NEGATIVE INOTROPIC EFFECT OF METHYLECGONIDINE, A MAJOR PRODUCT OF COCAINE BASE PYROLYSIS, ON FERRET AND HUMAN MYOCARDIUM

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 ventricu lar papillary muscles and human ventricular trabeculae were isolated a nd placed in a physiological solution at 30 degrees C containing 2.5 m M Ca2+ and stimulated at 0.33 Hz. MEG decreased peak tension and peak intracellular Ca2+ transients in a concentration-dependent manner (10 mu M-1 mM). The negative inotropic effect (NIE) of MEG was reversible by atropine (1 mu M). Atropine shifted the concentration-response curv e of MEG rightward (pA(2) = 9.17) similar to that of carbachol (pA(2) = 8.70). With prior addition of histamine (1 mu M) and Ca2+ (4.5 mM) i n equiinotropic concentrations, MEG and carbachol decreased contractil ity to a greater extent in the histamine-stimulated muscles. To clarif y whether the treatments altered responsiveness of the contractile ele ments to Ca2+, the effect of 2,3-butanedione monoxime (BDM), an agent that interferes with the interaction of actin and myosin, was tested a fter prior addition of histamine or increased Ca2+. No differential ef fect occurred. Moreover, the nitric oxide synthase inhibitor N-G-nitro -L-arginine methylester (L-NAME; 0.1 mM), lessened the NIE of MEG comp ared 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 calc ium availability: the effect is not the result of a local anesthetic a ction but is mediated by stimulation of cholinergic receptors. This ef fect is potentiated by the nitric oxide pathway.