Veitch K, Maisin L, Hue L
Hormone and Metabolic Research Unit, International Institute of Cellular and Molecular Pathology, Brussels, Belgium.
Am J Cardiol. 1995 Aug 24;76(6):25B-30B.
Trimetazidine (TMZ) is an anti-ischemic compound whose precise mode of action is unknown, although several studies have suggested a metabolic effect, and there have been reports of protection of mitochondria against oxidative stress damage. Using a Langendorff rat heart model, we examined the effects of TMZ on the mitochondrial damage following 30 minutes of ischemia and 5 minutes of reperfusion. Mitochondrial respiration with succinate, glutamate-malate and ascorbate-N,N,N',N'-tetramethylphenylenediamine (TMPD) as substrates was significantly decreased following ischemia-reperfusion. Preperfusion with 10(-5) M TMZ had no effect on these rates in normoxic or ischemic hearts. However, 10(-3) M TMZ significantly decreased the glutamate-malate rate in mitochondria from normoxic hearts, and this rate was not further decreased following ischemia-reperfusion, and 10(-3) M TMZ also partially protected ascorbate-TMPD activity. The effect on glutamate-malate was probably due to an inhibition of complex I by TMZ, which specifically inhibited reduced nicotinamide-adenine-dinucleotide-cytochrome c reductase and complex I in lysed mitochondria. We also studied the effects of TMZ on the activity of pyruvate dehydrogenase (PDH) in normoxic and ischemic hearts perfused with 0.5 mM palmitate, which caused the enzyme to be almost completely inactivated. After short periods of ischemia (10-20 minutes) the PDH inactivation by palmitate was progressively lost. Preperfusion with 10(-5) M TMZ had a tendency to decrease lactate dehydrogenase release, accompanied by a maintenance of the inhibition of PDH by palmitate. This may allow the heart to oxidize fatty acids preferentially during reperfusion, hence removing possible toxic acyl esters.
曲美他嗪（TMZ）是一种抗缺血化合物，其确切作用方式尚不清楚，尽管多项研究表明其具有代谢作用，并且有报道称其可保护线粒体免受氧化应激损伤。我们使用Langendorff大鼠心脏模型，研究了TMZ对缺血30分钟和再灌注5分钟后线粒体损伤的影响。缺血再灌注后，以琥珀酸、谷氨酸-苹果酸和抗坏血酸-N，N，N'，N'-四甲基对苯二胺（TMPD）为底物的线粒体呼吸显著降低。在常氧或缺血心脏中，用10⁻⁵ M TMZ预灌注对这些速率没有影响。然而，10⁻³ M TMZ显著降低了常氧心脏线粒体中谷氨酸-苹果酸的速率，缺血再灌注后该速率没有进一步降低，并且10⁻³ M TMZ还部分保护了抗坏血酸-TMPD活性。对谷氨酸-苹果酸的影响可能是由于TMZ对复合体I的抑制，其特异性抑制了裂解线粒体中还原型烟酰胺腺嘌呤二核苷酸-细胞色素c还原酶和复合体I。我们还研究了TMZ对用0.5 mM棕榈酸灌注的常氧和缺血心脏中丙酮酸脱氢酶（PDH）活性的影响，棕榈酸可使该酶几乎完全失活。短暂缺血（10 - 20分钟）后，棕榈酸对PDH的失活作用逐渐消失。用10⁻⁵ M TMZ预灌注有降低乳酸脱氢酶释放的趋势，同时维持棕榈酸对PDH的抑制作用。这可能使心脏在再灌注期间优先氧化脂肪酸，从而去除可能有毒的酰基酯。
