Use of Nitric Oxide Synthase Inhibitors as a Novel Treatment for Septic Shock

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Abstract
Objective: To review the current literature regarding the role of nitric oxide (NO) in the pathogenesis of septic shock and to describe the potential role of NO synthase (NOS) inhibitors in the treatment of septic shock. Data sources: A MEDLINE, Cancerlit, Biosis, Scisearch, CBAC, bibliography, and current journal search of applicable articles on the involvement of NO in mediating septic shock and the use of NOS inhibitors in septic shock was conducted. Articles that were searched included animal and human studies from January 1990 to August 1994. Study selection: Because of the preliminary nature of the research involving NOS inhibitors in septic shock, all available studies were evaluated. Data synthesis: NO appears to have a role in the mediation of the hemodynamic instability associated with septic shock. Cytokines and endotoxin stimulate synthesis of the inducible NOS, which produces large amounts of NO over an extended period of time. NO may be the key mediator in the pathogenesis of septic shock. Derivatives of the precursor to NO, l-arginine, have been used to investigate the role of NO in septic shock and as possible therapeutic agents. Comparison of study results among animal studies shows much variability. This variability may be attributable to differences in dosing regimens and models of septic shock. Data obtained from human studies are more consistent, but are limited to a few case series. Results indicate that NOS inhibitors increase blood pressure and systemic vascular resistance and decrease cardiac output. The effects of NOS inhibitors on morbidity and mortality have not been assessed because of the lack of an appropriate sample size. Conclusions: NO appears to play a role in septic shock; however, the use of NOS inhibitors to treat septic shock requires further studies to determine an appropriate dosing regimen and to determine the effects of these agents on morbidity and mortality.