COCAINE EFFECTS ON CARDIAC MUSCLE CELLS

Project Details

Description

The heart is a major locus for the toxic and lethal effects of cocaine.
Cocaine ingestion leads to increases in heart rate and blood pressure, and
at higher levels a number of serious cardiovascular consequences can
result. These include depression of cardiac contractility, arrhythmia,
ischemia, myocardial infarction and sudden death. Chronic cocaine abuse
is also associated with cardiomyopathy. The complex cardiovascular
effects of cocaine are believed to be a function of both its
sympathomimetic action and its local anesthetic effects. We have
demonstrated that cocaine has a direct effect on cardiac muscle cells to
depress contractility, and that this results from inhibition of the
cytosolic Ca2+ transients that underlie excitation-contraction coupling.
Our preliminary data suggest that the major targets of cocaine involved in
this action are sarcolemmal ion channels. We plan to continue our studies
by investigating how the effects of cocaine on these ion channels
contribute to the cocaine-induced depression of myocardial function. The
direct effects of cocaine on myocardial cells occur against a background
of elevated catecholamines in vivo. Since cocaine interacts with ion
channels that are important targets for the adrenergic control of cardiac
contractility, we will also investigate how cocaine modifies the
regulation of these channels by catecholamines. The best characterized of
the cardiac targets of cocaine is the Na+ channel, and it is likely that
this contributes to both the depression of cardiac contractility and the
altered conduction properties of the myocardium. We will investigate the
mechanism of cocaine block using cloned Na+ channels from human and rat
heart expressed in a mammalian cell line. This system will also be used
for site-directed mutagenesis studies designed to characterize the
molecular components involved in cocaine binding to the cardiac Na+
channel. The work proposed in this application will utilize a combination
of fluorescent Ca2+ indicator, electrophysiology and molecular biology
approaches. The long-term aim of these studies is to elucidate the role
of the direct effects of cocaine on heart muscle cells in terms of the
overall responses of the cardiovascular system to this drug in vivo.
StatusFinished
Effective start/end date8/1/926/30/99

Funding

  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse

ASJC

  • Cardiology and Cardiovascular Medicine

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