Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity.
Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity.
复制标题
DOI：
10.1161/circresaha.111.258251
复制
发表时间：
2012-03-16
影响因子：
20.1
通讯作者：
Dudley SC Jr
中科院分区：
文献类型：
--
作者：
Lovelock JD;Monasky MM;Jeong EM;Lardin HA;Liu H;Patel BG;Taglieri DM;Gu L;Kumar P;Pokhrel N;Zeng D;Belardinelli L;Sorescu D;Solaro RJ;Dudley SC Jr
先前，我们证明了醋酸脱氧皮质酮（DOCA）盐高血压小鼠模型产生心脏氧化应激和舒张功能障碍，并保留收缩功能。氧化应激已被证明增加晚期内向钠电流（INa），减少净胞质Ca2+外排。doca -盐模型中的氧化应激可增加晚期INa，导致舒张功能障碍，可用雷诺嗪治疗。超声心动图显示，雷诺嗪治疗后高血压小鼠舒张功能障碍改善（E/E′，假手术31.9±2.8，假手术+雷诺嗪30.2±1.9,DOCA-salt 41.8±2.6，DOCA-salt+雷诺嗪31.9±2.6,p = 0.018）。DOCA-salt小鼠舒张末期压容积关系斜率升高，经治疗后改善至假手术水平（假手术0.16±0.01 vs假手术+雷诺嗪0.18±0.01 vs DOCA-salt 0.23±0.2 vs DOCA-salt+雷诺嗪0.17±0.01 mm Hg/L, p < 0.005）。多巴胺盐组肌细胞松弛受损，τ值改善（多巴胺盐0.18±0.02，多巴胺盐+雷诺嗪0.13±0.01，假药0.11±0.01，假药+雷诺嗪0.09±0.02 s, p = 0.0004）。晚期INa和Ca2+瞬态与假性肌细胞均无差异。从doca盐心脏中提取的洗涤剂纤维束表明，肌球蛋白结合蛋白c的谷胱甘肽化增加了肌丝对Ca2+的反应，用雷诺嗪处理改善了Ca2+反应和过桥动力学。因此，雷诺嗪可以逆转舒张功能障碍，这可能是由于它对肌丝的直接作用，表明心脏氧化应激可能通过改变收缩装置介导舒张功能障碍。
Previously, we demonstrated that a deoxycorticosterone acetate (DOCA)-salt hypertensive mouse model produces cardiac oxidative stress and diastolic dysfunction with preserved systolic function. Oxidative stress has been shown to increase late inward sodium current (INa), reducing the net cytosolic Ca2+ efflux. Oxidative stress in the DOCA-salt model may increase late INa resulting in diastolic dysfunction amenable to treatment with ranolazine. Echocardiography detected evidence of diastolic dysfunction in hypertensive mice that improved after treatment with ranolazine (E/E′, sham 31.9 ± 2.8, sham+ranolazine 30.2 ± 1.9, DOCA-salt 41.8 ± 2.6, and DOCA-salt+ranolazine 31.9 ± 2.6, p = 0.018). The end diastolic pressure volume relationship slope was elevated in DOCA-salt mice, improving to sham levels with treatment (sham 0.16 ± 0.01 vs. sham+ranolazine 0.18 ± 0.01 vs. DOCA-salt 0.23 ± 0.2 vs. DOCA-salt+ranolazine 0.17 ± 0.01 mm Hg/L, p < 0.005). DOCA-salt myocytes demonstrated impaired relaxation, τ, improving with ranolazine (DOCA-salt 0.18 ± 0.02, DOCA-salt + ranolazine 0.13 ± 0.01, Sham 0.11 ± 0.01, Sham + ranolazine 0.09 ± 0.02 s, p = 0.0004). Neither late INa nor the Ca2+ transients were different from sham myocytes. Detergent extracted fiber bundles from DOCA-salt hearts demonstrated increased myofilament response to Ca2+ with glutathionylation of myosin binding protein C. Treatment with ranolazine ameliorated the Ca2+ response and cross-bridge kinetics. Therefore, diastolic dysfunction could be reversed by ranolazine, likely resulting from a direct effect on myofilaments, indicating that cardiac oxidative stress may mediate diastolic dysfunction through altering the contractile apparatus.