Characterization and regulation of prostaglandin E2 receptor and receptor-coupled functions in the choroidal vasculature of the pig during development.
Ontogenic changes in choroidal vascular prostaglandin E2 (PGE2) receptors (EP1, EP2, EP3, and EP4), changes in receptor-coupled functions, and the possible role of high perinatal prostaglandin levels in regulating expression and function of these receptors were studied. PGE2 receptors and their functions on choroidal tissues were characterized by radioligand binding; by measurements of second messengers to receptor stimulation; and by vasomotor response to EP1, EP2, EP3, and EP4 ligands on perfused choroidal vascular beds from saline- and ibuprofen-treated (40 mg/kg every 4 every 4 hours for 48 hours) newborn pigs and from adult animals. PGE2 as well as EP2- and EP4-attributed choroidal stimulation elicited greater vasorelaxation in the saline-treated newborn and was associated with higher nitrite (oxidation product of NO, N omega-nitro-L-arginine inhibitable) production than in adult tissues. In contrast, EP1 and EP3 stimulation caused significantly more constriction in the adult than in the newborn, and this was associated with increased production of inositol 1,4,5-trisphosphate (IP3) and greater reduction of cAMP synthesis in the adult. Maximum [3H]PGE2 binding was also higher (3-fold) in adult than in newborn tissues. Competition binding studies revealed that of the PGE2 receptors in the adult choroid, approximately 55% were of the EP1 subtype, 8% were EP2, 22% were EP3, and 15% were EP4. Newborn choroid contained approximately 33% each of EP1 and EP2 receptors, 20% of EP3, and 15% of EP4. Inhibition of endogenous prostaglandin synthesis for 48 hours with ibuprofen in newborns to attain levels found in the adult resulted in an upregulation of [3H]PGE2 binding, EP1- and EP3-mediated vasoconstriction, and increases and decreases in IP3 and cAMP production, respectively, in newborn tissues compared with adult tissues. On the other hand, ibuprofen treatment of newborns led to a decrease in PGE2- and EP4-mediated vasorelaxation and nitrite synthesis (associated with decreased expression of endothelial NO synthase) to levels observed in adults: EP2-elicited responses in newborns were not affected by ibuprofen. In conclusion, fewer EP1 receptors (associated with vasoconstriction), more EP2 receptors, and greater EP4-coupled NO production (coupled to vasorelaxation) seem to be responsible for the increased vasodilation to PGE2 in the newborn. The decrease in prostaglandin levels with age appears to cause, on one hand, upregulation of EP1 and EP3 receptors and receptor-coupled vasoconstriction and, on the other hand, decreased EP4-coupled NO synthesis and choroidal vasodilation. Altogether, these factors result in increased vasorelaxation to PGE2 in the newborn compared with the adult. These findings may help to explain the inability of the newborn to autoregulate choroidal blood flow.
Abran
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Centre de Recherche de l'Hôpital Sainte-Justine, Department of Pediatrics, Montréal, Canada.
Dumont
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Hardy
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Peri
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Li
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Molotchnikoff
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Varma
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Chemtob
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D000367:Age Factors; D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001713:Biphenyl Compounds / Q000494:pharmacology; D002829:Choroid / Q000098:blood supply* / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D006152:Cyclic GMP / Q000096:biosynthesis; D015232:Dinoprostone / Q000819:agonists / Q000031:analogs & derivatives / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007052:Ibuprofen / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D011453:Prostaglandins; D018078:Receptors, Prostaglandin E; D019335:Nitroarginine; D009569:Nitric Oxide; C046926:AH 23848; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D000527:Alprostadil; D006152:Cyclic GMP; C048491:butaprost; D015232:Dinoprostone; D007052:Ibuprofen