Satoh K, Ichihara K
Department of Pharmacology, Hokkaido College of Pharmacy, Otaru, Japan.
Eur J Pharmacol. 1995 Mar 16;292(3-4):271-5. doi: 10.1016/0926-6917(95)90032-2.
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.
本研究的目的是检测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效果。给予溶剂（0.5%羧甲基纤维素）、普伐他汀（每天2或4mg/kg）或辛伐他汀（每天1或2mg/kg）灌胃3周。在人工呼吸条件下，通过结扎麻醉开胸大鼠的主动脉60分钟诱导缺血。取出心脏，分离线粒体，以谷氨酸和琥珀酸为底物，采用极谱法测定呼吸。当以琥珀酸为底物时，缺血可使二磷酸腺苷（ADP）刺激的呼吸（QO3）和每单位氧的三磷酸腺苷（ATP）生成量（ADP/O比值）降低。普伐他汀和辛伐他汀治疗组QO3和ADP/O比值的降低似乎比溶剂治疗组更显著。在辛伐他汀治疗组尤其如此。溶剂治疗的心脏中，以琥珀酸为底物的ADP限制呼吸（QO4）在缺血时略有增加，而普伐他汀或辛伐他汀治疗的心脏中则降低。总之，HMG-CoA还原酶抑制剂可能导致缺血期间心肌线粒体呼吸功能恶化。
