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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1998 Oct;125(3):542–548. doi: 10.1038/sj.bjp.0702075

Essential role for endothelin ETB receptors in fever induced by LPS (E. coli) in rats

Aline S C Fabricio 1, Carlos A A Silva 1, Giles A Rae 2, Pedro D'Orléans-Juste 3, Glória E P Souza 1,*
PMCID: PMC1565640  PMID: 9806338

Abstract

  1. The influence of endothelin receptor antagonists on febrile responses to E. coli lipopolysaccharide (LPS), interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α) and endothelin-1 (ET-1) was assessed in conscious rats.

  2. Intravenous (i.v.) LPS (5.0 μg kg−1) markedly increased rectal temperature to a peak of 1.30°C over baseline at 2.5 h. Pretreatment with the mixed endothelin ETA/ETB receptor antagonist bosentan (10 mg kg−1, i.v.) or the selective endothelin ETB receptor antagonist BQ-788 (N-cis-2,6-dimethyl-piperidinocarbonyl-L-γ-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°C, respectively. The selective endothelin ETA 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-1β (180 fmol, i.c.v.), TNF-α (14.4 pmol, i.c.v.) or IL-1β (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°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 ETB receptor-mediated mechanism possibly not situated downstream from IL-1β or TNF-α in the fever cascade.

Keywords: Fever (rat), LPS, TNF-α, IL-1β, endothelins, ETA and ETB receptors, bosentan, BQ-123, BQ-788, indomethacin

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