Department of Anesthesiology, The Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Pharmacol Res. 2011 Oct;64(4):381-92. doi: 10.1016/j.phrs.2011.06.018. Epub 2011 Jun 29.
Ranolazine is a clinically approved drug for treating cardiac ventricular dysrhythmias and angina. Its mechanism(s) of protection is not clearly understood but evidence points to blocking the late Na+ current that arises during ischemia, blocking mitochondrial complex I activity, or modulating mitochondrial metabolism. Here we tested the effect of ranolazine treatment before ischemia at the mitochondrial level in intact isolated hearts and in mitochondria isolated from hearts at different times of reperfusion. Left ventricular (LV) pressure (LVP), coronary flow (CF), and O2 metabolism were measured in guinea pig isolated hearts perfused with Krebs-Ringer's solution; mitochondrial (m) superoxide (O2·-), Ca2+, NADH/FAD (redox state), and cytosolic (c) Ca2+ were assessed on-line in the LV free wall by fluorescence spectrophotometry. Ranolazine (5 μM), infused for 1 min just before 30 min of global ischemia, itself did not change O2·-, cCa2+, mCa2+ or redox state. During late ischemia and reperfusion (IR) O2·- emission and m[Ca2+] increased less in the ranolazine group vs. the control group. Ranolazine decreased c[Ca2+] only during ischemia while NADH and FAD were not different during IR in the ranolazine vs. control groups. Throughout reperfusion LVP and CF were higher, and ventricular fibrillation was less frequent. Infarct size was smaller in the ranolazine group than in the control group. Mitochondria isolated from ranolazine-treated hearts had mild resistance to permeability transition pore (mPTP) opening and less cytochrome c release than control hearts. Ranolazine may provide functional protection of the heart during IR injury by reducing cCa2+ and mCa2+ loading secondary to its effect to block the late Na+ current. Subsequently it indirectly reduces O2·- emission, preserves bioenergetics, delays mPTP opening, and restricts loss of cytochrome c, thereby reducing necrosis and apoptosis.
雷诺嗪是一种临床批准用于治疗心脏室性心律失常和心绞痛的药物。其保护机制尚不清楚，但有证据表明，它可以阻断缺血时产生的晚期钠离子电流、阻断线粒体复合物 I 活性，或调节线粒体代谢。在这里，我们在完整的分离心脏和不同再灌注时间的心脏线粒体中，测试了缺血前雷诺嗪处理对线粒体水平的影响。豚鼠分离心脏用 Krebs-Ringer 溶液灌注，测量左心室（LV）压力（LVP）、冠状血流（CF）和 O2 代谢；通过荧光分光光度法在线评估 LV 游离壁的线粒体（m）超氧阴离子（O2·-）、Ca2+、NADH/FAD（氧化还原状态）和细胞质（c）Ca2+。雷诺嗪（5 μM）在 30 分钟全缺血前 1 分钟输注，本身不会改变 O2·-、cCa2+、mCa2+或氧化还原状态。在晚期缺血和再灌注（IR）期间，与对照组相比，雷诺嗪组的 O2·-发射和 m[Ca2+]增加较少。雷诺嗪仅在缺血期间降低 c[Ca2+]，而 NADH 和 FAD 在 IR 期间在雷诺嗪组与对照组之间没有差异。在整个再灌注期间，LVP 和 CF 较高，室性颤动较少发生。与对照组相比，雷诺嗪组的梗死面积较小。与对照组相比，来自雷诺嗪处理心脏的线粒体对通透性转换孔（mPTP）开放具有轻度抗性，并且细胞色素 c 释放较少。雷诺嗪可能通过阻断晚期钠离子电流来减少 cCa2+和 mCa2+的负荷，从而减轻心脏在再灌注损伤期间的功能损伤。随后，它间接减少 O2·-发射，保持生物能量，延迟 mPTP 开放，并限制细胞色素 c 的损失，从而减少坏死和凋亡。
