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A voltage clamp study of the effects of AR-L 115 BS on the pacemaker current of cardiac Purkinje fibres

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Summary

The new cardiotonic agent AR-L 115 BS was investigated by means of the double-micro-electrode voltage clamp technique on sheep cardiac Purkinje fibres.

Clinical and pharmacological studies show that AR-L 115 BS increases heart rate as a side effect at medium to high therapeutic doses. The classical analysis of the pacemaker current was therefore performed to study the possible mechanism of this effect at a cellular level. The kinetic parameter s∞ and the reversal potential of the pacemaker current were shifted in the depolarizing direction after exposure to AR-L 115 BS. Peak values of the fully activated pacemaker current were either increased or diminished, while potassium leakage was slightly increased. These results are not related to the action of AR-L 115 BS on beta-adrenergic receptors but possibly due to enhanced intracellular calcium (see third paper in this series). Despite its tendency to increase heart rate, high concentrations of AR-L 115 BS should not be expected to promote arrhythmias in the Purkinje system since the electrophysiological effects tend to counteract each other.

Zusammenfassung

Die neuartige kardiotonisch wirkende Substanz AR-L 115 BS wurde mit Hilfe der ZweiMikroelektroden-voltage-clamp-Technik an Purkinjefäden des Schafherzens untersucht.

Klinische und pharmakologische Voruntersuchungen zeigen, daß AR-L 115 BS die Herzfrequenz erhöht im Sinne einer Nebenwirkung unter mittlere bis hoher therapeutischer Dosierung. Es wurde deshalb der Schrittmacherstrom analysiert, um den Mechanismus dieses Effekts auf zellulärer Ebene zu ermitteln. Der kinetische Parameter s∞ und das Umkehrpotential des Schrittmacherstroms wurden beide in depolarisierender Richtung nach Gabe von AR-L 115 BS verschoben. Maximalwerte des vollaktivierten Schrittmacherstroms wurden entweder erhöht oder erniedrigt; Kaliumleckströme erhöhten sich leicht. Diese Befunde beruhen möglicherweise auf einer Erhöhung intrazellulären Calciums (siehe die 3. Studie dieser Reihe), da eine Beteiligung einer Wirkung von AR-L 115 BS auf β-adrenerge Rezeptoren ausgeschlossen werden konnte. Trotz der Erhöhung der Herzfrequenz sollten hohe Konzentrationen von AR-L 115 BS nicht arrhythmogen auf das Purkinje-System wirken, statt; denn die elektrophysiologischen Wirkungen zeigen eine gegenläufige Tendenz.

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Author notes

  1. R. Ziskoven, C. Achenbach, J. Wiemer & O. Hauswirth

    Present address: Dept. of Physiology II, University of Bonn, Wilhelmstr. 31, D-5300, Bonn, Federal Republic of Germany

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    1. R. Ziskoven
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    2. C. Achenbach
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    3. J. Wiemer
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    4. O. Hauswirth
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    Ziskoven, R., Achenbach, C., Wiemer, J. et al. A voltage clamp study of the effects of AR-L 115 BS on the pacemaker current of cardiac Purkinje fibres. Basic Res Cardiol 77, 536–551 (1982). https://doi.org/10.1007/BF01907945

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    • DOI: https://doi.org/10.1007/BF01907945

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