The goal of this study was to test the hypothesis that the novel anti-ischemic 
drug ranolazine, which is known to inhibit late I(Na), could reduce 
intracellular [Na(+)](i) and diastolic [Ca(2+)](i) overload and improve 
diastolic function. Contractile dysfunction in human heart failure (HF) is 
associated with increased [Na(+)](i) and elevated diastolic [Ca(2+)](i). 
Increased Na(+) influx through voltage-gated Na(+) channels (late I(Na)) has 
been suggested to contribute to elevated [Na(+)](i) in HF. In isometrically 
contracting ventricular muscle strips from end-stage failing human hearts, 
ranolazine (10 micromol/L) did not exert negative inotropic effects on twitch 
force amplitude. However, ranolazine significantly reduced frequency-dependent 
increase in diastolic tension (i.e., diastolic dysfunction) by approximately 30% 
without significantly affecting sarcoplasmic reticulum (SR) Ca(2+) loading. To 
investigate the mechanism of action of this beneficial effect of ranolazine on 
diastolic tension, Anemonia sulcata toxin II (ATX-II, 40 nmol/L) was used to 
increase intracellular Na(+) loading in ventricular rabbit myocytes. ATX-II 
caused a significant rise in [Na(+)](i) typically seen in heart failure via 
increased late I(Na). In parallel, ATX-II significantly increased diastolic 
[Ca(2+)](i). In the presence of ranolazine the increases in late I(Na), as well 
as [Na(+)](i) and diastolic [Ca(2+)](i) were significantly blunted at all 
stimulation rates without significantly decreasing Ca(2+) transient amplitudes 
or SR Ca(2+) content. In summary, ranolazine reduced the frequency-dependent 
increase in diastolic tension without having negative inotropic effects on 
contractility of muscles from end-stage failing human hearts. Moreover, in 
rabbit myocytes the increases in late I(Na), [Na(+)](i) and [Ca(2+)](i) caused 
by ATX-II, were significantly blunted by ranolazine. These results suggest that 
ranolazine may be of therapeutic benefit in conditions of diastolic dysfunction 
due to elevated [Na(+)](i) and diastolic [Ca(2+)](i).