Block of IKs by the diuretic agent indapamide modulates cardiac electrophysiological effects of the class III antiarrhythmic drug dl-sotalol.
Indapamide is a diuretic agent with direct electrophysiological effects on ionic currents involved in cardiac repolarization. In particular, indapamide blocks the slow component of delayed rectifier potassium current. In contrast, most class III antiarrhythmic agents, such as dl-sotalol, block the rapid component of delayed rectifier potassium current. Computer simulations have suggested potentiation of drug effects on cardiac repolarization by the combined block of the rapid component of delayed rectifier potassium current and the slow component of delayed rectifier potassium current. Therefore, the objective of our study was to evaluate the modulation of cardiac electrophysiological effects of dl-sotalol by indapamide. Two indices of cardiac repolarization, monophasic action potential duration at 90% repolarization and effective refractory period, at two basic cycle lengths (800 and 400 msec) were determined in 24 anesthetized open-chest dogs. In two treatment groups (n = 6/group), data were obtained at base line and every 2 min during steadily increasing concentrations of dl-sotalol (0-40 microg/ml) either alone or in the presence of indapamide (500 ng/ml). Data were also obtained in dogs receiving either a low-dose (500 ng/ml) or a high-dose (up to 7.5 microg/ml) infusion regimen of indapamide alone. Administration of dl-sotalol was associated with concentration-dependent increases in monophasic action potential duration at 90% repolarization and effective refractory period, whereas repolarization was only slightly altered by the administration of indapamide alone. However, concentration-response curves of dl-sotalol were shifted to the left in dogs treated with the combination of dl-sotalol and indapamide, and the EC50 values of dl-sotalol estimated for the prolongation of monophasic action potential duration at 90% repolarization and effective refractory period were decreased 3-fold during the coadministration of both drugs (P < .05 vs. dl-sotalol alone). Thus, under conditions of normal K+ levels, clinically relevant concentrations of indapamide modulate dl-sotalol effects on cardiac repolarization. Additional block of cardiac K+ currents, especially the rapid component of delayed rectifier potassium current and the slow component of delayed rectifier potassium current could explain these observations.
Fiset
C
C
Quebec Heart Institute, Laval Hospital and Faculty of Pharmacy, Laval University, Sainte-Foy, Canada.
Drolet
B
B
Hamelin
B A
BA
Turgeon
J
J
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004232:Diuretics / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007190:Indapamide / Q000494:pharmacology*; D008297:Male; D026902:Potassium Channel Blockers; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013015:Sotalol / Q000493:pharmacokinetics / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D004232:Diuretics; D026902:Potassium Channel Blockers; D013015:Sotalol; D007190:Indapamide