The objective of this project is to test the hypothesis that platelets of patients with essential hypertension exhibit increased sensitivity to agonists that exert their effect through the Ca messenger system. This sensitivity would be expressed by a higher cytosolic free Ca (Cai) response. It may reflect a higher agonist mediated Ca entry or mobilization, inappropriate response of the Ca-ATPase and the Na-H antiport feedback system or both. To explore these alternatives, platelets and their plasma membrane fractions (i.e., the external plasma and dense tabular system membranes) from hypertensives and nonmotensives will be examined under basal conditions and after treatments by agonists and experimental perturbations that are known to: 1) raise Cai, 2) stimulate phospholipase C (PLC), and 3) activate the Na-H antiport via protein kinase C dependent and independent mechanisms. The role of extracellular and intracellular Ca in possible differences of Cai homeostasis between platelets from hypertensives and normotensives will be evaluated by performing experiments in the presence and absence of extracellular Ca, in the presence of Ca channel blockers and Ca ionophores, and after the quenching of cellular Ca. Kinetics of activation of Ca-ATPase in the external plasma membrane, activation of the Na-H antiport and measurement of Ca in intact platelets, will be performed using fluorescent methods. The fluorescent probes 2', 7'-bis (carboxyethyl)-5, 6'carboxyfluorescein (BCECF) and fura-2 will be respectively used for the measurements of cytosolic pH and Cai. Results of these studies will be instrumental in gaining a better insight, at the cellular level, into the pathophysiology of essential hypertension. Understanding the links between abnormalities in the cellular regulation of Cai and elevated blood pressure will aid in formulating the appropriate approaches to prevent and treat essential hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL042856-03
Application #
3361188
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1990-08-01
Project End
1993-07-31
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Type
Schools of Medicine
DUNS #
605799469
City
Newark
State
NJ
Country
United States
Zip Code
07107
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Zentay, Z; Raguwanshi, M; Reddi, A et al. (1995) Cytosolic Ca profile of resting and thrombin-stimulated platelets from black women with NIDDM. J Diabetes Complications 9:74-80
Nakamura, K; Kimura, M; Fenton 2nd, J W et al. (1995) Duality of plasmin effect on cytosolic free calcium in human platelets. Am J Physiol 268:C958-67
Yang, X Y; Fekete, Z; Gardner, J et al. (1994) Endothelin mobilizes calcium and enhances glucose uptake in cultured human skeletal myoblasts and L6 myotubes. Hypertension 23:1075-81
Kimura, M; Cho, J H; Reeves, J P et al. (1994) Inhibition of Ca2+ entry by Ca2+ overloading of intracellular Ca2+ stores in human platelets. J Physiol 479 ( Pt 1):1-10
Kimura, M; Cho, J H; Lasker, N et al. (1994) Differences in platelet calcium regulation between African Americans and Caucasians: implications for the predisposition of African Americans to essential hypertension. J Hypertens 12:199-207
Aviv, A (1994) Cytosolic Ca2+, Na+/H+ antiport, protein kinase C trio in essential hypertension. Am J Hypertens 7:205-12
Kimura, M; Aviv, A; Reeves, J P (1993) K(+)-dependent Na+/Ca2+ exchange in human platelets. J Biol Chem 268:6874-7
Kimura, M; Aviv, A (1993) Regulation of the cytosolic pH set point for activation of the Na+/H+ antiport in human platelets: the roles of the Na+/Ca2+ exchange, the Na(+)-K(+)-2Cl- cotransport and cellular volume. Pflugers Arch 422:585-90
Kimura, M; Lasker, N; Aviv, A (1993) Thapsigargin-evoked changes in human platelet Ca2+, Na+, pH and membrane potential. J Physiol 464:1-13

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