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 exercise.
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