Vasopressin induced cyclooxygenase dependent superoxide generation contributes to K+ channel function impairment after brain injury

This study determined if vasopressin generates superoxide anion (O-2(-)) 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 O-2(-) 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, 1-(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 O-2(-) 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 O-2(-) generation contributes to K-ATP and K-ca channel function impairment after FPI. (C) 2001 Elsevier Science B.V. All rights reserved.