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Effects of the class III antiarrhythmic drug ambasilide on outward currents in human atrial myocytes

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Abstract

We have studied the inhibitory influence of the class III antiarrhythmic drug ambasilide (LU 47110) on the transient outward current I to1 and the sustained current T so following inactivation of I to1 in human atrial myocytes. The two currents are separated by a mathematical procedure based on the amplitudes and time constants of the biexponential inactivation of the total outward current. The frequency dependence, the recovery from inactivation and the kinetics of activation and inactivation are described. Ambasilide reversibly and concentration dependently inhibited I to1, I so and the sodium current I Na. Concentration required for half maximal inhibition (IC50) for the effects on I to1 and I so were 23.3 μmol/l and 45.7 μmol/l respectively, concentrations shown by others to be effective in terminating and preventing fibrillation in a dog atrial arrhythmia model. Ambasilide not only reduced the amplitude of I to1 and I so but also accelerated the time course of inactivation from 14.22 to 6.69 ms and from 202.3 to 87.9 ms respectively. The amplitude of I to1 showed only a small dependence on stimulation frequency characteristic for human atrial myocytes, whereas I so was reduced significantly at higher stimulation frequencies. Ambasilide did not change these relationships (0.1–4 Hz) and therefore did not show the reverse use-dependence known from other class III antiarrhythmic agents and which is an important property for a prospective antiarrhythmic drug. The lack of an effect of ambasilide on both steady-state activation and inactivation of I to1, and the time constant of recovery from inactivation, suggests that ambasilide acts by changing conductance rather than by influencing the gating mechanism. The described characteristics make ambasilide an interesting substance in the group of class III antiarrhythmic drugs.

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Authors and Affiliations

  1. Institut für Medizinische Physik und Biophysik, Universität Graz, Harrachgasse 21/IV, A-8010, Graz, Austria

    Bernd Koidl, Peter Flaschberger, Peter Schaffer, Brigitte Pelzmann & Eva Bernhart

  2. Universitätsklinik für Chirurgie, Universität Graz, Auenbruggerplatz 5, A-8036, Graz, Austria

    Heinrich Mächler & Bruno Rigler

Authors
  1. Bernd Koidl
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  2. Peter Flaschberger
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  3. Peter Schaffer
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  4. Brigitte Pelzmann
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  5. Eva Bernhart
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  6. Heinrich Mächler
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  7. Bruno Rigler
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Koidl, B., Flaschberger, P., Schaffer, P. et al. Effects of the class III antiarrhythmic drug ambasilide on outward currents in human atrial myocytes. Naunyn-Schmiedeberg's Arch Pharmacol 353, 226–232 (1996). https://doi.org/10.1007/BF00168761

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  • DOI: https://doi.org/10.1007/BF00168761

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