title: Cholinergic stimulation modulates negative inotropic effect of cocaine on ferret ventricular myocardium.
abstract: We tested the hypothesis that the negative inotropic effect (NIE) of cocaine is mediated, at least in part, by cholinergic stimulation and can be correlated with the degree of adenosine 3',5'-cyclic monophosphate (cAMP) dependency of the inotropic state. Cardiac myocytes were isolated from left ventricles of ferrets and loaded with the fluorescent Ca2+ indicator indo 1. Cells were placed in physiological solution containing 2.0 mM Ca2+ and stimulated at 0.5 Hz and 30 degrees C. Cocaine decreased peak cell shortening and peak intracellular Ca2+ in a concentration-dependent manner (10(-8)-10(-4) M). The concentration-response curve of cocaine was shifted significantly downward compared with those of lidocaine and procaine in the same range of concentrations. Atropine (10(-6) M) shifted the concentration-response curve of cocaine, but not those of lidocaine and procaine, rightward, with a pA2 value (7.66) similar to that obtained with carbachol (7.99). With prior addition of isoproterenol (ISO, 10(-8) M) or increased Ca2+ (4.0 mM) to increase cell shortening to the same degree (approximately 60%), cocaine and carbachol decreased contractility to a significantly greater extent in ISO-stimulated myocytes. To clarify whether these treatments changed responsiveness of the contractile elements to Ca2+, the effect of 2,3-butanedione monoxime, an agent that interferes with the interaction of myosin and actin, was tested with previous addition of ISO or increased Ca2+, and no differential effect occurred. Therefore, we postulate that 1) the NIE of cocaine on myocytes is caused by decreased Ca2+ availability; 2) this effect is due to specific stimulation of cholinergic receptors in addition to other direct myocardial (probably local anesthetic) effects; and 3) the NIE correlates with the level of cAMP dependence of the inotropic state.
authors.affiliation: Charles A. Dana Research Institute, Boston, Massachusetts, USA.
authors.forename: L
authors.initials: L
authors.lastname: Miao
authors.forename: Z
authors.initials: Z
authors.lastname: Qiu
authors.forename: J P
authors.initials: JP
authors.lastname: Morgan
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002469:Cell Separation; D018678:Cholinergic Agents / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D005289:Ferrets; D007425:Intracellular Membranes / Q000378:metabolism; D008012:Lidocaine / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology; D010210:Papillary Muscles / Q000187:drug effects; D011343:Procaine / Q000494:pharmacology; D016276:Ventricular Function / Q000187:drug effects*
chemical_list: D018678:Cholinergic Agents; D011343:Procaine; D001285:Atropine; D002217:Carbachol; D008012:Lidocaine; D000242:Cyclic AMP; D003042:Cocaine