Deleterious effects of levamisole, a cocaine adulterant, in rabbit aorta

• Published in: Vascular pharmacology 2022-06, Vol.144, p.106992-106992, Article 106992
• Main Authors: Guerra-Ojeda, Sol, Marchio, Patricia, Aldasoro, Martin, Valles, Soraya L., Genovés, Patricia, Mauricio, Maria D., Vila, José M.
• Format: Article
• Language: English
• Subjects: Adrenergic receptors; Adrenergic system; Adulterants; Antiparasitic agents; Aorta; Bioavailability; Cocaine; Contractility; Endothelial dysfunction; Endothelium; Isometric; Levamisole; Neurotransmission; Nitric oxide; Noradrenaline; Norepinephrine; Oxidative stress; Phenylephrine; Potentiation; Receptors (physiology); Superoxide dismutase
• ISSN: 1537-1891; 1879-3649
• DOI: 10.1016/j.vph.2022.106992

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 (10−5–10−3 M) induced a concentration-dependent relaxation in rings precontracted with noradrenaline (10−7–3 × 10−7 M). Furthermore, it reduced the contractile response to phenylephrine (10−9–3 × 10−5 M) that was not modified by cocaine (10−5–10−4 M), and reduced α1-adrenergic receptor expression. Levamisole (10−6–10−4 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 (10−3 M) abolished adrenergic neurotransmission whether administered alone or with cocaine (10−4 M). In addition, levamisole (10−5–10−3 M) also decreased endothelium-dependent relaxation to acetylcholine that was not further impaired by cocaine (10−4 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 α2-adrenergic receptors, while at high concentrations, the effect of the antagonism of α1-adrenergic receptor prevails. In addition, levamisole induces endothelial dysfunction by reducing NO bioavailability, and this effect could be in part mediated by oxidative stress. [Display omitted] •In rabbit aorta, levamisole acts as an antagonist of α-adrenergic receptors.•Levamisole blocks α2-adrenergic receptors increasing sympathetic response.•Levamisole downregulates eNOS expression and decreases relaxation to acetylcholine.•Superoxide dismutase partially prevents impairment of levamisole-induced relaxation.•Levamisole vascular effects are independent of the presence of cocaine.