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1 Department of Physiology, Medical College of Georgia, Augusta, Georgia 30912 and 2 Institute of General and Molecular Biology, University of Nicolaus Copernicus, 87-100 Torun, Poland
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 µg/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 µl/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.
biotelemetry; body temperature; endotoxin; turpentine; fever mechanism; nitric oxide; gene knockout mice
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