Acute desensitization of acetylcholine and endothelin-1 activated inward rectifier K+ current in myocytes from the cardiac atrioventricular node

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, I-KACh. 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 I-KACh in rabbit single AVN cells was investigated using whole-cell patch clamp at 37 degrees C. 0.1-1 mu M acetylcholine (ACh) rapidly activated a robust I-KACh 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 mu M). During sustained ACh exposure the elicited I-KACh exhibited bi-exponential fade (tau(f) of 2.0 s and tau(s) 76.9 s at - 120 mV; 1 mu M ACh). 10 nM ET-1 elicited a current similar to I-KACh, which faded with a mono-exponential time-course (tau 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. (C) 2012 Elsevier Inc. All rights reserved.