The antipyretic effect of dipyrone is unrelated to inhibition of PGE 2 synthesis in the hypothalamus
BACKGROUND AND PURPOSE 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 investi...
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| Published in | British journal of pharmacology Vol. 162; no. 6; pp. 1401 - 1409 |
|---|---|
| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
01.03.2011
|
| Online Access | Get full text |
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| Abstract | BACKGROUND AND PURPOSE
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.
EXPERIMENTAL APPROACH
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
.
KEY 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 AND IMPLICATIONS
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. |
|---|---|
| AbstractList | BACKGROUND AND PURPOSE
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.
EXPERIMENTAL APPROACH
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
.
KEY 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 AND IMPLICATIONS
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. |
| Author | Fabrício, Aline SC Figueiredo, Maria J Soares, Denis M Malvar, David do C Rae, Giles A Kanashiro, Alexandre Machado, Renes R de Souza, Glória EP |
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