Selective inhibition of inducible nitric oxide synthase: A promising strategy in the therapy of septic shock?

Abstract

Nitric oxide (NO) is a short-lived effector molecule which is produced from L-arginine by several NO synthase (NOS) isoforms. Physiologically, small amounts of NO are produced by an endothelial constitutive NOS (ecNOS), which is involved in the regulation of vascular tone and blood flow distribution. On stimulation by bacterial products and various cytokines, an inducible NOS (iNOS) becomes diffusely expressed, producing large amounts of NO for extended periods of time, which are implicated in the pathogenesis of septic shock. The pharmacological inhibition of NO synthesis has been, therefore, proposed as a new therapy in this setting. Unfortunately, such inhibition has been frequently reported to be detrimental, and recent evidence reveals that this deleterious potential is a consequence of ecNOS blockade by nonselective NOS inhibitors. Thus, interest is now focusing in the identification of compounds able to selectively inhibit iNOS activity. Although the effects of such selective agents have been only poorly investigated so far, they appear extremely promising. Indeed, in various animal models of septic shock, selective iNOS inhibitors have produced a marked improvement in hemodynamics, tissue oxygenation, and organ function, leading to a reduced mortality. These favorable results, which markedly contrast with the deleterious influence of nonselective NOS inhibitors in similar conditions, suggest that selective iNOS inhibitors might become useful adjuncts to septic shock therapy in the future.