Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 285, Issue 4, Pages E871-E875Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00004.2002
Keywords
arginine; endotoxin; nitric oxide; stable isotope; constitutive nitric oxide synthase; inducible nitric oxide synthase
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Increased nitric oxide (NO) production is the cause of hypotension and shock during sepsis. In the present experiments, we have measured the contribution of endothelial (e) and inducible (i) nitric oxide synthase (NOS) to systemic NO production in mice under baseline conditions and upon LPS treatment (100 mug/10 g ip LPS). NO synthesis was measured by the rate of conversion of L-[guanidino-N-15(2)] arginine to L-[ureido-N-15] citrulline, and the contribution of the specific NOS isoforms was evaluated by comparing NO production in eNOS-deficient [(-/-)] and iNOS(-/-) mice 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.10 g body wt(-1).min(-1)]. In response to the challenge with LPS ( 5 h), 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.10 g body wt(-1).min(-1)]. After 5 h of LPS treatment, blood pressure had dropped 14 mmHg in WT but not in iNOS(-/-) mice. The present findings provide firm evidence that, upon treatment with bacterial LPS, the increase of NO production is solely dependent on iNOS, whereas that mediated by cNOS is reduced. Furthermore, the data show that the LPS-induced blood pressure response is dependent on iNOS.
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