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Effect of verapamil on tachycardia-induced early cellular electrical remodeling in rabbit atrium

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Abstract

We investigated the effects of a 7-day verapamil pretreatment (VPT, 7.5 mg/kg bodyweight subcutaneously every 12 h) on ionic currents and molecular mechanisms underlying tachycardia-induced early electrical remodeling after 24-h rapid atrial pacing (RAP, 600 bpm) in rabbit atrium. Animals were divided into four groups (n = 6 each group): control (not paced, no verapamil), paced only, verapamil only and verapamil and paced, respectively. VPT doubled ICa,L [7.0 ± 0.7 pA/pF (control) vs 14.2 ± 0.6 pA/pF (verapamil only)]. RAP reduced ICa,L by 48% to 3.6 ± 0.7 pA/pF (paced only). RAP did not affect ICa,L in verapamil-treated animals and averaged 15.3 ± 0.2 pA/pF (paced and verapamil). RAP resulted in a significant decrease of the expression of the α1c subunit (−24.7%) and the β2A subunit (−13.3%), respectively. VPT led to a similar alteration of subunit expression as RAP [“control” vs “verapamil only”, decrease of α1c subunit (−25.4%), but no significant change in β2A subunit expression]. However, after VPT, further diminishment of α1c and β2A subunit expression after rapid atrial pacing was absent. (“verapamil” vs “verapamil and paced”, n = 6 both groups). RAP decreased Ito [−45%, 51.5 ± 3.9 pA/pF (control) vs 26.8 ± 1.5 pA/pF (paced only)] and was not influenceable by VPT. IK1 was neither affected by RAP nor verapamil pretreatment. Downregulation of α1c and β2A subunit expression and the resulting decay of ICa,L current densities were prevented by verapamil. However, these effects are abolished by multiple other adverse effects of verapamil on atrial electrophysiology.

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Acknowledgments

The work was supported by the Bundesministerium für Bildung und Forschung Germany (BMBF)/University of Tübingen (IZKF; No. 01KS9602) and the “Kompetenznetz Vorhofflimmern” (No. 01GI0204). The authors thank Jeannette Gogel for expert technical assistance and Hannelore Haase (Max-Dellbrück Zentrum Berlin, Germany) for supply of antibodies.

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  1. Department of Cardiology, University of Tübingen, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany

    Roman Laszlo, Christoph Winkler, Stefan Wöhrl, Ralf E. Wessel, Mathias C. Busch, Jürgen Schreieck & Ralph F. Bosch

  2. Department of Pharmacology, University of Tübingen, Tübingen, Germany

    Sara Laszlo

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  1. Roman Laszlo
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Laszlo, R., Winkler, C., Wöhrl, S. et al. Effect of verapamil on tachycardia-induced early cellular electrical remodeling in rabbit atrium. Naunyn-Schmied Arch Pharmacol 376, 231–240 (2007). https://doi.org/10.1007/s00210-007-0188-0

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