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Physiology and Pharmacology of Temperature Regulation

Central endothelin ET_B receptors mediate IL-1-dependent fever induced by preformed pyrogenic factor and corticotropin-releasing factor in the rat

¹Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil; ²Department of Pharmacology, Biological Sciences Center, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil; ³Department of Pharmacology, Biological Sciences Section, Universidade Federal do Paraná, Curitiba, Paraná, Brazil; ⁴Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Canada

Submitted 11 May 2005 ; accepted in final form 19 August 2005

Blockade of central endothelin ET_B receptors inhibits fever induced by LPS in conscious rats. The contribution of ET_B receptor-mediated mechanisms to fever triggered by intracerebroventricular IL-6, PGE₂, PGF₂, corticotropin-releasing factor (CRF), and preformed pyrogenic factor derived from LPS-stimulated macrophages (PFPF) was examined. The influence of natural IL-1 receptor antagonist or soluble TNF receptor I on endothelin (ET)-1-induced fever was also assessed. The selective ET_B receptor antagonist BQ-788 (3 pmol icv) abolished fever induced by intracerebroventricular ET-1 (1 pmol) or PFPF (200 ng) and reduced that caused by ICV CRF (1 nmol) but not by IL-6 (14.6 pmol), PGE₂ (1.4 nmol), or PGF₂ (2 nmol). CRF-induced fever was also attenuated by bosentan (dual ET_A/ET_B receptor antagonist; 10 mg/kg iv) but unaffected by BQ-123 (selective ET_A receptor antagonist; 3 pmol icv). -Helical CRF_9–41 (dual CRF₁/CRF₂ receptor antagonist; 6.5 nmol icv) attenuated fever induced by CRF but not by ET-1. Human IL-1 receptor antagonist (9.1 pmol) markedly reduced fever to IL-1 (180 fmol) or ET-1 and attenuated that caused by PFPF or CRF. Murine soluble TNF receptor I (23.8 pmol) reduced fever to TNF- (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 ET_B receptor-mediated IL-1-dependent fever.

prostaglandins; cytokines; interleukin-1 receptor antagonist

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