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Am J Physiol Regul Integr Comp Physiol (August 25, 2005). doi:10.1152/ajpregu.00337.2005
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Submitted on May 11, 2005
Accepted on August 19, 2005

Central endothelin ETB receptors mediate IL-1-dependent fever induced by pre-formed pyrogenic factor and corticotropin-releasing factor in the rat

Aline S. C Fabricio1, Giles A Rae2, Aleksander R Zampronio3, Pedro D'Orleans-Juste4, and Gloria E. P Souza1*

1 Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Universidade de Sao Paulo, Ribeirao Preto, SP, Brazil
2 Dept. of Pharmacology, Biological Sciences Center, Universidade Federal de Santa Catarina, Florianopolis, SC, Brazil
3 Dept. of Pharmacology, Biological Sciences Section, Universidade Federal do Parana, Curitiba, PR, Brazil
4 Dept. of Pharmacology, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Canada

* To whom correspondence should be addressed. E-mail: gepsouza{at}fcfrp.usp.br.

Blockade of central endothelin ETB receptors inhibits fever induced by lipopolysaccharide (LPS) in conscious rats. The contribution of ETB receptor-mediated mechanisms to fever triggered by i.c.v. interleukin (IL)-6, prostaglandin (PG)E2, PGF2{alpha}, corticotropin-releasing factor (CRF) and pre-formed pyrogenic factor derived from LPS-stimulated macrophages (PFPF) was examined. The influence of natural IL-1 receptor antagonist (IL-1ra) or soluble tumor necrosis factor receptor I (sTNFRI) on endothelin (ET)-1-induced fever was also assessed.The selective ETB receptor antagonist BQ-788 (3 pmol, i.c.v.) abolished fever induced by i.c.v. ET-1 (1 pmol) or PFPF (200 ng) and reduced that caused by i.c.v. CRF (1 nmol), but not by IL-6 (14.6 pmol), PGE2(1.4 nmol) or PGF2{alpha} (2 nmol). CRF-induced fever was also attenuated by bosentan (dual ETA/ETB receptor antagonist; 10 mg/kg, i.v.), but unaffected by BQ-123 (selective ETA receptor antagonist; 3 pmol, i.c.v.). {alpha}-helical CRF9-41 (dual CRF1/CRF2 receptor antagonist; 6.5 nmol, i.c.v.) attenuated fever induced by CRF, but not by ET-1. Human IL-1ra (9.1 pmol) markedly reduced fever to IL-1{beta} (180 fmol) or ET-1, and attenuated that caused by PFPF or CRF. Murine sTNFRI (23.8 pmol) reduced fever to TNF-{alpha} (14.7 pmol), but not to ET-1. The results of the present study suggest that PFPF and CRF recruit the brain ET system to cause ETB receptor-mediated IL-1-dependent fever.




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