The high frequency relationship: implications for torsadogenic hERG blockers
P Champeroux1, J Y Le Guennec2, S Jude1
1Centre de Recherches Biologiques, CERB, Chemin de Montifault, 18800, Baugy, France.
British Journal of Pharmacology
|November 22, 2015
Summary
Transient sympathetic activation during high-frequency oscillations, triggered by torsadogenic hERG blockers, is mediated by β1-adrenoceptors. The heart rate-QT interval relationship may serve as a novel biomarker for Torsades de Pointes risk assessment.
Area of Science:
- Cardiovascular Pharmacology
- Electrophysiology
- Drug Safety
Background:
- Ventricular arrhythmias linked to hERG channel blockers arise from repolarization changes and high-frequency (HF) oscillations.
- The autonomic nervous system modulates this arrhythmogenic process.
Purpose of the Study:
- Investigate the role of β1-adrenoceptors in the HF relationship between heart rate and QT interval changes.
- Assess the implications for torsadogenic hERG blockers.
Main Methods:
- Studied the HF relationship in beagle dogs under autonomic blockade with atenolol (a β1-adrenoceptor blocker).
- Examined the effects of 14 hERG blockers, alone and with atenolol.
Main Results:
- Torsadogenic hERG blockers caused a vertical shift in the HF relationship; non-torsadogenic ones did not.
- Atenolol prevented or reduced the effects of torsadogenic agents, identifying two types.
- Transient sympathetic activation during HF oscillations is mediated by β1-adrenoceptors.
Conclusions:
- The HF relationship can serve as a novel biomarker for Torsades de Pointes liability.
- Findings have implications for preclinical drug safety assessment and clinical practice.
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