The antipyretic effect of dipyrone is unrelated to inhibition of PGE(2) synthesis in the hypothalamus.
OBJECTIVE
Bacterial lipopolysaccharide (LPS) induces fever through two parallel pathways; one, prostaglandin (PG)-dependent and the other, PG-independent and involving endothelin-1 (ET-1). For a better understanding of the mechanisms by which dipyrone exerts antipyresis, we have investigated its effects on fever and changes in PGE(2) content in plasma, CSF and hypothalamus induced by either LPS or ET-1.


METHODS
Rats were given (i.p.) dipyrone (120 mg·kg(-1)) or indomethacin (2 mg·kg(-1)) 30 min before injection of LPS (5 µg·kg(-1), i.v.) or ET-1 (1 pmol, i.c.v.). Rectal temperature was measured by tele-thermometry. PGE(2) levels were determined in the plasma, CSF and hypothalamus by elisa.


RESULTS
LPS or ET-1 induced fever and increased CSF and hypothalamic PGE(2) levels. Two hours after LPS, indomethacin reduced CSF and hypothalamic PGE(2) but did not inhibit fever, while at 3 h it reduced all three parameters. Three hours after ET-1, indomethacin inhibited the increase in CSF and hypothalamic PGE(2) levels but did not affect fever. Dipyrone abolished both the fever and the increased CSF PGE(2) levels induced by LPS or ET-1 but did not affect the increased hypothalamic PGE(2) levels. Dipyrone also reduced the increase in the venous plasma PGE(2) concentration induced by LPS.


CONCLUSIONS
These findings confirm that PGE(2) does not play a relevant role in ET-1-induced fever. They also demonstrate for the first time that the antipyretic effect of dipyrone was not mechanistically linked to the inhibition of hypothalamic PGE(2) synthesis.
Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
David do C
Ddo C
Malvar
Denis M
DM
Soares
Aline S C
AS
Fabrício
Alexandre
A
Kanashiro
Renes R
RR
Machado
Maria J
MJ
Figueiredo
Giles A
GA
Rae
Glória E P
GE
de Souza
D000818:Animals; D058633:Antipyretics / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis* / Q000097:blood / Q000134:cerebrospinal fluid; D004177:Dipyrone / Q000494:pharmacology*; D019332:Endothelin-1 / Q000494:pharmacology; D004926:Escherichia coli; D005334:Fever / Q000188:drug therapy* / Q000503:physiopathology; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D011749:Pyrogens / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D058633:Antipyretics; D016861:Cyclooxygenase Inhibitors; D019332:Endothelin-1; D008070:Lipopolysaccharides; D011749:Pyrogens; D004177:Dipyrone; D015232:Dinoprostone; D007213:Indomethacin