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

Male C57BL/6J mice deficient in nitric oxide synthase ( NOS) genes ( knockout) and control (wild-type) mice were implanted intraabdominally with battery-operated miniature biotelemeters ( model VMFH MiniMitter, Sunriver, OR) to monitor changes in body temperature. Intravenous injection of lipopolysaccharide (LPS; 50 mug/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 mul/animal) into the left hindlimb. Oral administration ( gavage) of N-G-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 (N-G-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 similar to60%, whereas it augmented fever by similar to65% 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.