Project Details

Description

The planned research program integrates two distinct areas of
investigation: (1) The mechanisms by which ethanol interferes with
excitation-contraction coupling and depresses the contractile function
of the heart; (2) The mechanisms and functional consequences of
ethanol interaction with the inositol lipid signaling system in the
liver. These projects are linked by a common focus on signaling
processes mediated by Ca2+. It is also likely that some of the
targets of ethanol action are common to both tissues. The
experimental work in the heart will focus on the use of advanced
techniques for studying ethanol action, including measurements of the
dynamics of cytosolic Ca2+ and sarcomere shortening using digital
imaging fluorescence microscopy techniques, together with whole-cell
voltage-clamp measurements of sarcolemmal ion currents. Hypotheses to
be investigated for the mechanism of ethanol action include a
reduction in Ca2+ sequestering properties of the sarcoplasmic
reticulum, alterations in Ca2+ and/or Na+ channel activity in the
sarcolemma and a shift in the relation between Ca2+ and contractile
activity of the muscle proteins. In addition, the interactions
between ethanol and catecholamines, and the deleterious effects of
ethanol and cocaine in combination, will be investigated. These
studies, carried out using isolated rat ventricular myocytes, will
examine the effects of both acute ethanol and long term ethanol-
feeding. Studies of ethanol action on Ca2+ signaling in liver will
also utilize imaging of Ca2+ in single isolated hepatocytes. This
work will investigate the effects of ethanol on the spatial and
temporal organization of Ca2+ signaling at the subcellular level,
determine how the direct acute effects of ethanol are modulated by
protein kinases, and examine the mechanism by which ethanol modifies
the responses to hormones that regulated hepatic metabolism through
changes in cytosolic Ca2+. In addition, the mechanisms by which
ethanol affects the inositol lipid signal transduction system will be
investigated using an isolated turkey erythrocyte membrane
preparation. This retains a functional, hormone-coupled inositol
lipid-specific phospholipase C (PLC) that generates the second
messengers inositol 1,4,5-triphosphate and diacylglycerol. The turkey
erythrocyte membrane PLC is sensitive to both acute stimulation by
ethanol alone, and to inhibition of hormone activation by ethanol
pretreatment. This research program will contribute to the
elucidation of the mechanisms by which ethanol perturbs the normal
function of liver and heart tissue.
StatusFinished
Effective start/end date7/1/946/30/99

Funding

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

ASJC

  • Medicine(all)

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