Abstract
Amiodarone is a widely used antiarrhythmic drug, the mechanisms of action of which remain incompletely understood. Indirect evidence suggests that the class III properties of amiodarone may be mediated by cardiac antithyroid effects. We sought to determine whether the effects of chronic amiodarone on repolarization in guinea pig hearts can be attributed to an antithyroid action by studying the changes in dofetilide-sensitive rapid (IKr) and dofetilide-resistant slow (IKs) delayed rectifier currents, inward rectifier K+ current (IK1), and action potentials of ventricular myocytes from five groups of guinea pigs: control, hypothyroid, amiodarone-treated for 7 days, hypothyroid plus amiodarone, and vehicle (dimethyl sulfoxide) treated. IKs was reduced by amiodarone (to 61% of control, P < .05, at 50 mV) but was more strongly reduced by hypothyroidism (to 35% of control, P < .01, 50 mV). Amiodarone significantly reduced IKr andIK1 (by 55 and 64% at 10 mV and −50 mV, respectively), which were unaffected by hypothyroidism. Amiodarone alone and hypothyroidism alone had similar action potential-prolonging actions. Hypothyroid animals treated with amiodarone showed a combination of ionic effects (strong IKsreduction, similar to hypothyroidism alone; reducedIKr and IK1, similar to amiodarone alone), along with action potential prolongation significantly greater than that caused by either intervention alone. We conclude that chronic amiodarone and hypothyroidism have different effects on ionic currents and that their combination prolongs action potential duration to a greater extent than either alone in guinea pig hearts, suggesting that the class III actions of amiodarone are not mediated by a cardiac hypothyroid state.
Footnotes
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Send reprint requests to: Dr. Stanley Nattel, M.D., Research Center, Montreal Heart Institute, 5000 Bélanger Street East, Montreal, Quebec, Canada H1T 1C8. E-mail:nattel{at}icm.umontreal.ca
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↵1 This work was supported by grants from the Medical Research Council of Canada, the Quebec Heart Foundation, and the Fonds de Recherche de l’Institut de Cardiologie de Montréal. Dr. Bosch is a fellow of the Deutsche Forschungsgemeinschaft, Dr. Li held a research scholarship of the Fonds de la Recherche en Santé du Québec, and Dr. Gaspo was a fellow of the Medical Research Council of Canada and the Pharmaceutical Manufacturers Association of Canada (MRC-PMAC fellow).
- Abbreviations:
- APD
- action potential duration
- APD90
- action potential duration to 90% repolarization
- DMSO
- dimethyl sulfoxide
- PTU
- propylthiouracil
- IKr
- rapid component of delayed rectifier current
- IKs
- slow component of delayed rectifier current
- IK1
- inward rectifier current
- Ito
- transient outward current
- RS
- series resistance
- Received July 24, 1998.
- Accepted November 2, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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