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Actions of dolasetron and its major metabolite on guinea‐pig papillary muscle fibres and the α‐subunit of human heart sodium channels expressed in Xenopus oocytes

The present study evaluated the effects of the anti‐emetic 5‐HT3 antagonist dolasetron and its major metabolite MDL 73,405 on guinea‐pig papillary muscle fibres and human heart sodium channels expressed in Xenopus oocytes. Dolasetron and MDL 73,405 (3–10 μM) reduced the maximum depolarization rate during phase I of the action potential (Vmax) in papillary muscle fibres without significantly changing the action potential duration. The reduction in Vmax was both use‐ and concentration‐dependent. In Xenopus oocytes expressing the α‐subunit of human heart sodium channels, extracellular application of dolasetron or MDL 73,405 induced only a low affinity tonic block of the sodium channel; the apparent Kd values were 1.1 and 1.2 mM, respectively. In contrast to guinea‐pig sodium channels, neither compound induced a marked use‐dependent block of the human channel α‐subunit at a concentration of 100 μM (3 and 7% block, respectively). Flecainide produced a reversible, tonic, and use‐dependent block in the concentration range of 10 to 100 μM; the Kd value for tonic block was 50 μM. The present results demonstrate that dolasetron and MDL 73,405 do not act directly on the human heart sodium channel α‐subunit and further emphasise the need to study drug action on human ionic channels and/or receptors. © 1996 Wiley‐Liss, Inc.