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

AbstractThe 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. 0.1–1μM acetylcholine (ACh) rapidly activated a robust IKACh in AVN myocytes during a descending voltage-ramp protocol. This response was inhibited by tertiapin-Q (TQ; 300nM) and by the M2 muscarinic ACh receptor antagonist AFDX-116 (1μM). During sustained ACh exposure the elicited IKACh exhibited bi-exponential fade (τf of 2.0s and τs 76.9s at −120mV; 1μM ACh). 10nM ET-1 elicited a current similar to IKACh, which faded with a mono-exponential time-course (τ of 52.6s at −120mV). 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

Activation of Glibenclamide-Sensitive ATP-Sensitive K+ Channels During β-Adrenergically Induced Metabolic Stress Produces a Substrate for Atrial Tachyarrhythmia

Background— Cardiac ATP-sensitive K + channels have been suggested to contribute to the adaptive physiological response to metabolic challenge after β-adrenoceptor stimulation. However, an increased atrial K + -conductance might be expected to be proarrhythmic. We investigated the effect of ATP-sensitive K + channel blockade on the electrophysiological responses to β-adrenoceptor-induced metabolic challenge in intact atria. Methods and Results— Atrial electrograms were recorded from the left atrial epicardial surface of Langendorff-perfused rat hearts using a 5×5 electrode array. Atrial effective refractory period and conduction velocity were measured using an S 1 –S 2 protocol. The proportion of hearts in which atrial tachyarrhythmia was produced by burst-pacing was used as an index of atrial tachyarrhythmia-inducibility. Atrial nucleotide concentrations were measured by high performance liquid chromatography. Perfusion with ≥10 –9 mol/L of the β-adrenoceptor agonist, isoproterenol (ISO), resulted in a concentration-dependent reduction of atrial effective refractory period and conduction velocity. The ISO-induced changes produced a proarrhythmic substrate such that atrial tachyarrhythmia could be induced by burst-pacing. Atrial [ATP] was significantly reduced by ISO (10 –6 mol/L). Perfusion with either of the ATP-sensitive K + channel blockers, glibenclamide (10 –5 mol/L) or tolbutamide (10 –3 mol/L), in the absence of ISO had no effect on basal atrial electrophysiology. On the other hand, the proarrhythmic substrate induced by 10 –6 mol/L ISO was abolished by either of the sulfonylureas, which prevented induction of atrial tachyarrhythmia. Conclusions— Atrial ATP-sensitive K + channels activate in response to β-adrenergic metabolic stress in Langendorff-perfused rat hearts, resulting in a proarrhythmic substrate. </jats:sec