Endothelial cell derived relaxing factor has been identified to be nitric oxide and the pathway responsible for its synthesis in human cells has been partially elucidated. Further, antagonists of this pathway have been synthesized and shown to block the hypotension caused by tumor necrosis factor, an important mediator of septic shock. In this study, an antagonist of nitric oxide production will be examined for therapeutic efficacy in a well characterized canine model of septic shock. Its effects on the cardiovascular abnormalities of septic shock will also be investigated. In addition, methods are being developed to look at the level of activity of this pathway in human septic shock and in normal volunteers following administration of endotoxin. In vitro studies will also be conducted to investigate the effect of this pathway on phagocytic cell function. Antagonists of the nitric oxide pathway may prove useful in the treatment of septic shock and the above studies are being conducted to investigate this possibility. This investigation may lead to therapeutic trials in patients with this highly lethal syndrome.
