The proposed research program focuses on the vascular Alpha-adrenergic receptor. The general approach involves the use of ligand binding assays to characterize the receptor in arterial homogenates and in cultured vascular smooth muscle cells. The general objective is to elucidate the molecular and cellular mechanisms which are involved in controlling vascular smooth muscle cell responsiveness to Alpha-adrenergic agonists. The role of sympathetic innervation in regulating the Alpha-adrenergic receptor mechanisms controlling post-junctional catecholamine sensitivity will be determined. Estrogen regulates vascular sensitivity to Alpha-adrenergic agonists and Alpha-receptor affinity in rat mesenteric arteries. Defining the cellular mechanisms for these effects is a major objective. Preliminary data indicate that guanine nucleotides modulate vascular Alpha 1-adrenergic receptor affinity, a unique effect among Alpha 1-receptors. Characterizing the effects of guanine nucleotides on vascular Alpha 1-receptor affinity and defining Alpha 1-receptor heterogeneity with reference to the unique features of the vascular receptor is a major objective. Also, mesenteric arterial Alpha-adrenergic receptors in spontaneously hypertensive rats will be characterized to gain insight into the mechanism resulting in hypersensitivity of these vessels to contraction by catecholamines. The application of cell culture techniques to the study of Alpha-adrenergic receptor mechanisms in isolated intact vascular smooth muscle cells is a developmental aspect of this proposal. An objective is to define the cellular mechanisms by which estrogens and innervation modulate Alpha-adrenergic receptor expressions in vascular smooth muscle cells. These studies should enhance our understanding of the molecular and cellular mechanisms involved in the interaction of catecholamines with Alpha-adrenergic receptors in vascular smooth muscle cells. The increased understanding of these mechanisms will provide new insight into the physiologic and pathophysiologic mechanisms by which catecholamines control blood pressure normally and in hyypertension.
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