Beta-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 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.
Groh
W J
WJ
Department of Medicine, Oregon Health Sciences University, Portland 97201-3098.
Gibson
K J
KJ
McAnulty
J H
JH
Maylie
J G
JG
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
D000319:Adrenergic beta-Antagonists; D013015:Sotalol; D007545:Isoproterenol