The mechanism of atrial antiarrhythmic action of RSD1235.
BACKGROUND
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.


RESULTS
Ischemic arrhythmias were inhibited with an ED50 of 1.5 micromol/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 microM on hKv1.5 (1 Hz) versus 38 and 30 microM on Kv4.2 and Kv4.3, respectively, and 21 microM on hERG channels. RSD1235 did not block IK1 (IC50 > 1 mM) nor ICa,L (IC50= 220 microM) at 1 Hz in guinea pig ventricular myocytes (n = 4-5). The drug displayed mild (IC50= 43 microM 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 microM at 0.25 Hz, to an IC50= 9 microM at 20 Hz, and with depolarization increasing from 107 microM at -120 mV to 31 microM 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 INa.
Fedida
David
D
Cardiome Pharma Corporation, University of British Columbia, Vancouver, British Columbia, Canada. fedida@interchange.ubc.ca
Orth
Peter M R
PM
Chen
Janet Y C
JY
Lin
Shunping
S
Plouvier
Bertrand
B
Jung
Grace
G
Ezrin
Alan M
AM
Beatch
Gregory N
GN
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D022062:Electrophysiologic Techniques, Cardiac; D006168:Guinea Pigs; D066298:In Vitro Techniques; D051381:Rats
D000889:Anti-Arrhythmia Agents