Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts--role of late sodium current and intracellular ion accumulation.

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(+) and diastolic Ca(2+) overload and improve diastolic function. Contractile dysfunction in human heart failure (HF) is associated with increased Na(+) and elevated diastolic Ca(2+). Increased Na(+) influx through voltage-gated Na(+) channels (late I(Na)) has been suggested to contribute to elevated Na(+) 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(+) typically seen in heart failure via increased late I(Na). In parallel, ATX-II significantly increased diastolic Ca(2+). In the presence of ranolazine the increases in late I(Na), as well as Na(+) and diastolic Ca(2+) 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(+) and Ca(2+) 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(+) and diastolic Ca(2+).