Combined Na+/Ca2+ Exchanger and L-Type Calcium Channel Block as a Potential Strategy to Suppress Arrhythmias and Maintain Ventricular Function
2013
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 pointesarrhythmias (TdP), while maintaining calcium homeostasis and hemodynamics. Methods and Results— Left
ventricular pressure(LVP) and ECG were monitored during infusion of SEA-0400 and
verapamilin anesthetized dogs. Different doses were tested against
dofetilide-induced TdP in chronic
atrioventricular blockdogs. In ventricular myocytes, effects of SEA-0400 were tested on action potentials, calcium transients, and early
afterdepolarizations. In cardiomyocytes, SEA-0400 (1 μmol/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
repolarizationand suppressed early
afterdepolarizations. In vivo, SEA-0400 (0.4 and 0.8 mg/kg) had no effect on left
ventricular pressureand 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
verapamilwithout effects on left
ventricular pressure(0.06 mg/kg) was not antiarrhythmic. Conclusions— In chronic
atrioventricular blockdogs, 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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