The role of nitric oxide in sepsis - an overview

Nitric oxide (NO) is normally produced in the endothelium by the constituti ve isoform of the NO synthase. This physiological production of NO is impor tant for blood pressure regulation and blood flow distribution. Several lin es of evidence suggest that a hyperproduction of NO by the inducible form o f NO synthase (iNOS) may contribute to the hypotension, cardiodepression an d vascular hyporeactivity in septic shock. Lipopolysaccarides and cytokines , such as tumor necrosis factor, interleukin-1 and interferon-gamma, have b een shown to induce iNOS in the endothelium, vascular smooth muscle cells, macrophages and different parenchymal cells. Treatment with inhibitors of N O synthesis has been shown to improve hemodynamic variables and survival in several animal models of septic shock. In human septic shock, inhibition o f NO synthesis has been shown to alter hemodynamic variables in short-term studies, but it is uncertain whether this treatment has beneficial long-ter m effects. The aim of this review is to give an overview of the physiologic al role of NO and to discuss the role of NO in sepsis and the potential the rapeutic implications of NO as a target in treatment of human septic shock. A main new aspect of this review is a critical discussion of previous repo rts measuring plasma nitrite/nitrate during septic shock and an evaluation of the validity of interpreting these data as evidence for a hyperproductio n of NO. This review also emphasizes that many septic patients have preexis ting endothelial dysfunction and lung diseases, which may contribute to adv erse effects by systemic inhibition of NO synthesis. Another new aspect of the present review is a focus on the lack of direct evidence of iNOS expres sion in human septic shock.