MECHANISMS OF MYOCARDIAL CA++ REGULATION DURING ISCHEMIA

Project: Research project

Project Details

Description

The focus of my research is on the regulation of cytosolic calcium in the
heart under normal conditions and in disease states. Specifically, I plan
to determine the mechanisms through which intracellular calcium [Ca++]i
overload is produced during acute cardiac ischemia and to determine the
role of cellular second messengers on the regulation of [Ca++]i and other
cellular functions during acute ischemia. Over the last three years, the applicant has developed techniques to
measure [Ca++]i in cardiac myocytes and in isolated mammalian hearts. Our
work has provided valuable insight into the role of [Ca++]i in excitation-
contraction coupling and into the behavior of [Ca++]i during acute
ischemia. The current proposal is an extension of our previous
observations and attempts to determine the mechanisms through which [Ca++]i
elevations are mediated during acute ischemia. First, the hypothesis that the increase in [Ca++]i during acute ischemia is
dependent on receptor-mediated phosphoinositide (PI) hydrolysis will be
tested. The effect of ischemia and the metabolites of ischemia (such as
extracellular ATP) on cardiac PI hydrolysis will be examined. Second, the second messenger function of inositol 1,4,5-triphosphate
(InsP3) in cardiac myocytes will be determined. InsP3 will be introduced
into isolated cardiac myocytes by internal perfusion with a patch
micropipette. The effect of InsP3 on cellular electrical, Ca2+, and
mechanical activities will be determined. Third, the source of cytosolic Ca++ associated with acute cardiac ischemia
will be determined through specific pharmacologic interventions. Fourth, the role of guanine nucleotide-binding proteins (G proteins) in the
regulation of [Ca++]i during early cardiac ischemia will be examined by
using cholera and pertussis toxins. With the new techniques that we have developed, new observations are being
made and new hypotheses can be tested. Through the proposed experiments,
we may learn about the cellular mechanisms that regulate intracellular
calcium which in turn govern the contractile and the electrical activities
of the heart. Our results may help to gain insight into the cellular
abnormalities responsible for lethal arrhythmias in patients with heart
disease and may improve our approach to the prevention and treatment of
these conditions.
StatusFinished
Effective start/end date9/1/908/31/96

Funding

  • National Institutes of Health
  • National Institutes of Health: $96,742.00
  • National Institutes of Health
  • National Institutes of Health: $122,488.00
  • National Institutes of Health: $82,244.00

ASJC

  • Medicine(all)

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