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 COX-1 or COX-2 isoform, upregulates cerebrovascular prostaglandin E-2 (PGE(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 evidence that COX-2-generated prostaglandins govern PGE(2) and PGF(2 alpha) receptor density and function in the cerebral vasculature of the newborn. Hence, we determined PGE(2) and PGF(2 alpha) receptor density and functions in brain vasculature by using newborn pigs treated with saline, ibuprofen, COX-1 inhibitor (valerylsalicylate), or COX-2 inhibitors (DUP-697 and NS-398). Newborn brain PGE(2) and PGF(2 alpha), concentrations 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 brain microvessels were increased to adult levels; there was also a significant increase in inositol 1,4,5-trisphosphate (IP3) production and cerebral vasoconstrictor effects of 17-phenyl trinor PGE(2) (EP1 receptor agonist), M&B-28767 (EP3 receptor agonist), PGF(2 alpha) and fenprostalene (PGF(2 alpha) analog). Treatment with ibuprofen or DUP-697 also increased the upper blood pressure Limit of cerebral cortex and periventricular blood flow autoregulation from 85 to greater than or equal to 125 mmHg (uppermost blood pressure studied). However, valerylsalicylate treatment did not affect cerebrovascular PGE(2) and PGF(2 alpha) receptors, IP3 production, or vasoconstrictor effects in newborn animals. These in vivo and in vitro observations indicate that COX-2 is mainly responsible for the regulation of PGE(2) and PGF(2 alpha) receptors and their functions in the newborn cerebral vasculature.