PTK, ERK and p38 MAPK contribute to impaired NMDA-induced vasodilation after brain injury.
N-Methyl-D-aspartate (NMDA)-induced pial artery dilation is reversed to vasoconstriction following fluid percussion brain injury (FPI). This study investigated the contribution of activation of protein tyrosine kinase (PTK) and the extracellular signal-regulated kinase (ERK) and p38 isoforms of mitogen-activated protein kinase (MAPK) in impaired vasodilation to NMDA after fluid percussion brain injury in pigs equipped with a closed cranial window. NMDA (10(-8), 10(-6) M)-induced vasodilation was reversed to vasoconstriction following fluid percussion brain injury, but such responses were partially restored by genistein (4',5,7-trihydroxy isoflavone), U0126 [1,4-diamino-2,3-dicyano-1,4-bis (0-aminophenylmercapto)butadiene] and SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole], PTK, ERK and p38 MAPK inhibitors (9+/-1% and 16+/-1%, sham control; -6+/-2% and -11+/-3%, fluid percussion brain injury; and 3+/-1% and 6+/-1%, fluid percussion brain injury-genistein, respectively). However, the robustness of the protection to NMDA dilation was significantly greater for U0126 vs. SB203580 (4+/-1% and 7+/-1% vs. 1+/-1% and 1+/-2%). Similar results were observed for glutamate. These data show that PTK, ERK and p38 MAPK activation contribute to impaired NMDA cerebrovasodilation after fluid percussion brain injury. These data suggest that activation of the ERK isoform of MAPK contributes to such impairment more than the p38 MAPK isoform.
Armstead
William M
WM
Department of Anesthesia and Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA. armsteaw@uphs.upenn.edu
D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D008576:Meningeal Arteries / Q000187:drug effects / Q000201:enzymology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016202:N-Methylaspartate / Q000494:pharmacology*; D010841:Pia Mater / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D016202:N-Methylaspartate; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases