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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL034874-01
Application #
3348332
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1985-01-01
Project End
1985-12-31
Budget Start
1985-01-01
Budget End
1985-12-31
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
Tsuda, T; Alexander, R W (1990) Angiotensin II stimulates phosphorylation of nuclear lamins via a protein kinase C-dependent mechanism in cultured vascular smooth muscle cells. J Biol Chem 265:1165-70
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Berk, B C; Alexander, R W (1989) Vasoactive effects of growth factors. Biochem Pharmacol 38:219-25
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Griendling, K K; Tsuda, T; Alexander, R W (1989) Endothelin stimulates diacylglycerol accumulation and activates protein kinase C in cultured vascular smooth muscle cells. J Biol Chem 264:8237-40
Fish, R D; Sperti, G; Colucci, W S et al. (1988) Phorbol ester increases the dihydropyridine-sensitive calcium conductance in a vascular smooth muscle cell line. Circ Res 62:1049-54
Berk, B C; Vallega, G; Griendling, K K et al. (1988) Effects of glucocorticoids on Na+/H+ exchange and growth in cultured vascular smooth muscle cells. J Cell Physiol 137:391-401
Colucci, W S; Akers, M; Wise, G M (1988) Differential effects of norepinephrine and phorbol ester on alpha-1 adrenergic receptor number and surface-accessibility in DDT1 MF-2 cells. Biochem Biophys Res Commun 156:924-30
Sperti, G; Colucci, W S (1987) Phorbol ester-stimulated bidirectional transmembrane calcium flux in A7r5 vascular smooth muscle cells. Mol Pharmacol 32:37-42
Berk, B C; Brock, T A; Gimbrone Jr, M A et al. (1987) Early agonist-mediated ionic events in cultured vascular smooth muscle cells. Calcium mobilization is associated with intracellular acidification. J Biol Chem 262:5065-72

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