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The Mechanism of Atrial Antiarrhythmic Action of RSD1235
Author(s) -
FEDIDA DAVID,
ORTH PETER M.R.,
CHEN JANET Y.C.,
LIN SHUNPING,
PLOUVIER BERTRAND,
JUNG GRACE,
EZRIN ALAN M.,
BEATCH GREGORY N.
Publication year - 2005
Publication title -
journal of cardiovascular electrophysiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.193
H-Index - 138
eISSN - 1540-8167
pISSN - 1045-3873
DOI - 10.1111/j.1540-8167.2005.50028.x
Subject(s) - repolarization , herg , medicine , depolarization , potassium channel , potassium channel blocker , anti arrhythmia agents , ic50 , electrophysiology , myocyte , pharmacology , cardiac action potential , mechanism of action , patch clamp , chemistry , atrial fibrillation , in vitro , biochemistry
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 ED 50 of 1.5 μmol/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 IC 50 values of 13 μM on hKv1.5 (1 Hz) versus 38 and 30 μM on Kv4.2 and Kv4.3, respectively, and 21 μM on hERG channels. RSD1235 did not block I K1 (IC 50 > 1 mM) nor I Ca,L (IC 50 = 220 μM) at 1 Hz in guinea pig ventricular myocytes (n = 4–5). The drug displayed mild (IC 50 = 43 μM at 1 Hz) open‐channel blockade of Nav1.5 with rapid recovery kinetics after rate reduction (10→1 Hz, 75% recovery with τ= 320 msec). Nav1.5 blocking potency increased with stimulus frequency from an IC 50 = 40 μM at 0.25 Hz, to an IC 50 = 9 μM at 20 Hz, and with depolarization increasing from 107 μM at −120 mV to 31 μM 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.