The effects of selective and nonselective cyclooxygenase inhibitors on endothelin-1-induced fever in rats.
It was previously shown that sustained fever can be induced in rats by central injection of endothelin-1 (ET-1). This peptide appears to participate in the mechanism(s) of LPS-induced fever, which is reduced by pretreatments with ET(B) receptor antagonists. In this study, we compared the effects of a nonselective cyclooxygenase (COX) inhibitor, indomethacin, with those of two selective COX-2 inhibitors, celecoxib and lumiracoxib, on ET-1-induced fever in rats. Fever induced in conscious animals by ET-1 (1 pmol icv) or LPS (5 mug/kg iv) was prevented by pretreatments with celecoxib (5 and 10 mg/kg) or lumiracoxib (5 mg/kg) given by oral gavage 1 h before stimuli. Lower doses of celecoxib had partial (2.5 mg/kg) or no effect (1 mg/kg). Indomethacin (2 mg/kg ip) partially inhibited fever induced by LPS but had no effect on ET-1-induced fever. The levels of PGE(2) and PGF(2alpha) in the cerebrospinal fluid (CSF) of pentobarbital sodium-anesthetized rats were significantly increased 3 h after the injection of LPS or ET-1. The latter increase was abolished by celecoxib at all tested doses and by indomethacin. In conclusion, selective COX-2 inhibitors were able to prevent ET-1-induced fever, indicating a role for COX-2 in this phenomenon. However, the fact that reduced CSF PG levels obtained with indomethacin and a low dose of celecoxib are not accompanied by changes in fever induced by ET-1, along with the lack of inhibitory effects of indomethacin on ET-1 fever, suggests that the latter might also involve COX-2-independent mechanisms.
Fabricio
Aline S C
AS
Institute of Pharmacology, Catholic University Medical School, Largo Francesco Vito 1, 00168 Rome, Italy. alinefabricio@hotmail.com
Veiga
Fabiane H
FH
Cristofoletti
Rodrigo
R
Navarra
Pierluigi
P
Souza
Gloria E P
GE
D000818:Animals; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004008:Diclofenac / Q000031:analogs & derivatives; D015237:Dinoprost / Q000134:cerebrospinal fluid; D015232:Dinoprostone / Q000134:cerebrospinal fluid; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000008:administration & dosage; D005334:Fever / Q000134:cerebrospinal fluid / Q000139:chemically induced* / Q000503:physiopathology* / Q000517:prevention & control; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007441:Intubation, Gastrointestinal; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D009930:Organic Chemicals / Q000008:administration & dosage / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D019332:Endothelin-1; D008070:Lipopolysaccharides; D009930:Organic Chemicals; D011720:Pyrazoles; D013449:Sulfonamides; D004008:Diclofenac; D015237:Dinoprost; D000068579:Celecoxib; D015232:Dinoprostone; C473384:lumiracoxib; D007213:Indomethacin