Endothelin production links superoxide generation to altered opioid-induced pial artery vasodilation after brain injury in pigs
Endothelin production links superoxide generation to altered opioid-induced pial artery vasodilation after brain injury in pigs
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DOI：
10.1161/01.str.28.1.190
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发表时间：
1997-01-01
期刊：
影响因子：
8.3
通讯作者：
Armstead, WM
中科院分区：
文献类型：
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作者：
Kasemsri, T;Armstead, WM
背景和目的 创伤性脑损伤给婴儿和儿童带来显着的发病率和死亡率。在新生猪中，阿片类药物会导致液体冲击损伤 (FPI) 后软脑膜动脉血管收缩。 FPI 减弱甲硫氨酸脑啡肽 (Met) 和亮氨酸脑啡肽 (Leu) 的血管舒张作用和 cGMP 产生，并将强啡肽 (Dyn) 从扩张剂逆转为收缩剂。超氧阴离子 (O-2(-)) 的产生导致 FPI 后脑血流动力学改变，O-2(-) 清除剂部分恢复 FPI 后降低的扩张器反应。内皮素-1 (ET-1) 据称是脑血管痉挛的介质，已被认为可以改变一氧化氮功能和 cGMP 浓度。本研究旨在确定 ET-1 对 FPI 后阿片类药物引起的扩张改变的贡献，以及 O-2(-) 在这种改变的反应中的作用。 方法 采用侧向 FPI 技术，对配备封闭颅窗的麻醉新生猪产生中等严重程度的损伤（1.9 至 2.3 atm）。超氧化物歧化酶 (SOD) 抑制的硝基蓝四唑 (NBT) 减少被确定为 O-2(-) 生成的指标。结果 FPI 将脑脊液 ET-1 从 20+/-2 增加到 93+/-6 pg/mL（大约 10(-10) mol/L）。局部 ET-1 (10(-10) mol/L) 可使 SOD 抑制的 NBT 减少从 1+/-1 增加至 16+/-3 pmol/mm(2)，类似于之前报道的 FPI 后 NBT 减少 (14+/-2 pmol/mm(2))。 BQ123 (10(-6) mol/L) 是一种 ET-1 拮抗剂，可减弱 FPI 后观察到的 NET 减少 (4+/-1 pmol/mm(2))。 Met 产生的软脑膜血管舒张作用被 FPI 减弱，并被 BQ123 预处理部分恢复（对于 10(-10)、10(-8) 和 10(-6)，7+/-1%、11+/-1% 和 17+/-1% 对比 3+/-1%、6+/-1% 和 9+/-2% 对比 5+/-1%、9+/-1% 和 14+/-2%分别在对照条件期间、FPI 后以及用 BQ123 预处理 FPI 后的 mol/L Met）。 Met 诱导的扩张与脑脊液 cGMP 增加相关，这些生化变化同样被 FPI 减弱，并被 BQ123 部分恢复（357+/-12、455+/-15、500+/-19 和 632+/-11 对比 264+/-4、267+/-4、295+/-12 和 305+/-15 对比 309+/-19，静息条件下为 432+/-11、529+/-10 和 593+/-4 pg/mL，对照条件下、FPI 后和用 BQ123 预处理 FPI 后分别为 10(-10)、10(-8) 和 10(-6) mol/L Met。 Leu 和 Dyn 也观察到类似的血管和生化参数部分恢复。 结论 这些数据表明 ET-1 的浓度与 FPI 后脑脊液中的浓度相似，可增加 O-2(-) 的产生。这些数据还表明，在 FPI 后，通过 ET-1 受体阻断，阿片类药物诱导的血管舒张和 cGMP 产生部分恢复。这些数据表明，ET-1 至少部分通过增加 O-2(-) 的产生来改变 FPI 后的脑血流动力学。
Background and Purpose Traumatic brain injury conveys significant morbidity and mortality to infants and children. In the newborn pig, opioids contribute to pial artery vasconstriction after fluid percussion injury (FPI). FPI attenuates vasodilation and cGMP production by methionine enkephalin (Met) and leucine enkephalin (Leu) and reverses dynorphin (Dyn) from a dilator to a constrictor. Superoxide anion (O-2(-)) production contributes to altered cerebral hemodynamics after FPI, and O-2(-) scavengers partially restore decreased dilator responses after FPI. Endothelin-1 (ET-1), a purported mediator of cerebral vasospasm, has been suggested to alter nitric Oxide function and cGMP concentration. The present study was designed to determine the contribution of ET-1 to altered opioid-induced dilation after FPI and the role of O-2(-) in such altered responses.Methods Injury of moderate severity (1.9 to 2.3 atm) was produced by the lateral FPI technique in anesthetized newborn pigs equipped with a closed cranial window. Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O-2(-) generation.Results FPI increased cerebrospinal fluid ET-1 from 20+/-2 to 93+/-6 pg/mL (approximate to 10(-10) mol/L). Topical ET-1 (10(-10) mol/L) increased SOD-inhibitable NBT reduction from 1+/-1 to 16+/-3 pmol/mm(2), similar to previously reported NBT reduction after FPI(14+/-2 pmol/mm(2)). BQ123 (10(-6) mol/L), an ET-1 antagonist, blunted the NET reduction observed after FPI (4+/-1 pmol/mm(2)). Met produced pial vasodilation that was attenuated by FPI and partially restored by BQ123 pretreatment (7+/-1%, 11+/-1%, and 17+/-1% versus 3+/-1%, 6+/-1%, and 9+/-2% versus 5+/-1%, 9+/-1%, and 14+/-2% for 10(-10), 10(-8), and 10(-6) mol/L Met during control conditions, after FPI, and after FPI pretreated with BQ123, respectively). Met-induced dilation was associated with increased cerebrospinal fluid cGMP, and these biochemical changes were likewise blunted by FPI and partially restored by BQ123 (357+/-12, 455+/-15, 500+/-19, and 632+/-11 versus 264+/-4, 267+/-4, 295+/-12, and 305+/-15 versus 309+/-19, 432+/-11, 529+/-10, and 593+/-4 pg/mL for resting conditions, 10(-10), 10(-8) and 10(-6) mol/L Met during control conditions,after FPI, and after FPI pretreated with BQ123, respectively). Similar partial restoration of vascular and biochemical parameters was observed for Leu and Dyn.Conclusions These data show that ET-1, in concentrations similar to that present in cerebrospinal fluid after FPI, increases O-2(-) production. These data also indicate the opioid-induced vasodilation and cGMP production are partially restored after FPI by ET-1 receptor blockade. These data suggest that ET-1 contributes to altered cerebral hemodynamics after FPI, at least in part, through elevated O-2(-) production.