Chronic amiodarone-induced inhibition of the Na+-K+ pump in rabbit cardiac myocytes is thyroid-dependent: comparison with dronedarone.
OBJECTIVE
To examine the thyroid-dependence of the effect of amiodarone on the sarcolemmal Na(+)-K(+) pump, and the effect on the pump of dronedarone, a deiodinated amiodarone congener without influence on thyroid status.


METHODS
New Zealand white rabbits underwent total thyroidectomy, sham thyroidectomy or thyroidectomy and concomitant oral amiodarone therapy. After 5 weeks, Na(+)-K(+) pump current was measured using the whole-cell patch-clamp technique in isolated ventricular myocytes. Pump current was also measured in myocytes isolated from a separate group of rabbits not subjected to thyroidectomy but treated with dronedarone, or placebo for 3 weeks.


RESULTS
Treatment of thyroidectomised rabbits with amiodarone caused a significant prolongation of the corrected QT interval (QT(c)) and sinus cycle length. Na(+)-K(+) pump current measured in myocytes isolated from thyroidectomised rabbits was significantly lower than pump current in myocytes from sham-operated controls. However, treatment of thyroidectomised rabbits with amiodarone did not cause any additional decrease in pump current. Treatment with dronedarone caused prolongation of QT(c). However, it had no effect on Na(+)-K(+) pump current.


CONCLUSIONS
The inhibitory effect of amiodarone on Na(+)-K(+) pump current is thyroid-dependent, whereas the effects on heart rate and QT(c) are at least partially mediated by thyroid-independent mechanisms. In contrast to its parent compound, dronedarone has no significant effects on the activity of the Na(+)-K(+) pump.
Pitt
Andrew D
AD
Department of Cardiology, Royal North Shore Hospital, Pacific Highway, St. Leonards, Sydney, NSW 2065, Australia.
Fernandes
Clyne
C
Bewick
Nerida L
NL
Hemsworth
Paul D
PD
Buhagiar
Kerrie A
KA
Hansen
Peter S
PS
Rasmussen
Helge H
HH
Delbridge
Leigh
L
Whalley
David W
DW
D000638:Amiodarone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D003864:Depression, Chemical; D000077764:Dronedarone; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013961:Thyroid Gland / Q000378:metabolism*; D013965:Thyroidectomy
D000889:Anti-Arrhythmia Agents; D000254:Sodium-Potassium-Exchanging ATPase; D000077764:Dronedarone; D000638:Amiodarone