Department of Medicine, Division of Cardiology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814.
Department of Medicine, Division of Cardiology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814.
J Card Fail. 2019 Oct;25(10):828-836. doi: 10.1016/j.cardfail.2019.08.015. Epub 2019 Aug 25.
To evaluate possible treatment-related hemodynamic changes, we administered ranolazine or mexiletine to swine with heart failure (HF) and to controls.
Ranolazine and mexiletine potently inhibit depolarizing late Na current (I) and Na entry into cardiomyocytes Blocking Na entry may increase forward-mode Na/Ca exchange and reduce cellular Ca load, further compromising systolic contraction during HF.
Anesthetized tachypaced HF swine received ranolazine (n = 9) or mexiletine (n = 7) as boluses, then as infusions; the same experiments were performed in 10 nonpaced controls. The swine with HF had characteristic elevated left ventricular end-diastolic pressure (LVEDP) and reduced maximal left ventricular pressure rise (+dP/dt) and left ventricular peak systolic pressure (LVSP). No significant change occurred after ranolazine dosing for any parameter: LVEDP, +dP/dt, LVSP, heart rate, maximal LV pressure fall rate (-dP/dt), or time constant for isovolumic relaxation. Similar results seen in additional swine with HF: 7 were given mexiletine, and 7 others were given ranolazine after a 27% rate decrement to maximize I. Patch-clamped HF cardiomyocytes confirmed drug-induced I blockade.
Ranolazine or mexiletine blocking I neither worsened nor improved hemodynamics during advanced HF. Although results must be clinically confirmed, they suggest inhibition of I by ranolazine or mexiletine may not exacerbate HF in patients.
为了评估可能与治疗相关的血流动力学变化，我们给心力衰竭（HF）猪和对照组猪施用雷诺嗪或米贝地尔。
雷诺嗪和米贝地尔能强力抑制去极化晚期钠电流（I）和钠进入心肌细胞。钠内流阻断可能会增加正向模式钠/钙交换，减少细胞内钙负荷，在 HF 期间进一步损害收缩功能。
麻醉的快速起搏 HF 猪接受雷诺嗪（n=9）或米贝地尔（n=7）推注，然后是输注；10 只非起搏对照组进行了相同的实验。HF 猪具有特征性的升高的左心室舒张末期压力（LVEDP）和降低的最大左心室压力上升（+dP/dt）和左心室峰值收缩压（LVSP）。雷诺嗪给药后，任何参数均未发生明显变化：LVEDP、+dP/dt、LVSP、心率、最大 LV 压力下降率（-dP/dt）或等容舒张时间常数。HF 猪的其他实验结果相似：7 只猪给予米贝地尔，7 只猪在 27%的心率降低后给予雷诺嗪，以最大限度地增加 I。在 HF 心肌细胞中证实了药物诱导的 I 阻断。
雷诺嗪或米贝地尔阻断 I 既没有使晚期 HF 的血液动力学恶化，也没有改善。尽管结果必须在临床上得到证实，但它们表明雷诺嗪或米贝地尔对 I 的抑制作用不会使患者的 HF 恶化。
