Combined Na+/Ca2+ Exchanger and L-Type Calcium Channel Block as a Potential Strategy to Suppress Arrhythmias and Maintain Ventricular Function.

BACKGROUND: -L-type calcium channel (LTCC) and Na+/Ca2+ exchanger (NCX) have been implicated in repolarization-dependent arrhythmias, but also modulate calcium and contractility. While 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 (CAVB), we investigated if 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 CAVB dogs. In ventricular myocytes, effects of SEA-0400 were tested on action potentials (AP), calcium transients, and early afterdepolarizations (EAD). In cardiomyocytes, SEA-0400 (1 muM) 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 AP shortening, and increased diastolic calcium. SEA-0400 stabilized dofetilide-induced lability of repolarization and suppressed EADs. In vivo, SEA-0400 (0.4 and 0.8 mg/kg) had no effect on LVP, and suppressed dofetilide-induced TdPs dose-dependently. Verapamil (0.3 mg/kg) also inhibited TdP, but caused a 15+/-8% drop of LVP. A lower dose of verapamil without effects on LVP (0.06 mg/kg) was not anti-arrhythmic. CONCLUSIONS: -In CAVB 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