Department of Anesthesiology, Pharmacology, and Therapeutics, Life Sciences Institute, University of British Columbia, Vancouver, Canada.
Am J Physiol Heart Circ Physiol. 2014 Mar;306(6):H867-81. doi: 10.1152/ajpheart.00704.2013. Epub 2014 Jan 24.
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 (SHRs), where left ventricular relaxation is impaired and stiffness increased. The objective of this study was to determine whether ranolazine improves diastolic function in SHRs and identify the mechanism(s) by which improvement is achieved. Specifically, to test the hypothesis that ranolazine, by inhibiting late sodium current, reduces Ca(2+) overload and promotes ventricular relaxation and reduction in diastolic stiffness, the effects of ranolazine or vehicle on heart function and the response to dobutamine challenge were evaluated in aged male SHRs and Wistar-Kyoto rats by echocardiography and pressure-volume loop analysis. The effects of ranolazine and the more specific sodium channel inhibitor tetrodotoxin 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 tetrodotoxin also enhanced cardiomyocyte relaxation and reduced myoplasmic free Ca(2+) during diastole at high-stimulus rates in the SHR. The density of the late sodium current was elevated in SHRs. In conclusion, 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 Ca(2+) overload.
舒张功能障碍可导致射血分数保留的心力衰竭，目前对此尚无有效治疗方法。已有报道称雷诺嗪可减轻舒张功能障碍，但具体作用机制尚不清楚。本研究旨在观察雷诺嗪对左心室舒张功能受损、僵硬度增加的自发性高血压大鼠（SHR）的影响，并确定其改善舒张功能的作用机制。具体而言，为验证雷诺嗪通过抑制晚期钠电流减少 Ca（2+）过载，从而促进心室舒张和降低舒张僵硬度的假说，通过超声心动图和压力-容积环分析评估了雷诺嗪或载体对老年雄性 SHR 和 Wistar-Kyoto 大鼠心功能和多巴酚丁胺挑战反应的影响。通过检测晚期钠电流、肌节长度和分离心肌细胞内的 Ca（2+），确定了雷诺嗪和更特异的钠通道抑制剂河豚毒素对晚期钠电流的影响。雷诺嗪降低了 SHR 的舒张末期压力-容积关系斜率，并在多巴酚丁胺挑战期间改善了舒张功能。雷诺嗪和河豚毒素还增强了 SHR 高刺激率时的心肌细胞舒张，并降低了舒张期的胞质游离 Ca（2+）。晚期钠电流在 SHR 中增加。综上所述，雷诺嗪可有效减轻 SHR 的舒张功能障碍。其作用机制至少部分与其抑制 SHR 中增加的晚期钠电流，从而减少 Ca（2+）过载有关。
