Electrophysiologic effects of chronic amiodarone therapy and hypothyroidism, alone and in combination, on guinea pig ventricular myocytes

Amiodarone is a widely used antiarrhythmic drug, the mechanisms of action o f 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 o n repolarization in guinea pig hearts can be attributed to an antithyroid a ction by studying the changes in dofetilide-sensitive rapid (I-Kr) and dofe tilide-resistant slow (I-Ks) delayed rectifier currents, inward rectifier K + current (I-Kl), and action potentials of ventricular myocytes from five g roups of guinea pigs: control, hypothyroid, amiodarone-treated for 7 days, hypothyroid plus amiodarone, and vehicle (dimethyl sulfoxide) treated. I-Ks was reduced by amiodarone (to 61% of control, P < .05, at 50 mV) but was m ore strongly reduced by hypothyroidism (to 35% of control, P < .01, 50 mV). Amiodarone significantly reduced I-Kr and I-Kl (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 act ions. Hypothyroid animals treated with amiodarone showed a combination of i onic effects (strong I-Ks reduction, similar to hypothyroidism alone; reduc ed I-Kr and I-Kl, 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 differe nt effects on ionic currents and that their combination prolongs action pot ential 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.