Up-regulation of brain PGE2 and PGF2 alpha receptors and receptor-coupled second messengers by cyclooxygenase inhibition in newborn pigs.
We recently reported that brain synaptosomes of newborn pigs contained fewer PGE2 (EP) and PGF2 alpha (FP) receptors than adult tissues. In the present study we investigated whether this was the result of down-regulation of these receptors by high levels of PGE2 and PGF2 alpha in the brain of newborn animals. Newborn pigs (1-3 days old) were treated with ibuprofen (40 mg/kg) or indomethacin (5 mg/kg) i.v. every 4 hr for 24 hr to reduce prostaglandins to adult levels. At the end of the treatment, EP and FP receptor density and receptor-linked second messenger formation in brain synaptosomes were measured. It was found that ibuprofen and indomethacin treatment increased EP and FP receptor densities in brain synaptosomes of newborn animals to levels found in the adult; this up-regulation of EP receptors was prevented by EP receptor agonist, 16,16-dimethyl-PGE2, and the up-regulation of FP receptors was prevented by the FP agonist, fenprostalene. PGE2, butaprost (an agonist for EP2 receptor subtype mediating cAMP stimulation) and 11-deoxy-PGE1 (an agonist for EP2 and EP3 receptors) caused a comparable increase of cAMP in brain synaptosomes of ibuprofen-treated and adult animals, which was significantly greater than in those of vehicle-treated animals. Also, PGF2 alpha and its analog, fenprostalene, caused a much greater increase in IP3 production in brain synaptosomes of ibuprofen-treated than in vehicle-treated pigs. These findings suggest that the relatively low EP and FP receptor densities in newborn pigs are caused by the high levels of prostaglandins and that these receptors can be up-regulated by inhibiting prostaglandin synthesis.
Li
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Department of Pediatrics, McGill University, Montreal, Canada.
Varma
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Chemtob
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D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D007052:Ibuprofen / Q000494:pharmacology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D015290:Second Messenger Systems; D013552:Swine; D013574:Synaptosomes; D015854:Up-Regulation / Q000187:drug effects
D011461:Prostaglandins F, Synthetic; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; C034671:prostaglandin F2alpha receptor; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D015064:16,16-Dimethylprostaglandin E2; D007052:Ibuprofen; C039153:fenprostalene; D007213:Indomethacin