title: Essential role for endothelin ET(B) receptors in fever induced by LPS (E. coli) in rats.
abstract: 1. The influence of endothelin receptor antagonists on febrile responses to E. coli lipopolysaccharide (LPS), interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and endothelin-1 (ET-1) was assessed in conscious rats. 2. Intravenous (i.v.) LPS (5.0 microg kg(-1)) markedly increased rectal temperature to a peak of 1.30 degrees C over baseline at 2.5 h. Pretreatment with the mixed endothelin ET(A)/ET(B) receptor antagonist bosentan (10 mg kg(-1), i.v.) or the selective endothelin ET(B) receptor antagonist BQ-788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D -1-methoxycarboyl-D-norleucine; 3 pmol, into a lateral cerebral ventricle-i.c.v.) reduced the peak response to LPS to 0.90 and 0.75 degrees C, respectively. The selective endothelin ET(A) receptor antagonist BQ-123 (cyclo[D-Trp-D-Asp-Pro-D-Val-Leu]; 3 pmol, i.c.v.) was ineffective. 3. Increases in temperature caused by IL-1beta (180 fmol, i.c.v.), TNF-alpha (14.4 pmol, i.c.v.) or IL-1beta (150 pmol kg(-1), i.v.) were unaffected by BQ-788 (3 pmol, i.c.v.). 4. Central injection of endothelin-1 (0.1 to 3 fmol, i.c.v.) caused slowly-developing and long-lasting increases in rectal temperature (starting 2 h after administration and peaking at 4-6 h between 0.90 and 1.15 degrees C) which were not clearly dose-dependent. The response to endothelin-1 (1 fmol, i.c.v.) was prevented by BQ-788, but not by BQ-123 (each at 3 pmol, i.c.v.). Intraperitoneal pretreatment with the cyclo-oxygenase inhibitor indomethacin (2 mg kg(-1)), which partially reduced LPS-induced fever, did not modify the hyperthermic response to endothelin-1 (3 fmol, i.c.v.). 5. Therefore, central endothelin(s) participates importantly in the development of LPS-induced fever, via activation of a prostanoid-independent endothelin ET(B) receptor-mediated mechanism possibly not situated downstream from IL-1beta or TNF-alpha in the fever cascade.
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Universidade de São Paulo, Ribeirão Preto, Brazil.
authors.forename: A S
authors.initials: AS
authors.lastname: Fabricio
authors.forename: C A
authors.initials: CA
authors.lastname: Silva
authors.forename: G A
authors.initials: GA
authors.lastname: Rae
authors.forename: P
authors.initials: P
authors.lastname: D'Orléans-Juste
authors.forename: G E
authors.initials: GE
authors.lastname: Souza
mesh_terms: D000818:Animals; D065128:Endothelin Receptor Antagonists; D004926:Escherichia coli / Q000737:chemistry; D005334:Fever / Q000139:chemically induced*; D007213:Indomethacin / Q000494:pharmacology; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D065128:Endothelin Receptor Antagonists; D007375:Interleukin-1; D008070:Lipopolysaccharides; D017466:Receptors, Endothelin; D014409:Tumor Necrosis Factor-alpha; D007213:Indomethacin