Effects of endothelin and nitric oxide on organ injury, mesenteric ischemia, and survival in experimental models of septic shock

The development of potent drugs to treat cardiopulmonary failure in sepsis, such as antibiotics and new immunomodulatory therapeutic approaches have not prevented sepsis from being a major health problem. Dysfunction of the vascular endothelium is an early event in septic shock. The recognition of endothelium-derived substances, such as nitric oxide and endothelin, important mediators of systemic inflammatory response syndrome, led to the proposal that pharmacological inhibition of nitric oxide and endothelin production could represent a useful strategy in the treatment of septic shock. Splanchnic ischemia and translocation of endotoxin from the gut to the circulation contributes significantly to the high mortality rate in sepsis-related syndromes. This vasoconstriction in the splanchnic circulation can be partially blocked by inducible nitric oxide synthase inhibitor aminoguanidine or endothelin receptor antagonist bosentan in experimental models of septic shock. It can be suggested that endothelin and nitric oxide may affect survival. Although septic shock is a highly complex pathophysiological state, the course of septic shock has different phases with different characteristics which need different (special) treatment strategy. The inhibition of nitric oxide production during hyperdynamic, earlier phase of sepsis combined with the blockade of endothelin receptors at a later stage during the hypodynamic, late phase appears to be a novel promising strategy for the therapy of septic shock. The aim of this review is to discuss the role of nitric oxide and endothelin in sepsis and the potential therapeutic implications of blockade of nitric oxide and endothelin as a target in treatment of human septic shock. Briefly the importance of timing of intervention is also emphasized.