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

RSD 921 is a novel, structurally unique, class I Na + channel blocking drug under development as a local anaesthetic agent and possibly for the treatment of cardiac arrhythmias. The effects of RSD 921 on wild‐type heart, skeletal muscle, neuronal and non‐inactivating IFMQ3 mutant neuronal Na + channels expressed in Xenopus laevis oocytes were examined using a two‐electrode voltage clamp. RSD 921 produced similarly potent tonic block of all three wild‐type channel isoforms, with EC 50 values between 35 and 47 μ M , whereas the EC 50 for block of the IFMQ3 mutant channel was 110±5.5 μ M . Block of Na + channels by RSD 921 was concentration and use‐dependent, with marked frequency‐dependent block of heart channels and mild frequency‐dependent block of skeletal muscle, wild‐type neuronal and IFMQ3 mutant channels. RSD 921 produced a minimal hyperpolarizing shift in the steady‐state voltage‐dependence of inactivation of all three wild‐type channel isoforms. Open channel block of the IFMQ3 mutant channel was best fit with a first order blocking scheme with k on equal to 0.11±0.012×10 6   M −1  s −1 and k off equal to 12.5±2.5 s −1 , resulting in K D of 117±31 μ M . Recovery from open channel block occurred with a time constant of 14±2.7 s −1 . These results suggest that RSD 921 preferentially interacts with the open state of the Na + channel, and that the drug may produce potent local anaesthetic or anti‐arrhythmic action under conditions of shortened action potentials, such as during anoxia or ischaemia.British Journal of Pharmacology (1999) 127 , 9–18; doi: 10.1038/sj.bjp.0702488