Rationale: Diastolic dysfunction can lead to heart failure with preserved ejection fraction, for which there is no effective therapeutic. Ranolazine has been reported to reduce diastolic dysfunction, but the specific mechanisms of action are unclear. The effect of ranolazine on diastolic function was examined in spontaneously hypertensive rats (SHR), where left ventricular relaxation is impaired and stiffness increased. Objective: Determine whether ranolazine improves diastolic function in SHR and identify the mechanism(s) by which improvement is achieved. Specifically, to test the hypothesis that ranolazine, by inhibiting late sodium current, reduces Ca2+ overload and promotes ventricular relaxation and reduction in diastolic stiffness. Methods and Results: The effects of ranolazine or vehicle on heart function and the response to dobutamine challenge were evaluated in aged male SHR and Wistar Kyoto (WKY) rats by echocardiography and pressure-volume loop analysis. The effects of ranolazine and the more specific sodium channel inhibitor, TTX, were determined on the late sodium current, sarcomere length and intracellular calcium in isolated cardiomyocytes. Ranolazine reduced the end-diastolic pressure-volume relationship slope and improved diastolic function during dobutamine challenge in the SHR. Ranolazine and TTX also enhanced cardiomyocyte relaxation and reduced myoplasmic free Ca2+ during diastole at high stimulus rates in the SHR. The density of the late sodium current was elevated in SHR. Conclusions: Ranolazine was effective in reducing diastolic dysfunction in the SHR. Its mechanism of action, at least in part, is consistent with inhibition of the increased late sodium current in the SHR leading to reduced Ca2+ overload. 

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