Results of many clinical and experimental studies indicate that a mechanism other than renal must be involved in the overall chronic effect of mineralocorticoids on circulation-increased peripheral resistance and hypertension. We have previously found evidence for the presence of a molecular mechanism for action of these steroids in the arterial walls. We have also found (in corroboration of the findings of other investigators) that chronically elevated levels of mineralocorticoids cause a marked increase in the permeability of arterial smooth muscle cell membrane to sodium ions; this is thought to lead, through a chain of biochemical events, to increased peripheral resistance and hypertension. We propose: 1) to determine further important characteristics of the molecular mechanism for action of mineralocorticoids in arterial walls, by: (a) delineating physico-chemical differences between the glucocorticoid- and mineralocorticoid-receptors; (b) determining whether molecular mechanisms for action of these steroids, analogous to those found by us in rabbit arteries, exist also in arteries of other animal species, and in the human; (c) examining if mineralocorticoids cause an increase in the rate of synthesis of nuclear RNA in rabbit aorta and determining the characteristics of the newly synthesized RNA. 2) To test the hypothesis that the effect of mineralocorticoids on arterial cell-membrane permeability to electrolytes is elicited through the receptor-mediated mechanism for action of these steroids in the arterial wall, by: (a) conducting the permeability studies in the presence or absence of a mineralocorticoid-receptor blocker (""""""""anti-inducer""""""""); (b) determining if a correlation exists between receptor occupancy and the degree of the alteration in cell-membrane permeability to sodium; (c) determining if a mineralocorticoid-induced increase in amiloride binding-sites (""""""""sodium channels"""""""") can be prevented by an """"""""anti-inducer""""""""; (d) investigating if the mineralocorticoid-induced increase in arterial smooth muscle cell membrane permeability to electrolytes is due to an alteration in the pattern of synthesis of cell-membrane proteins, by a 2-dimensional electrophoretic study of sarcolemmal proteins, and by isotope-labelled studies of these proteins, and the pattern of their phosphorylation.

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National Heart, Lung, and Blood Institute (NHLBI)
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Experimental Cardiovascular Sciences Study Section (ECS)
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Rush University Medical Center
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