Preoptic nitric oxide attenuates endotoxic fever in guinea pigs by inhibiting the POA release of norepinephrine

Abstract

Lipopolysaccharide (LPS) administration induces hypothalamic nitric oxide (NO); NO is antipyretic in the preoptic area (POA), but its mechanism of action is uncertain. LPS also stimulates the release of preoptic norepinephrine (NE), which mediates fever onset. Because NE upregulates NO synthases and NO induces cyclooxygenase (COX)-2-dependent PGE2, we investigated whether NO mediates the production of this central fever mediator. Conscious guinea pigs with intra-POA microdialysis probes received LPS intravenously (2 μg/kg) and, thereafter, an NO donor (SIN-1) or scavenger (carboxy-PTIO) intra-POA (20 μg/μl each, 2 μl/min, 6 h). Core temperature (Tc) was monitored constantly; dialysate NE and PGE2 were analyzed in 30-min collections. To verify the reported involvement of α2-adrenoceptors (AR) in PGE2 production, clonidine (α2-AR agonist, 2 μg/μl) was microdialyzed with and without SIN-1 or carboxy-PTIO. To assess the possible involvement of oxidative NE and/or NO products in the demonstrated initially COX-2-independent POA PGE2 increase, (+)-catechin (an antioxidant, 3 μg/μl) was microdialyzed, and POA PGE2, and Tc were determined. SIN-1 and carboxy-PTIO reduced and enhanced, respectively, the rises in NE, PGE2, and Tc produced by intravenous LPS. Similarly, they prevented and increased, respectively, the delayed elevations of PGE2 and Tc induced by intra-POA clonidine. (+)-Catechin prevented the LPS-induced elevation of PGE2, but not of Tc. We conclude that the antipyretic activity of NO derives from its inhibitory modulation of the LPS-induced release of POA NE. These data also implicate free radicals in POA PGE2 production and raise questions about its role as a central LPS fever mediator.