Abstract
Amiodarone (AMD) is a potent antiarrhythmic drug with high efficacy for treating atrial fibrillation and tachycardia. The pharmacologic profile of AMD is complex. AMD possesses biophysical characteristics of all of class I, II, III, and IV agents. Despite its adverse side effects, AMD remains the most commonly prescribed antiarrhythmic drug. AMD was described to prolong the QT interval and can lead to torsades de pointes. Our goal was to study the effects of AMD on peak and late sodium currents (INa,P and INa,L) and determine whether these effects change as AMD is metabolized into N-desethylamiodarone (DES). We hypothesized that AMD and DES block both INa,P and INa,L with similar profiles due to structural similarities. Given the inherent small amounts of INa,L in NaV1.5, we screened AMD and DES against the Long QT-3-causing mutation, ΔKPQ, to better detect any drug-mediated effect on INa,L. Our results show that AMD and DES do not affect WT or ΔKPQ activation; however, both drugs altered the apparent valence of steady-state fast-inactivation. In addition, AMD and DES preferentially block ΔKPQ peak conductance compared to WT. Both compounds significantly increase INa,L and window currents. We conclude that both compounds have pro-arrhythmic effects on NaV1.5, especially ΔKPQ; however, DES seems to have a greater pro-arrhythmic effect than AMD.
Highlights
In the 1960s, an iodine-containing benzofuran compound called amiodarone (AMD) was developed as a therapeutic vasodilator (Phillips and Bauman, 1995)
We examined the effects of AMD and DES on activation in NaV1.5 and KPQ channels
To quantify the effects of each compound at 0.5 and 2.5 μM on fast-inactivation, we compared the apparent valence (z) and midpoint (V1/2) from Boltzmann fits to steady-state fast-inactivation (SSFI) data for NaV1.5 (Figures 3A,B) and KPQ (Figures 3C,D)
Summary
In the 1960s, an iodine-containing benzofuran compound called amiodarone (AMD) was developed as a therapeutic vasodilator (Phillips and Bauman, 1995). Decades of research and clinical trials have shown the effects of AMD in a range of organ systems. AMD slowly became a widely used antiarrhythmic drug, with a high efficacy for treating conditions including atrial fibrillation and tachycardia (Pollak, 1998). AMD has been classified primarily as a class III antiarrhythmic drug, it has biophysical characteristics of class I, II, and IV agents in that it blocks L-type calcium, potassium, and sodium currents (Singh and Vaughan Williams, 1970; Kodama et al, 1997; Nattel and Singh, 1999; Wu et al, 2008). AMD is the most commonly prescribed antiarrhythmic drug despite its potentially serious side effects, including adverse effects on thyroid glands, the pulmonary system, and the liver (Danzi and Klein, 2015)
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