Cholinergic stimulation modulates the negative inotropic effect of
cocaine on ferret ventricular myocardium.
Miao, Lin, Zhihua Qiu, and James P. Morgan.
Charles A. Dana Research Institute and the Harvard-Thorndike
Laboratory of Beth Israel Hospital and Cardiovascular Division,
Department of Medicine, Beth Israel Hospital and Harvard Medical
School, Boston, Massachusetts
APStracts 2:0359H, 1995.
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 cyclic AMP dependency of the
inotropic state. Cardiac myocytes were isolated from the left
ventricles of ferrets and loaded with the fluorescent Ca2- indicator,
indo-1. Cells were placed in physiologic solution containing 2.0 mM
Ca2-, stimulated at 0.5 Hz; 30 degrees C. Cocaine decreased peak cell
shortening and peak intracellular Ca2- in a concentration-dependent
manner (10-8 M - 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 (around 60%), cocaine and carbachol
decreased contractility to a significantly greater extent in the ISO
stimulated myocytes. To clarify if these treatments changed
responsiveness of the contractile elements to Ca2-, the effect of
2,3-butanedione monoxime (BDM), 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 cyclic AMP dependence of the inotropic
state.
Received 10 January 1995; accepted in final form 11 August 1995.
APS Manuscript Number H20-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 24 August 1995.