Abstract
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 asdl-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 ofdl-sotalol (0–40 μg/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 μg/ml) infusion regimen of indapamide alone. Administration ofdl-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 ofdl-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.
Footnotes
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Send reprint requests to: Dr. Jacques Turgeon, Ph.D., Centre de recherche, Hôpital Laval, 2725 Chemin Ste-Foy, Sainte-Foy, Québec, Canada, G1V 4G5.
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↵1 This study was supported by the Medical Research Council of Canada (MT-11876) and by the Heart and Stroke Foundation of Canada (Québec). J.T. is the recipient of a scholarship from the Joseph C. Edwards Foundation. B.A.H. is the recipient of a scholarship from the Fonds de la Recherche en Santé du Québec. During the course of this study, C.F. was the recipient of a studentship from the Medical Research Council and Pharmaceutical Manufacturers Association of Canada. B.D. is the recipient of studentships from Merck Frosst Canada and the Fonds pour la Formation de Chercheurs et l’Aide àla Recherche (FCAR).
- Abbreviations:
- BCL400
- a basic cycle length of stimulation of 400 msec
- BCL800
- a basic cycle length of stimulation of 800 msec
- EADs
- early afterdepolarizations
- ERP
- effective refractory period
- IK
- delayed rectifier potassium current
- IKr
- the rapid component of IK
- IKs
- the slow component of IK
- MAPD90
- monophasic action potential duration at 90% repolarization
- Received December 12, 1996.
- Accepted June 25, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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