Nitric Oxide Synthase Inhibition as Therapy for Sepsis: A Decade of Promise

Abstract

Background: Inhibition of nitric oxide synthase (NOS) has held promise as a novel and important therapeutic target for sepsis for over a decade. However, the question as to whether an inhibitor of NOS will prove to be efficacious in human septic shock remains unanswered. Methods: Review of the pertinent English-language medical literature. Results: Observations of the induction of NOS (iNOS, NOS2) by proinflammatory cytokines led to the hypothesis that nitric oxide (NO) relaxes vascular smooth muscle, thereby producing vasodilation and hypotension in sepsis. Other effects of NO in vascular tone may be manifested by refractoriness to vasopressors or myocardial dysfunction. However, such negative effects of NO are balanced by the role of NO in maintaining microvascular perfusion and host defenses against invading pathogens. Initial animal studies of septic shock modulated by the administration of competitive inhibitors of NOS demonstrated that NOS inhibition might be beneficial therapy for clinical septic shock. However, subsequent animal studies have produced variable results, and a phase III clinical trial of a nonselective NOS inhibitor has failed to show benefit for therapy of septic shock. Conclusion: A better understanding of the effects of NOS and its inhibitors is needed as is an understanding of the underlying pathophysiology of sepsis. Moreover, a nontoxic, short-acting, titratable, specific inhibitor of NOS2 has yet to be identified and tested. Until then, efforts should be designed to describe more completely the role of NO in the pathophysiology of sepsis.