NO serves as a ubiquitous signalling molecule in the cardiovascular, central nervous and immune systems. NO regulates vascular tone and prevents the adhesion of blood-borne cells to the endothelium. In the lung, the formation of NO by the NO synthase (NOS) located in the endothelium (eNOS) helps to maintain a low vascular resistance and acts to oppose hypoxic pulmonary vasoconstriction. An enhanced formation of NO following the induction of the inducible isoform of NOS (iNOS), however, contributes to the pathophysiology of several diseases including circulatory shock. Although the inhibition of NO formation with agents which non-selectively inhibit all isoforms of NOS exerts some beneficial effects (due to the inhibition of iNOS activity), they also exert side effects, which are secondary to the inhibition of eNOS activity. Using circulatory shock as one example of a disease associated with a significant overproduction of NO, this article reviews the effects and side effects of pharmacological approaches aimed at enhancing (e.g. NO gas, NO donors) or reducing (NOS inhibitors) the formation and/or availability of NO. In addition, results of therapeutic approaches designed to limit the side effects of non-selective inhibitors of NOS activity by combining these agents with either the administration of NO donors or NO inhalation will be discussed.