Project Details


Studies demonstrate that in the exercising dog, i.c. injection of the
specific alpha1-receptor antagonist prazosin increases both coronary flow
and myocardial contractile function (dp/dtmax and regional segmental
shortening). The increase in contractile function was not due to
activation of myocardial beta1-receptors since the effect was not blunted
by atenolol. It is proposed that during exercise, an alpha-adrenergic
constriction limits the increase in coronary flow and causes a
flow-limitation of myocardial performance. Using a chronically
instrumented, exercising dog model, this proposal will be examined as
follows: (1) Studies suggest that in addition to an alpha1-constriction in
the coronary circulation, an alpha2-constrictor tone may also be present.
Study 1 will examine the effects of specific postsynaptic alpha2-blockade
on coronary flow and myocardial function in exercise. (2) The increase in
coronary flow after alpha1-blockade during exercise is not due to increased
beta1-receptor stimulation with accompanying metabolic vasodilation. Study
2 will address the possibility that the increase in coronary flow is due to
a direct dilation caused by stimulation of vascular beta2-receptors. For
this purpose, the effects of alpha-blockade during exercise will be
examined in the presence of general beta-blockade with propranolol. (3) If
the increase in contractile function accompanying alpha-blockade is due to
an increase in myocardial perfusion, the increase in contractile
performance should also be noted if myocardial perfusion is elicited by
direct coronary vasodilators. Therefore, in Study 3 i.c. administration of
direct coronary dilators, e.g. adenosine and nitroglycerine, will be used.
(4) Study 4 will determine the local effects of specific alpha-blockade on
transmural myocardial perfusion (tracer microspheres), regional oxygen
extraction (regional venous effluents), and regional MV02. To further
examine the possibility that the effects of alpha-blockade observed are due
to presynaptic actions, the effects of alpha-blockade on regional
norepinephrine release will also be determined. (5) Previous experiments
showing an increase in contractile function associated with the increase in
coronary flow following alpha-blockade employed segment length crystals
implanted within the endocardial layers of the heart. Study 5 will more
closely examine whether high levels of cardiac sympathetic stimulation can
cause a flow-limitation of function in endocardium without epicardial
function. In these studies, effects of specific blockade on regional
epicardial and endocardial function will be examined during stellate
ganglion stimulation. Results of these studies will be important to
understanding adrenergic effects on myocardial perfusion and function in
Effective start/end date30/09/8529/09/86