Central involvement of kinin B1 and B2 receptors in the febrile response induced by endotoxin in rats.
1. The effect of central injection of selective kinin B1 and B2 receptor antagonists on the febrile response induced by endotoxin (E. coli lipopolysaccharide, LPS) in rats was investigated. 2. Intracerebroventricular (i.c.v.) injection of a selective B2 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 microgram kg-1). 3. Co-administration of Hoe-140 (8 nmol, i.c.v.) with LPS (0.5 microgram kg-1, i.v.), followed 2.5 h later by the i.c.v. injection of a selective B1 receptor antagonist [des-Arg9-Leu8]-bradykinin (BK, 8 nmol), significantly reduced the febrile response induced by LPS throughout the whole experimental period. 4. Intravenous injection of Hoe-140 (1 mg kg-1) significantly reduced the febrile response induced by LPS (0.5 microgram kg-1, i.p.). 5. Pretreatment (24 h) with LPS (0.5 microgram kg-1, i.v.) reduced the febrile response induced by BK or [Tyr8]-BK (both, 5 nmol, i.c.v.), but markedly increased the febrile response induced by [des-Arg9]-BK (5 nmol, i.c.v.). The response induced by [des-Arg9]-BK in LPS-pretreated rats was significantly inhibited by co-injection of [des-Arg9-Leu8]-BK (15 nmol, i.c.v.). 6. The results suggest that kinins are involved in the induction of LPS-induced fever and that central B2 and B1 receptors are activated during the initial and late phase of this response, respectively. The results also suggest that downregulation and/or desensitization of B2 receptors and induction and/or upregulation of B1 receptors in LPS-pretreated animals may have a significant pathophysiological 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-Arg9]-BK, so far considered an inactive metabolite, acquires an active and relevant role with the progressive expression of B1 receptors that occurs in such states.
Coelho
M M
MM
Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil.
Oliveira
C R
CR
Pajolla
G P
GP
Calixto
J B
JB
Pelá
I R
IR
D000818:Animals; D001920:Bradykinin / Q000009:adverse effects / Q000031:analogs & derivatives*; D002490:Central Nervous System / Q000187:drug effects*; D004731:Endotoxins / Q000494:pharmacology*; D005334:Fever / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018002:Receptors, Bradykinin / Q000187:drug effects*
D004731:Endotoxins; D008070:Lipopolysaccharides; D018002:Receptors, Bradykinin; C065679:icatibant; D001920:Bradykinin