An engineered cocaine hydrolase blunts and reverses cardiovascular responses to cocaine in rats
An engineered cocaine hydrolase blunts and reverses cardiovascular responses to cocaine in rats
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DOI：
10.1124/jpet.104.068122
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发表时间：
2004-09-01
影响因子：
3.5
通讯作者：
Brimijoin, S
中科院分区：
文献类型：
--
作者：
Gao, Y;Brimijoin, S
越来越多的证据表明，人血浆丁酰胆碱酯酶可以降低可卡因过量的毒性。最近，通过基于结构的蛋白质工程，我们将这种酶转化为更有效的可卡因水解酶（CocE）。在大鼠身上进行测试时，CocE缩短了可卡因的血浆半衰期，并减少了心脏和大脑中的药物积聚。在这里，我们研究了CocE拮抗可卡因对心血管反应的潜力。麻醉大鼠的血压连续记录从股动脉的仪器。钴（7 mg/kg i.v.）导致血压在30 s内升高25 - 37 mm Hg，但血压在60 s内恢复至基线水平。当用阿托品（1 mg/kg）阻断迷走神经反射时，这些短暂的升压反应延长至5 min。在此条件下，CocE（3 mg/kg i. v.）的减少可卡因的升压作用，而延迟治疗与CocE迅速恢复正常的平均血压。CocE在未用可卡因处理的对照动物中没有血流动力学效应。CocE可以对抗可卡因预先建立的生理作用的发现表明，类似或改进的水解酶可能有助于拯救患者免于药物过量的危及生命的毒性。
There is increasing evidence that human plasma butyrylcholinesterase can lower the toxicity of cocaine overdose. Recently, with structure-based protein engineering, we converted this enzyme into a more efficient cocaine hydrolase (CocE). When tested in rats, CocE shortened cocaine's plasma half-life and decreased drug accumulation in heart and brain. Here, we have investigated the potential of CocE to antagonize cardiovascular responses to cocaine. Anesthetized rats were instrumented for continuous recording of blood pressure from the femoral artery. Cocaine ( 7 mg/kg i.v.) caused blood pressure to rise within 30 s by 25 to 37 mm Hg, but pressure returned to baseline within 60 s. These transient pressor responses were prolonged up to 5 min when vagal reflexes were blocked with atropine ( 1 mg/kg). Under such conditions, pretreatment with CocE ( 3 mg/kg i. v.) reduced cocaine's pressor effect, whereas delayed treatment with CocE rapidly restored normal mean blood pressure. CocE had no hemodynamic effects in control animals not treated with cocaine. The finding that CocE can oppose pre-established physiologic actions of cocaine suggests that similar or improved hydrolases might help rescue patients from the life-threatening toxicity of drug overdose.