The effects of selective and nonselective cyclooxygenase inhibitors on endothelin-1-induced fever in rats

Abstract

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 g/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 PGE2 and PGF2␣ 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.cyclooxygenase-2 inhibitors; indomethacin; prostaglandins; cerebrospinal fluid; lipopolysaccharide IT IS NOW WELL ESTABLISHED that the PGs represent the final mediators of fever induced by exogenous and endogenous pyrogens through an action on PG receptor-expressing neurons in the preoptic area (POA) of the anterior hypothalamus (33). In fact, PGE 2 induces fever when injected centrally (13,33,38), and its levels in the cerebrospinal fluid (CSF) and in the POA rise in parallel with the generation of fever caused by several stimuli (9,12,16,19,23,27,35,42). Moreover, the inhibition of PG synthesis by cyclooxygenase (COX) inhibitors attenuates fever in humans and experimental animals, whereas these drugs do not affect fever induced by the administration of PGs (4,7,12,13,37,39). PGF 2␣ also induces fever when injected centrally (13, 34), and its levels are increased in rat CSF in response to LPS (10).We have previously observed that endothelin-1 (ET-1), a member of the ET family of peptides (29), acts as a mediator of LPS-induced fever (15). In fact, intracerebroventricular (icv) pretreatment with the selective ET B receptor antagonist BQ-788 blunted fever induced by intravenous LPS or intracerebroventricular ET-1 (15). The rise in core temperature induced by intracerebroventricular ET-1 was accompanied by such thermoeffector response as cutaneous vasoconstriction, measured as a decrease in tail skin temperature (Fabricio, unpublished observation). The simultaneous occurrence of increased core temper...

Febrile response induced by cecal ligation and puncture (CLP) in rats: involvement of prostaglandin E2 and cytokines

“…System). Preliminary experiments revealed that LPS-induced fever recorded using the radio-telemetry system was indistinguishable from that assessed by the rectal probe method [22].…”

STAT3 and COX-2 activation in the guinea-pig brain during fever induced by the Toll-like receptor-3 agonist polyinosinic:polycytidylic acid

“…COX-2 is predominantly inducible under conditions of inflammation but basal levels of COX-2 are present in the brain (for a review, see Botting 2006). The use of selective COX-2 inhibitors (Cao et al 1997;Steiner et al 2001;Zhang et al 2003;Fabricio et al 2004) or of COX-2-deficient ("knockout") mice (Li et al 1999;Steiner et al 2005) suggest a critical role for COX-2 as a mediator of fever induced by bacterial LPS.…”

Central endothelin ETBreceptors mediate IL-1-dependent fever induced by preformed pyrogenic factor and corticotropin-releasing factor in the rat

“…The proposal was supported by the fact that ICV administration of the selective ET B receptor antagonist BQ-788 substantially attenuates the fever induced by intravenous E. coli LPS, indicating that endogenous ETs contribute significantly to this response (7). Moreover, ICV ET-1 also causes a potent pyrogenic effect of ET-1 in the rat, which is fully prevented by prior ICV injection of the selective ET B receptor antagonist BQ-788 but is unaffected by the selective ET A receptor antagonist BQ-123 or prior systemic treatment with indomethacin (7,8). In contrast, fever induced by either ICV IL-1␤ or TNF-␣ is sensitive to inhibition by indomethacin but resistant to pretreatment with the ET B receptor antagonist (5,7).…”