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, 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.
School of Physiology & Pharmacology and Cardiovascular Research Laboratories, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
Stéphanie C M
SC
Choisy
Andrew F
AF
James
Jules C
JC
Hancox
D000109:Acetylcholine / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D001283:Atrioventricular Node / Q000187:drug effects / Q000502:physiology*; D001514:Bee Venoms / Q000494:pharmacology; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying; D011817:Rabbits; D043585:Receptor, Muscarinic M2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*
D001514:Bee Venoms; D019332:Endothelin-1; D024661:Potassium Channels, Inwardly Rectifying; D043585:Receptor, Muscarinic M2; C029738:tertiapin; D010890:Pirenzepine; D000109:Acetylcholine; C048593:otenzepad