β-Adrenergic blocking property of dl-sotalol maintains class III efficacy in guinea pig ventricular muscle after isoproterenol

Background: Catecholamines antagonize the efficacy of several class III antiarrhythmic agents. To determine the role of the intrinsic β-adrenergic blocking property of dl-sotalol in maintaining class III efficacy during a high-catecholamine state, we compared the electrophysiological properties of dl-sotalol with those of d-sotalol, which is devoid of significant β- adrenergic blocking effect, before and after isoproterenol infusion. Methods and Results: Action potential duration at 90% repolarization (APD₉₀) was prolonged in isolated guinea pig papillary muscles perfused with d-sotalol and dl-sotalol 10^-4 mol/L over stimulation cycle lengths from 200 to 2000 ms. The increases in APD₉₀ for d-sotalol and dl-sotalol over control were 10.9±2.5 to 23.7±4.8 ms and 27.9±4.0 to 39.0±5.6 ms, respectively. APD₉₀ shortened to less than control in papillary muscles treated with d- sotalol but not dl-sotalol on addition of isoproterenol 10^-6 mol/L: - 31.2±3.5 to -18.3±4.8 ms and 10.5±3.6 to 33.3±7.8 ms, respectively, P<.003. Single guinea pig ventricular myocytes were studied by the whole- cell patch clamp method. Time-dependent (I(out)) and total (I(tot)) outward current in response to a 300-ms pulse to 20 mV and tail current (I(tail)) to -35 mV were measured after Ca²⁺ channel block and Na⁺ channel inactivation. I(out), I(tail), and I(tot) were reduced in myocytes perfused with d-sotalol and dl-sotalol 10^-4 mol/L: I(out), 36.1±4.1%, -40.5±3.3%; I(tail), -59.3±4.6%, -62.2±11.1%; I(tot), -27.3±4.3%, -50.0±11.8%. I(out) and I(tot) increased to a greater degree in myocytes treated with d-sotalol than dl-sotalol on addition of isoproterenol 10^-6 mol/L: I(out), 100.3±20.6%, 11.3±7.6%, P=.002; I(tot), 86.8±39.2%, -41.1±20.9%, P=.01. I(tail) tended to increase more in myocytes treated with d-sotalol than dl- sotalol on addition of isoproterenol, but the difference was not significant (-9.1±13.5%, -28.0±9.0%). Conclusions: The β-adrenergic blocking property of dl-sotalol maintains APD prolongation and repolarizing outward current block during isoproterenol infusion in guinea pig ventricular muscle. Extrapolation of these data to a clinical setting may explain the efficacy of dl-sotalol in diminishing ventricular arrhythmia recurrence.