K is the major intracellular cation yet the hemodynamic effects of chronic changes in dietary K intake on blood pressure control are debated. Both increases and decreases in dietary K have been shown to prevent and reverse hypertension in experimental animals. The protective effect of both K excess and K depletion is mediated by a decrease in systemic vascular resistance and in angiotensin II (AII) pressor sensitivity. AII-induced vascular contraction follows binding of the hormone to a plasma membrane receptor and a series of post-binding biochemical events which include interaction with a guanine nucleotide regulatory protein, polyphosphoinositide hydrolysis, and intracellular calcium mobilization. Decreases in K have been demonstrated to offset the interaction of AII with the AII receptor and to cause post-receptor defects in mesenteric artery membrane particles prepared from intact animals. However, the specific post-binding defects have not been studied because K and AII cannot be independently varied in intact animals and because the specific biochemical pathways cannot be studied in vivo. Our plan is to use a system, vascular smooth muscle cells in culture, where K and AII can be independently controlled to study the interaction of K and AII on receptor binding and post-binding biochemical events.
Our specific aims are to determine if K excess or K depletion alters: 1. AII binding to its putative membrane receptor 2. The interaction between the AII receptor and guanine nucleotide regulatory proteins 3. The interaction between the AII receptor and protein kinase C 4. AII-induced polyphosphoinositide hydrolysis and intracellular free calcium mobilization 5. The composition of vascular smooth muscle plasma membranes These investigations require the application of a variety of biochemical and morphologic techniques including cell culture, receptor analysis, measurement of polyphosphoinositides, inositol phosphates, cytosolic free calcium, membrane phospholipids and transmission electron microscopy. The results of these studies will improve our basic understanding of the biochemical events which mediate the pressor action of AII and provide much needed information on the specific effects of K in hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL037694-02
Application #
3353594
Study Section
(SRC)
Project Start
1986-09-30
Project End
1990-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Thekkumkara, T J; Cookson, R; Linas, S L (1998) Angiotensin (AT1A) receptor-mediated increases in transcellular sodium transport in proximal tubule cells. Am J Physiol 274:F897-905
Hanson, A S; Linas, S L (1995) Beta-adrenergic receptor function in rat proximal tubule epithelial cells in culture. Am J Physiol 268:F553-60
Schelling, J R; Linas, S L (1994) Angiotensin II-dependent proximal tubule sodium transport requires receptor-mediated endocytosis. Am J Physiol 266:C669-75
Hanson, A S; Linas, S L (1994) Parathyroid hormone/adenylate cyclase coupling in vascular smooth muscle cells. Hypertension 23:468-75
Schelling, J R; Singh, H; Marzec, R et al. (1994) Angiotensin II-dependent proximal tubule sodium transport is mediated by cAMP modulation of phospholipase C. Am J Physiol 267:C1239-45
Schelling, J R; Hanson, A S; Marzec, R et al. (1992) Cytoskeleton-dependent endocytosis is required for apical type 1 angiotensin II receptor-mediated phospholipase C activation in cultured rat proximal tubule cells. J Clin Invest 90:2472-80
Dixon, B S; Breckon, R; Fortune, J et al. (1990) Effects of kinins on cultured arterial smooth muscle. Am J Physiol 258:C299-308
Linas, S L; Marzec-Calvert, R; Ullian, M E (1990) K depletion alters angiotensin II receptor expression in vascular smooth muscle cells. Am J Physiol 258:C849-54
Ullian, M E; Linas, S L (1990) Angiotensin II surface receptor coupling to inositol trisphosphate formation in vascular smooth muscle cells. J Biol Chem 265:195-200
Ullian, M E; Linas, S L (1989) Role of receptor cycling in the regulation of angiotensin II surface receptor number and angiotensin II uptake in rat vascular smooth muscle cells. J Clin Invest 84:840-6

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