title: Negative inotropic effect of methylecgonidine, a major product of cocaine base pyrolysis, on ferret and human myocardium.
abstract: This study examined the physiological effects and potential mechanisms of action of methylecgonidine (MEG), the major pyrolysis product from smoking "crack cocaine," on cardiac function. Ferret right ventricular papillary muscles and human ventricular trabeculae were isolated and placed in a physiological solution at 30 degrees C containing 2.5 mM Ca2+ and stimulated at 0.33 Hz. MEG decreased peak tension and peak intracellular Ca2+ transients in a concentration-dependent manner (10 microM-1 mM). The negative inotropic effect (NIE) of MEG was reversible by atropine (1 microM). Atropine shifted the concentration-response curve of MEG rightward (pA2 = 9.17) similar to that of carbachol (pA2 = 8.70). With prior addition of histamine (1 microM) and Ca2+ (4.5 mM) in equiinotropic concentrations, MEG and carbachol decreased contractility to a greater extent in the histamine-stimulated muscles. To clarify whether the treatments altered responsiveness of the contractile elements to Ca2+, the effect of 2,3-butanedione monoxime (BDM), an agent that interferes with the interaction of actin and myosin, was tested after prior addition of histamine or increased Ca2+. No differential effect occurred. Moreover, the nitric oxide synthase inhibitor NG-nitro-L-arginine methylester (L-NAME; 0.1 mM), lessened the NIE of MEG compared with prior (pre-L-NAME) values. Furthermore, in human ventricular trabeculae (n = 7), MEG exhibited an NIE that was also reversible by atropine. We concluded that the NIE of MEG is caused by decreased calcium availability; the effect is not the result of a local anesthetic action but is mediated by stimulation of cholinergic receptors. This effect is potentiated by the nitric oxide pathway.
authors.affiliation: Charles A. Dana Research Institute, Boston, Massachusetts, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Woolf
authors.forename: L
authors.initials: L
authors.lastname: Huang
authors.forename: Y
authors.initials: Y
authors.lastname: Ishiguro
authors.forename: J P
authors.initials: JP
authors.lastname: Morgan
mesh_terms: D000759:Adjuvants, Anesthesia / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D003042:Cocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D006801:Humans; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects
chemical_list: D000759:Adjuvants, Anesthesia; D000779:Anesthetics, Local; D018765:Dopamine Uptake Inhibitors; C068464:anhydroecgonine methyl ester; D001285:Atropine; D008012:Lidocaine; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D003042:Cocaine