title: Beta-adrenergic blocking property of dl-sotalol maintains class III efficacy in guinea pig ventricular muscle after isoproterenol.
abstract: BACKGROUND
  Catecholamines antagonize the efficacy of several class III antiarrhythmic agents. To determine the role of the intrinsic beta-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 beta-adrenergic blocking effect, before and after isoproterenol infusion.
  
  
  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 (Iout) and total (Itot) outward current in response to a 300-ms pulse to 20 mV and tail current (Itail) to -35 mV were measured after Ca2+ channel block and Na+ channel inactivation. Iout, Itail, and Itot were reduced in myocytes perfused with d-sotalol and dl-sotalol 10(-4) mol/L: Iout, -36.1 +/- 4.1%, -40.5 +/- 3.3%; Itail, -59.3 +/- 4.6%, -62.2 +/- 11.1%; Itot, -27.3 +/- 4.3%, -50.0 +/- 11.8%. Iout and Itot increased to a greater degree in myocytes treated with d-sotalol than dl-sotalol on addition of isoproterenol 10(-6) mol/L: Iout, 100.3 +/- 20.6%, 11.3 +/- 7.6%, P = .002; Itot, 86.8 +/- 39.2%, -41.1 +/- 20.9%, P = .01. Itail 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 beta-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.
authors: Department of Medicine, Oregon Health Sciences University, Portland 97201-3098.
authors: W J
authors: WJ
authors: Groh
authors: K J
authors: KJ
authors: Gibson
authors: J H
authors: JH
authors: McAnulty
authors: J G
authors: JG
authors: Maylie
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D006168:Guinea Pigs; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D010210:Papillary Muscles / Q000187:drug effects*; D013015:Sotalol / Q000494:pharmacology*; D016276:Ventricular Function
chemical_list: D000319:Adrenergic beta-Antagonists; D013015:Sotalol; D007545:Isoproterenol