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 S₁-S₂ 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.