(Stroke. 2000;31:1990.)
© 2000 American Heart Association, Inc.
Original Contributions |
Superoxide Generation Links Nociceptin/Orphanin FQ (NOC/oFQ) Release to Impaired N-Methyl-D-Aspartate Cerebrovasodilation After Brain Injury
From the Departments of Anesthesia and Pharmacology, University of Pennsylvania, Philadelphia, Pa.
Correspondence to William M. Armstead, PhD, Department of Anesthesia, University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104. E-mail armsteaw{at}mail.med.upenn.edu
Background and Purpose—Although activation of the N-methyl-D-aspartate (NMDA) receptor is thought to contribute to altered cerebrovascular regulation after traumatic brain injury, the effects of such injury on the vascular response to NMDA itself has been less well appreciated. The newly described opioid nociceptin/orphanin FQ (NOC/oFQ) elicits pial artery dilation, at least in part, in a prostaglandin-dependent manner and is released into cerebrospinal fluid after fluid percussion brain injury (FPI). Generation of superoxide anion (O2-) occurs after FPI, and a byproduct of cyclooxygenase metabolism is the generation of O2-. This study was designed to determine whether NOC/oFQ generates O2-, which in turn could link NOC/oFQ release to impaired NMDA-induced pial artery dilation after FPI.
Methods—Injury of moderate severity (1.9 to 2.1 atm) was produced by the lateral FPI technique in anesthetized newborn pigs equipped with a closed cranial window. Superoxide dismutase–inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O2- generation.
Results—Under non–brain injury conditions, topical NOC/oFQ (10-10 mol/L, the concentration present in cerebrospinal fluid after FPI) increased superoxide dismutase–inhibitable NBT reduction from 1±1 to 20±3 pmol/mm2 but had no effect itself on pial artery diameter. Indomethacin (5 mg/kg IV) blunted such NBT reduction (1±1 to 6±2 pmol/mm2), whereas the NOC/oFQ receptor antagonist [F/G] NOC/oFQ (1-13) NH2 (10-6 mol/L) blocked NBT reduction. [F/G] NOC/oFQ (1-13) NH2 and indomethacin also blunted the NBT reduction observed after FPI (1±1 to 15±1 versus 1±1 to 4±1 versus 1±1 to 4±1 pmol/mm2 for sham, NOC/oFQ antagonist, and indomethacin-treated animals, respectively). NMDA (10-8 and 10-6 mol/L)–induced pial artery dilation was reversed to vasoconstriction after FPI, and [F/G] NOC/oFQ (1-13) NH2 attenuated such vasoconstriction (sham 9±1% and 16±1% versus FPI -7±1% and -12±1% versus FPI–[F/G] NOC/oFQ (1-13) NH2–pretreated animals -2±1% and -3±1%). Indomethacin and the free radical scavengers polyethylene glycol superoxide dismutase and catalase also partially restored NMDA-induced vasodilation.
Conclusions—These data show that NOC/oFQ, in concentrations present in cerebrospinal fluid after FPI, increased O2- production in a cyclooxygenase-dependent manner and contributes to such production after FPI. These data show that NOC/oFQ contributes to impaired NMDA-induced pial artery dilation after FPI. Therefore, these data suggest that cyclooxygenase-dependent O2- generation links NOC/oFQ release to impaired NMDA-induced cerebrovasodilation after brain injury.
Editorial Comment
Medical College of Virginia Virginia Commonwealth University Richmond, Virginia
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