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

Abstract

This study was designed to determine if altered release of prostaglandins contributes to impaired pial 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 O 2 to 35±3 mmHg with unchanged P CO 2 . NOC/oFQ (10 −8 and 10 −6 M) modestly increased cerebrospinal fluid (CSF) 6-Keto PGF 1α and TXB 2, 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 1α and TXB 2, respectively). In 1 h post ischemia/reperfusion (I+R) animals, basal levels of 6-Keto PGF 1α and TXB 2 were elevated. NOC/oFQ-stimulated release of 6-Keto PGF 1α was blocked while such release of TXB 2 was enhanced (526±15 to 822±36 pg/ml for control and 10 −6 M NOC/oFQ CSF TXB 2). 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.