IONIC CONTROL OF CARDIAC MUSCLE CONTRACTION

Project: Research project

Project Details

Description

The long term goal of this project is to understand the regulation of
cardiac muscle contraction, particularly E-C coupling and the regulation of
Ca fluxes. Isolated cardiac myocytes will be used with whole cell voltage
clamp and the intracellular Ca indicator, indo-1. Experiments are also
planned using multicellular preparations and isolated membrane vesicles.
The specific goals for the next period will be to: a) Critically evaluate intracellular calibrations of indo-1 fluorescence
signals rather than rely on in vitro calibrations which are likely to be
inaccurate. This will allow several important quantitative issues to be
addressed (e.g. direct assessment of the pCai vs tension relation in intact
cardiac muscle).
b) Measure intracellular Ca buffering by measuring Ca entry, Ca extrusion
and [Ca]i, providing direct information about the overall Cai required for
cardiac muscle activation.
c) Estimate "normal" and maximal SR Ca content in different species &
conditions (e.g. in "Ca overload").
d) Determine the fraction of SR Ca released during normal and modified
contractions.
e) Evaluate if Em itself can alter SR Ca release at constant SR Ca load and
constant ICa "trigger".
f) Evaluate whether Ca entry via Na/Ca exchange can induce SR Ca release.
These two studies (e & f) are important in the evaluation of postulated
mechanisms of E-C coupling.
g) Determine the influence of Nao on Cai transients and assess the
competition between the SR and Na/Ca exchange during relaxation (and [Ca]i
decline).
h) Characterize Em-dependent Ca binding at the inner sarcolemmal surface
which could be involved in E-C coupling since depolarization may release Ca
bound to the inner sarcolemmal surface.
i) Evaluate if indo-1 alters sarcolemmal Na/Ca exchange or SR Ca-ATPase
complicating the use of indo-1. These studies are focused on providing important new fundamental
information of a quantitative nature about the regulation of intracellular
Ca and the mechanism of E-C coupling in cardiac muscle cells (e.g. force vs
pCai, Cai-buffering, SR Ca content & fractional release, role of Em, Na/Ca
exchange and SR in E-C coupling and relaxation). They will also provide
useful new information about the use of indo-1 in cardiac muscle. Cellular Ca fluxes are in a dynamic, yet delicate balance, which will be
studied in detail. The consequences of disturbing this balance can include
contractile failure, spontaneous contractions (i.e. arrhythmogenic) and
impair relaxation. Any of these dysfunctions will compromise the ability
of the heart to function effectively as a pump. Thus, comprehensive
understanding of Ca regulation in the heart is crucial.
StatusFinished
Effective start/end date7/1/823/31/19

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $376,250.00
  • National Institutes of Health: $420,750.00
  • National Institutes of Health: $362,526.00
  • National Institutes of Health: $209,974.00
  • National Institutes of Health: $469,961.00
  • National Institutes of Health: $360,308.00
  • National Institutes of Health: $360,308.00
  • National Institutes of Health
  • National Institutes of Health: $402,423.00
  • National Institutes of Health
  • National Institutes of Health: $371,250.00
  • National Institutes of Health: $376,250.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $376,250.00
  • National Institutes of Health: $375,938.00
  • National Institutes of Health: $269,979.00
  • National Institutes of Health
  • National Institutes of Health: $376,250.00
  • National Institutes of Health: $466,931.00
  • National Institutes of Health
  • National Institutes of Health: $352,319.00
  • National Institutes of Health: $352,012.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $417,564.00
  • National Institutes of Health: $417,012.00
  • National Institutes of Health: $217,156.00
  • National Institutes of Health
  • National Institutes of Health: $418,924.00

ASJC

  • Medicine(all)

Fingerprint Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.