CHARACTERIZATION AND REGULATION OF PROSTAGLANDIN E(2) RECEPTOR AND RECEPTOR-COUPLED FUNCTIONS IN THE CHOROIDAL VASCULATURE OF THE PIG DURING DEVELOPMENT

Ontogenic changes in choroidal vascular prostaglandin E(2) (PGE(2)) re ceptors (EP(1), EP(2), EP(3), and EP(4)), changes in receptor-coupled functions, and the possible role of high perinatal prostaglandin level s in regulating expression and function of these receptors were studie d. PGE(2) receptors and their functions on choroidal tissues were char acterized by radioligand binding; by measurements of second messengers to receptor stimulation; and by vasomotor response to EP(1), EP(2), E P(3), and EP(4) ligands on perfused choroidal vascular beds from salin e- and ibuprofen-treated (40 mg/kg every 4 hours for 48 hours) newborn pigs and from adult animals. PGE(2) as well as EP(2)- and EP(4)-attri buted choroidal stimulation elicited greater vasorelaxation in the sal ine-treated newborn and was associated with higher nitrite (oxidation product of NO, N-omega-nitro-L-arginine inhibitable) production than i n adult tissues. In contrast, E(P)1 and EP(3) stimulation caused signi ficantly more constriction in the adult than in the newborn, and this was associated with increased production of inositol 1,4,5-trisphospha te (IP3) and greater reduction of cAMP synthesis in the adult. Maximum [H-3]PGE(2) binding was also higher (3-fold) in adult than in newborn tissues. Competition binding studies revealed that of the PGE(2) rece ptors in the adult choroid, approximate to 55% were of the EP(1) subty pe, 8% were EP(2), 22% were EP(3), and 15% were EP(4). Newborn choroid contained approximate to 33% each of EP(1) and EP(2) receptors, 20% o f EP(3), and 15% of EP(4). Inhibition of endogenous prostaglandin synt hesis for 48 hours with ibuprofen in newborns to attain levels found i n the adult resulted in an upregulation of [H-3]PGE(2) binding, EP(1)- and EP(3)-mediated vasoconstriction, and increases and decreases in I P3 and cAMP production, respectively, in newborn tissues compared with adult tissues. On the other hand, ibuprofen treatment of newborns led to a decrease in PGE(2)- and EP(4)-mediated vasorelaxation and nitrit e synthesis (associated with decreased expression of endothelial NO sy nthase) to levels observed in adults; EP(2)-elicited responses in newb orns were not affected by ibuprofen. In conclusion, fewer EP(1) recept ors (associated with vasoconstriction), more EP(2) receptors, and grea ter EP(4)-coupled NO production (coupled to vasorelaxation) seem to be responsible for the increased vasodilation to PGE(2) in the newborn. The decrease in prostaglandin levels with age appears to cause, on one hand, upregulation of EP(1) and EP(3) receptors and receptor-coupled vasoconstriction and, on the other hand, decreased EP(4)-coupled NO sy nthesis and choroidal vasodilation. Altogether, these factors result i n increased vasorelaxation to PGE(2) in the newborn compared with the adult. These findings may help to explain the inability of the newborn to autoregulate choroidal blood flow.