Differential role of PTK, ERK and p38 MAPK in superoxide impairment of NMDA cerebrovasodilation.
Previous studies in piglets have shown that the generation of oxygen free radicals (O(-)(2)) following traumatic brain injury and hypoxia/ischemia contribute to the reversal of N-methyl-D-aspartate (NMDA)-induced pial artery dilation to vasoconstriction. This study determined the contribution of protein tyrosine kinase (PTK) and mitogen-activated protein (MAPK) activation to impairment of NMDA cerebrovasodilation by O(-)(2) in piglets equipped with a closed window. Exposure of the cerebral cortex to a xanthine oxidase O(-)(2) generating system (OX) reversed NMDA (10(-8), 10(-6) M) dilation to vasoconstriction but such impairment was partially prevented by the PTK inhibitor, genistein, the MAPK (ERK isoform) inhibitor, U0126, and the MAPK (p38 isoform) inhibitor, SB203580 (9+/-1 and 15+/-1 vs. -1+/-1 and -1+/-1 vs. 5+/-1 and 9+/-1% for sham control, OX and OX in the presence of genistein, respectively). However, the p38 MAPK inhibitor, SB203580, prevented NMDA dilator impairment significantly less than the ERK MAPK inhibitor, U0126. Similar results were obtained for glutamate. These data show that PTK and MAPK activation by the presence of O(-)(2) contributes to the impairment of NMDA dilation. Furthermore, these data indicate a differential role for ERK and p38 MAPK activation in impairment of NMDA dilation by O(-)(2) in the brain.
Philip
Shaji
S
Department of Anesthesia, University of Pennsylvania, 3400 Spruce Street, 19104, Philadelphia, PA, USA.
Armstead
William M
WM
D000818:Animals; D000831:Animals, Newborn; D001158:Arteries / Q000187:drug effects; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016202:N-Methylaspartate / Q000378:metabolism; D010841:Pia Mater / Q000098:blood supply / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D013552:Swine; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; D013481:Superoxides; D018698:Glutamic Acid; D016202:N-Methylaspartate; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases