Nitric oxide in sepsis-syndrome: potential treatment of septic shock by nitric oxide synthase antagonists

Nitric oxide (NO) is an effector molecule with multiple effects on various organ systems. The most prominent physiological actions of NO as a biological mediator include cGMP-dependent vasodilation and cytotoxicity against pathogens in the unspecific immune defense. Sepsis syndrome is a complex disease entity mostly caused by overwhelming bacterial infections. It has a high mortality rate of 40 to 60%. Catecholamine-resistant hypotension and myocardial depression are regarded as major factors contributing to death in septic patients. In septic shock, a pathophysiologically increased NO production occurs due to an excessive induction of the inducible NO synthase (iNOS). Inducible nitric oxide synthase up-regulation is probably caused by bacterial endo- and exotoxins as well as by an increase of circulating pro-inflammatory cytokines. It may be a key factor leading to pronounced vasodilation and myocardial toxicity. Experimental studies have confirmed that NO overproduction causes severe hypotension in septic animals. Treatment with competitive NOS-inhibitors abolishes this hypotension in animals as well as in septic patients. However, their use is complicated by concomitant decreases in cardiac index and oxygen delivery. Conclusive data on mortality in animals and patients with sepsis-syndrome treated by NOS antagonists are not available. This article discusses current concepts concerning the L-arginine/NO system in the pathophysiology of and as a potential therapeutic target in septic shock.