There is good evidence from a large number of studies that humans suffering from sepsis syndrome also have increased systemic nitric oxide production. The higher the nitric oxide level, the more pronounced the septic hypotension seems to be.
Animal studies using nitric oxide synthase inhibitors have mixed results. Researchers have reported that nitric oxide synthase inhibitors restored the responsiveness of septic vasculature to catecholamines and improved survival in endotoxin-challenged animals. Other investigators have reported opposite and harmful effects. These investigators found that the administration of a nitric oxide synthase inhibitor increased systemic and renal vascular resistance, decreased renal blood flow, increased capillary leak, decreased cardiac output, and increased mortality.
Only a handful of studies using an iNOS antagonist, such as arginine analogues, in septic patients has been published. In a small placebo-controlled study with 12 individuals, an arginine analogue was shown to be an effective pressor but was associated with diminished cardiac output and continued high mortality rates. Other limited, uncontrolled studies have shown that the septic patients treated with nitric oxide inhibitors demonstrated transient improvements in blood pressure but no effect on overall mortality. The role of nitric oxide in septic shock warrants further investigation. To date, only nonselective nitric oxide synthetase inhibitors that block both forms of nitric oxide synthase inhibitors have been extensively studied. Future research is most likely to be performed with highly selective inhibitors.
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