Molecular analysis of the Na+ channel blocking actions of the novel class I anti-arrhythmic agent RSD 921

1 RSD 921 is a novel, structurally unique, class I Na+ channel blocking dru g under development as a local anaesthetic agent and possibly for the treat ment of cardiac arrhythmias. The effects of RSD 921 on wild-type heart, ske letal muscle, neuronal and non-inactivating IFMQ3 mutant neuronal Nai chann els expressed in Xenopus laevis oocytes were examined using a two-electrode voltage clamp. 2 RSD 921 produced similarly potent tonic block of all three wild-type chan nel isoforms, with EC50 values between 35 and 47 mu M, whereas the EC50 for block of the IFMQ3 mutant channel was 110+/-5.5 mu M. 3 Block of Na+ channels by RSD 921 was concentration and use-dependent, wit h marked frequency-dependent block of heart channels and mild frequency-dep endent block of skeletal muscle, wild-type neuronal and IFMQ3 mutant channe ls. 4 RSD 921 produced a minimal hyperpolarizing shift in the steady-state volt age-dependence of inactivation of all three wild-type channel isoforms. 5 Open channel block of the IFMQ3 mutant channel was best fit with a first order blocking scheme with k(on) equal to 0.11 +/- 0.012 x 10(6) M-1 s(-1) and k(off) equal to 12.5 +/- 2.5 s(-1), resulting in K-D of 117+/-31 mu M. Recovery from open channel block occurred with a time constant of 14+/-2.7 s(-1) 6 These results suggest that RSD 921 preferentially interacts with the open state of the Na+ channel, and that the drug may produce potent local anaes thetic or anti-arrhythmic action under conditions of shortened action poten tials, such as during anoxia or ischaemia.