Mechanism of Ethanol's Cardiac Inotropic Depression

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): A major site for the damaging effects of
chronic excessive ethanol (EtOH) consumption is the heart. Acutely, EtOH is
negatively inotropic, in part, by interfering with excitation-contraction
coupling, reducing the magnitude of electrically triggered Ca2+ transients. At
low concentrations, EtOH inhibits myocardial contractions without detectable
Ca2+ changes, suggesting that force transduction is a second target of its
acute effects, whose mechanisms are unknown. This project is based upon the
hypothesis that cardiodepressant effects of EtOH are the result of its direct
effects on the contractile apparatus. To test this hypothesis, the following
specific aims will be addressed using normal rat trabeculae. Aim 1: Determine
the dose-response of EtOH on resting stiffness and the mechanics of
electrically stimulated trabeculae (stiffness, T0 or peak isometric tension,
work, and dT/dt). This will determine the range of EtOH] that alters
cytoskeletal and cross-bridge mechanics. Aim 2: Determine the direct effects of
EtOH on cross-bridge mechanics. Chemically skinned trabeculae will be studied,
bypassing the normal excitation-contraction pathway, directly controlling the
contractile apparatus environment. The effects of EtOH] on T0, the [Ca]-tension
relation, maximum shortening velocity, work, and passive and active stiffness
will be determined. This will determine the [EtOH] required to effect directly
force transduction and work output by the cardiac contractile system and the
mechanical parameter most sensitive to EtOH. Aim 3: Determine the step in the
cross-bridge cycle (force producing transition, phosphate release, detachment
rate) responsible for the EtOH-sensitive mechanical parameters from aim 2.
Laser photolysis of caged-compounds will initiate or perturb contractions of
skinned trabeculae while monitoring force and stiffness. Aim 4: Determine the
effects of chronic ethanol exposure on myocardial mechanics. Studies identical
to the previous aims will be performed on trabeculae from rats fed EtOH for 2
to 26 weeks and normal controls. These studies will characterize the changes in
mechanics produced by chronic EtOH exposure, identify the site of action, test
for changes in EtOH sensitivity, and detect adaptations. The proposed studies
will provide a more complete understanding of the cellular and molecular
mechanisms responsible for the depressant effects of ethanol on myocardial
contractility.
StatusFinished
Effective start/end date5/1/024/30/03

Funding

  • National Institute on Alcohol Abuse and Alcoholism: $314,000.00

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