CYCLOSPORINE-A DECREASES RAT SKELETAL-MUSCLE MITOCHONDRIAL RESPIRATION IN-VITRO
CYCLOSPORINE-A DECREASES RAT SKELETAL-MUSCLE MITOCHONDRIAL RESPIRATION IN-VITRO
复制标题
DOI：
10.1164/ajrccm.151.6.7767529
复制
发表时间：
1995-06-01
影响因子：
24.7
通讯作者：
BROOKS, GA
中科院分区：
文献类型：
--
作者：
HOKANSON, JF;MERCIER, JG;BROOKS, GA
环孢素A（CsA）是一种有效的免疫抑制剂，用于减少器官移植手术后的排斥反应。已报告使用CsA的局限性为肝毒性和肾毒性。此外，即使动脉氧运输能力得到修复，移植后的运动能力也远低于预期。本研究的目的是确定CsA在体外对骨骼肌线粒体呼吸的影响，并确定CsA骨骼肌线粒体损伤的部位。差速离心后，从大鼠后肢肌肉匀浆中分离线粒体。在37 ℃下，在蔗糖和甘露醇呼吸介质中，使用Rank氧极谱仪测定线粒体呼吸。CsA抑制最大呼吸（ADP刺激）在琥珀酸和鱼藤酮的存在下，由18.3%，在苹果酸和丙酮酸的存在下，由34.7%。CsA使琥珀酸和鱼藤酮或丙酮酸加苹果酸的解偶联呼吸速率（加羰基氰对三氟甲氧基苯腙）分别降低19.6%和32.0%。我们的结论是CsA抑制最大耦合和解耦联骨骼肌线粒体呼吸在体外。此外，虽然CsA的影响更大的电子通量通过复合物I，线粒体病变引起的CsA是不是特定的电子传递链（ETC）的复合物I或复合物II。尽管移植患者有足够的动脉氧合和全身和局部氧输送，但运动表现不佳可能部分归因于免疫抑制治疗对骨骼肌线粒体FTC能力的影响。
Cyclosporine A (CsA) is a potent immunosuppressant used to decrease organ rejection after transplantation surgery. Reported limitations to use of CsA have been hepatotoxicity and nephrotoxicity. Additionally exercise capacity is much less than expected following transplantation even if arterial oxygen transport capacity is repaired. Purposes of the present study were to determine the effects of CsA on skeletal muscle mitochondrial respiration in vitro and to determine the site of the CsA skeletal muscle mitochondrial lesion. Mitochondria were isolated from rat hind limb muscle homogenates after differential centrifugation. Mitochondrial respiration was determined using a Rank oxygen polarograph at 37 degrees C in a sucrose and mannitol respiration medium. CsA inhibited maximal respiration (ADP stimulated) in the presence of succinate and rotenone by 18.3% and in the presence of malate and pyruvate by 34.7%. CsA decreased the rate of uncoupled respiration (addition of carbonyl cyanide p-trifluoromethozyphenylhydrazone) by 19.6% and 32.0% for succinate and rotenone, or pyruvate plus malate, respectively No significant effect of CsA on ADP/O for either substrate was observed. We conclude that CsA inhibits maximal coupled and uncoupled skeletal muscle mitochondrial respiration in vitro. Moreover, although the effects of CsA were greater on electron flux through Complex I, mitochondrial lesions caused by CsA were not specific to either Complex I or Complex II of the electron transport chain (ETC). Poor exercise performance despite adequate arterial oxygenation and systemic and regional oxygen deliveries in transplant patients may be attributed, in part, to the effects of immunosuppressive therapy on FTC capacity of skeletal muscle mitochondria.