PDF(Pubmed)
Abstract：
Levamisole is an anthelmintic drug restricted to veterinary use but is currently detected as the most widely used cocaine cutting agent in European countries. Levamisole-adulterated cocaine has been linked to acute kidney injury, marked by a decrease in glomerular filtration rate, which involves reduced renal blood flow, but data on the alteration of renovascular response produced by levamisole are scarce. Renal arteries were isolated from healthy rabbits and used for isometric tension recording in organ baths and protein analysis. We provide evidence that depending on its concentration, levamisole modulates renovascular tone by acting as a non-selective α-adrenergic receptor blocker and down-regulates α1-adrenoceptor expression. Furthermore, levamisole impairs the endothelium-dependent relaxation induced by acetylcholine without modifying endothelial nitric oxide synthase (eNOS) expression. However, exposure to superoxide dismutase (SOD) partially prevents the impairment of ACh-induced relaxation by levamisole. This response is consistent with a down-regulation of SOD1 and an up-regulation of NADPH oxidase 4 (Nox4), suggesting that endothelial NO loss is due to increased local oxidative stress. Our findings demonstrate that levamisole can interfere with renal blood flow and the coordinated response to a vasodilator stimulus, which could worsen the deleterious consequences of cocaine use.
摘要：
左旋咪唑是一种限制兽医使用的驱虫药，但目前在欧洲国家被发现是最广泛使用的可卡因切割剂。左旋咪唑掺杂的可卡因与急性肾损伤有关，以肾小球滤过率下降为标志，这包括减少肾血流量，但是关于左旋咪唑产生的肾血管反应改变的数据很少。从健康的兔子中分离出肾动脉，并用于器官浴中的等距张力记录和蛋白质分析。我们提供的证据表明，根据其浓度，左旋咪唑通过充当非选择性α-肾上腺素能受体阻滞剂来调节肾血管张力，并下调α1-肾上腺素受体的表达。此外，左旋咪唑会损害乙酰胆碱诱导的内皮依赖性舒张，而不会改变内皮一氧化氮合酶（eNOS）的表达。然而,暴露于超氧化物歧化酶（SOD）可以部分防止左旋咪唑对ACh诱导的松弛的损害。这种反应与SOD1的下调和NADPH氧化酶4（Nox4）的上调一致，提示内皮NO丢失是由于局部氧化应激增加所致。我们的发现表明左旋咪唑可以干扰肾血流和对血管扩张剂刺激的协调反应，这可能会加剧可卡因使用的有害后果。
