Effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischemic rat hearts

Kumi Satoh, Kazuo Ichihara
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引用次数: 21

Abstract

The aim of the present study was to examine the effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on mitochondrial respiration in ischemic rat hearts, and to compare the effects between water-soluble pravastatin and lipid-soluble simvastatin. Either vehicle (0.5% carboxymethyl cellulose), pravastatin (2 or 4 mg/kg per day), or simvastatin (1 or 2 mg/kg per day) was orally administered for 3 weeks. Ischemia was induced by ligating the aorta for 60 min in anesthetized open chest rats under artificial respiration. The hearts were removed, mitochondria were isolated, and the respiration was determined by polarography using glutamate and succinate as substrates. When succinate was used as a substrate, the ADP-stimulated respiration (QO3) and ATP production per unit oxygen (ADP/O ratio) were decreased by ischemia. The decreases in QO3 and ADP/O ratio in the pravastatin-and simvastatin-treated groups appeared to be more prominent than those in the vehicle-treated group. This was especially true in the simvastatin-treated group. The ADP-limited respiration (QO4) with succinate in the vehicle-treated heart was slightly increased by ischemia, while that in the pravastatin- or simvastatin-treated hearts was decreased. In conclusion, HMG-CoA reductase inhibitors may result in worsening of myocardial mitochondrial respiration during ischemia.

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3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂对缺血大鼠心脏线粒体呼吸的影响
本研究的目的是研究3-羟基-3-甲基戊二酰辅酶A (HMG-CoA)还原酶抑制剂对缺血大鼠心脏线粒体呼吸的影响,并比较水溶性普伐他汀和脂溶性辛伐他汀的作用。两种载体(0.5%羧甲基纤维素)、普伐他汀(2或4mg /kg /天)或辛伐他汀(1或2mg /kg /天)口服3周。在人工呼吸条件下,结扎主动脉60 min诱导开胸麻醉大鼠缺血。去除心脏,分离线粒体,以谷氨酸和琥珀酸为底物,用极谱法测定呼吸作用。当使用琥珀酸盐作为底物时,ADP刺激的呼吸(QO3)和单位氧ATP产量(ADP/O比率)因缺血而降低。普伐他汀组和辛伐他汀组的QO3和ADP/O比值的下降比载药组更明显。在辛伐他汀治疗组尤其如此。经琥珀酸处理的心脏adp限制性呼吸(QO4)因缺血而略有增加,而普伐他汀或辛伐他汀处理的心脏QO4则下降。综上所述,HMG-CoA还原酶抑制剂可导致缺血时心肌线粒体呼吸恶化。
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