(Stroke. 1999;30:153-159.)
© 1999 American Heart Association, Inc.
Original Contributions |
Superoxide Generation Links Protein Kinase C Activation to Impaired ATP-Sensitive K+ Channel Function After Brain Injury
From the Departments of Anesthesia and Pharmacology, University of Pennsylvania and The Children's Hospital of Philadelphia, Philadelphia, Pa.
Correspondence to William M. Armstead, PhD, Department of Anesthesia, The Children's Hospital of Philadelphia, 34th and Civic Center Blvd, Philadelphia, PA 19104. Email armsteaw{at}mail.med.upenn.edu
Background and Purpose—Endothelin-1, in concentrations similar to that present in cerebrospinal fluid after fluid percussion brain injury (FPI), increases superoxide anion (O2-) production. Endothelin-1 also contributes to altered cerebral hemodynamics after FPI through impairment of ATP-sensitive K+ (KATP) channel function through protein kinase C (PKC) activation. Generation of O2- additionally occurs after FPI. Nitric oxide and cGMP elicit pial artery dilation through KATP channel activation. The present study was designed to determine whether PKC activation generates O2-, which, in turn, could link such activation to impaired KATP channel function 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—Phorbol 12,13-dibutyrate (10-6 mol/L), a PKC activator, increased superoxide dismutase-inhibitable NBT reduction from 1±1 to 37±5 pmol/mm2. Staurosporine (10-7 mol/L), a PKC antagonist, blocked the NBT reduction after phorbol 12,13-dibutyrate and blunted the NBT reduction observed after FPI (1±1 to 15±2 versus 1±1 to 5±1 pmol/mm2 after FPI in the absence versus presence of staurosporine). Exposure of the cerebral cortex to a xanthine oxidase O2--generating system increased NBT reduction in a manner similar to FPI and blunted pial artery dilation to the KATP channel agonists cromakalim and calcitonin gene–related peptide, the nitric oxide releasers sodium nitroprusside and S-nitroso-N-acetylpenicillamine, and the cGMP analogue 8-bromo-cGMP (10±1% and 21±1% versus 4±1% and 9±1% for 10-8 and 10-6 mol/L cromakalim before and after activated oxygen-generating system exposure).
Conclusions—These data show that PKC activation increases O2- production and contributes to such production observed after FPI. These data also show that an activated system that generates an amount of O2- similar to that observed with FPI blunted pial artery dilation to KATP channel agonists and nitric oxide/cGMP. These data suggest, therefore, that O2- generation links PKC activation to impaired KATP channel function after FPI.
Editorial Comment
Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, Nebraska
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