Clarke B, Wyatt K M, McCormack J G
Department of Pharmacology, Heriot-Watt University Research Park, Edinburgh, Scotland, UK.
J Mol Cell Cardiol. 1996 Feb;28(2):341-50. doi: 10.1006/jmcc.1996.0032.
Ranolazine has shown anti-anginal efficacy in humans and cardiac anti-ischaemic activity in models, but without affecting haemodynamics or baseline contraction. In isolated normoxic rat hearts, Langendorff-perfused for 30 min with 11 mM glucose, 3% albumin, and 0.4 mM or 0.8 mM palmitate, 20 microM ranolazine significantly increased active, dephosphorylated, pyruvate dehydrogenase (PDHa), but not with no palmitate or 1.2 mM palmitate. Dichloroactetate (DCA, 1 mM), a PDHa kinase inhibitor, significantly increased PDHa in hearts perfused with 0, 0.4 or 0.8 mM but not 1.2 mM palmitate. PDHa was significantly increased with 1.2 mM palmitate by DCA plus ranolazine, and additive effects were also seen at 0.8 mM palmitate. Activation of PDH by ranolazine and promotion of glucose oxidation offers a plausible means by which the drug may be anti-ischaemic nonhaemodynamically. Extensive studies with extracted enzymes and isolated rat heart mitochondria failed to demonstrate any effects of ranolazine on PDH kinase or phosphatase, or on PDH catalytic activity, whereas effects of other known effectors (such as DCA) were readily demonstrable, suggesting that ranolazine activates PDH indirectly. Further analyses of the hearts revealed that ranolazine reduced acetyl CoA content under all conditions where fatty acid was present, and +/- DCA which itself had little effect. In the absence of fatty acid, ranolazine and/or DCA raised acetyl CoA. In perfusions where octanoate (+/- albumin) replaced palmitate, ranolazine still decreased acetyl CoA, but not when acetate replaced palmitate. In octanoate-perfused hearts, the contents of the C4, C6 and C8 CoA esters were all increased by ranolazine. This is consistent with ranolazine causing an inhibition of fatty acid beta-oxidation leading to decreased acetyl CoA and activation of PDH.
雷诺嗪已在人体中显示出抗心绞痛疗效，并在模型中展现出心脏抗缺血活性，但不影响血流动力学或基线收缩。在离体常氧大鼠心脏中，用含11 mM葡萄糖、3%白蛋白以及0.4 mM或0.8 mM棕榈酸的溶液进行Langendorff灌注30分钟，20 μM雷诺嗪显著增加了活性、去磷酸化的丙酮酸脱氢酶（PDHa），但在无棕榈酸或1.2 mM棕榈酸的情况下则未出现此现象。二氯乙酸（DCA，1 mM），一种PDHa激酶抑制剂，在灌注0、0.4或0.8 mM但非1.2 mM棕榈酸的心脏中显著增加了PDHa。在1.2 mM棕榈酸存在时，DCA加雷诺嗪使PDHa显著增加，在0.8 mM棕榈酸时也观察到了相加效应。雷诺嗪对PDH的激活以及对葡萄糖氧化的促进为该药物可能通过非血流动力学方式发挥抗缺血作用提供了一种合理的途径。对提取的酶和分离的大鼠心脏线粒体进行的广泛研究未能证明雷诺嗪对PDH激酶或磷酸酶以及对PDH催化活性有任何影响，而其他已知效应物（如DCA）的作用则很容易得到证明，这表明雷诺嗪间接激活了PDH。对心脏的进一步分析表明，在所有存在脂肪酸的条件下，雷诺嗪均降低了乙酰辅酶A含量，且无论有无DCA（其本身影响很小）。在无脂肪酸的情况下，雷诺嗪和/或DCA升高了乙酰辅酶A。在灌注中用辛酸（±白蛋白）替代棕榈酸时，雷诺嗪仍降低了乙酰辅酶A，但用乙酸替代棕榈酸时则不然。在辛酸灌注的心脏中，C4、C6和C8辅酶A酯的含量均因雷诺嗪而增加。这与雷诺嗪导致脂肪酸β氧化受抑制从而使乙酰辅酶A减少以及PDH激活相一致。
