NOC/oFQ contributes to hypoxic-ischemic impairment of N-methyl-D-aspartate-induced cerebral vasodilation.
Previous studies in piglets show that either hypoxia, ischemia-reperfusion (I+R) or combined hypoxia-ischemia-reperfusion (H+I+R) attenuated N-methyl-D-aspartate (NMDA)-induced pial artery dilation. This study was designed to determine the contribution of the newly described opioid nociceptin orphanin FQ (NOC/oFQ) to hypoxic-ischemic impairment of NMDA induced cerebral vasodilation in piglets equipped with a closed cranial window. Global cerebral ischemia was produced via elevated intracranial pressure. Hypoxia decreased P(O(2)) to 35+/-3 mmHg with unchanged P(CO(2)). I+R elevated CSF NOC/oFQ from 67+/-4 to 266+/-29 pg/ml ( approximately 10(-10) M) while H+I+R elevated CSF NOC/oFQ to 483+/-67 pg/ml within 1 h of reperfusion. Such elevated NOC/oFQ levels returned to control within 4 h in I+R animals and within 12 h in H+I+R animals. Topical NOC/oFQ (10(-10) M) had no effect on pial artery diameter by itself but attenuated NMDA (10(-8), 10(-6) M) induced pial dilation (control, 9+/-1 and 16+/-1; coadministered NOC/oFQ, 5+/-1 and 10+/-1%). NMDA induced pial artery dilation was attenuated by I+R or H+I+R; but such dilation was partially restored by pretreatment with the putative NOC/oFQ antagonist [F/G] NOC/oFQ (1-13) NH(2) (10(-6) M) (control, 9+/-1 and 16+/-1; I+R, 3+/-1 and 5+/-1; I+R+NOC/oFQ antagonist, 6+/-1 and 11+/-1%) Similar results were obtained for glutamate. These data suggest that NOC/oFQ release contributes to impaired NMDA and glutamate-induced cerebrovasodilation following I+R or H+I+R.
Armstead
W M
WM
Departments of Anesthesia and Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA. armsteaw@mail.med.upenn.edu
D000818:Animals; D000831:Animals, Newborn; D001784:Blood Gas Analysis; D001794:Blood Pressure; D002545:Brain Ischemia / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D002534:Hypoxia, Brain / Q000503:physiopathology*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D018847:Opioid Peptides / Q000502:physiology*; D010841:Pia Mater / Q000098:blood supply; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D015427:Reperfusion Injury / Q000503:physiopathology; D013552:Swine; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D000097629:Nociceptin
D018690:Excitatory Amino Acid Agonists; D018698:Glutamic Acid; D016202:N-Methylaspartate; D018847:Opioid Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D000097629:Nociceptin