Wickman K, Nemec J, Gendler S J, Clapham D E
Department of Cardiology, Harvard Medical School, Children's Hospital, Boston, Massachusetts 02115, USA.
Neuron. 1998 Jan;20(1):103-14. doi: 10.1016/s0896-6273(00)80438-9.
Acetylcholine (ACh) released from the stimulated vagus nerve decreases heart rate via modulation of several types of ion channels expressed in cardiac pacemaker cells. Although the muscarinic-gated potassium channel I(KACh) has been implicated in vagally mediated heart rate regulation, questions concerning the extent of its contribution have remained unanswered. To assess the role of I(KACh) in heart rate regulation in vivo, we generated a mouse line deficient in I(KACh) by targeted disruption of the gene coding for GIRK4, one of the channel subunits. We analyzed heart rate and heart rate variability at rest and after pharmacological manipulation in unrestrained conscious mice using electrocardiogram (ECG) telemetry. We found that I(KACh) mediated approximately half of the negative chronotropic effects of vagal stimulation and adenosine on heart rate. In addition, this study indicates that I(KACh) is necessary for the fast fluctuations in heart rate responsible for beat-to-beat control of heart activity, both at rest and after vagal stimulation. Interestingly, noncholinergic systems also appear to modulate heart activity through I(KACh). Thus, I(KACh) is critical for effective heart rate regulation in mice.
刺激迷走神经释放的乙酰胆碱（ACh）通过调节心脏起搏细胞中表达的几种离子通道来降低心率。虽然毒蕈碱门控钾通道I（KACh）参与迷走神经介导的心率调节，但关于其作用程度的问题仍未得到解答。为了评估I（KACh）在体内心率调节中的作用，我们通过靶向破坏编码通道亚基之一GIRK4的基因，生成了I（KACh）缺陷的小鼠品系。我们使用心电图（ECG）遥测技术，分析了无束缚清醒小鼠在静息状态下以及药理操作后的心率和心率变异性。我们发现，I（KACh）介导了迷走神经刺激和腺苷对心率产生的约一半负性变时作用。此外，本研究表明，I（KACh）对于静息状态下以及迷走神经刺激后负责心脏活动逐搏控制的心率快速波动是必需的。有趣的是，非胆碱能系统似乎也通过I（KACh）调节心脏活动。因此，I（KACh）对小鼠有效的心率调节至关重要。
