β-Adrenergic Blocking Property of dl -Sotalol Maintains Class III Efficacy in Guinea Pig Ventricular Muscle After Isoproterenol

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Abstract
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 (APD 90 ) 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 APD 90 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. APD 90 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 Ca 2+ 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.

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