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Disturbed atrio-ventricular conduction and normal contractile function in isolated hearts from Cav1.3-knockout mice.

Jan Matthes, Leyla Yildirim, Georg Wietzorrek, Daniel Reimer, Jörg Striessnig, Stefan Herzig

Naunyn Schmiedebergs Arch. Pharmacol., 2004 Jun , 369, 554-62

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.