Toxicology Letters 123 (2001) 43 – 50 Cocaine toxic effect on endothelium-dependent vasorelaxation: an in vitro study on rabbit aorta Giuseppina I. Togna *, Manuela Graziani, Pierluigi Russo, Luciano Caprino Department of Human Physiology and Pharmacology, Uniersity of Rome ‘‘La Sapienza’’, P.le A. Moro, 5, 00185 Rome, Italy Received 19 February 2001; received in revised form 25 May 2001; accepted 25 May 2001 Abstract Effects of cocaine on vascular endothelium relaxing properties and the related mechanism were investigated in vitro in rabbit aorta. Several vasorelaxing agents with different mechanisms, i.e. acetylcholine, substance P, calcium ionophore A23187, 2,5-di-tert -butylhydroquinone, or sodium nitroprusside, were employed. Cocaine effects on the vascular response to relaxing agents in cumulative (acetylcholine, substance P, or A23187) or single dose (2,5-di-tert - butyl-hydroquinone) were performed in endothelium-intact aortic rings precontracted with phenylephrine. Relaxing activity of cumulative doses of sodium nitroprusside was evaluated in endothelium-denuded aortic rings, in the presence of cocaine. Cocaine significantly reduced endothelium-dependent relaxations induced by acetylcholine, or substance P. By contrast A23187 endothelium-mediated relaxation as well as endothelium-independent relaxation by sodium nitroprusside were unaffected by cocaine. Furthermore, cocaine significantly increased endothelium-dependent relaxation response to 2,5-di-tert -butylhydroquinone, a sarcoplasmic Ca 2 + -ATPase pump inhibitor, in the aortic rings. These findings indicate that cocaine reduces nitric oxide release from vascular endothelium apparently through the inhibiting action of Ca 2 + -ATPase pump. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cocaine; Endothelium; Nitric oxide; Rabbit aorta www.elsevier.com/locate/toxlet 1. Introduction Interest in the cardiovascular toxicity of cocaine has greatly increased due to its more diffused use as a recreational drug. Illicit use of cocaine is frequently associated with acute cardiovascular events, including stroke, myocardial infarction, coronary thrombosis, arrhythmia and sudden death (Rezkalla et al., 1990; Isner and Chokshi, 1991; Minor et al., 1991; Om, 1992; Mouhaffel et al., 1995; Kaufman et al., 1998). Premature atherosclerosis has also been reported after chronic cocaine abuse (Billman, 1990; Kolodgie et al., 1991). Although it has been established that inhibitory action on catecholamine re-uptake is the main basis for cocaine-induced cardiovascular toxic effects (Billman, 1990; Isner and Chokshi, 1991; Om, 1992) alternative explanations, includ- ing alterations in platelet and vascular endothe- lium functions induced by cocaine, have also been suggested. * Corresponding author. Tel.: +39-6-499-12905; fax: +39- 6-499-12363. E-mail address: giuseppina.togna@uniroma1.it (G.I. Togna). 0378-4274/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII:S0378-4274(01)00379-4