ACTION OF CA-CHANNEL AGONIST BAY K 8644 ON THE SR

Project: Research project

Project Details

Description

The Ca channel agonist, Bay K 8644, inhibits post-rest contractions (PRCs)
in ferret ventricular muscle, in addition to its effects on sarcolemmal
(SL) Ca channels. As PRCs are supported primarily by sarcoplasmic
reticulum (SR) Ca release, this indicates that Bay K 8644 may interfere
with normal SR function (possibly by inducing a loss of SR Ca). The
central issue to be addressed is whether this depressant effect of Bay K
8644 on the SR is linked to a primary action on SL Ca channels rather than
a direct action on the SR (e.g. is there evidence for direct coupling
between the SL and SR Ca channels?). To address this we will measure PRCs, rapid cooling contractures (RCCs) and
caffeine-induced contractures to assess the rest-dependent decline in SR Ca
content. The loss of SR Ca to the cytoplasm and from the cell will also
assessed (e.g. with Ca-electrodes). Whole cell voltage clamp will be used
to measure calcium current (Ica). To examine the possible interaction
between the SL and SR Ca channels, we will also measure ryanodine and
dihydropyridine binding characteristics in isolated cardiac myocytes,
fractionated cardiac preparations (e.g. diads and SR) as well as in triads
(and SR vesicles) from rabbit skeletal muscle. Our specific goals will be
to answer the following questions: 1. Are the effects of Bay K 8644 on SR function and on SL Ica
mediated by the same receptor?
2. Is Bay K 8644 itself or the Ica change which it induces
responsible for rest depression?
3. Does Bay K 8644 decrease PRCs by reducing SR Ca pool size or the
fractional release of SR Ca?
4. Does Bay K 8644 decrease PRCs due to either sub- or supra-
optimal trigger for SR Ca release?
5. Is Na/Ca exchange involved in the enhanced diastolic efflux of SR Ca
promoted by Bay K 8644?
6. Does Bay K 8644 produce an increase in SR Ca loss and/or cellular Ca
efflux during rest?
7. Does Bay K 8644 alter ryanodine binding to isolated triads (or Heavy
SR) from skeletal muscle?
8. Does Bay K 8644 modify the ryanodine binding in intact cardiac myocytes
and subcellular fractions? This detailed analysis of the Bay K 8644 induced rest depression and
interaction with ryanodine binding will provide insight into: a) the
mechanism of this novel action of Bay K 8644 and b) the coupling between
the SL Ca channel and the SR Ca release channel. This will provide insight
into the most important remaining fundamental question about excitation-
contraction coupling in cardiac (and skeletal) muscle.
StatusFinished
Effective start/end date1/1/912/28/95

Funding

  • National Institutes of Health: $141,010.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $89,476.00

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.