Altered release of prostaglandins contributes to hypoxic/ischemic impairment of NOC/oFQ cerebrovasodilation

This study was designed to determine if altered release of prostaglandins contributes to impaired pi:ll artery dilation to the newly described opioid, nociceptin/orphanin FQ (NOC/oFQ), following hypoxia/ischemia in newborn pigs equipped with a closed cranial window. Global cerebral ischemia (20 min) was induced via elevation of intracranial pressure, while hypoxia (10 min) decreased P-O2 to 35 +/- 3 mmHg with unchanged P-CO2. NOC/oFQ (10(-8) and 10(-6) M) modestly increased cerebrospinal fluid (CSF) 6-Keto PGF(1 alpha) and TXB2, the stable breakdown products of PGI(2) and TXA(2), in sham animals (1199 +/- 39 to 1704 +/- 104 and 299 +/- 9 to 409 +/- 12 pg/ml for control and 10(-6) M NOC/oFQ 6-Keto PGF(1 alpha) and TXB2, respectively). In 1 h post ischemia/reperfusion (I + R) animals, basal levels of 6-Keto PGF(1 alpha) and TXB2 were elevated. NOC/oFQ-stimulated release of 6-Keto PGF(1 alpha) was blocked while such release of TXB2 was enhanced (526 +/- 15 to 822 +/- 36 pg/ml for control and 10(-6) M NOC/oFQ CSF TXB2). Similar, though more pronounced, changes were observed in hypoxia/ischemia/reperfusion (H + I + R) animals. Pretreatment with indomethacin (5 mg/kg i.v.) or SQ 29.548 (10(-4) M), cyclooxygenase and PGH(2)/TXA(2) receptor antagonists, partially restored attenuated NOC/oFQ pial artery dilation 1 h after I + R (9 +/- 1 and 18 +/- 1 vs. 3 +/- 1 and 6 +/- 1 vs. 8 +/- 1 and 13 +/- 1% for 10(-8) and 10(-6) M NOC/oFQ in sham, I + R, and I + R - SQ 29,548 pretreated animals). In contrast, NOC/oFQ-induced vasodilation was reversed to vasoconstriction in H + I + R animals and indomethacin or SQ 29,548 similarly partially restored such pial vasodilation. These data indicate that altered stimulated prostaglandin release contributes to hypoxic/ischemic impairment of NOC/oFQ-mediated pial artery dilation. (C) 2000 Elsevier Science B.V. All rights reserved.