NOC/oFQ and NMDA Contribute to Piglet Hypoxic Ischemic Hypotensive Cerebrovasodilation Impairment

Abstract

Previous studies have observed that hypotensive pial artery dilation was blunted after hypoxia-ischemia. In unrelated studies, the opioid nociceptin/orphanin FQ (NOC/oFQ) was observed to contribute to hypoxic ischemic impairment of N-methyl-d-aspartate (NMDA)-induced pial dilation. This study determined the contribution of NOC/oFQ and NMDA to hypoxic ischemic hypotensive cerebrovasodilation impairment in newborn pigs equipped with a closed cranial window. Global cerebral ischemia was produced via elevated intracranial pressure. Hypoxia decreased Po2 to 33 ± 3 mm Hg. Topical NOC/oFQ (10−10 M), the cerebrospinal fluid concentration after hypoxia-ischemia, had no effect on pial artery diameter by itself but attenuated hypotension (mean arterial blood pressure decrease of 44 ± 2%) -induced pial artery dilation (35 ± 2%versus 22 ± 3%). Hypotensive pial artery dilation was blunted by hypoxia-ischemia, but such dilation was partially protected by pretreatment with the putative NOC/oFQ receptor antagonist, [F/G] NOC/oFQ (1–13) NH2 (10−6 M; 29 ± 2%, sham control; 7 ± 2%, hypoxia-ischemia; and 13 ± 2%, hypoxia-ischemia and [F/G] NOC/oFQ (1–13) NH2). Coadministration of the NMDA antagonist MK801 (10−5 M) with NOC/oFQ(10−10 M) partially prevented hypotensive pial dilation impairment. Similarly, pretreatment with MK801 partially protected hypoxic ischemia impairment of hypotensive pial dilation (35 ± 2%, sham control; 7 ± 1%, hypoxia-ischemia; 22 ± 2%, hypoxia-ischemia + MK801). These data show that NOC/oFQ and NMDA contribute to hypoxic ischemic hypotensive cerebrovasodilation impairment. These data suggest that NOC/oFQ modulation of NMDA vascular activity also contributes to such hypotensive impairment.