Short- and long-term effects of amiodarone on the two components of cardiac delayed rectifier K+ current

Abstract

Background - Amiodarone is the most promising drug for the treatment of life-threatening tachyarrhythmias in patients with structural heart disease. The pharmacological effects of amiodarone on cardiac ion channels are complex and may differ for short-term and long-term administration. Methods and Results - The delayed rectifier K+ current (IK) of ventricular myocytes isolated from rabbit hearts was recorded with the whole-cell voltage-clamp technique. IK was separated into 2 components by use of specific blockers for either IKs (chromanol 293B, 30 μmol/L) or IKr (E-4031, 10 μmol/L). Short-term application of amiodarone caused a concentration-dependent decrease in IKr with an IC50 of 2.8 μmol/L (n=8) but only a minimal reduction in IKs. The short-term effects of amiodarone were also determined in Xenopus oocytes expressing the cloned human channels that conduct IKr and IKs (HERG and KvLQT1/minK). HERG current in oocytes was reduced by amiodarone (IC50=38 μmol/L), whereas KvLQT1/minK current was unaffected by 300 μmol/L amiodarone. To study the effects of long-term drug administration, rabbits were treated for 4 weeks with oral amiodarone (100 mg · kg-1 · d-1) before cell isolation. Long-term administration of amiodarone decreased IK to 55% (n=10) in control rabbits and altered the relative density of IKr and IKs. The majority (92%) of current was IKr. mRNA levels of rabbit ERG, KVLQT1, and minK in left ventricular myocardium did not differ between control and long-term amiodarone. Conclusions - Amiodarone has differential effects on the 2 components of IK, depending on the application period; short-term treatment inhibits primarily IKr, whereas long-term treatment reduces IKs.