Does dolasetron and its metabolite MDL 73,405 block human heart sodium channels expressed in Xenopus oocytes?
Dolasetron and its metabolite do not directly block the human heart sodium channel α-subunit, highlighting species differences in cardiac electrophysiology.
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.
Dumaine et al. (Mon,) studied this question.