Role of sarcolemmal ATP-sensitive K+ channels in the regulation of sinoatrial node automaticity:: an evaluation using Kir6.2-deficient mice
Role of sarcolemmal ATP-sensitive K+ channels in the regulation of sinoatrial node automaticity:: an evaluation using Kir6.2-deficient mice
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DOI：
10.1113/jphysiol.2007.148932
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发表时间：
2008-06-01
影响因子：
5.5
通讯作者：
Nakaya, Haruaki
中科院分区：
文献类型：
--
作者：
Fukuzaki, Koichi;Sato, Toshiaki;Nakaya, Haruaki
心肌肌膜ATP敏感性K（+）（K（ATP））通道在调节窦房结（SAN）自律性中的作用尚不明确。利用Kir6.2（心脏K（ATP）通道的成孔亚基）基因纯合敲除（KO）小鼠，我们研究了缺氧时SAN细胞中K（ATP）通道的病理生理作用。Langendorff灌注的小鼠心脏暴露于缺氧和无葡萄糖条件（缺氧）。缺氧5分钟后，野生型（WT）心脏的窦性周期长度（CL）从207 +/- 10延长至613 +/- 84 ms（P < 0.001）。在Kir6.2 KO心脏中，CL从198 +/- 17略微延长至265 +/- 32 ms。在电流钳模式中记录的WT SAN细胞的自发动作电位的CL从410 +/- 56显著延长至605 +/- 108 ms（n = 6，P < 0.05），在应用K（+）通道开放剂吡那地尔（100 μ M）后舒张期去极化（SDD）的斜率降低。吡那地尔诱导格列本脲（1 μ M）敏感的外向电流，这是记录在电压钳模式，只有在WT SAN细胞。在2，4-二硝基苯酚的代谢抑制过程中，WT SAN细胞的CL从292 +/- 38延长至585 +/- 91 ms（P < 0.05），SDD降低，但Kir6.2 KO SAN细胞没有。在短期代谢抑制后，通过fluo-3荧光测量的舒张期Ca（2+）浓度在WT SAN细胞中降低，但在Kir6.2 KO SAN细胞中升高。总之，本研究使用Kir6.2 KO小鼠表明，在缺氧期间，在SAN细胞中的肌膜K（ATP）通道的激活抑制SAN自律性，这是重要的SAN细胞的保护。
The role of cardiac sarcolemmal ATP-sensitive K(+) (K(ATP)) channels in the regulation of sinoatrial node (SAN) automaticity is not well defined. Using mice with homozygous knockout (KO) of the Kir6.2 (a pore-forming subunit of cardiac K(ATP) channel) gene, we investigated the pathophysiological role of K(ATP) channels in SAN cells during hypoxia. Langendorff-perfused mouse hearts were exposed to hypoxic and glucose-free conditions (hypoxia). After 5 min of hypoxia, sinus cycle length (CL) was prolonged from 207 +/- 10 to 613 +/- 84 ms (P < 0.001) in wild-type (WT) hearts. In Kir6.2 KO hearts, CL was slightly prolonged from 198 +/- 17 to 265 +/- 32 ms. The CL of spontaneous action potentials of WT SAN cells, recorded in the current-clamp mode, was markedly prolonged from 410 +/- 56 to 605 +/- 108 ms (n = 6, P < 0.05) with a decrease of the slope of the diastolic depolarization (SDD) after the application of the K(+) channel opener pinacidil (100 mu M). Pinacidil induced a glibenclamide (1 mu M)-sensitive outward current, which was recorded in the voltage-clamp mode, only in WT SAN cells. During metabolic inhibition by 2,4-dinitrophenol, CL was prolonged from 292 +/- 38 to 585 +/- 91 ms (P < 0.05) with a decrease of SDD in WT SAN cells but not in Kir6.2 KO SAN cells. Diastolic Ca(2+) concentration, measured by fluo-3 fluorescence, was decreased in WT SAN cells but increased in Kir6.2 KO SAN cells after short-term metabolic inhibition. In conclusion, the present study using Kir6.2 KO mice indicates that, during hypoxia, activation of sarcolemmal K(ATP) channels in SAN cells inhibits SAN automaticity, which is important for the protection of SAN cells.