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Updated: Aug 24, 2026
Isolation and Kv Channel Recordings in Murine Atrial and Ventricular Cardiomyocytes
Published on: March 12, 2013
Disturbed atrio-ventricular conduction and normal contractile function in isolated hearts from Cav1.3-knockout mice
Jan Matthes1, Leyla Yildirim, Georg Wietzorrek
1Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany.
Insights
Cav1.3 channels are crucial for heart rhythm, not ventricular function. Their absence causes bradycardia and AV node dysfunction, impacting cardiac electrophysiology and drug development.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Ion Channel Function
Background:
- Cardiac L-type calcium channels (Cav1.2 and Cav1.3) regulate heart function.
- Cav1.3 channels are highly expressed in the sino-atrial node (SAN) and atria, unlike Cav1.2.
- Cav1.3 knockout mice exhibit bradycardia, suggesting a role in cardiac rhythm.
Purpose of the Study:
- To investigate the functional role of Cav1.3 channels in the working heart.
- To determine the impact of Cav1.3 suppression on ventricular contractility and cardiac electrophysiology.
- To explore Cav1.3 as a potential pharmacological target for bradycardic agents.
Main Methods:
- Utilized isolated working hearts from wild-type and Cav1.3 knockout mice.
- Performed histological analysis to assess cardiac pathology.
- Recorded electrocardiograms (ECGs) and measured ventricular contractility.
- Assessed the effects of isoproterenol on cardiac function and electrophysiology.
Main Results:
- Cav1.3 knockout hearts showed no pathological changes and maintained normal ventricular contractility.
- Severe sinus bradycardia and ventricular extrasystoles were observed in Cav1.3 knockout hearts, partially improved by isoproterenol.
- Delayed atrio-ventricular (AV) conduction and a decoupling of heart rate and PR interval were evident.
- Isoproterenol did not ameliorate the AV conduction disturbances.
Conclusions:
- Cav1.3 channel suppression does not impair ventricular contractile function.
- Reduced sinus node frequency is compensated by adrenergic stimulation, but AV node dysfunction persists.
- Bradyarrhythmia in Cav1.3 deficient hearts involves intrinsic AV node dysfunction resistant to adrenergic effects.
- Findings predict the clinical presentation of selective Cav1.3 blockade.
Abstract:
Cardiac L-type calcium channels are formed by two alpha-subunits, Cav1.2 (alpha(1C)) and Cav1.3 (alpha(1D)). In contrast to the uniform expression pattern of Cav1.2, Cav1.3 is highly expressed in sino-atrial node (SAN) and atrial tissue, but not in the ventricle. Accordingly, knockout of Cav1.3 (Cav1.3(-/-)) in mice was shown to lead to a cardiac phenotype characterised by severe bradycardia in vivo and in isolated SAN cells. Cav1.3 may therefore constitute a novel pharmacological target for specific bradycardic agents. RNAse protection assays of murine wild type hearts revealed rather high Cav1.3 levels comparable to Cav1.2, suggesting functional relevance of Cav1.3 outside specialised tissues such as SAN. Due to the lack of specific Cav1.3 blockers, we directly examined the functional role of Cav1.3 using isolated working hearts from adult wild type (WT) and Cav1.3(-/-) mice. Histological analysis of hearts revealed no pathological changes. Ventricular contractility and inotropic effects of isoproterenol were unaltered in Cav1.3(-/-) hearts. Severe sinus bradycardia already noted in vivo was accompanied by ventricular extrasystoles. This phenotype was restored to nearly normal values by the cumulative addition of isoproterenol. Electrocardiograms of Cav1.3(-/-) hearts revealed delayed atrio-ventricular (AV) conduction and a decoupling of heart rate and PR interval duration. Isoproterenol did not improve disturbance of AV conduction. In conclusion, suppression of Cav1.3 does not alter ventricular contractile function, and the decrease in sinus node frequency is counterbalanced by adrenergic stimulation. Importantly, bradyarrhythmia is partly due to an intrinsic AV node dysfunction, which is resistant to adrenergic counterbalance. These findings help to predict the clinical pattern of selective Cav1.3 blockade.
