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
✍ Scribed by Robert Dumaine; Hali A. Hartmann; Derek J. Leishman; Arthur M. Brown; Martin Galvan
- Publisher
- John Wiley and Sons
- Year
- 1996
- Tongue
- English
- Weight
- 695 KB
- Volume
- 37
- Category
- Article
- ISSN
- 0272-4391
No coin nor oath required. For personal study only.
✦ Synopsis
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 p M ) 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 a-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 K, 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 a-subunit at a concentration of 100 pM (3 and 7% block, respectively).
Flecainide produced a reversible, tonic, and use-dependent block in the concentration range of 10 to 100 p.M; the K, value for tonic block was 50 pM. The present results demonstrate that dolasetron and MDL 73,405 do not act directly on the human heart sodium channel a-subunit and further emphasise the need to study drug action on human ionic channels and/or receptors.