Protective roles of nitric oxide and testosterone in endotoxemia: evidencefrom NOS-2-deficient mice

Lipopolysaccharide (LPS)-induced septic shock, which triggers nitric oxide (NO) overproduction, multiple organ dysfunction, and death, can be affected by gender and sex hormones. We hypothesized that NO is beneficial during e ndotoxemia and that this beneficial effect is influenced by sex hormones. C 57BL/6 wild-type (WT) mice and congenic inducible NO synthase knockout (KO) mice were injected with LPS, and mortality was recorded for 4 days. After 5 mg/kg LPS, female KO mice had significantly higher mortality than WT. Aft er 12.5 mg/kg LPS, both male and female KO mice had significantly higher mo rtality than WT. Ovariectomy did not alter mortality, but orchiectomy drama tically increased mortality in KO mice. After 5 mg/kg LPS, exogenous testos terone completely prevented the increased mortality in KO female and orchie ctomized KO male mice. WT survival was not affected by exogenous testostero ne. After 12.5 mg/kg LPS, exogenous testosterone significantly improved sur vival of female KO mice. Serum enzymes and organ edema, which may not corre late with mortality, were significantly and similarly increased in both WT and KO endotoxemic mice; however, edema was not observed in KO hearts. Thus , NO plays a protective role in endotoxemia while having differential effec ts on different organs. Importantly, testosterone is beneficial in endotoxe mia when NO production is deficient, and may be therapeutic in certain sept ic patients.