吡格列酮减轻大鼠离体心脏急性可卡因毒性：代谢调节的潜在保护作用。
Pioglitazone attenuates acute cocaine toxicity in rat isolated heart: potential protection by metabolic modulation.
机构信息
Department of Anesthesiology, University of Illinois, College of Medicine at Chicago, Illinois, USA.
出版信息
Anesthesiology. 2011 Jun;114(6):1389-95. doi: 10.1097/ALN.0b013e318218a7f6.
BACKGROUND
The authors tested whether cocaine depresses mitochondrial acylcarnitine exchange and if a drug that enhances glucose metabolism could protect against cocaine-induced cardiac dysfunction.
METHODS
Oxygen consumption with and without cocaine was compared in rat cardiac mitochondria using octanoylcarnitine (lipid) or pyruvate (nonlipid) substrates. Isolated hearts from rats with or without a pioglitazone-supplemented diet were exposed to cocaine.
RESULTS
The 0.5 mM cocaine inhibited respiration supported by octanoylcarnitine (82 ± 10.4 and 45.7 ± 4.24 ngatomO min⁻¹ · mg⁻¹ · protein ± SEM, for control and cocaine treatment, respectively; P < 0.02) but not pyruvate-supported respiration (281 ± 12.5 and 267 ± 12.7 ngatomO min⁻¹ · mg⁻¹ · protein ± SEM; P = 0.45). Cocaine altered contractility, lusitropy, coronary resistance, and lactate production in isolated heart. These effects were each blunted in pioglitazone-treated hearts. The pioglitazone diet attenuated the drop in the rate-pressure product (P = 0.002), cocaine-induced diastolic dysfunction (P = 0.04), and myocardial vascular resistance (P = 0.05) compared with that of controls. Lactate production was higher in pretreated hearts (P = 0.008) and in ventricular myocytes cultured with pioglitazone (P = 0.0001).
CONCLUSIONS
Cocaine inhibited octanoylcarnitine-supported mitochondrial respiration. A pioglitazone diet significantly attenuated the effects of cocaine on isolated heart. The authors postulate that inhibition of acylcarnitine exchange could contribute to cocaine-induced cardiac dysfunction and that metabolic modulation warrants additional study.
背景
作者测试了可卡因是否会抑制线粒体酰基辅酶 A 交换，以及是否有一种增强葡萄糖代谢的药物可以预防可卡因引起的心脏功能障碍。
方法
使用辛酰基辅酶 A（脂质）或丙酮酸（非脂质）作为底物，比较大鼠心脏线粒体中存在和不存在可卡因时的耗氧量。用补充有吡格列酮的饮食或不补充有吡格列酮的饮食喂养大鼠，然后用可卡因处理其离体心脏。
结果
0.5mM 可卡因抑制了辛酰基辅酶 A 支持的呼吸作用（分别为 82±10.4 和 45.7±4.24ngatomO min ⁻¹ · mg ⁻¹ · protein ± SEM，对照和可卡因处理组；P<0.02），但不抑制丙酮酸支持的呼吸作用（分别为 281±12.5 和 267±12.7ngatomO min ⁻¹ · mg ⁻¹ · protein ± SEM；P=0.45）。可卡因改变了离体心脏的收缩性、松弛性、冠状阻力和乳酸产生。这些作用在吡格列酮处理的心脏中都减弱了。与对照组相比，吡格列酮饮食减轻了心率-压力乘积的下降（P=0.002）、可卡因引起的舒张功能障碍（P=0.04）和心肌血管阻力（P=0.05）。预处理的心脏（P=0.008）和用吡格列酮培养的心室肌细胞中乳酸产生更高（P=0.0001）。
结论
可卡因抑制了辛酰基辅酶 A 支持的线粒体呼吸作用。吡格列酮饮食显著减轻了可卡因对离体心脏的作用。作者推测，酰基辅酶 A 交换的抑制可能导致可卡因引起的心脏功能障碍，代谢调节值得进一步研究。
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