Febrigenic signaling to the brain does not involve nitric oxide - PubMed (original) (raw)

Comparative Study

. 2004 Apr;141(7):1204-13.

doi: 10.1038/sj.bjp.0705713. Epub 2004 Mar 8.

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Comparative Study

Febrigenic signaling to the brain does not involve nitric oxide

Alexandre A Steiner et al. Br J Pharmacol. 2004 Apr.

Abstract

1. The involvement of peripheral nitric oxide (NO) in febrigenic signaling to the brain has been proposed because peripherally administered NO synthase (NOS) inhibitors attenuate lipopolysaccharide (LPS)-induced fever in rodents. However, how the unstable molecule of NO can reach the brain to trigger fever is unclear. It is also unclear whether NOS inhibitors attenuate fever by blocking febrigenic signaling or, alternatively, by suppressing thermogenesis in brown fat. 2. Male Wistar rats were chronically implanted with jugular catheters; their colonic and tail skin temperatures (T(c) and T(sk)) were monitored. 3. Study 1 was designed to determine whether the relatively stable, physiologically relevant forms of NO, that is, S-nitrosoalbumin (SNA) and S-nitrosoglutathione (SNG), are pyrogenic and whether they enhance LPS fever. At a neutral ambient temperature (T(a)) of 31 degrees C, afebrile or LPS (1 microg kg(-1), i.v.)-treated rats were infused i.v. with SNA (0.34 or 4.1 micromol kg(-1); the controls received NaNO(2) and albumin) or SNG (10 or 60 micromol kg(-1); the controls received glutathione). T(c) of SNA- or SNG-treated rats never exceeded that of the controls. 4. In Study 2, we tested whether the known fever-attenuating effect of the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) at a subneutral T(a) (when fever is brought about by thermogenesis) also occurs at a neutral T(a) (when fever is brought about by skin vasoconstriction). At a subneutral T(a) of 24 degrees C, L-NAME (2.5 mg kg(-1), i.v.) attenuated LPS (10 microg kg(-1), i.v.) fever, presumably by inhibiting thermogenesis. At 31 degrees C, L-NAME enhanced LPS fever by augmenting skin vasoconstriction (T(sk) fall). 5. In summary, both SNA and SNG had no pyrogenic effect of their own and failed to enhance LPS fever; peripheral L-NAME attenuated only fever brought about by increased thermogenesis. It is concluded that NO is uninvolved in febrigenic signaling to the brain.

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Figures

Figure 1

Figure 1

Effects of SNA (infusion rate indicated) on the MAP (a), colonic temperature (b), and HLI (c) of afebrile rats at a neutral ambient temperature of 31°C. The controls received the corresponding amounts of NaNO2 and BSA; see Methods for details. The black bars indicate the duration of infusions. *In panel (a), _n_=3 for each group.

Figure 2

Figure 2

Effects of SNG (infusion rate indicated) on the MAP (a), colonic temperature (b), and HLI (c) of afebrile rats at 31°C. The controls received reduced glutathione. The black bars indicate the duration of infusions. *In panel (a), _n_=3 for each group.

Figure 3

Figure 3

Effects of SNA (infusion rate indicated) on the colonic temperature of afebrile rats (a) and on the colonic temperature (b) and HLI (c) of LPS (1 _μ_g kg−1, i.v.)-treated rats at 31°C. The controls were infused with the corresponding amounts of NaNO2 and BSA. The black bars indicate the duration of infusions.

Figure 4

Figure 4

Effects of SNG (infusion rate indicated) on the colonic temperature of afebrile rats (a) and on the colonic temperature (b) and HLI (c) of LPS (1 _μ_g kg−1, i.v.)-treated rats at 31°C. The controls received reduced glutathione. The black bars indicate the duration of infusions.

Figure 5

Figure 5

Effect of intravenous injection of the NOS inhibitor

L

-NAME (doses indicated) or its inactive enantiomer

D

-NAME (doses indicated) on the colonic temperature of rats at an ambient temperature of 24°C (a) or 31°C (b).

Figure 6

Figure 6

Effect of pretreatment with

L

-NAME (2.5 mg kg−1, i.v.) or

D

-NAME on the colonic temperature (a) and HLI (b) of LPS (10 _μ_g kg−1, i.v.)-treated rats exposed to an ambient temperature of 24°C.

Figure 7

Figure 7

Effect of

L

-NAME (2.5 mg kg−1, i.v.) or

D

-NAME on the colonic temperature (a) and HLI (b) of LPS (10 mg kg−1, i.v.)-treated rats exposed to an ambient temperature of 31°C.

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