(Stroke. 2001;32:1408.)
© 2001 American Heart Association, Inc.
Original Contributions |
Vasopressin-Induced Protein Kinase C–Dependent Superoxide Generation Contributes to ATP-Sensitive Potassium Channel but Not Calcium-Sensitive Potassium Channel Function Impairment After Brain Injury
From the Departments of Anesthesia and Pharmacology, University of Pennsylvania (Philadelphia).
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—Pial artery dilation in response to activators of the ATP-sensitive K+ (KATP) and calcium-sensitive K+ (KCa) channels is impaired after fluid percussion brain injury (FPI). Vasopressin, when coadministered with the KATP and KCa channel agonists cromakalim and NS1619 in a concentration approximating that observed in cerebrospinal fluid (CSF) after FPI, blunted KATP and KCa channel–mediated vasodilation. Vasopressin also contributes to impaired KATP and KCa channel vasodilation after FPI. In addition, protein kinase C (PKC) activation generates superoxide anion (O2-), which in turn contributes to KATP channel impairment after FPI. We tested whether vasopressin generates O2- in a protein kinase C (PKC)-dependent manner, which could link vasopressin release to impaired KATP and KCa channel–induced pial artery dilation after FPI.
Methods—Injury of moderate severity (1.9 to 2.1 atm) was produced with 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 sham injury conditions, topical vasopressin (40 pg/mL, the concentration present in CSF after FPI) increased superoxide dismutase–inhibitable NBT reduction from 1±1 to 23±4 pmol/mm2. Chelerythrine (10-7 mol/L, a PKC inhibitor) blunted such NBT reduction (1±1 to 9±2 pmol/mm2), whereas the vasopressin antagonist l-(ß-mercapto-ß,ß-cyclopentamethylene propionic acid)2-(o-methyl)-Tyr-arginine vasopressin (MEAVP) blocked NBT reduction. Chelerythrine and MEAVP also blunted the NBT reduction observed after FPI (1±1 to 15±1, 1±1 to 4±1, and 1±1 to 5±1 pmol/mm2 for sham-, chelerythrine-, and MEAVP-treated animals, respectively). Under sham injury conditions, vasopressin (40 pg/mL) coadministered with cromakalim or NS1619 blunted dilation in response to these K+ channel agonists, whereas chelerythrine partially restored such impaired vasodilation for cromakalim but not NS1619. Cromakalim- and NS1619-induced pial artery dilation also was blunted after FPI. MEAVP partially protected dilation to both K+ channel agonists after FPI, whereas chelerythrine did so for only cromakalim responses (for cromakalim at 10-8 and 10-6 mol/L, 13±1% and 23±1%, 2±1% and 5±1%, 9±1% and 15±2%, and 9±1% and 16±2% for sham-, FPI-, FPI-MEAVP–, and FPI-chelerythrine–pretreated animals, respectively).
Conclusions—These data show that vasopressin, in concentrations present in CSF after FPI, increased O2- production in a PKC-dependent manner and contributes to such production after FPI. These data show that vasopressin contributes to KATP but not KCa channel function impairment in a PKC-dependent manner after FPI and suggest that vasopressin contributes to KCa channel function impairment after FPI via a mechanism independent of PKC activation.
Key Words: brain injuries • cerebral circulation • free radicals • newborn • potassium channels • vasopressin
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