McCormack J G, Barr R L, Wolff A A, Lopaschuk G D
Department of Pediatrics, University of Alberta, Edmonton, Canada.
Circulation. 1996 Jan 1;93(1):135-42. doi: 10.1161/01.cir.93.1.135.
Ranolazine is a novel antianginal agent that may reduce symptoms without affecting hemodynamics and has shown cardiac antiischemic effects in in vivo and in vitro models. In one study it increased active pyruvate dehydrogenase (PDHa). Other agents that increase PDHa and so increase glucose and decrease fatty acid (FA) oxidation are beneficial in ischemic-reperfused hearts. Effects of ranolazine on glucose and palmitate oxidation and glycolysis were assessed in isolated rat hearts.
Working hearts were perfused with Krebs-Henseleit buffer plus 3% albumin under normoxic conditions and on reperfusion after 30-minute no-flow ischemia and under conditions designed to give either low [low (Ca) (1.25 mmol/L), high [FA] (1.2 mmol/L palmitate; with/without insulin] or high (2.5 mmol/L Ca, 0.4 mmol/L palmitate; with/without pacing) glucose oxidation rates; Langendorff-perfused hearts (high Ca, low FA) were subjected to varying degrees of low-flow ischemia. Glycolysis and glucose oxidation were measured with the use of [5-3H/U-14C]-glucose and FA oxidation with the use of [1-14C]- or [9,10-3H]-palmitate. In working hearts, 10 micromol/L ranolazine significantly increased glucose oxidation 1.5-fold to 3-fold under conditions in which the contribution of glucose to overall ATP production was low (low Ca, high FA, with insulin), high (high Ca, low Fa, with pacing), or intermediate. In some cases, reductions in FA oxidation were seen. No substantial changes in glycolysis were noted with/without ranolazine; rates were approximately 10-fold glucose oxidation rates, suggesting that pyruvate supply was not limiting. Insulin increased basal glucose oxidation and glycolysis but did not alter ranolazine responses. In normoxic Langendorff hearts (high Ca, low FA; 15 mL/min), all basal rates were lower compared with working hearts, but 10 micromol/L ranolazine similarly increased glucose oxidation; ranolazine also significantly increased it during flow reduction to 7, 3, and 0.5 mL/min. Ranolazine did not affect baseline contractile or hemodynamic parameters or O2 use. In reperfused ischemic working hearts, ranolazine significantly improved functional outcome, which was associated with significant increases in glucose oxidation, a reversal of the increased FA oxidation seen in control reperfusions (versus preischemic), and a smaller but significant increase in glycolysis.
Beneficial effects of ranolazine in cardiac ischemia/reperfusion may be due, at least in part, to a stimulation of glucose oxidation and a reduction in FA oxidation, allowing improved ATP/O2 and reduction in the buildup of H+, lactate, and harmful fatty acyl intermediates.
雷诺嗪是一种新型抗心绞痛药物，可减轻症状而不影响血流动力学，并且在体内和体外模型中均显示出心脏抗缺血作用。在一项研究中，它增加了活性丙酮酸脱氢酶（PDHa）。其他增加PDHa从而增加葡萄糖利用并减少脂肪酸（FA）氧化的药物对缺血再灌注心脏有益。本研究评估了雷诺嗪对离体大鼠心脏葡萄糖和棕榈酸氧化及糖酵解的影响。
在常氧条件下，用Krebs-Henseleit缓冲液加3%白蛋白灌注工作心脏，在30分钟无血流缺血后再灌注，并在设计为提供低[低（钙）（1.25 mmol/L）、高[脂肪酸]（1.2 mmol/L棕榈酸；加/不加胰岛素）或高（2.5 mmol/L钙，0.4 mmol/L棕榈酸；加/不加起搏）葡萄糖氧化率的条件下进行灌注；Langendorff灌注心脏（高钙，低脂肪酸）经历不同程度的低流量缺血。使用[5-³H/U-¹⁴C]-葡萄糖测量糖酵解和葡萄糖氧化，使用[1-¹⁴C]-或[9,10-³H]-棕榈酸测量脂肪酸氧化。在工作心脏中，10 μmol/L雷诺嗪在葡萄糖对总ATP产生的贡献较低（低钙，高脂肪酸，加胰岛素）、较高（高钙，低脂肪酸，加起搏）或中等的条件下，显著将葡萄糖氧化增加1.5至3倍。在某些情况下，可见脂肪酸氧化减少。无论有无雷诺嗪，糖酵解均无实质性变化；其速率约为葡萄糖氧化速率的10倍，表明丙酮酸供应不受限。胰岛素增加基础葡萄糖氧化和糖酵解，但不改变雷诺嗪的反应。在常氧Langendorff心脏（高钙，低脂肪酸；15 mL/min）中，所有基础速率均低于工作心脏，但10 μmol/L雷诺嗪同样增加葡萄糖氧化；在流量降至7、3和0.5 mL/min时，雷诺嗪也显著增加葡萄糖氧化。雷诺嗪不影响基线收缩或血流动力学参数或氧气消耗。在再灌注的缺血工作心脏中，雷诺嗪显著改善功能结局，这与葡萄糖氧化显著增加、对照再灌注（与缺血前相比）中增加的脂肪酸氧化逆转以及糖酵解较小但显著增加有关。
雷诺嗪在心脏缺血/再灌注中的有益作用可能至少部分归因于刺激葡萄糖氧化和减少脂肪酸氧化，从而改善ATP/氧气比值，并减少H⁺、乳酸和有害脂肪酰中间体的积累。
