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INFLAMMATION AND CYTOKINES

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

Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee

Submitted 30 January 2007 ; accepted in final form 14 June 2007

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 (T_c) was monitored constantly; dialysate NE and PGE₂ were analyzed in 30-min collections. To verify the reported involvement of ₂-adrenoceptors (AR) in PGE₂ production, clonidine (₂-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 T_c were determined. SIN-1 and carboxy-PTIO reduced and enhanced, respectively, the rises in NE, PGE₂, and T_c produced by intravenous LPS. Similarly, they prevented and increased, respectively, the delayed elevations of PGE₂ and T_c induced by intra-POA clonidine. (+)-Catechin prevented the LPS-induced elevation of PGE₂, but not of T_c. 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.

nitric oxide donors; nitric oxide scavengers; clonidine; prostaglandin E₂; body temperature; free radicals; catechin; lipopolysaccharides

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				N. Quan Living history: Clark M. Blatteis Advan Physiol Educ, March 1, 2009; 33(1): 1 - 6. [Abstract] [Full Text] [PDF]