title: Cocaine long-term administration induces myocardial depressant effects and adrenoceptors desensitization.
abstract: Cocaine as a drug of abuse can cause many cardiovascular toxic effects. The objective of this work was to study the mechanism of the negative inotropic effect of cocaine on isolated right ventricle strips and its relationship with myocardial catecholamines desensitization after long- term cocaine administration. Right ventricle strips were incubated in oxygenated Krebs solution at 37 degrees C, and driven with 2 ms, 15 mA, 1.8 Hz electric square pulses. Beat tension force was recorded with a force-displacement transducer. In control long-term saline (0.9% NaCl) treated rats (0.1 mL/Kg x 15 days, s.c.), in vitro 0.1-30 microM cocaine progressively increased the ventricle strip force up to 53% over baseline value. On the contrary, a negative inotropic effect of cocaine was observed in strips obtained from long-term cocaine treated rats (3 mg/Kg x 15 days, s.c.). The contractile force change ("Bowditch" phenomenon) induced by short (30s) rising of myocardial stimulating frequency to 2.7, 3.5 and 4.3 Hz respectively, was completely reversed in ventricular strips obtained from long-term cocaine treated rats. Myocardial desensitization to isoproterenol (saline 4.67 nM Vs cocaine 13.17 nM DE50) and to phenylephrine (saline 5.44 nM Vs cocaine 8.6 nM DE50) was observed in long term cocaine treated rats when compared to the control group. Aorta desensitization to phenylephrine-induced constriction in long-term cocaine treated rats was also observed; phenylephrine DE50 increased from 1.9 nmol/l in control rats to 15.5 nmol/l in long-term cocaine treated ones. Cocaine metabolites, benzoylecgonine and ecgonine methyl ester were excreted (121.6 micrograms/ml) in urine samples from all cocaine treated rats and not in the saline treated group. Long-term cocaine treatment seems to interfere with the cytosolic calcium increase that normally occurs during systole; this could explain its negative inotropic effect observed during in vitro cocaine reexposure. The adrenergic receptor desensitization induced by chronic cocaine administration could lead to a full expression of the negative inotropic effect of this drug. Extrapolated to clinical grounds, this mechanism could explain some clinical cases of heart failure reported in cocaine overdosed addicts.
authors.affiliation: Laboratory of Cardiovascular Research, Departament of Pharmacology and Pathophysiology, José María Vargas School of Medicine, Central University of Venezuela, Edif. II, Plaza San Lorenzo, San José, Caracas 1010, Venezuela.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Romero Vecchione
authors.forename: José
authors.initials: J
authors.lastname: Vázquez
authors.forename: Mélida
authors.initials: M
authors.lastname: Bermudez
authors.forename: Domingo
authors.initials: D
authors.lastname: Negrín
authors.forename: Rafael
authors.initials: R
authors.lastname: Antequera
mesh_terms: D000322:Adrenergic Agonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles / Q000187:drug effects; D007545:Isoproterenol / Q000378:metabolism / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D010656:Phenylephrine / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000322:Adrenergic Agonists; D010656:Phenylephrine; D003042:Cocaine; D007545:Isoproterenol