PHARMACOLOGY OF CORONARY ARTERY CALCIUM REGULATION

Project: Research project

Description

The long-term goal of this research program is to determine the cellular
and molecular ion transport mechanisms underlying coronary artery
contraction. Most vasoactive agents regulate membrane ion channels and
intracellular Ca release in vascular endothelial and smooth muscle cells.
The immediate goal of this research program is the project described
here. The purpose of this project is to understand how potassium (K)
depolarization, endothelin (ET), and nifedipine (NIF) regulate myoplasmic
free Ca (Ca/im) in coronary artery smooth muscle. NIF is postulated to
inhibit these processes by high affinity binding to the VGCC. ET also
releases Ca from the sarcoplasmic reticulum (SR) and may activate ligand-
gated channels (LGC), thus increasing Ca/im with minimal depolarization
of the cell and negligible activation of VGCC. Therefore, additional
mechanisms, including interactions between VGCC and the SR, should be
determined for the action of NIF. Methods involve the use of single
cells that are freshly dispersed from bovine and porcine coronary artery.
Three measures of Ca/im regulation are: 1) whole-cell VGCC and LGC
currents studied with patch-clamp, 2) Ca/im measured with fura-2
microfluorometry, and 3) contraction monitored by video. Specific aims
are to determine: 1) NIF inhibition of VGCC. The decrease of VGCC
current and Ca/im caused by NIF is hypothesized to be related directly
to the amount of membrane depolarization during voltage-clamp. 2) NIF
inhibition of SR Ca release/sequestration. Any direct effects of NIF on
Ca release channels will be determined in lipid bilayers. 3)
Potentiation of VGCC or LGC by ET. ET is hypothesized to shift the
voltage-dependence for VGCC activation and activate LGC such that
increased Ca influx occurs near the resting membrane potential. 4) NIF
inhibition of VGCC or LGC that have been potentiated by ET. The
environment at this institution is very conducive to achieving these
specific aims. Physical facilities meet research needs and scientific
interactions with other cardiovascular and membrane physiologists are
frequent, because these specialties comprise 80% of the research
activities in the department. The institution's development plans are
to support basic cardiovascular research if extramural funding is
available; otherwise, teaching and service activities would take
priority. This RCDA would enhance my individual scientific development
by protecting valuable time for intense research and by acquisition of
new laboratory skills in the molecular biology of ion channels. These
activities would foster synthesis, refinement, and important growth of
knowledge in ion transport mechanisms in coronary artery smooth muscle.
StatusFinished
Effective start/end date2/1/931/31/98

Funding

  • National Institutes of Health
  • National Institutes of Health: $65,739.00
  • National Institutes of Health: $67,500.00
  • National Institutes of Health
  • National Institutes of Health

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Nifedipine
Ligand-Gated Ion Channels
Endothelins
Coronary Vessels
Pharmacology
Calcium
Sarcoplasmic Reticulum
Ion Channels
Research
Ion Transport
Smooth Muscle
Membranes
Lipid Bilayers
Vascular Smooth Muscle
Membrane Potentials
Smooth Muscle Myocytes
Molecular Biology
Potassium
Teaching
Swine

ASJC

  • Medicine(all)