Project Details


One hour of myocardial ischemia results in increased beta-adrenergic
receptor density but uncoupling of the beta-adrenergic receptor from
adenylate cyclase associated with decreases in the GTP regulatory protein,
G(s-alpha). The goals of this research proposal are directed at examining
the mechanism and time course of these changes as well as whether the
changes are reversible with coronary artery reperfusion. One major feature
is the combined study of physiology in the conscious animal instrumented
for measurement of subendocardial and subepicardial wall motion in ischemic
and nonischemic zones with biochemical measurements from the same hearts.
Coronary artery occlusion and reperfusion will be verified by direct
measurement of coronary blood flow (Doppler technique) and regional
myocardial blood flow (radioactive microsphere technique). The second
critical feature of the experimental design is the study of the changes in
subendocardial and subepicardial regions of the ischemic zone compared with
respective control values in the subendocardium and subepicardium in the
non-ischemic zone from the same hearts. Specifically ,beta-adrenergic
receptor agonist and antagonist binding, adenylate cyclase activity, cyclic
AMP, and GTP regulatory proteins will be examined in models of acute
myocardial ischemia. After determining the time course of changes in
autonomic receptors and coupling to adenylate cyclase, it will be
determined whether the changes are reversible by coronary artery
reperfusion.Another major goal is to determine whether changes are
transmural or affected regionally across the myocardial wall varying with
the level of ischemia across the myocardial wall. These experiments will be
compared where ischemia is more intense subendocardially and where ischemia
is equally intense in subepi- and subendocardium. In addition to examining
the responsiveness of in vivo myocardial wall motion and cellular changes
to beta-adrenergic stimulation with isoproterenol, mechanisms will be
addressed by examining the effects of coronary artery occlusion and
reperfusion in the presence and absence of alpha- and beta-adrenergic
receptor blockades and also in the desensitized heart, induced by
chronically elevated norepinephrine levels.
Effective start/end date7/1/906/30/95


  • National Institutes of Health: $55,707.00
  • National Institutes of Health
  • National Institutes of Health: $225,050.00
  • National Institutes of Health
  • National Institutes of Health: $150,460.00
  • National Institutes of Health


  • Medicine(all)

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