Vasopressin induced cyclooxygenase dependent superoxide generation contributes to K(+) channel function impairment after brain injury.
This study determined if vasopressin generates superoxide anion (O2(-)) in a cyclooxygenase dependent manner and if such production contributes to impairment of dilation to activators of ATP sensitive K(+) (K(ATP)) and calcium sensitive K(+) (K(ca)) channels following fluid percussion brain injury (FPI) in newborn pigs equipped with closed cranial windows. Superoxide dismutase (SOD) inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O2(-) generation. Under non-brain injury conditions, topical vasopressin (40 pg/ml, the concentration present in CSF following FPI) increased SOD inhibitable NBT reduction from 1+/-1 to 25+/-4 pmol/mm(2). Indomethacin, a cyclooxygenase inhibitor, blunted such NBT reduction (1+/-1 to 5+/-1 pmol/mm(2)), while the vasopressin antagonist, l-(beta-mercapto-beta beta-cyclopentamethylene propionic acid) 2-(o-methyl)-Tyr-AVP (MEAVP) blocked NBT reduction. MEAVP and indomethacin also blunted the NBT reduction observed after FPI. Under non-brain injury conditions, vasopressin (40 pg/ml) coadministered with the K(ATP) and K(ca) channel agonists, cromakalim and NS1619 (10(-8), 10(-6) M) diminished dilation to these K(+) channel agonists while indomethacin partially prevented such impairment (13+/-1 and 23+/-1 vs. 4+/-1 and 10+/-2 vs. 8+/-1 and 19+/-1% for cromakalim in untreated, vasopressin, and vasopressin plus indomethacin treated piglets, respectively). Cromakalim and NS1619 induced pial artery dilation was attenuated following FPI, while indomethacin or MEAVP preadministration partially prevented such impairment (13+/-1 and 23+/-1, sham control; 1+/-1 and 4+/-1, FPI; 8+/-1 and 16+/-3%, FPI-indomethacin pretreated for responses to cromakalim 10(-8), 10(-6) M, respectively). These data show that vasopressin increased O2(-) production in a cyclooxygenase dependent manner and contributed to this production after FPI. These data also show that vasopressin blunted K(ATP) and K(ca) channel mediated cerebrovasodilation in a cyclooxygenase dependent manner. These data suggest that vasopressin induced cyclooxygenase dependent O2(-) generation contributes to K(ATP) and K(ca) channel function impairment after FPI.
Armstead
W M
WM
Department of Anesthesia, University of Pennsylvania, Philadelphia, PA 19104, USA. armsteaw@mail.med.upenn.edu
D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001127:Arginine Vasopressin / Q000031:analogs & derivatives / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001769:Blood / Q000187:drug effects / Q000378:metabolism; D001930:Brain Injuries / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D002545:Brain Ischemia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D019806:Cromakalim / Q000494:pharmacology; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D014667:Vasopressins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001562:Benzimidazoles; D015221:Potassium Channels; D014665:Vasodilator Agents; C089517:vasopressin, 1-(2-mercapto-2,2-(cyclopentamethylene)propionic acid)-2-(O-methyl)Tyr-8-Arg-; D019806:Cromakalim; D014667:Vasopressins; D013481:Superoxides; D001127:Arginine Vasopressin; C086491:NS 1619; D011451:Prostaglandin-Endoperoxide Synthases; D015740:Calcitonin Gene-Related Peptide; D007213:Indomethacin