Project Details


The heart is a major locus for the toxic and lethal effects of cocaine.
An important action of cocaine in the heart is to inhibit presynaptic
catecholamine reuptake, leading to an elevated sympathomimetic state.
While this undoubtedly plays a role in the harmful effects of cocaine, it
is probable that other factors also contribute to cocaine cardiotoxicity
since most sympathomimetic interventions do not have the deleterious
effects associated with cocaine use. In preliminary experiments using
isolated ventricular heart muscle cells, we have observed a direct action
of cocaine to interfere with the cytosolic Ca2+ transients responsible
for excitation-contraction coupling. It is proposed that the direct
actions of cocaine on cardiomyocytes may contribute to the cardiotoxic
effects of cocaine. In particular, the combination of elevated
catecholamine levels (which activate specific Ca2+ flux components of the
Ca2+ transient), together with the inhibitory actions of cocaine, could
lead to abnormalities of excitationcontraction coupling. The objective
of the present proposal is to characterize the direct effects of cocaine
on the Ca2+ transient and contractility of isolated cardiac myocytes and
to elucidate the mechanisms responsible for these effects. In addition,
the interactions between cocaine and catecholamines at the level of
excitation-contraction coupling will be investigated in the-isolated
cardiomyocyte system. The primary experimental approaches will involve
the use of fluorescent Ca2+ indicators and a high-speed digital imaging
system to follow Ca2+ fluxes in electrically stimulated myocytes at the
single cell level. This technique allows us to measure the kinetic
parameters and subcellular distribution of these Ca2+ fluxes with
millisecond time resolution, while simultaneously monitoring cell
contraction. We will also use the whole-cell configuration of
patch-clamp to study the effects of cocaine on individual sarcolemmal ion
conductances under voltage-clamp. The voltage-clamp and Ca2+ imaging
methods will be combined to investigate how the effects of cocaine on ion
channels might play a role in the inhibitory effect of cocaine on the
Ca2+ transient. The long term objective of the proposed study is to
understand the basic mechanisms which underlie the cardiotoxic actions of
cocaine and to determine how each of these mechanisms contributes to the
harmful effects of cocaine in vivo.
Effective start/end date8/1/926/30/99


  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health


  • Medicine(all)

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