Amiodarone's class III effects may be due to inhibition of the cardiac effects of thyroid hormone. If so, amiodarone would not be expected to cause QT prolongation in hypothyroid subjects. The electrocardiographic (ECG) changes induced after treatment with amiodarone were compared in euthyroid and hypothyroid guinea pigs. Hypothyroidism was induced with intraperitoneal (i.p.) administration of 1 mCi I131 (eight animals). Three of these animals also received oral methimazole to block any residual thyroid hormone production. Significant increases in body weight (28 +/- 9%), RR (14 +/- 8%), QT (14 +/- 5%), and QTc (7 +/- 2%) intervals occurred after induced hypothyroidism. Pilot studies with amiodarone treatment for 4 weeks in euthyroid guinea pigs demonstrated that maximal effects on ECG intervals were achieved after 1 week of drug therapy. Therefore, both euthyroid and hypothyroid groups were treated with daily i.p. amiodarone (80 mg/kg) for 7 days. Euthyroid guinea pigs treated with amiodarone had significant increases in RR (33 +/- 10%), QT (31 +/- 15%), and corrected QT (13 +/- 11%) intervals. In contrast, when hypothyroid animals were treated with amiodarone, no statistically significant changes occurred in ECG intervals. Plasma concentrations of amiodarone did not differ between the two groups (0.7 +/- 0.6 vs. 0.7 +/- 0.4 mg/L in hypothyroid and euthyroid groups, respectively). We conclude that intact thyroid function is a prerequisite for class III and sinus node effects of amiodarone in the guinea pig. This implies that at least some of amiodarone's effects are mediated through antagonism of thyroid action.