Central involvement of kinin B 1 and B 2 receptors in the febrile response induced by endotoxin in rats

The effect of central injection of selective kinin B 1 and B 2 receptor antagonists on the febrile response induced by endotoxin ( E. coli lipopolysaccharide, LPS) in rats was investigated. Intracerebroventricular (i.c.v.) injection of a selective B 2 receptor antagonist (Hoe‐140, 8 nmol) reduced the early (0–2 h), but increased the late phase (4–6 h) of the febrile response induced by intravenous (i.v.) injection of LPS (0.5 μg kg −1 ). Co‐administration of Hoe‐140 (8 nmol, i.c.v.) with LPS (0.5 μg kg −1 , i.v.), followed 2.5 h later by the i.c.v. injection of a selective B 1 receptor antagonist [des‐Arg 9 ‐Leu 8 ]‐bradykinin (BK, 8 nmol), significantly reduced the febrile response induced by LPS throughout the whole experimental period. Intravenous injection of Hoe‐140 (1 mg kg −1 ) significantly reduced the febrile response induced by LPS (0.5 μg kg −1 , i.p.). Pretreatment (24 h) with LPS (0.5 μg kg −1 , i.v.) reduced the febrile response induced by BK or [Tyr 8 ]‐BK (both, 5 nmol, i.c.v.), but markedly increased the febrile response induced by [des‐Arg 9 ]‐BK (5 nmol, i.c.v.). The response induced by [des‐Arg 9 ]‐BK in LPS‐pretreated rats was significantly inhibited by co‐injection of [des‐Arg 9 ‐Leu 8 ]‐BK (15 nmol, i.c.v.). The results suggest that kinins are involved in the induction of LPS‐induced fever and that central B 2 and B 1 receptors are activated during the initial and late phase of this response, respectively. The results also suggest that downregulation and/or desensitization of B 2 receptors and induction and/or upregulation of B 1 receptors in LPS‐pretreated animals may have a significant pathophysiologcal role in the induction and maintenance of fever. These observations may be specifically important in the case of chronic inflammatory conditions, because the BK metabolite [des‐Arg 9 ]‐BK, so far considered an inactive metabolite, acquires an active and relevant role with the progressive expression of B 1 receptors that occurs in such states.British Journal of Pharmacology (1997) 121 , 296–302; doi: 10.1038/sj.bjp.0701110