School of Physiology & Pharmacology and Cardiovascular Research Laboratories, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
Biochem Biophys Res Commun. 2012 Jul 6;423(3):496-502. doi: 10.1016/j.bbrc.2012.05.148. Epub 2012 Jun 5.
The atrioventricular node (AVN) is a vital component of the pacemaker-conduction system of the heart, co-ordinating conduction of electrical excitation from cardiac atria to ventricles and acting as a secondary pacemaker. The electrical behaviour of the AVN is modulated by vagal activity via activation of muscarinic potassium current, IKACh. However, it is not yet known if this response exhibits 'fade' or desensitization in the AVN, as established for the heart's primary pacemaker--the sinoatrial node. In this study, acute activation of IKACh in rabbit single AVN cells was investigated using whole-cell patch clamp at 37 °C. 0.1-1 μM acetylcholine (ACh) rapidly activated a robust IKACh in AVN myocytes during a descending voltage-ramp protocol. This response was inhibited by tertiapin-Q (TQ; 300 nM) and by the M2 muscarinic ACh receptor antagonist AFDX-116 (1 μM). During sustained ACh exposure the elicited IKACh exhibited bi-exponential fade (τf of 2.0 s and τs 76.9 s at -120 mV; 1 μM ACh). 10 nM ET-1 elicited a current similar to IKACh, which faded with a mono-exponential time-course (τ of 52.6 s at -120 mV). When ET-1 was applied following ACh, the ET-1 activated response was greatly attenuated, demonstrating that ACh could desensitize the response to ET-1. For neither ACh nor ET-1 was the rate of current fade dependent upon the initial response magnitude, which is inconsistent with K+ flux mediated changes in electrochemical driving force as the underlying mechanism. Collectively, these findings demonstrate that TQ sensitive inwardly rectifying K+ current in cardiac AVN cells, elicited by M2 muscarinic receptor or ET-1 receptor activation, exhibits fade due to rapid desensitization.
房室结（AVN）是心脏起搏-传导系统的重要组成部分，协调来自心房的电兴奋向心室的传导，并充当次级起搏点。AVN 的电行为通过激活毒蕈碱型钾电流 IKACh 来调节迷走神经活动。然而，目前尚不清楚 AVN 中的这种反应是否表现出“衰减”或脱敏，就像心脏的主要起搏点——窦房结一样。在这项研究中，使用全细胞膜片钳在 37°C 下研究了兔单个 AVN 细胞中 IKACh 的急性激活。在下降电压 ramp 方案中，0.1-1 μM 乙酰胆碱（ACh）迅速激活 AVN 心肌细胞中的强大 IKACh。该反应被 tertiapin-Q（TQ；300 nM）和 M2 毒蕈碱 ACh 受体拮抗剂 AFDX-116（1 μM）抑制。在持续 ACh 暴露期间，诱发的 IKACh 表现出双指数衰减（-120 mV 时 τf 为 2.0 s，τs 为 76.9 s；1 μM ACh）。10 nM ET-1 引起的电流类似于 IKACh，其衰减具有单指数时间过程（-120 mV 时 τ 为 52.6 s）。当 ACh 后应用 ET-1 时，ET-1 激活的反应大大减弱，表明 ACh 可以使对 ET-1 的反应脱敏。对于 ACh 或 ET-1，电流衰减的速度都不依赖于初始反应幅度，这与电化学驱动力变化引起的 K+ 通量变化作为潜在机制不一致。总的来说，这些发现表明，由 M2 毒蕈碱受体或 ET-1 受体激活引起的心脏 AVN 细胞中的 TQ 敏感内向整流 K+ 电流表现出衰减，这是由于快速脱敏所致。
