Role of nitric oxide in tolerance to lipopolysaccharide in mice

• Published in: Journal of applied physiology (1985) 2005-04, Vol.98 (4), p.1322-1327
• Main Authors: Dias, Mirela B, Almeida, Maria C, Carnio, Evelin C, Branco, Luiz G. S
• Format: Article
• Language: English
• Subjects: Adaptation, Physiological - drug effects; Animals; Bacterial diseases; Biological and medical sciences; Drug Tolerance; Experimental bacterial diseases and models; Fever - chemically induced; Fever - metabolism; Infectious diseases; Lipopolysaccharides - administration & dosage; Lipopolysaccharides - poisoning; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase - deficiency; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase Type II; Pharmacology; Rodents; Temperature
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/japplphysiol.01243.2004

1 Department of Physiology, Medical School of Ribeirão Preto, University of São Paulo, 2 Department of General and Specialized Nursing, Nursing School of Ribeirão Preto, and 3 Department of Morphology, Estomatology and Physiology, Dental School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil Submitted 4 November 2004 ; accepted in final form 30 November 2004 The injection of repeated doses of lipopolysaccharide (LPS) results in attenuation of the febrile response, which is called endotoxin tolerance. We tested the hypothesis that nitric oxide (NO) arising from inducible NO synthase (iNOS) plays a role in endotoxin tolerance, using not only pharmacological trials but also genetically engineered mice. Body core temperature was measured by biotelemetry in mice treated with N G -monomethyl- L -arginine ( L -NMMA, 40 mg/kg; a nonselective NO synthase inhibitor) or aminoguanidine (AG, 10 mg/kg; a selective iNOS inhibitor) and in mice deficient in the iNOS gene (iNOS KO) mice. Tolerance to LPS was induced by means of three consecutive LPS (100 µg/kg) intraperitoneal injections at 24-h intervals. In wild-type mice, we observed a significant reduction of the febrile response to repeated administration of LPS. Injection of L -NMMA and AG markedly enhanced the febrile response to LPS in tolerant animals. Conversely, iNOS-KO mice repeatedly injected with LPS did not become tolerant to the pyrogenic effect of LPS. These data are consistent with the notion that NO modulates LPS tolerance in mice and that iNOS isoform is involved in NO synthesis during LPS tolerance. body temperature; thermoregulation; fever; nitric oxide synthase Address for reprint requests and other correspondence: L. G. S. Branco, Departamento de Morfologia, Estomatologia e Fisiologia, Faculdade de Odontologia de Ribeirão Preto, USP, 14040-904 Ribeirão Preto, SP, Brazil (E-mail: branco{at}forp.usp.br )