INHIBITION OF PROSTAGLANDIN SYNTHESIS IN NEWBORN PIGS INCREASES CEREBRAL MICROVESSEL PROSTAGLANDIN-F2-ALPHA AND PROSTAGLANDIN E(2) RECEPTORS, THEIR 2ND MESSENGERS AND VASOCONSTRICTOR RESPONSE TO ADULT LEVELS

We recently reported that the density of prostaglandin (PG) F-2 alpha and E(2) receptors (FP and EP) on the cerebral microvasculature of the newborn is less than on that of the adult animal. This study tests th e hypothesis that higher levels of PGF(2 alpha) and PGE(2) in the newb orn than in the adult brain might down-regulate FP and EP and their fu nctions 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 ce rebrovascular FP and EP density, receptor-coupled second messenger pro duction and cerebral vasoconstrictor responses to PGF(2 alpha) and PGE (2) were determined. The results showed that ibuprofen treatment in th e 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 in cubated for 48 h with ibuprofen. PGF(2 alpha), fenprotalene (PGF(2 alp ha) analog), PGE(2), 17-phenyl trinor PGE(2) (EP(1) receptor subtype a gonist) and M&B 28,767 (EP3 agonist) caused a significantly greater in crease in inositol 1,4,5-triphosphate production in brain microvessels of ibuprofen-treated than in brain microvessels of saline-treated new born pigs. The cerebral vasoconstrictor effects of PGF(2 alpha), 17-ph enyl trinor PGE(2) 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 microva sculature did not differ between saline-treated newborn, ibuprofen-tre ated newborn and adult pigs. It is concluded that the low FP and EP de nsities in newborn brain microvessels are a result of high levels of b rain prostaglandins and that these receptors, receptor-coupled second messengers and cerebral vasoconstrictor responses to FP, EP(1) and EP( 3) stimulation can be up-regulated to adult levels by decreasing endog enous prostaglandin production. The changes in receptor levels were no t related to steady-state levels of receptro mRNA in brain microvessel s.