ARRHYTHMOGENIC ACTIONS OF CLASS-III ANTIARRHYTHMIC DRUGS IN SPONTANEOUSLY BEATING RABBIT SINOATRIAL NODE CELLS

1. Arrhythmogenic actions induced by class III antiarrhythmic drugs (amiodarone, bretylium and sotalol) in spontaneously beating rabbit sino-atrial node cells were investigated by using a two microelectrode voltage-clamp technique. 2. Amiodarone (10(-6) mol/1) caused a negative chronotropic effect. Dysrhythmias at 10(-5) mol/l occurred in 3 out of 10 preparations. Amiodarone elicited a transient inward current. After wash out, the regular rhythm was resumed and the transient inward current also disappeared. 3. Bretylium (10(-5) mol/1) also induced dysrhythmias more often (in 5 of 11 preparations). Sotalol (10(-5) mol/1) caused dysrhythmias in only 1 of 10 preparations. 4. Changes in the cytosolic Ca2+ concentration in single sino-atrial node cells were monitored with fura-2, a Ca2+-sensitive fluorescent dye. Amiodarone (3 x 10(-5) mol/1) and bretylium (10(-5) mol/1) elevated the cytosolic Ca2+ level significantly, but sotalol even at 10(-3) mol/I did not affect it, 5. These results indicate that class III antiarrhythmic drugs possess arrhythmogenic actions, probably resulting from elevation of cellular Ca2+ concentration due to direct and indirect actions.