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Bourgonje, VJA; Vos, MA; Ozdemir, S; Doisne, N; Acsai, K; Varro, A; Sztojkov-Ivanov, A; Zupko, I; Rauch, E; Kattner, L; Bito, V; Houtman, M; van der Nagel, R; Beekman, JD; van Veen, TAB; Sipido, KR; Antoons, G; .
Combined Na+/Ca2+ Exchanger and L-Type Calcium Channel Block as a Potential Strategy to Suppress Arrhythmias and Maintain Ventricular Function.
Circ Arrhythm Electrophysiol. 2013; 6(2):371-379 Doi: 10.1161/CIRCEP.113.000322 [OPEN ACCESS]
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Antoons Gudrun

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Background-L-type calcium channel (LTCC) and Na+/Ca2+ exchanger (NCX) have been implicated in repolarization-dependent arrhythmias, but also modulate calcium and contractility. Although LTCC inhibition is negative inotropic, NCX inhibition has the opposite effect. Combined block may, therefore, offer an advantage for hemodynamics and antiarrhythmic efficiency, particularly in diseased hearts. In a model of proarrhythmia, the dog with chronic atrioventricular block, we investigated whether combined inhibition of NCX and LTCC with SEA-0400 is effective against dofetilide-induced torsade de pointes arrhythmias (TdP), while maintaining calcium homeostasis and hemodynamics. Methods and Results-Left ventricular pressure (LVP) and ECG were monitored during infusion of SEA-0400 and verapamil in anesthetized dogs. Different doses were tested against dofetilide-induced TdP in chronic atrioventricular block dogs. In ventricular myocytes, effects of SEA-0400 were tested on action potentials, calcium transients, and early afterdepolarizations. In cardiomyocytes, SEA-0400 (1 mol/L) blocked 66 +/- 3% of outward NCX, 50 +/- 2% of inward NCX, and 33 +/- 9% of LTCC current. SEA-0400 had no effect on systolic calcium, but slowed relaxation, despite action potential shortening, and increased diastolic calcium. SEA-0400 stabilized dofetilide-induced lability of repolarization and suppressed early afterdepolarizations. In vivo, SEA-0400 (0.4 and 0.8 mg/kg) had no effect on left ventricular pressure and suppressed dofetilide-induced TdPs dose dependently. Verapamil (0.3 mg/kg) also inhibited TdP, but caused a 15 +/- 8% drop of left ventricular pressure. A lower dose of verapamil without effects on left ventricular pressure (0.06 mg/kg) was not antiarrhythmic. Conclusions-In chronic atrioventricular block dogs, SEA-0400 treatment is effective against TdP. Unlike specific inhibition of LTCC, combined NCX and LTCC inhibition has no negative effects on cardiac hemodynamics.
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Action Potentials - drug effects
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Animals -
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Arrhythmias, Cardiac - drug therapy Arrhythmias, Cardiac - physiopathology
Calcium Channels, L-Type - drug effects Calcium Channels, L-Type - metabolism
Disease Models, Animal -
Dogs -
Electrocardiography -
Heart Ventricles - drug effects Heart Ventricles - physiopathology
Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology
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Sodium-Calcium Exchanger - antagonists & inhibitors Sodium-Calcium Exchanger - metabolism
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Find related publications in this database (Keywords)
antiarrhythmic drug
calcium channel
heart failure
long QT syndrome
Na+/Ca2+ exchange
Torsade de Pointes
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