Several commonly encountered clinical conditions are associated with changes in neurohumoral influences of the heart and coronary vessels. Adrenergic supersensitivity of coronary vessels may result following chronic cardiac denervation or following alterations of neurotransmitter disposition. These conditions may augment coronary constriction to either endogenous or exogenous catecholamines and may thus significantly alter myocardial perfusion under conditions of stress and adrenergic stimulation. One goal of these studies will be to determine if coronary alpha and beta adrenergic sensitivity is regulated principally by circulating or neuronal catecholamines or if there is redundant control, i.e. regulation by both circulating and neuronal norepinephrine. Responses of both large and small coronary vessels will be examined in vitro and selected experiments will be performed on coronary microvessels in vivo. Unique applications of autoradiographic ligand binding studies will be performed to determine if either beta (large and small vessels) or alpha 2 (small vessels) adrenergic receptor number of affinity is altered by either chronic sympathectomy or depletion of circulating norepinephrine. A second goal will be to determine if following sympathectomy there is an augmentation of extraneural metabolism of norepinephrine beyond that observed following acute inhibition of neuronal uptake of norepinephrine. Augmentation of extraneuronal norepinephrine metabolism would prevent the development of prejunctional supersensitivity following sympathectomy. The third goal of these studies will be to determine if changes in the disposition of norepinephrine can produce adrenergic supersensitivity in either small or large coronary vessels. In these experiments both in vitro and in vivo methodology will be employed. These studies will employ a variety of unique in vivo and in vitro approaches which should provide important new information regarding the regulation of adrenergic sensitivity and neuroeffector mechanisms in coronary vascular smooth muscle.
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