Nitric oxide. A key mediator in sepsis and endotoxaemia?

A very large number of biologically active substances are released into the circulation under conditions of endotoxaemia and sepsis. One of the most important of these is nitric oxide. Under these conditions nitric oxide is produced through an induced enzyme (nitric oxide synthase) in a variety of tissues and the nitric oxide so generated is largely responsible for the loss of vascular reactivity, which occurs under these conditions, for the resulting unrelenting hypotension associated with the hypodynamic phase of septic shock. Nitric oxide also contributes to the myocardial depression in this condition. The question as to whether it is a worthwhile therapeutic approach to inhibit nitric oxide synthase is discussed with particular reference to the generation of inhibitors selective for the induced form of the enzyme. This approach has certain benefits but may also be detrimental. The fact that nitric oxide is not the key mediator involved in ultimate mortality in this condition is suggested by the failure to improve mortality in iNOS knockout mice given endotoxin.