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Na+ channel blockers are often used to treat atrial fibrillation (AF), but may sometimes cause ventricular contractile dysfunction. However, amiodarone, a multi-channel blocker with Na+ channel block, causes less contractile dysfunction. In this study, we tested the hypothesis that Na+ channel block by amiodarone is selective in atrial myocytes (AM) compared with ventricular myocytes (VM).Na+ currents (INa) were measured using whole-cell patch-clamp technique in isolated rabbit AM and VM. Amiodarone inhibited INa in AM (IC50: 1.8 ± 1.1 μM; n = 8) much more than in VM (40.4 ± 11.9 μM; n = 7, P < 0.01). Amiodarone at 10 μM shifted the steady-state inactivation relationship in AM (−16.2 ± 1.7 mV shift, n = 12) compared with VM (−5.9 ± 0.7 mV shift; n = 13; P < 0.01). For mexiletine, the inhibition of INa and inactivation curve shifts were comparable for AM and VM. The effects of amiodarone and mexiletine on conduction velocity (CV) in Langendorff-perfused rabbit hearts were evaluated using an optical mapping system. The decrease of CV by 3 μM amiodarone was significantly larger in the atrium (−18.9 ± 3.8% change; n = 5) compared with the ventricle (−3.7 ± 3.7%; n = 5; P < 0.01). In contrast, mexiletine reduced CV equally in the atrium and the ventricle.Amiodarone preferentially inhibits INa of AM compared with VM. Atrial selective Na+ channel block by amiodarone may contribute to treating AF with less effect on ventricular contractility than other Na+ channel blockers.