Cyclooxygenase-2-dependent superoxide generation contributes to age-dependent impairment of G protein-mediated cerebrovasodilation.
BACKGROUND
Previous studies have observed that activation of cyclooxygenase-2 contributes to generation of superoxide anion 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 cyclooxygenase-2-dependent superoxide anion generation in such effects as a function of age.


METHODS
Lateral FPI was induced in anesthetized newborn (1-5-day-old) and juvenile (3-4-week-old) pigs equipped with a closed cranial window.


RESULTS
Mastoparan (10(-8), 10(-6) M) elicited pial artery dilation that was blunted more in newborn versus juvenile pigs (9 +/- 1 and 16 +/- 1 vs. 3 +/- 1 and 5 +/- 1%, newborn; 9 +/- 1 and 15 +/- 1 vs. 6 +/- 1 and 9 +/- 1%, juveniles). Similar results were observed for mastoparan-7 but the inactive analog mastoparan-17 had no effect on pial artery diameter. Indomethacin (a cyclooxygenase-1 and cyclooxygenase-2 inhibitor), NS398 (a cyclooxygenase-2 inhibitor), and polyethylene glycol superoxide dismutase and catalase (free radical scavengers) partially restored impaired mastoparan dilation after FPI in the newborn in a roughly equivalent manner but not in the juvenile (3 +/- 1 and 5 +/- 1 vs. 8 +/- 1 and 13 +/- 1% newborn, 6 +/- 1 and 9 +/- 1 vs. 7 +/- 1 and 10 +/- 1% juvenile for NS398 pretreatment).


CONCLUSIONS
These data show that G protein activation elicits cerebrovasodilation that is blunted following FPI in an age-dependent manner, and suggest that cyclooxygenase-2-dependent superoxide anion generation contributes to G protein activation-induced dilator impairment after the insult in an age-dependent manner.
Armstead
William M
WM
Department of Anesthesia, University of Pennsylvania, Philadelphia, 19104, USA. armsteaw@uphs.upenn.edu
D000375:Aging / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001158:Arteries / Q000502:physiology; D001774:Blood Chemical Analysis; D001930:Brain Injuries / Q000503:physiopathology; D002374:Catalase / Q000494:pharmacology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology*; D007213:Indomethacin / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D009578:Nitrobenzenes / Q000494:pharmacology; D010455:Peptides; D037342:Pertussis Toxin / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D013552:Swine; D014664:Vasodilation / Q000502:physiology*; D014862:Wasp Venoms / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016166:Free Radical Scavengers; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D009578:Nitrobenzenes; D010455:Peptides; D013449:Sulfonamides; D014862:Wasp Venoms; D013481:Superoxides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C037500:mastoparan; D002374:Catalase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D013482:Superoxide Dismutase; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D007213:Indomethacin