KEY ROLE FOR CYCLOOXYGENASE-2 IN PGE(2) AND PGF(2-ALPHA) RECEPTOR REGULATION AND CEREBRAL BLOOD-FLOW OF THE NEWBORN

Ibuprofen, a cyclooxygenase (COX) inhibitor nonselective for either CO X-1 or COX-2 isoform, upregulates cerebrovascular prostaglandin E-2 (P GE(2)) and PGF(2 alpha) receptors in newborn pigs. COX-2 was shown to be the predominant form of COX and the main catalyst of prostaglandin synthesis in the newborn brain. We proceeded to establish direct evide nce that COX-2-generated prostaglandins govern PGE(2) and PGF(2 alpha) receptor density and function in the cerebral vasculature of the newb orn. Hence, we determined PGE(2) and PGF(2 alpha) receptor density and functions in brain vasculature by using newborn pigs treated with sal ine, ibuprofen, COX-1 inhibitor (valerylsalicylate), or COX-2 inhibito rs (DUP-697 and NS-398). Newborn brain PGE(2) and PGF(2 alpha), concen trations were signifrcantly reduced by ibuprofen, DUP-697, and NS-398 but not by valerylsalicylate. In newborn pigs treated with DUP-697, NS -398, and ibuprofen, PGE(2) and PGF(2 alpha), receptor densities in br ain microvessels were increased to adult levels; there was also a sign ificant increase in inositol 1,4,5-trisphosphate (IP3) production and cerebral vasoconstrictor effects of 17-phenyl trinor PGE(2) (EP1 recep tor agonist), M&B-28767 (EP3 receptor agonist), PGF(2 alpha) and fenpr ostalene (PGF(2 alpha) analog). Treatment with ibuprofen or DUP-697 al so increased the upper blood pressure Limit of cerebral cortex and per iventricular blood flow autoregulation from 85 to greater than or equa l to 125 mmHg (uppermost blood pressure studied). However, valerylsali cylate treatment did not affect cerebrovascular PGE(2) and PGF(2 alpha ) receptors, IP3 production, or vasoconstrictor effects in newborn ani mals. These in vivo and in vitro observations indicate that COX-2 is m ainly responsible for the regulation of PGE(2) and PGF(2 alpha) recept ors and their functions in the newborn cerebral vasculature.