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


RESULTS
The delayed rectifier K(+) current (I(K)) of ventricular myocytes isolated from rabbit hearts was recorded with the whole-cell voltage-clamp technique. I(K) was separated into 2 components by use of specific blockers for either I(Ks) (chromanol 293B, 30 micromol/L) or I(Kr) (E-4031, 10 micromol/L). Short-term application of amiodarone caused a concentration-dependent decrease in I(Kr) with an IC(50) of 2.8 micromol/L (n=8) but only a minimal reduction in I(Ks). The short-term effects of amiodarone were also determined in Xenopus oocytes expressing the cloned human channels that conduct I(Kr) and I(Ks) (HERG and KvLQT1/minK). HERG current in oocytes was reduced by amiodarone (IC(50)=38 micromol/L), whereas KvLQT1/minK current was unaffected by 300 micromol/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 I(K) to 55% (n=10) in control rabbits and altered the relative density of I(Kr) and I(Ks). The majority (92%) of current was I(Kr). 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 I(K), depending on the application period; short-term treatment inhibits primarily I(Kr), whereas long-term treatment reduces I(Ks).
Kamiya
K
K
Department of Circulation, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan. kamiya@riem.nagoya-u.ac.jp
Nishiyama
A
A
Yasui
K
K
Hojo
M
M
Sanguinetti
M C
MC
Kodama
I
I
D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D027682:Cation Transport Proteins; D002478:Cells, Cultured; D051668:Delayed Rectifier Potassium Channels; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology*; D016276:Ventricular Function; D014981:Xenopus
D027682:Cation Transport Proteins; D051668:Delayed Rectifier Potassium Channels; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D014665:Vasodilator Agents; C059983:potassium channel protein I(sk); D000638:Amiodarone