Genetic Models in Applied Physiology Selected Contribution: Differential role of nitric oxide synthase isoforms in fever of different etiologies: studies using Nos gene-deficient mice

Kozak, Wieslaw, and Anna Kozak. Selected Contribution: Differential role of nitric oxide synthase isoforms in fever of different etiologies: studies using Nos gene-deficient mice. J Appl Physiol 94: 2534–2544, 2003. First published January 31, 2003; 10.1152/japplphysiol.01042.2002.—Male C57BL/6J mice deficient in nitric oxide synthase (NOS) genes (knockout) and control (wild-type) mice were implanted intra-abdominally with battery-operated miniature biotelemeters (model VMFH MiniMitter, Sunriver, OR) to monitor changes in body temperature. Intravenous injection of lipopolysaccharide (LPS; 50 g/kg) was used to trigger fever in response to systemic inflammation in mice. To induce a febrile response to localized inflammation, the mice were injected subcutaneously with pure turpentine oil (30 l/animal) into the left hindlimb. Oral administration (gavage) of NG-monomethyl-L-arginine (L-NMMA) for 3 days (80 mg kg 1 day 1 in corn oil) before injection of pyrogens was used to inhibit all three NOSs (NG-monomethyl-D-arginine acetate salt and corn oil were used as control). In normal male C57BL/6J mice, L-NMMA inhibited the LPS-induced fever by 60%, whereas it augmented fever by 65% in mice injected with turpentine. Challenging the respective NOS knockout mice with LPS and with L-NMMA revealed that inducible NOS and neuronal NOS isoforms are responsible for the induction of fever to LPS, whereas endothelial NOS (eNOS) is not involved. In contrast, none of the NOS isoforms appeared to trigger fever to turpentine. Inhibition of eNOS, however, exacerbates fever in mice treated with L-NMMA and turpentine, indicating that eNOS participates in the antipyretic mechanism. These data support the hypothesis that nitric oxide is a regulator of fever. Its action differs, however, depending on the pyrogen used and the NOS isoform.