(Circulation. 2001;103:1317.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Short- and Long-Term Effects of Amiodarone on the Two Components of Cardiac Delayed Rectifier K+ Current
From the Department of Circulation, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan, and the Department of Internal Medicine, University of Utah, Salt Lake City, Utah (M.C.S.).
Correspondence to Dr Kaichiro Kamiya, Department of Circulation, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. E-mail kamiya{at}riem.nagoya-u.ac.jp
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.
Key Words: amiodarone • potassium • mRNA
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