Nitric oxide and fever: immune-to-brain signaling vs. thermogenesis in chicks.

Nitric oxide (NO) plays a role in thermogenesis but does not mediate immune-to-brain febrigenic signaling in rats. There are suggestions of a different situation in birds, but the underlying evidence is not compelling. The present study was designed to clarify this matter in 5-day-old chicks challenged with a low or high dose of bacterial LPS. The lower LPS dose (2 µg/kg im) induced fever at 3-5 h postinjection, whereas 100 µg/kg im decreased core body temperature (Tc) (at 1 h) followed by fever (at 4 or 5 h). Plasma nitrate levels increased 4 h after LPS injection, but they were not correlated with the magnitude of fever. The NO synthase inhibitor (N(G)-nitro-l-arginine methyl ester, l-NAME; 50 mg/kg im) attenuated the fever induced by either dose of LPS and enhanced the magnitude of the Tc reduction induced by the high dose in chicks at 31-32°C. These effects were associated with suppression of metabolic rate, at least in the case of the high LPS dose. Conversely, the effects of l-NAME on Tc disappeared in chicks maintained at 35-36°C, suggesting that febrigenic signaling was essentially unaffected. Accordingly, the LPS-induced rise in the brain level of PGE2 was not affected by l-NAME. Moreover, l-NAME augmented LPS-induced huddling, which is indicative of compensatory mechanisms to run fever in the face of attenuated thermogenesis. Therefore, as in rats, systemic inhibition of NO synthesis attenuates LPS-induced fever in chicks by affecting thermoeffector activity and not by interfering with immune-to-brain signaling. This may constitute a conserved effect of NO in endotherms.

Interleukin-1 receptor antagonist decreases cerebrospinal fluid nitric oxide levels and increases vasopressin secretion in the late phase of sepsis in rats.

The aim of this study was to analyze the effect of IL-1ra (an Interleukin-1 receptor antagonist) on sepsis-induced alterations in vasopressin (AVP) and nitric oxide (NO) levels. In addition, IL-1ra effect on the hypothalamic nitric oxide synthase (NOS) activities and survival rate was also analyzed. After Wistar rats were intracerebroventricular injected with IL-1ra (9 pmol) or vehicle (PBS 0.01 M), sepsis was induced by cecal-ligation and puncture (CLP). Blood, CSF, and hypothalamic samples were collected from different groups of rats (n = 8/group) after 4, 6, and 24 h. AVP and NO levels were greatly increased in CLP. Both total NOS and inducible NOS (iNOS) activities were also greatly increased in CLP rats. These changes in AVP, NO, and NOS were not observed in sham-operated control rats. IL-1ra administration did not alter plasma AVP levels after 4 and 6 h as compared to vehicle in CLP animals but after 24 h were significantly (P < 0.01) higher in IL-1ra-treated animals. IL-1ra administration significantly (P < 0.01) decreased NO concentration in CSF but not in plasma. Both total NOS and iNOS activities were also significantly decreased by IL-1ra at 24 h in CLP animals. Moreover, the 24 h survival rate of IL-1ra-treated rats increased by 38 % in comparison to vehicle administered animals. The central administration of IL-1ra increased AVP secretion in the late phase of sepsis which was beneficial for survival. We believe that one of the mechanisms for this effect of IL-1ra is through reduction of NO concentration in CSF and hence lower hypothalamic iNOS activities in the septic rats.