Endothelin-induced cyclooxygenase-dependent superoxide generation contributes to K+ channel functional impairment after brain injury
Endothelin-induced cyclooxygenase-dependent superoxide generation contributes to K+ channel functional impairment after brain injury
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DOI：
10.1089/08977150152693737
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发表时间：
2001-10-01
影响因子：
4.2
通讯作者：
Armstead, WM
中科院分区：
文献类型：
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作者：
Armstead, WM
本研究确定了内皮素（ET-1）是否以环加氧酶依赖的方式产生超氧阴离子（O-2（-）），以及这种产生是否有助于损害液体冲击脑损伤（FPI）后的ATP敏感性K+（K-ATP）和钙敏感性K+（K-ATP）通道激活剂的扩张。以超氧化物歧化酶（SOD）-硝基四氮唑蓝（NBT）还原反应为指标，测定了O-2（-）的产生。在非脑损伤条件下，局部ET-1（10（-10）M，FPI后CSF中的浓度）可使SOD可降解NBT的减少从1 +/- 1增加到17 +/- 3 pmol/mm（2）。环氧化酶抑制剂吲哚美辛可抑制NBT的减少（1 +/- 1至4 +/- 1 pmol/mm 2），而ET-1拮抗剂BQ 123可阻断NBT的减少。BQ 123和吲哚美辛也减弱了FPI后观察到的NBT减少。在非脑损伤条件下，ET-1（10（-10）M）与K-ATP和K-Ca通道激动剂cromakalim和NS 1619（10（-8），10（-6）M）联合给药可减少这些K+通道激动剂的扩张，而吲哚美辛可部分预防这种损害（未处理、ET-1和ET-1+吲哚美辛处理仔猪中色满卡林分别为13 +/- 1和23 +/-1 vs. 2 +/- 1和6 +/- 1 vs. 6 +/- 1和14 +/- 2%）。Cromakalim和NS 1619诱导的软脑膜动脉扩张在FPI后减弱，而吲哚美辛或BQ 123预给药部分防止了这种损伤（13 +/-1和23 +/-1，假手术对照; 1 +/-1和4 +/-1，FPI;分别为8 +/- 1和16 +/-3%，FPI和吲哚美辛预处理对克罗卡林10（-8）和10（-6）M的反应）。这些数据表明，ET-1增加O-2（-）的生产在环氧化酶依赖性的方式，并有助于这种生产后FPI。这些数据还表明ET-1以环氧合酶依赖性方式减弱K-ATP和K-Ca通道介导的血管舒张。这些数据表明，ET-1诱导的环氧合酶依赖性O-2（-）的产生有助于FPI后K-ATP和K-Ca通道功能受损。
This study determined if endothelin (ET-1) 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-ATP) 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 ET-1 (10(-10) M, the concentration present in CSF following FPI) increased SOD-inhibitable NBT reduction from 1 +/- 1 to 17 +/- 3 pmol/mm(2). Indomethacin, a cyclooxygenase inhibitor, blunted such NBT reduction (1 +/- 1 to 4 +/- 1 pmol/mm(2)), while the ET-1 antagonist BQ123 blocked NBT reduction. BQ123 and indomethacin also blunted the NBT reduction observed after FPI. Under non-brain injury conditions, ET-1 (10(-10) M) 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. 2 +/- 1 and 6 +/- 1 vs. 6 +/- 1 and 14 +/- 2% for cromakalim in untreated, ET-1, and ET-1 plus indomethacin-treated piglets, respectively). Cromakalim- and NS1619-induced pial artery dilation was attenuated following FPI, while indomethacin or BQ123 preadministration partially prevented such impairment (13 +/- 1 and 23 +/- 1, sham control; 1 +/- 1 and 4 +/- 1, FPI; 8 +/- 1 and 16 +/- 3%, FPI and indomethacin-pretreated for responses to cromakalim 10(-8), 10(-6) M, respectively). These data show that ET-1 increased O-2(-) production in a cyclooxygenase-dependent manner and contributed to this production after FPI. These data also show that ET-1 blunted K-ATP and K-ca channel-mediated cerebrovasodilation in a cyclooxygenase dependent manner. These data suggest that ET-1-induced cyclooxygenase-dependent O-2(-) generation contributes to K-ATP and K-ca channel function impairment after FPI.