Comparative pyrogenic potency of endogenous prostanoids and of prostanoid-mimetics injected into the anterior hypothalamic/preoptic region of the cat.
In both pyrogen-induced fever and fever subsequent to acute hypothalamic trauma, pyrexia is believed to be mediated by cyclooxygenase products acting within the anterior hypothalamic/preoptic (AH/PO) region of the brain. The goal of the present study was to assess, through a potency analysis, the likely contributions of various prostanoids to pyrexia production. Prostanoids and prostanoid-mimetics were injected bilaterally into the AH/PO region of conscious, indomethacin pretreated cats, and partial dose-response curves for pyrexic activity were obtained. ED1 degrees doses (doses producing a 1 degree C fever) for PGE2, PGE1 and 6-keto-PGE1 (a metabolite of PGI2 and/or of the PGI2 hydrolysis product, 6-keto-PGF1 alpha) ranged between 2 and 15 pmol. PGF2 alpha and the stable PGI2-mimetics, iloprost and 6-beta-PGI1, required doses of 900-1100 pmol. PGD2 and 6-keto-PGF1 alpha had ED1 degrees doses of 2200-2400 pmol. PGI2, thromboxane (TX) B2 and the TXA2/PGH2-mimetics, SQ26655, 9,11-azo-PGH2 and U46619, were incapable of producing a 1 degrees C rise at the maximum dose of 30,000 pmol. The results offer no support for an involvement in fever of PGF2 alpha, PGD2, TXA2, TXB2, PGH2, PGI2 or 6-keto-PGF1 alpha. Only the 3 E-series prostaglandins were sufficiently potent to merit serious consideration as mediators of pyrexia. Of these, only PGE2 is known to be produced in abundance by cat brain; no information is available regarding PGE1 production, and our results with PGI2 and 6-keto-PGF1 alpha indicate that cat brain may not synthesize 6-keto-PGE1. The results thus suggest an important role for PGE2 in fever production in the cat and are compatible with an involvement of PGE1.
Gollman
H M
HM
School of Pharmacy, University of Wisconsin, Madison 53706.
Rudy
T A
TA
D000818:Animals; D002415:Cats; D004305:Dose-Response Relationship, Drug; D005260:Female; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D011301:Preoptic Area / Q000187:drug effects / Q000502:physiology*; D011453:Prostaglandins / Q000494:pharmacology*; D011465:Prostaglandins, Synthetic / Q000494:pharmacology*; D011749:Pyrogens; D013329:Structure-Activity Relationship
D011453:Prostaglandins; D011465:Prostaglandins, Synthetic; D011749:Pyrogens; D007213:Indomethacin