NO production by cNOS and iNOS reflects blood pressure changes in LPS-challenged mice

Increased NO production is the cause of hypotension and shock during sepsis. In the present experiments we have measured the contribution of eNOS and iNOS to systemic NO production in mice under baseline conditions and upon endotoxin treatment (LPS 100 micro g/10g i.p.). NO synthesis was measured by the rate of conversion of L-[guanidino-(15)N2]arginine to L-[ureido-(15)N]citrulline, and the contribution of the specific NOS isoforms was evaluated by comparing NO production in eNOS(-/-) and iNOS(-/-) with that in wild-type (WT) mice. Under baseline conditions, NO production was similar in WT and iNOS(-/-) mice, but lower in eNOS(-/-) mice (WT: 1.2 +/- 0.2; iNOS(-/-): 1.2 +/- 0.2; eNOS(-/-): 0.6 +/- 0.3 nmol/10g Bw.min(-1)). In response to the challenge with endotoxin (5h), systemic NO production increased in WT and eNOS(-/-) mice, but fell in iNOS(-/-) mice (WT: 2.7 +/- 0.3; eNOS(-/-): 2.2 +/- 0.6; iNOS(-/-): 0.7 +/- 0.1 nmol/10g Bw.min(-1)). After 5h of LPS treatment, blood pressure had dropped 14 mm Hg in WT, but not iNOS(-/-) mice. The present findings provide firm evidence that upon treatment with bacterial endotoxin, the increase of NO production is solely dependent upon iNOS, whereas that mediated by cNOS is reduced. Furthermore, the data show that the LPS-induced blood pressure response is dependent on iNOS.