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Bradycardic and proarrhythmic properties of sinus node inhibitors
Juliane Stieber1, Karen Wieland, Georg Stöckl
1Institut für Pharmakologie und Toxikologie, TU München, Biedersteiner Str. 29, 80802 München, Germany. stieber@ipt.med.tu-muenchen.de
Molecular Pharmacology
|January 3, 2006
Summary
Sinus node inhibitors like cilobradine, ivabradine, and zatebradine block pacemaker channels (HCN) in the heart. These drugs reduce heart rate but also carry an unrecognized proarrhythmic potential, causing heart rhythm disturbances.
Area of Science:
- Cardiovascular Pharmacology
- Ion Channel Physiology
Background:
- Sinus node inhibitors lower heart rate by blocking the If pacemaker current in the cardiac conduction system.
- This current is mediated by four hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels.
Purpose of the Study:
- To investigate the subtype-specificity of sinus node inhibitors (cilobradine, ivabradine, zatebradine) on cloned HCN channels.
- To evaluate the in vivo effects and proarrhythmic potential of these drugs in mice.
Main Methods:
- Utilized cloned human HCN1-4 channels and native If currents from mouse sinoatrial node cells.
- Performed electrophysiological recordings to assess current block and IC50 values.
- Conducted in vivo telemetric ECG recordings in mice to analyze heart rate and rhythm effects.
Main Results:
- Cilobradine, ivabradine, and zatebradine blocked all tested HCN channel subtypes without significant subtype-specificity.
- In vivo, all compounds dose-dependently reduced heart rate in mice.
- Higher drug concentrations induced dysrhythmic heart rates, resembling sick sinus syndrome, indicating a proarrhythmic effect.
Conclusions:
- Available sinus node inhibitors lack HCN channel subtype-specificity.
- These drugs exhibit a significant proarrhythmic potential, leading to heart rhythm disturbances.
- The findings highlight an unrecognized risk associated with current sinus node inhibitor therapies.