Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts — Role of late sodium current and intracellular ion accumulation

Abstract

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 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) 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.