Protein kinase C activation generates superoxide and contributes to impairment of cerebrovasodilation induced by G protein activation after brain injury.
Previous studies have observed that activation of protein kinase C (PKC) contributes to generation of superoxide anion (O(-)(2)) after fluid percussion brain injury (FPI). This study was designed to characterize the effects of FPI on the vascular activity of two activators of a pertussis toxin sensitive G protein, mastoparan and mastoparan-7, and the role of PKC dependent O(-)(2) generation in such effects in newborn pigs equipped with a closed cranial window. Mastoparan (10(-8), 10(-6) M) elicited pial artery dilation that was blunted by FPI and partially restored by the PKC inhibitor chelerythrine (10(-7) M) or the O(-)(2) free radical scavengers polyethylene glycol superoxide dismutase and catalase (SODCAT) (9+/-1 and 16+/-1, sham control; 3+/-1 and 5+/-1, FPI; and 7+/-1 and 11+/-1%, FPI SODCAT pretreated). Similar results were observed for mastoparan-7 but the inactive analogue mastoparan-17 had no effect on pial artery diameter. Exposure of the cerebral cortex to a xanthine oxidase O(-)(2) generating system blunted mastoparan induced pial artery dilation similar to FPI (10+/-1 and 17+/-1 vs. 2+/-1 and 3+/-1%). Pertussis toxin (1 microg/ml) exposure blocked mastoparan and mastoparan-7 vasodilation. These data show that pertussis toxin sensitive G protein activation elicits cerebrovasodilation that is blunted following FPI in a PKC dependent manner. These data also show that O(-)(2) generation similarly blunts G protein mediated cerebrovasodilation. These data suggest that PKC dependent O(-)(2) generation contributes to impaired G protein mediated cerebrovasodilation after FPI.
Armstead
William M
WM
Department of Anesthesia, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA. armsteaw@mail.med.upenn.edu
D000470:Alkaloids; D000818:Animals; D000831:Animals, Newborn; D053119:Benzophenanthridines; D001930:Brain Injuries / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D002374:Catalase / Q000494:pharmacology; D002536:Cerebral Arteries / Q000187:drug effects* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D010100:Oxygen / Q000378:metabolism; D010455:Peptides; D037342:Pertussis Toxin / Q000494:pharmacology; D010617:Phenanthridines / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*; D014862:Wasp Venoms / Q000145:classification / Q000494:pharmacology
D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D010617:Phenanthridines; D014862:Wasp Venoms; D013481:Superoxides; D011092:Polyethylene Glycols; C037500:mastoparan; C016299:chelerythrine; D002374:Catalase; D013482:Superoxide Dismutase; C063471:polyethylene glycol-superoxide dismutase; D037342:Pertussis Toxin; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D010100:Oxygen