Pathological conditions, including ischemia and heart failure, are associated 
with altered sodium channel function and increased late sodium current 
(I(Na,L)), leading to prolonged action potential duration, increased 
intracellular sodium and calcium concentrations, and arrhythmias. We used 
anemone toxin (ATX)-II to study the effects of increasing I(Na,L) on 
intracellular calcium cycling in rat isolated hearts. Cardiac contraction was 
abolished using paralytic agents. Ranolazine (RAN) was used to inhibit late 
I(Na). Hearts were loaded with fluo-4-acetoxymethyl ester, and myocyte 
intracellular calcium transients (CaTs) were measured using laser scanning 
confocal microscopy. ATX (1 nM) prolonged CaT duration at 50% recovery in hearts 
paced at a basal rate of 2 Hz and increased the sensitivity of the heart to the 
development of calcium alternans caused by fast pacing. ATX increased the time 
required for recovery of CaT amplitude following a previous beat, and ATX 
induced spontaneous calcium release waves during rapid pacing of the heart. ATX 
prolonged the duration of repolarization from the initiation of the activation 
to terminal repolarization in the pseudo-electrocardiogram. All actions of ATX 
were both reversed and prevented by subsequent or prior exposure, respectively, 
of hearts to RAN (10 microM). Most importantly, the increased vulnerability of 
the heart to the development of calcium alternans during rapid pacing was 
reversed or prevented by 10 microM RAN. These results suggest that enhancement 
of I(Na,L) alters calcium cycling. Reduction by RAN of I(Na,L)-induced 
dysregulation of calcium cycling could contribute to the antiarrhythmic actions 
of this agent in both reentrant and triggered arrhythmias.