Project Details

Description

The majority of experiments examining the effects of myocardial ischemia
have been conducted in laboratory animals, most commonly dogs, cats and
rats. There are relatively little data available on the effects of
myocardial ischemia in primates. The objective of this research proposal
is to examine the effects of coronary artery occlusion and reperfusion
on measurements of regional myocardial function, i.e. endocardial and
epicardial wall thickening and segment shortening, regional blood flow
(radioactive microspheres), and regional biochemistry and molecular
biology in chronically instrumented, conscious baboons, pigs, and dogs.
There are seven specific aims. 1) To determine the relationship among
the timing of coronary artery reperfusion on infarct size and recovery
of regional myocardial function in conscious dogs, pigs, and baboons.
2) To determine whether the salvaged myocardium or stunned myocardium
responds appropriately to inotropic stress in terms of either mechanical
function or beta-adrenergic receptor signalling. 3) To determine whether
collateral dependent myocardium responds appropriately to inotropic
stress in terms of either mechanical function or beta-adrenergic receptor
signalling. 4) To determine if the decrease in adenylyl cyclase activity
in reperfused or collateralized hearts is due to a decrease in the number
of units of catalyst per mg sarcolemma or due to a decrease in specific
activity of the catalyst. To do this, we will: a) Use highly purified
sarcolemma and perform immunoblotting to detect the amount of catalyst
per mg sarcolemma. In addition, messenger RNA levels will be quantitated
for the predominant cardiac isoforms of adenylyl cyclase, i.e., Types IV,
V and VI. b) The catalyst of adenylyl cyclase will be purified from
sarcolemma by affinity chromatography and the specific activity
determined. 5) To determine whether myocardial stunning is augmented by
pretreatment with Nw-nitro-L-arginine or diminished by pretreatment with
L-arginine. 6) To determine whether pre-treatment can reduce "myocardial
stunning" with brief periods of coronary artery occlusion in the
conscious baboon using agents that affect: a. O2 free radicals or b.
Calcium. 7) To determine ryanodine and dihydropyridine receptor density
in membrane preparations from canine, baboon, and porcine hearts during
myocardial stunning. These studies are designed to provide insight into
basic mechanisms of myocardial ischemia and its relief by coronary artery
reperfusion by comparing responses in chronically instrumented, conscious
dogs, pigs and baboons. there are three novel features of this
application. 1) To study mechanisms of myocardial ischemia in conscious
primates. 2) The direct and continuous measurement of regional
subendocardial vs. subepicardial function in response to ischemia in
chronically-instrumented, conscious animals. 3) The ability to correlate
the physiological studies above with studies at the cellular and
molecular level.Description
StatusFinished
Effective start/end date1/1/8411/30/01

Funding

  • National Institutes of Health: $298,649.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $375,717.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $277,446.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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