Fantini E, Demaison L, Sentex E, Grynberg A, Athias P
I.N.R.A., Unité de Nutrition Lipidique, Dijon, France.
J Mol Cell Cardiol. 1994 Aug;26(8):949-58. doi: 10.1006/jmcc.1994.1116.
This study was undertaken to evaluate the direct cardioprotective effect of trimetazidine (TMZ), an anti-anginal drug devoid of haemodynamic action, on isolated myocytes. Cultured rat ventricular myocytes were treated with the drug 16 h and 1 h before the experiments. The drug-treated cells and control cells were placed in a substrate free medium and submitted in a specially designed device to either normoxia (N4), or hypoxia (150 min, H2.5, or 240 min, H4), or 150 min hypoxia followed by 90 min reoxygenation (HR). The treatment of the cells with TMZ (5 x 10(-4) M) resulted in a significant decrease of lactate dehydrogenase (LDH) leakage (-58% in H2.5, -36% in H4 and -37% in HR). The LDH release provoked by oxidizing agents. H2O2 and 13-s-HpOTrE (13(S)-hydroperoxyoctadecatrienoic acid) during post-hypoxic reoxygenation was also lowered by TMZ. However, this effect reflected the beneficial action of TMZ during hypoxia since the drug was not efficient in altering the LDH leakage induced by the oxidizing agents in normal conditions. Moreover, the hypoxia-induced decrease of ATP content was not affected by TMZ, and resynthesis of ATP during substrate-free reoxygenation was similar in TMZ-treated and control cells. The respiration parameters have been studied in rat heart mitochondria isolated from control and TMZ-treated rats, in the presence or absence of TMZ in the respiration medium (10(-4) M). The main result was a rapid and potent inhibition of palmitoylcarnitine oxidation, when TMZ was added to the respiration medium. The chronic treatment only resulted in a slight alteration of pyruvate oxidation. In conclusion, a pre-treatment of ventricular myocytes with TMZ resulted in an increased cell resistance to hypoxic stress, as evidenced by LDH leakage. This cytoprotective effect of TMZ should not be mediated through an antioxidant activity, but could be related to a modification of lipid metabolism.
本研究旨在评估抗心绞痛药物曲美他嗪（TMZ）对离体心肌细胞的直接心脏保护作用，该药物无血流动力学作用。在实验前16小时和1小时用该药物处理培养的大鼠心室肌细胞。将药物处理的细胞和对照细胞置于无底物培养基中，并在专门设计的装置中进行常氧（N4）、缺氧（150分钟，H2.5，或240分钟，H4）或150分钟缺氧后再氧合90分钟（HR）处理。用TMZ（5×10⁻⁴M）处理细胞导致乳酸脱氢酶（LDH）泄漏显著减少（H2.5时为-58%，H4时为-36%，HR时为-37%）。TMZ还降低了缺氧后再氧合期间由氧化剂H₂O₂和13 - s - HpOTrE（13(S)-氢过氧化十八碳三烯酸）引起的LDH释放。然而，这种作用反映了TMZ在缺氧期间的有益作用，因为该药物在正常条件下对改变氧化剂诱导的LDH泄漏无效。此外，TMZ不影响缺氧诱导的ATP含量降低，并且在无底物再氧合期间，TMZ处理的细胞和对照细胞中ATP的再合成相似。在存在或不存在呼吸培养基中TMZ（10⁻⁴M）的情况下，研究了从对照和TMZ处理的大鼠分离的大鼠心脏线粒体的呼吸参数。主要结果是，当将TMZ添加到呼吸培养基中时，棕榈酰肉碱氧化迅速且有力地受到抑制。长期处理仅导致丙酮酸氧化略有改变。总之，用TMZ预处理心室肌细胞导致细胞对缺氧应激的抵抗力增加，这通过LDH泄漏得以证明。TMZ的这种细胞保护作用不应通过抗氧化活性介导，而可能与脂质代谢的改变有关。
