Description:
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<jats:p>RSD 921 is a novel, structurally unique, class I Na<jats:sup>+</jats:sup> 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<jats:sup>+</jats:sup> channels expressed in <jats:italic>Xenopus laevis</jats:italic> oocytes were examined using a two‐electrode voltage clamp.</jats:p>
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<jats:p>RSD 921 produced similarly potent tonic block of all three wild‐type channel isoforms, with EC<jats:sub>50</jats:sub> values between 35 and 47 μ<jats:sc>M</jats:sc>, whereas the EC<jats:sub>50</jats:sub> for block of the IFMQ3 mutant channel was 110±5.5 μ<jats:sc>M</jats:sc>.</jats:p>
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<jats:p>Block of Na<jats:sup>+</jats:sup> 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.</jats:p>
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<jats:p>RSD 921 produced a minimal hyperpolarizing shift in the steady‐state voltage‐dependence of inactivation of all three wild‐type channel isoforms.</jats:p>
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<jats:p>Open channel block of the IFMQ3 mutant channel was best fit with a first order blocking scheme with k<jats:sub>on</jats:sub> equal to 0.11±0.012×10<jats:sup>6</jats:sup> <jats:sc>M</jats:sc><jats:sup>−1</jats:sup> s<jats:sup>−1</jats:sup> and k<jats:sub>off</jats:sub> equal to 12.5±2.5 s<jats:sup>−1</jats:sup>, resulting in <jats:italic>K<jats:sub>D</jats:sub></jats:italic> of 117±31 μ<jats:sc>M</jats:sc>. Recovery from open channel block occurred with a time constant of 14±2.7 s<jats:sup>−1</jats:sup>.</jats:p>
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<jats:p>These results suggest that RSD 921 preferentially interacts with the open state of the Na<jats:sup>+</jats:sup> 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.</jats:p>
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</jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (1999) <jats:bold>127</jats:bold>, 9–18; doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0702488">10.1038/sj.bjp.0702488</jats:ext-link></jats:p>