The mechanism of atrial antiarrhythmic action of RSD1235

Mechanism of Action of RSD1235. Introduction: RSD1235 is a novel drug recently shown to convert AF rapidly and safely in patients.(1) Its mechanism of action has been investigated in a rat model of ischemic arrhythmia, along with changes in action potential (AP) morphology in isolated rat ventricular myocytes and effects on cloned channels. Methods and Results: Ischemic arrhythmias were inhibited with an ED50 of 1.5 mu mol/kg/min, and repolarization times increased with non-significant effects on PR and QRS durations. AP prolongation was observed in rat myocytes at low doses, with plateau elevation and a reduction in the AP overshoot at higher doses. RSD1235 showed selectivity for voltage-gated K+ channels with IC50 values of 13 mu M on hKv1.5 (1 Hz) versus 38 and 30 mu M on Kv4.2 and Kv4.3, respectively, and 21 mu M on hERG channels. RSD1235 did not block I-K1 (IC50 > 1 mM) nor I-Ca,I-L (IC50= 220 mu M) at 1 Hz in guinea pig ventricular myocytes (n = 4-5). The drug displayed mild (IC50= 43 mu M at 1 Hz) open-channel blockade of Nav1.5 with rapid recovery kinetics after rate reduction (10 -> 1 Hz, 75% recovery with tau= 320 msec). Nav1.5 blocking potency increased with stimulus frequency from an IC50= 40 mu M at 0.25 Hz, to an IC50= 9 mu M at 20 Hz, and with depolarization increasing from 107 mu M at -120 mV to 31 mu M at -60 mV (1 Hz). Conclusions: These data suggest that RSD1235's clinical selectivity and AF conversion efficacy result from block of potassium channels combined with frequency- and voltage-dependent block of I-Na.