Zhang Weirong, Carreño Flávia R, Cunningham J Thomas, Mifflin Steve W
Dept. of Pharmacology, MSC 7764, UT Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Am J Physiol Regul Integr Comp Physiol. 2008 Nov;295(5):R1555-62. doi: 10.1152/ajpregu.90390.2008. Epub 2008 Sep 10.
Activation of neuronal ATP-sensitive potassium (K(ATP)) channels is an important mechanism that protects neurons and conserves neural function during hypoxia. We investigated hypoxia (bath gassed with 95% N(2)-5% CO(2) vs. 95% O(2)-5% CO(2) in control)-induced changes in K(ATP) current in second-order neurons of peripheral chemoreceptors in the nucleus of the solitary tract (NTS). Hypoxia-induced K(ATP) currents were compared between normoxic (Norm) rats and rats exposed to 1 wk of either chronic sustained hypoxia (CSH) or chronic intermittent hypoxia (CIH). Whole cell recordings of NTS second-order neurons identified after 4-(4-(dihexadecylamino)styryl)-N-methylpyridinium iodide (DiA) labeling of the carotid bodies were obtained in a brain stem slice. In Norm cells (n = 9), hypoxia (3 min) induced an outward current of 12.7 +/- 1.1 pA with a reversal potential of -73 +/- 2 mV. This current was completely blocked by the K(ATP) channel blocker tolbutamide (100 muM). Bath application of the K(ATP) channel opener diazoxide (200 muM, 3 min) evoked an outward current of 21.8 +/- 5.8 pA (n = 6). Hypoxia elicited a significantly smaller outward current in both CSH (5.9 +/- 1.4 pA, n = 11; P < 0.01) and CIH (6.8 +/- 1.7 pA, n = 6; P < 0.05) neurons. Diazoxide elicited a significantly smaller outward current in CSH (3.9 +/- 1.0 pA, n = 5; P < 0.05) and CIH (2.9 +/- 0.9 pA, n = 3; P < 0.05) neurons. Western blot analysis showed reduced levels of K(ATP) potassium channel subunits Kir6.1 and Kir6.2 in the NTS from CSH and CIH rats. These results suggest that hypoxia activates K(ATP) channels in NTS neurons receiving monosynaptic chemoreceptor afferent inputs. Chronic exposure to either sustained or intermittent hypoxia reduces K(ATP) channel function in NTS neurons. This may represent a neuronal adaptation that preserves neuronal excitability in crucial relay neurons in peripheral chemoreflex pathways.
神经元ATP敏感性钾（K(ATP)）通道的激活是一种重要机制，在缺氧期间可保护神经元并维持神经功能。我们研究了缺氧（与对照中用95% O₂ - 5% CO₂ 相比，浴液用95% N₂ - 5% CO₂ 充气）诱导的孤束核（NTS）中周围化学感受器二级神经元K(ATP)电流的变化。比较了常氧（Norm）大鼠与暴露于1周慢性持续性缺氧（CSH）或慢性间歇性缺氧（CIH）的大鼠之间缺氧诱导的K(ATP)电流。在脑干切片中，对经4-(4-(二十六烷基氨基)苯乙烯基)-N-甲基碘化吡啶（DiA）标记颈动脉体后鉴定出的NTS二级神经元进行全细胞记录。在Norm细胞（n = 9）中，缺氧（3分钟）诱导出12.7±1.1 pA的外向电流，反转电位为 -73±2 mV。该电流被K(ATP)通道阻滞剂甲苯磺丁脲（100 μM）完全阻断。浴液中应用K(ATP)通道开放剂二氮嗪（200 μM，3分钟）诱发了21.8±5.8 pA的外向电流（n = 6）。在CSH（5.9±1.4 pA，n = 11；P < 0.01）和CIH（6.8±1.7 pA，n = 6；P < 0.05）神经元中，缺氧诱发的外向电流明显较小。在CSH（3.9±1.0 pA，n = 5；P < 0.05）和CIH（2.9±0.9 pA，n = 3；P < 0.05）神经元中，二氮嗪诱发的外向电流明显较小。蛋白质免疫印迹分析显示，CSH和CIH大鼠的NTS中K(ATP)钾通道亚基Kir6.1和Kir6.2的水平降低。这些结果表明，缺氧激活了接受单突触化学感受器传入输入的NTS神经元中的K(ATP)通道。长期暴露于持续性或间歇性缺氧会降低NTS神经元中K(ATP)通道的功能。这可能代表了一种神经元适应性变化，可在外周化学感受反射通路的关键中继神经元中维持神经元兴奋性。
