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d-Sotalol Induces Marked Action Potential Prolongation and Early Afterdepolarizations in M but Not Epicardial or Endocardial Cells of the Canine Ventricle

Laboratorio de Electrofisiologia Celular, Divison Cardiologia, Hospital Ramos Mejia, Buenos Aires, Argentina

Sandra Moro

Laboratorio de Electrofisiologia Celular, Divison Cardiologia, Hospital Ramos Mejia, Buenos Aires, Argentina

Marcelo V. Elizari

Laboratorio de Electrofisiologia Celular, Divison Cardiologia, Hospital Ramos Mejia, Buenos Aires, Argentina

Background: Despite its class III antiarrhythmic actions, experimental and clinical studies have shown that d-sotalol can also be proarrhythmic; a recent clinical trial that evaluated d- sotalol in postmyocardial patients (SWORD) had to be prematurely interrupted because of the excess mortality in the treated group. Previous studies have demonstrated the existence of a marked heterogeneity across the ventricular wall; epicardial, endocardial, and M cells have been shown to display distinct electrophysiologic characteristics and pharmacologic behav ior. The present study was designed to test the hypothesis that M cells are the primary target for the class III actions of d-sotalol in canine ventricular myocardium and may contribute to its proarrhythmic effects.

Methods and Results: We used standard microelectrode techniques to record transmem brane activity from endocardial, epicardial, midmyocardial, and transmural strips isolated from the canine left ventricle. d-Sotalol (100 µM, 60 minutes of exposure, [K+]o = 4 mM) prolongs the action potential in the three cell types, but more so in M than epicardial or endo cardial cells, especially at the slower rates. At a basic cycle length of 2000 ms, action poten tial duration after 90% repolarization increases from 199 ± 20 to 247.5 ± 28 ms in epi cardium (n = 10), from 212 ± 26 to 274 ± 27 ms in endocardium (n = 11), and from 309 ± 65 to 533 ± 207 ms in M cells (n = 13). d-Sotalol produces a marked steepening of action potential duration-rate relationships of M cells and an upward shift of restitution of action potential duration curves, more accentuated in M cells. Early afterdepolarizations were observed at slow rates (basic cycle lengths > 1000 ms) in 7 of 13 M cell preparations (54%) but not in endocardial or epicardial preparations. A sudden acceleration of the rate could also induce a transient prolongation of the action potential and early afterdepolarization activity. Conclusion: In canine ventricular tissues, d-sotalol manifests its class III effects preferen tially in the M cells, leading to the development of early afterdepolarizations and a marked increase in transmural dispersion of repolarization. The data suggest an important role of M cells in the proarrhythmic effects of the drug.

Key Words: cardiac electrophysiology • cardiac arrhythmias • sotalol • d-sotalol • M cells • epi cardium • endocardium • early afterdepolarization • triggered activity.

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 2, No. 1, 27-37 (1997)
DOI: 10.1177/107424849700200104


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