CENTRAL INVOLVEMENT OF KININ B-1 AND B-2 RECEPTORS IN THE FEBRILE RESPONSE INDUCED BY ENDOTOXIN IN RATS

1 The effect of central injection of selective kinin B-1 and B-2 recep tor antagonists on the febrile response induced by endotoxin (E. coli lipopolysaccharide, LPS) in rats was investigated. 2 Intracerebroventr icular (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.) injectio n of LPS (0.5 mu g kg(-1)). 3 Co-administration of Hoe-140 (8 nmol, i, c.v.) with LPS (0.5 mu g 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 respons e induced by LPS throughout the whole experimental period. 4 Intraveno us injection of Hoe-140 (I mg kg(-1)) significantly reduced the febril e response induced by LPS (0.5 mu g kg(-1), i.p.). 5 Pretreatment (24 b) with LPS (0.5 mu g kg(-1) i.v.) reduced the febrile response induce d by BI( 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 signif icantly inhibited by co-injection of [des-Arg(9)-Leu(8)]-BK (15 nmol, i.c.v.), 6 The results suggest that kinins are involved in the inducti on of LPS-induced fever and that central B-2 and B-1 receptors are act ivated during the initial and late phase of this response, respectivel y. The results also suggest that downregulation and/or desensitization of B-2 receptors and induction and/or upregulation of B-1 receptors i n 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 inact ive metabolite, acquires an active and relevant role with the progress ive expression of B-1 receptors that occurs in such states.