Demaison L, Fantini E, Sentex E, Grynberg A, Athias P
I.N.R.A., Unité de Nutrition Lipidique, Dijon, France.
Am J Cardiol. 1995 Aug 24;76(6):31B-37B.
The mechanism of action of the antianginal trimetazidine (TMZ) remains largely unknown. In cultured rat ventricular myocytes in physiologic conditions, TMZ (5 x 10(-4) M) reduced the plateau potential level, the upstroke velocity, and the spontaneous action potential rate. When the cardiomyocytes were submitted to hypoxia (150 or 240 minutes) in a glucose-free medium, treatment with TMZ largely prevented the hypoxia-induced electromechanical alterations, i.e., the decrease in plateau amplitude, in resting membrane potential, in action potential duration, in rate, and in contractility. No hypoxia-induced arrhythmia was observed in the TMZ-treated cells. Moreover, the lactate dehydrogenase leakage was significantly reduced in the TMZ-treated cardiomyocytes (-58% and -36%, after 150 and 240 minutes of hypoxia, respectively). The drug was not efficient in reducing the hypoxia-induced decrease in adenosine triphosphate (ATP) content. The cellular ATP content was slightly lower in the TMZ-treated cells in normoxic conditions and in hypoxic conditions, but only in the glucose-free medium. To investigate further the relation between TMZ and energy metabolism, the respiration parameters were measured in heart mitochondria isolated from control and TMZ-treated rats (6 mg/kg/day, 7 days) with different substrates. This treatment resulted in a slight alteration of pyruvate oxidation, which was observed in the absence and in the presence of TMZ (10(-4) M) in the respiration medium. Conversely, a potent inhibition of palmitoylcarnitine oxidation was measured when TMZ was added to the respiration medium. Neither pretreatment of the rats, nor addition of TMZ to the medium affected the oxidation of glutamate or citrate.(ABSTRACT TRUNCATED AT 250 WORDS)
抗心绞痛药物曲美他嗪（TMZ）的作用机制在很大程度上仍不清楚。在生理条件下培养的大鼠心室肌细胞中，TMZ（5×10⁻⁴ M）降低了平台期电位水平、除极速度和自发动作电位频率。当心肌细胞在无葡萄糖培养基中缺氧（150或240分钟）时，TMZ处理可在很大程度上预防缺氧诱导的机电改变，即平台期振幅、静息膜电位、动作电位时程、频率和收缩性的降低。在TMZ处理的细胞中未观察到缺氧诱导的心律失常。此外，TMZ处理的心肌细胞中乳酸脱氢酶泄漏显著减少（缺氧150和240分钟后分别减少58%和36%）。该药物在降低缺氧诱导的三磷酸腺苷（ATP）含量减少方面无效。在常氧和缺氧条件下，TMZ处理的细胞中细胞ATP含量略低，但仅在无葡萄糖培养基中如此。为了进一步研究TMZ与能量代谢之间的关系，在从对照和TMZ处理的大鼠（6 mg/kg/天，7天）分离的心脏线粒体中，用不同底物测量呼吸参数。这种处理导致丙酮酸氧化略有改变，在呼吸培养基中无论有无TMZ（10⁻⁴ M）均可观察到。相反，当向呼吸培养基中添加TMZ时，测量到棕榈酰肉碱氧化受到强烈抑制。大鼠的预处理或向培养基中添加TMZ均不影响谷氨酸或柠檬酸的氧化。（摘要截断于250字）
