Evidences of Antagonism between Amiodarone and Triiodothyronine on the K+ Channel Activities of Cultured Rat Cardiomyocytes

Abstract

Effects of acute and chronic treatments with amiodarone, both in the presence and the absence of exogenous triiodothyronine (T3), 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 (Ito, IC50=4.9μm) and the steady-state outward (IK, IC50=6.3μm) K+currents. The dose–response curve of this acute inhibitory action was unaffected by the presence of T3. When amiodarone was applied chronically, 72-h exposure to a low dose of the drug (1μm) significantly decreased the current densities of Itoand IKfor the cells cultured in a serum-supplemented medium containing 0.12 nM T3. In a serum-free medium without T3, chronic amiodarone treatment revealed null effect on either Itoor IK. In addition, 72-h in-vitro treatment with T3enhanced the current densities of both Ito(EC50=0.13 nm) and IK(EC50=0.33 nm). Concentration-response analysis indicated that amiodarone (1μm) showed competitive inhibition towards the action of T3on Itobut non-competitive inhibition towards the action of T3on IK. These results suggest that different ionic mechanisms are produced by acute and long-term treatments with amiodarone. The latter showed T3-dependent inhibition of cardiac Itoand IK. When chronically administered, amiodarone may antagonize T3and 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