Guerra-Ojeda Sol, Marchio Patricia, Aldasoro Martin, Valles Soraya L, Genovés Patricia, Mauricio Maria D, Vila José M
Department of Physiology, School of Medicine, University of Valencia and Institute of Health Research INCLIVA, Valencia, Spain.
Department of Physiology, School of Medicine, University of Valencia and Institute of Health Research INCLIVA, Valencia, Spain.
Vascul Pharmacol. 2022 Jun;144:106992. doi: 10.1016/j.vph.2022.106992. Epub 2022 Mar 28.
Levamisole, a veterinary anthelmintic drug, is one of the most widely used and dangerous cocaine adulterants. Like cocaine, levamisole acutely blocks noradrenaline reuptake but with much less potency, although its vascular effects are not well known. In this study, we evaluated the vascular effects of levamisole and cocaine in rabbit aortic rings used for isometric recording of tension in organ baths and protein expression by western blot. Our results indicated that levamisole (10-10 M) induced a concentration-dependent relaxation in rings precontracted with noradrenaline (10-3 × 10 M). Furthermore, it reduced the contractile response to phenylephrine (10-3 × 10 M) that was not modified by cocaine (10-10 M), and reduced α-adrenergic receptor expression. Levamisole (10-10 M) produced a potentiation of the electrical field stimulation that was not further enhanced by the combination of both drugs. However, high concentrations of levamisole (10 M) abolished adrenergic neurotransmission whether administered alone or with cocaine (10 M). In addition, levamisole (10-10 M) also decreased endothelium-dependent relaxation to acetylcholine that was not further impaired by cocaine (10 M), and that was partially reversed by superoxide dismutase (SOD, 200 U/ml). These results demonstrate that levamisole has a dual effect on the adrenergic system, and its effects are independent of the presence of cocaine. At lower concentrations, it enhances the contractile sympathetic response by blocking presynaptic α-adrenergic receptors, while at high concentrations, the effect of the antagonism of α-adrenergic receptor prevails. In addition, levamisole induces endothelial dysfunction by reducing NO bioavailability, and this effect could be in part mediated by oxidative stress.
左旋咪唑是一种兽用驱虫药，是使用最广泛且危险的可卡因掺杂物之一。与可卡因一样，左旋咪唑可急性阻断去甲肾上腺素的再摄取，但其效力要低得多，尽管其血管效应尚不清楚。在本研究中，我们通过器官浴中张力的等长记录和蛋白质印迹法评估了左旋咪唑和可卡因对兔主动脉环的血管效应及蛋白质表达。我们的结果表明，左旋咪唑（10-10 M）可使去甲肾上腺素（10-3×10 M）预收缩的血管环产生浓度依赖性舒张。此外，它降低了对苯肾上腺素（10-3×10 M）的收缩反应，而可卡因（10-10 M）对此无影响，并且它还降低了α-肾上腺素能受体的表达。左旋咪唑（10-10 M）可增强电场刺激，两种药物联合使用不会进一步增强这种作用。然而，高浓度的左旋咪唑（10 M）无论是单独给药还是与可卡因（10 M）联合使用，均会消除肾上腺素能神经传递。此外，左旋咪唑（10-10 M）还会降低对乙酰胆碱的内皮依赖性舒张，可卡因（10 M）不会使其进一步受损，超氧化物歧化酶（SOD，200 U/ml）可部分逆转这种作用。这些结果表明，左旋咪唑对肾上腺素能系统具有双重作用，其作用与可卡因的存在无关。在较低浓度下，它通过阻断突触前α-肾上腺素能受体来增强交感神经收缩反应，而在高浓度下，α-肾上腺素能受体拮抗作用占主导。此外，左旋咪唑通过降低一氧化氮生物利用度诱导内皮功能障碍，这种作用可能部分由氧化应激介导。
