Evidences of antagonism between amiodarone and triiodothyronine on the K+ channel activities of cultured rat cardiomyocytes

Effects of acute and chronic treatments with amiodarone, both in the presence and the absence of exogenous triiodothyronine (T-3), on repolarizing outward K+ currents were investigated by patch-clamp technique in cultured newborn rat ventricular cells. Acute exposure to amiodarone dose-dependently inhibited the transient outward (I(o)mega, IC50 = 4.9 mu M) and the steady-state outward (I-K, IC50 = 6.3 mu M) K+ currents. The dose-response curve of this acute inhibitory action was unaffected by the presence of T-3. When amiodarone was applied chronically, 72-h exposure to a low dose of the drug (1 mu M) significantly decreased the current densities of I-to and I-K for the cells cultured in a serum-supplemented medium containing 0.12 nM T-3. In a serum-free medium without T-3, chronic amiodarone treatment revealed null effect on either I-to or I-K. In addition, 72-h in-vitro treatment with T-3 enhanced the current densities of both I-to (EC50=0.13 nM) and I-K (EC50=0.33 nM). Concentration-response analysis indicated that amiodarone (1 mu M) showed competitive inhibition towards the action of T-3 on I-to but noncompetitive inhibition towards the action of T-3 on I-K. These results suggest that different ionic mechanisms are produced by acute and long-term treatments with amiodarone. The latter showed T-3-dependent inhibition of cardiac I-to and I-K. When chronically administered, amiodarone may antagonize T-3 and thereby counteract its hormonal effect on K+ channels. This implies that, at the myocyte level, antagonism of the action of thyroid hormones in K+ channel activities may contribute to the cardiac effects of chronic amiodarone therapy. (C) 1997 Academic Press Limited.