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 INa, could reduce intracellular [Na+]i and diastolic [Ca2+]i overload and improve diastolic function. Contractile dysfunction in human heart failure (HF) is associated with increased [Na+]i and elevated diastolic [Ca2+]i. Increased Na+ influx through voltage-gated Na+ channels (late INa) 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 µmol/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 ~ 30% without significantly affecting sarcoplasmic reticulum (SR) Ca2+ 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 INa. In parallel, ATX-II significantly increased diastolic [Ca2+]i. In the presence of ranolazine the increases in late INa, as well as [Na+]i and diastolic [Ca2+]i were significantly blunted at all stimulation rates without significantly decreasing Ca2+ transient amplitudes or SR Ca2+ 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 INa, [Na+]i and [Ca2+]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 [Ca2+]i.