Augmentation of late sodium current unmasks the proarrhythmic effects of amiodarone.
OBJECTIVE
Clinical use of amiodarone is associated with occasional development of torsade de pointes (TdP). However, preclinical models have failed to demonstrate the proarrhythmic potential of amiodarone. The objective of this study was to reveal and explain the pro- and anti-arrhythmic effects of acute exposure to amiodarone in an animal model.


RESULTS
Endo- and epicardial monophasic action potentials (MAPs) and 12-lead electrocardiogram were recorded in female rabbit isolated hearts. Ion channel currents were measured in human embryonic kidney cells expressing SCN5A Na+ and HERG K+ channels. Acute amiodarone alone caused an insignificant increase in duration of MAP (MAPD90) without causing TdP. In the presence of 3 nM sea anemone toxin (ATX-II), amiodarone (1-30 nM) prolonged MAPD90 from 217 +/- 5 to 250 +/- 8 ms (n = 16, P < 0.01), increased transmural dispersion of repolarization (TDR) from 59 +/- 9 to 70 +/- 10 ms and beat-to-beat variability (BVR) of MAPD(90) from 0.75 +/- 0.03 to 1.06 +/- 0.13 ms (P < 0.05). At 30-300 nM, amiodarone induced TdP in 16 out of 17 hearts. A further increase of amiodarone concentration to 1-10 microM abbreviated MAPD(90) to 211 +/- 9 ms, decreased BVR to 0.5 +/- 0.01 ms, decreased TDR (n = 7, P < 0.05), and suppressed TdP. Amiodarone inhibited HERG K+ and late Na+ currents with IC50s of 0.8 +/- 0.1 and 3.0 +/- 0.9 microM, respectively.


CONCLUSIONS
In hearts in which late INa is augmented to mimic congenital or acquired pathological conditions, amiodarone has a concentration-dependent biphasic effect to induce and then suppress arrhythmic activity, secondary to inhibition of HERG K+ and late Na+ currents. This is the first preclinical model demonstrating the potential for amiodarone to induce TdP.
Wu
Lin
L
Department of Pharmacological Sciences, CV Therapeutics, Inc. 3172 Porter Drive, Palo Alto, CA 94304, USA. lin971@yahoo.com
Rajamani
Sridharan
S
Shryock
John C
JC
Li
Hong
H
Ruskin
Jeremy
J
Antzelevitch
Charles
C
Belardinelli
Luiz
L
D000200:Action Potentials / Q000187:drug effects; D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D003064:Cnidarian Venoms / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000209:etiology; D009124:Muscle Proteins / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011817:Rabbits; D015222:Sodium Channels / Q000502:physiology*
D003064:Cnidarian Venoms; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; C028800:toxin II (Anemonia sulcata); D000638:Amiodarone