Studies with intact tissues to determine the role of a Na+-Ca2+ exchange system in the cell membrane of vascular smooth muscle have resulted in conflicting reports. However, a specific Na+- Ca2+ exchange system has been consistently observed in isolated cell membrane vesicles as well as in isolated cells. The goal of this project is to determine the role of this Na+-Ca2+ exchange system of the cell membrane of vascular smooth muscle in the regulation of cytosolic Ca2+ concentration and cell contraction. Studies are designed in this project (1) to elucidate the kinetic characteristics, the stoichiometry and the regulation of the Na+- Ca2+ exchange system of sarcolemmal vesicles isolated from dog mesenteric artery and (2) to determine the changes in cytosolic Ca2+ and contraction of isolated single cells of vascular smooth muscle under conditions when the specific activity or the equilibrium of the Na+-Ca2+ exchange system of cell membrane is altered by changing intracellular and extracellular Na+ concentration. The kinetic characteristics, the stoichiometry and the regulation of the Na+-Ca2+ exchange system will be studied in isolated sarcolemmal vesicles by measuring uptake or release of Ca2+ in exchange for Na+ by radiochemical assay with Millipore filtration. The cytosolic Ca2+ concentration will be measured with the calcium-sensitive dye fura-2 and digital imaging microscopy, and the contractile state will be assessed by utilizing an interactive computer graphics system to measure cell length. Since Na+ concentration has been shown to increase in vascular smooth muscle cells in several forms of hypertension and since cytosolic Ca2+ concentration plays an essential role in cell contraction, the proposed study will provide answers to the question of whether or not the Na+-Ca2+ exchange system of the cell membrane can play any role in the development or in the maintenance of hypertension by regulating cytosolic Ca2+ concentration. Elucidation of the role of this process is likely to be of considerable importance not only towards understanding vascular smooth muscle cell function in normal and in pathologic conditions but also towards rational development of therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL034664-06
Application #
3347812
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1985-08-01
Project End
1993-07-31
Budget Start
1990-08-01
Budget End
1991-07-31
Support Year
6
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Supaporn, T; Sandberg, S M; Borgeson, D D et al. (1996) Blunted cGMP response to agonists and enhanced glomerular cyclic 3',5'-nucleotide phosphodiesterase activities in experimental congestive heart failure. Kidney Int 50:1718-25
Cox, D A; Conforti, L; Sperelakis, N et al. (1993) Selectivity of inhibition of Na(+)-Ca2+ exchange of heart mitochondria by benzothiazepine CGP-37157. J Cardiovasc Pharmacol 21:595-9
Motley, E D; Paul, R J; Matlib, M A (1993) Role of Na(+)-Ca2+ exchange in the regulation of vascular smooth muscle tension. Am J Physiol 264:H1028-40
Cox, D A; Matlib, M A (1993) A role for the mitochondrial Na(+)-Ca2+ exchanger in the regulation of oxidative phosphorylation in isolated heart mitochondria. J Biol Chem 268:938-47
Matlib, M A (1991) Role of sarcolemmal membrane sodium-calcium exchange in vascular smooth muscle tension. Ann N Y Acad Sci 639:531-42
French, J F; Rapoport, R M; Matlib, M A (1989) Possible mechanism of benzodiazepine-induced relaxation of vascular smooth muscle. J Cardiovasc Pharmacol 14:405-11
Balasubramaniam, A; Grupp, I; Matlib, M A et al. (1988) Comparison of the effects of neuropeptide Y (NPY) and 4-norleucine-NPY on isolated perfused rat hearts;effects of NPY on atrial and ventricular strips of rat heart and on rabbit heart mitochondria. Regul Pept 21:289-99
Matlib, M A (1988) Na+-Ca2+ exchange in sarcolemmal membrane vesicles of dog mesenteric artery. Am J Physiol 255:C323-30
French, J F; Matlib, M A (1988) Identification of a high-affinity peripheral-type benzodiazepine binding site in rat aortic smooth muscle membranes. J Pharmacol Exp Ther 247:23-8
Matlib, M A; Kihara, M; Farrell, C et al. (1988) The Na+-Ca2+ exchange system in vascular smooth muscle cell membrane vesicles isolated from cultured cells and from tissue is similar. Biochim Biophys Acta 939:173-7

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