Atrial Selectivity in Sodium Channel Block by Amiodarone

Abstract

Introduction: Na+ channel blockers are usually applied to atrial fibrillation (AF), but may sometimes cause cardiac contractile dysfunction. However, amiodarone, a multi-channel blocker with Na+ channel block, does not induce cardiac dysfunction. In this study we tested the hypothesis that Na+ channel block by amiodarone is selective in atrial myocytes (AM) compared to ventricular myocytes (VM). Methods and Results: Na+ currents (INa) and resting membrane potentials (RMPs) were measured using whole cell patch-clamp technique in isolated rabbit AM and VM. Amiodarone inhibited INa in AM (IC50: 1.4 ± 0.3μM; n=8) much more than in VM (40.4 ± 11.9μM; n=7; P<0.01). Amiodarone at 10μM dramatically shifted steady state inactivation curve to hyperpolarized direction in AM (−19.6 ± 2.1mV shift; n=12) compared to VM (−6.3 ± 0.8mV shift; n=13; P<0.01). In mexiletine, there was no significant difference in INa inhibition between AM and VM. The shifts of inactivation curves by mexiletine at 10μM were comparable in AM and VM. RMPs in AM (−75.0 ± 1.3mV; n=4) were more depolarized than in VM (−82.1 ± 1.1mV; n=9; P<0.01). In the absence of drugs, the half inactivation voltage in AM (V1/2: −89.7 ± 0.9mV; n=19) was 12.5 mV more negative than VM (−77.2 ± 0.6mV; n=20; P<0.01). Furthermore, we evaluated the effects of amiodarone and mexiletine on conduction velocity (CV) in Langendorff-perfused rabbit hearts by optical mapping system. The decrease of CV by amiodarone at 5μM was significantly larger in atrium (−34.3 ± 5.6%; n=5) compared to ventricle (−4.8 ± 1.0%; n=5; P<0.01). However, the reduction of CV by mexiletine at 5uM in atrium was smaller than in ventricle. Conclusion: Amiodarone preferentially inhibits INa of AM compared to VM. This atrial-selective Na+ channel block by amiodarone may contribute to treating AF without affecting ventricular contractility.