ESSENTIAL ROLE FOR ENDOTHELIN ETB RECEPTORS IN FEVER INDUCED BY LPS (ESCHERICHIA-COLI) IN RATS

1 The influence of endothelin receptor antagonists on febrile response s to E. coli lipopolysaccharide (LPS), interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha) and endothelin-1 (ET-1) was assessed in conscious rats. 2 Intravenous (i.v.) LPS (5.0 mu g kg(-1)) markedly increased rectal temperature to a peak of 1.30 degrees C ove r baseline at 2.5 h. Pretreatment with the mixed endothelin ETA/ETB re ceptor antagonist bosentan (10 mg kg(-1), i.v.) or the selective endot helin ETB receptor antagonist BQ-788 imethylpiperidinocarbonyl-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 a nd 0.75 degrees 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-1 beta (180 f mol, i.c.v.). TNF-alpha (14.4 pmol, i.c.v.) or IL-1 beta (150 pmol kg( -1), i.v.) were unaffected by BQ-788 (3 pmol, i.c.v.). 4 Central injec tion 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 a dministration and peaking at 4-6 h between 0.90 and 1.15 degrees C) wh ich were not clearly dose-dependent. The response to endothelin-1 (1 f mol, i.c.v.) was prevented by BQ-788, but not by BQ-123 (each at 3 pmo l, i.c.v.). Intraperitoneal pretreatment with the cyclo-oxygenase inhi bitor indomethacin (2 mg kg(-1)), which partially reduced LPS-induced fever, did not modify the hyperthermic response to endothelin-1 (3 fmo l, i.c.v.). 5 Therefore, central endothelin(s) participates importantl y in the development of LPS-induced fever, via activation of a prostan oid-independent endothelin ETB receptor-mediated mechanism possibly no t situated downstream from IL-1 beta or TNF-alpha in the fever cascade .