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

Grupos y Plataformas de I+D+i

• Grupo de investigación de la función vascular

  

  Leading Researcher

  Maria Dolores Mauricio Aviño

Abstract

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 pre contracted with noradrenaline (10(-7)-3 x 10(-7) M). Furthermore, it reduced the contractile response to phenylephrine (10(-9)-3 x 10(-5) M) that was not modified by cocaine (10(-5)-10(-4) M), and reduced alpha 1-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 alpha(2)-adrenergic receptors, while at high concentrations, the effect of the antagonism of alpha(1)-adrenergic receptor prevails. In addition, levamisole induces endothelial dysfunction by reducing NO bioavailability, and this effect could be in part mediated by oxidative stress.

Keywords

• Levamisole; Cocaine; Adrenergic system; Endothelial dysfunction