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

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2007-09, Vol.293 (3), p.R1144-R1151
• Main Authors: Feleder, Carlos, Perlik, Vit, Blatteis, Clark M
• Format: Article
• Language: English
• Subjects: Acetaminophen - pharmacology; Adrenergic alpha-Antagonists - pharmacology; Animals; Body Temperature - physiology; Brain; Catheterization; Cyclooxygenase Inhibitors - pharmacology; Dinoprostone - metabolism; Fever; Fever - chemically induced; Fever - physiopathology; Free radicals; Guinea Pigs; Jugular Veins - physiology; Lipopolysaccharides; Male; Microdialysis; Nitric oxide; Norepinephrine - physiology; Prazosin - pharmacology; Preoptic Area - physiology; Rodents; Salmonella enteritidis - chemistry; Sugar; Yohimbine - pharmacology
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00068.2007

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 PGE 2 , 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 PGE 2 were analyzed in 30-min collections. To verify the reported involvement of 2 -adrenoceptors (AR) in PGE 2 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 PGE 2 increase, (+)-catechin (an antioxidant, 3 µg/µl) was microdialyzed, and POA PGE 2 , and T c were determined. SIN-1 and carboxy-PTIO reduced and enhanced, respectively, the rises in NE, PGE 2 , and T c produced by intravenous LPS. Similarly, they prevented and increased, respectively, the delayed elevations of PGE 2 and T c induced by intra-POA clonidine. (+)-Catechin prevented the LPS-induced elevation of PGE 2 , 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 PGE 2 production and raise questions about its role as a central LPS fever mediator. nitric oxide donors; nitric oxide scavengers; clonidine; prostaglandin E 2 ; body temperature; free radicals; catechin; lipopolysaccharides Address for reprint requests and other correspondence: C. M. Blatteis, Dept. of Physiology, College of Medicine, Univ. of Tennessee Health Science Center, 894 Union Ave., Memphis, TN 38163 (e-mail: blatteis{at}physio1.utmem.edu )