Inhibition of prostaglandin synthesis in newborn pigs increases cerebral microvessel prostaglandin F2 alpha and prostaglandin E2 receptors, their second messengers and vasoconstrictor response to adult levels.
We recently reported that the density of prostaglandin (PG) F2 alpha and E2 receptors (FP and EP) on the cerebral microvasculature of the newborn is less than on that of the adult animal. This study tests the hypothesis that higher levels of PGF2 alpha and PGE2 in the newborn than in the adult brain might down-regulate FP and EP and their functions in the cerebral microvasculature. Newborn pigs (1-2 days old) were treated with ibuprofen (40 mg/kg i.v.) every 6 h for 48 h; and cerebrovascular FP and EP density, receptor-coupled second messenger production and cerebral vasoconstrictor responses to PGF2 alpha and PGE2 were determined. The results showed that ibuprofen treatment in the newborn increased brain microvascular FP and EP densities to levels found in the brains of adult pigs. This up-regulation of prostaglandin receptors was also observed in isolated newborn brain microvessels incubated for 48 h with ibuprofen. PGF 2 alpha, fenprostalene (PGF2 alpha analog), PGE2, 17-phenyl trinor PGE2 (EP1 receptor subtype agonist) and M&B 28,767 (EP3 agonist) caused a significantly greater increase in inositol 1,4,5-triphosphate production in brain microvessels of ibuprofen-treated than in brain microvessels of saline-treated newborn pigs. The cerebral vasoconstrictor effects of PGF2 alpha, 17-phenyl trinor PGE2 and M&B 28,767 were also significantly increased in newborn pigs treated with ibuprofen to levels comparable to those of adults. However, the steady-state level of FP mRNA in cerebral microvasculature did not differ between saline-treated newborn, ibuprofen-treated newborn and adult pigs. It is concluded that the low FP and EP densities in newborn brain microvessels are a result of high levels of brain prostaglandins and that these receptors, receptor-coupled second messengers and cerebral vasoconstrictor responses to FP, EP1 and EP3 stimulation can be up-regulated to adult levels by decreasing endogenous prostaglandin production. The changes in receptor levels were not related to steady-state levels of receptor mRNA in brain microvessels.
Li
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Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
Abran
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Peri
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Varma
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Chemtob
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D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D001667:Binding, Competitive; D002560:Cerebrovascular Circulation / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007052:Ibuprofen / Q000494:pharmacology; D008833:Microcirculation; D011453:Prostaglandins / Q000096:biosynthesis*; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D015290:Second Messenger Systems / Q000502:physiology*; D013552:Swine; D014661:Vasoconstriction / Q000502:physiology
D011453:Prostaglandins; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D007052:Ibuprofen