(Hypertension. 1998;32:869-874.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Parameters of Lymphocyte Na+-Ca2+ Regulation and Blood Pressure
The Gender Effect
From the Hypertension Research Center and the Department of Preventive Medicine and Community Health, University of Medicine and Dentistry of NJ, New Jersey Medical School, Newark, NJ.
Correspondence to Abraham Aviv, Hypertension Research Center, University of Medicine and Dentistry of NJ, New Jersey Medical School, 185 S Orange Ave, Room F-464, Newark, NJ 07103. E-mail avivab{at}umdnj.edu
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Abstract |
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Abstract—Alterations in cellular Ca2+ and Na+ regulation play a role in the pathogenesis of essential hypertension. Using peripheral lymphocytes from 68 normal persons, we observed the following relationships for major cellular Ca2+ regulatory parameters. Among men and women, Na+-Ca2+ exchanger activity was positively correlated with the resting cytosolic free Ca2+ ([Ca2+]c) (r=0.43, P=0.0003), and the resting [Ca2+]c was positively correlated with cytosolic Na+ ([Na+]c) (r=0.50, P=0.0001). For men only, store-operated Ca2+ entry was positively correlated with Na+-Ca2+ exchanger activity (r=0.63, P=0.0001). In addition, systolic and diastolic blood pressures were positively correlated with [Na+]c in men (r=0.53, P=0.001, and r=0.41, P=0.017, respectively) but not in women (r=0.30, P=0.088, and r=0.24, P=0.17, respectively). Some of the relationships between cellular and blood pressure parameters were confounded by serum triglycerides. These observations indicate a gender effect on cellular Ca2+-Na+ regulation and its relationship with blood pressure.
Key Words: hypertension, essential • sodium • calcium • gender • blacks • ethnicity
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Introduction |
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Cytosolic Na+ ([Na+]c) plays a central role in controlling the cellular Ca2+ load in a number of cell types. The reason for this is that in these cells Na+-Ca2+ exchanger (NCE) is a major transport pathway responsible for the extrusion of cellular Ca2+ against a steep electrochemical gradient (reviewed in Reference 11 ). A number of intracellular and extracellular factors have been found to modify the protein expression and activity of the cardiac NCE,2 3 the most common exchanger among the 3 known NCEs (ie, cardiac, retinal, and brain NCEs).1 4 However, in the final analysis, [Na+]c is a pivotal determinant of NCE activity. The relationship between [Na+]c and cytosolic free Ca2+ ([Ca2+]c) is hence important for understanding altered regulation of cellular Ca2+ in essential hypertension, particularly because a major hypothesis proposes that in essential hypertension, reduced Na+-pump activity results in a rise in [Na+]c, inhibition of the NCE, and an increase in the cellular Ca2+ load.5 6 To explore this hypothesis, many studies examined the levels of [Ca2+]c and [Na+]c in circulating cells from humans. Platelets have been the focus of most investigations examining the relationships between [Ca2+]c and blood pressure (eg, References 77 to 13), whereas erythrocytes and to a lesser extent lymphocytes have been the main targets of studying the relationship between blood pressure and [Na+]c (reviewed in References 1414 to 16). In a number of studies lymphocytes were also used to study [Ca2+]c regulation in relation to blood pressure.17 18 19 20 Most of the studies in erythrocytes and lymphocytes have used flame photometry to assess cellular Na+ content and estimate [Na+]c. However, this measurement is fraught with multiple inaccuracies, including the need to estimate the intracellular and extracellular volumes to calculate the [Na+]c (reviewed in Reference 1414 ).
Recent investigations have shed a new light on mechanisms of external Ca2+ entry through store-operated Ca2+ channels21 and Ca2+ extrusion through the NCE22 23 24 25 in a number of cell types, including circulating lymphocytes. In the present investigation we used some of this new information to explore in lymphocytes the relationship between [Na+]c and [Ca2+]c and the relationship between 2 major and opposing Ca2+ regulatory systems, namely, the NCE and store-operated Ca2+ entry (SOCE). To this end we used the fluorescent probes sodium-binding benzofuran isophthalate (SBFI)26 to monitor [Na+]c and fura 2 to monitor [Ca2+]c.
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Subjects
We studied 68 whites and blacks (equally divided by race and gender). They were apparently healthy and on no medications (including analgesics, oral contraceptives, and hormonal supplements). None of the blacks had sickle cell trait. After an overnight fast (that is, no food and liquids other than water after dinner the night before the study), each subject arrived at the facilities of the Hypertension Research Center between 8 and 9 AM. Heights and weights were recorded, and the subjects rested in a sitting position for a period of 15 to 20 minutes, during which information was obtained regarding health status and family history of essential hypertension and non–insulin-dependent diabetes mellitus. Blood pressure measurements were then taken with a mercury sphygmomanometer with the subjects in a sitting position. The average of 3 blood pressure measurements, taken at 2-minute intervals, was used. Diastolic blood pressure was determined as the fifth Korotkoff sound. After blood pressure measurements were recorded, 50 mL venous blood was collected into acid dextrose buffer (20:1, vol/vol) of the following composition (in mmol/L): Na+ citrate 14, citric acid 1.8, dextrose 18 (pH 6.5). An additional 10 mL of blood was obtained for blood chemistries. All subjects signed informed consents approved by the institutional review board.
Lymphocyte Preparation
Peripheral lymphocytes were isolated by
density-gradient centrifugation as
described.17 22 Cells were suspended in
Ca2+-free HEPES buffer solution (HBS) comprising
(in mmol/L): NaCl 140, KCl 5, MgCl2 1,
glucose 10, HEPES 10, EGTA 0.3, and 0.1% BSA.
Monitoring of [Ca2+]c and
[Na+]c
Lymphocytes were incubated at 37°C in either
Ca2+-free HBS or Ca2+-containing HBS (ionized
Ca2+ adjusted to 1 mmol/L). For fura 2 loading, cells
were incubated for 30 minutes with fura 2-AM (5 µmol/L)
(Molecular Probes, Inc), centrifuged for 5 seconds to remove
external fura 2, and resuspended in Ca2+-free or
1 mmol/L Ca2+ HBS. For SBFI loading, cells
were incubated with 10 µmol/L SBFI-AM (Molecular Probes) for 60
minutes, centrifuged (5 seconds) to remove the extracellular
dye, and resuspended in 1 mmol/L Ca2+ HBS.
Fluorescence of fura 2–loaded cells was monitored at
excitation 340/380-nm and emission 505-nm wavelengths. Calibration of
[Ca2+]c was accomplished
by exposing cells to 100 µmol/L digitonin
(Rmax) followed by adding 15 mmol/L EGTA (pH
8.5; Rmin). Fluorescence in SBFI-loaded
cells was monitored at excitation 340/385-nm and emission 505-nm
wavelengths. Autofluorescence was taken with the use of
dye-unloaded cells. Calibration of
[Na+]c was performed with
modification of a previously described
protocol.26 Briefly, gramicidin D (2
µmol/L), nigericin (5 µmmol/L), and monensin (5
µmmol/L) were added to calibration solutions comprising (in
mmol/L): Na gluconate 0 to 115, K gluconate 0 to 115 (where Na
gluconate+K gluconate=115), KCl 30, CaCl2 1,
MgCl2 1, glucose 10, and HEPES 10 (pH 7.4). Eight
concentrations of Na+ were used in the
calibration solutions, ie, 0, 5, 10, 20, 30, 50, 80, and 115
mmol/L. Fluorescence was monitored in stirred cells at 37°C
in a Fluorolog II spectrofluorometer (SPEX Industries).
Na+-Ca2+ Exchanger Activity
Na+-dependent external
Ca2+ entry was taken as maximal NCE activity in
the reverse mode. The following steps were undertaken to measure this
parameter: Ouabain (0.1 mmol/L) was added during the
last 10 minutes of incubation with fura 2-AM in 1 mmol/L
Ca2+ HBS. Cells were rapidly centrifuged
and resuspended in either (1) Li+-containing,
Ca2+-free HBS, comprising (in mmol/L): LiCl
140, KCl 10, MgCl2 1, glucose 10, HEPES 10, and
0.1% BSA, or (2) Na+-containing,
Ca2+-free HBS, in which LiCl was equimolarly
replaced by NaCl. One millimole per liter (final concentration) of
ionized Ca2+ plus 1 µmol/L thapsigargin
were added, and the Ca2+ signal was monitored for
45 seconds. The difference in the
[Ca2+]c rise between
cells suspended in Na+-containing and
Na+-free medium after 45 seconds was considered
the Na+-dependent external
Ca2+ entry.
Store-Operated Ca2+ Entry
Thapsigargin (1 µmol/L) was added during the last 10
minutes of incubation with fura-2 AM in Ca2+-free
HBS. Cells were rapidly centrifuged and resuspended in
Ca2+-free HBS. Ca2+
(0.5 mmol/L final concentration) was rapidly added to the medium,
and the Ca2+ signal was monitored for 45
seconds.
Other Measurements
Levels of total serum cholesterol, HDL
cholesterol, triglycerides, glucose, and
creatinine were measured in a Kodak Ectachem DT 60
analyzer.
Data Analysis
The relationships among sodium and calcium
parameters and physiological
measurements were analyzed by simple linear correlation and
regression, partial correlation, and multiple regression. The effects
of gender and race were analyzed by ANOVA. All calculations
were performed with SAS statistical software (SAS Institute, Inc). The
criterion for statistical significance was P<0.05.
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Results |
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Table 1
presents the general
characteristics of the subjects: women were older than men, and the
body mass index was greater in blacks than in whites. HDL levels were
higher in women than in men and in whites than in blacks. In addition,
serum creatinine was higher in men than in women,
reflecting the greater muscle mass in men.
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Table 2 shows correlations among
parameters for all subjects combined and separately for men
and women. No differences in correlations were observed between blacks
and whites. NCE activity was strongly correlated with the resting
[Ca2+]c among both men
and women (for all subjects, r=0.43, P=0.0003;
for men, r=0.41, P=0.015; for women,
r=0.44, P=0.009). Resting
[Ca2+]c and
[Na+]c were highly
correlated in both men (r=0.46, P=0.007) and
women (r=0.57, P=0.005) (Figure 1). The activities of SOCE and NCE were
highly correlated among men (r=0.63, P=0.0001)
(Figure 2). However, the correlation
among women was minimal (r=0.10, P=0.58), and the
difference between correlation coefficients between men and women was
statistically significant. Activity of SOCE was not correlated with the
resting [Ca2+]c.
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Systolic blood pressure was highly correlated with
[Na+]c for men
(r=0.53, P=0.001) but not for women
(r=0.30, P=0.088) (Figure 3). Diastolic blood pressure
was also correlated with
[Na+]c for men
(r=0.41, P=0.017) but not for women
(r=0.24, P=0.17) (Figure 3). Although these
findings suggest stronger relationships between
[Na+]c and
systolic/diastolic blood pressure in men than in
women, the gender-related differences in correlation coefficients were
not statistically significant (P=0.13 and P=0.23
for systolic and diastolic blood pressure,
respectively). Correlations between blood pressure and resting
[Ca2+]c were not
statistically significant.
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Because triglycerides were highly correlated with resting
[Na+]c and
[Ca2+]c, correlations
were adjusted for the effect of triglycerides (Table 3). The
correlations of resting
[Ca2+]c with
[Na+]c and with NCE
activity remained strong (partial correlation coefficients
r=0.41, P=0.0006, and r=0.54,
P=0.0001, respectively), as did the correlation of SOCE and
NCE activity (partial correlation coefficient r=0.31,
P=0.013). Correlations of
[Na+]c with
systolic and diastolic blood pressures were
attenuated by adjustment for triglycerides (partial
correlation coefficients r=0.23, P=0.058, and
r=0.20, P=0.11, respectively). After adjustment
for triglycerides, the relationship between
systolic blood pressure and resting
[Na+]c did not differ
between men and women.
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No associations were observed between lymphocyte parameters and familial history of essential hypertension or non–insulin-dependent diabetes.
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Discussion |
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A relevant finding of this work is the strong positive correlation between the resting [Ca2+]c and [Na+]c in lymphocytes from a heterogeneous human population. This was observed in both men and women. Such a finding strongly suggests that [Na+]c and therefore the NCE play important roles in the regulation of the resting [Ca2+]c in human lymphocytes. Other related findings of interest are observations that the resting [Ca2+]c was strongly correlated with NCE in both men and women, suggesting that as [Ca2+]c rises, adaptive mechanisms are initiated to enhance Ca2+ extrusion through the NCE. This is probably mediated by the upregulation of NCE expression, since in the present investigation we examined the activity of NCE (in a reverse mode) at high (1 mmol/L) Ca2+ concentration, reflecting the maximal reaction velocity of the exchanger. Such a concept awaits proof by direct quantification of NCE protein.
Until recently it has been difficult to show the presence of NCE activity in human lymphocytes.27 Perhaps one reason for this difficulty relates to the substantial capacity of the sarco(endo)plasmic reticulum Ca2+-ATPase to sequester Ca2+ into the sarco(endo)plasmic reticulum.28 Thus, an acute increase in the cellular Ca2+ load might result in a substantial Ca2+ sequestration in the sarco(endo)plasmic reticulum with little effect on the level of the resting [Ca2+]c. However, in human lymphocytes 45Ca2+ fluxes, and [Ca2+]c after inhibition of the sarco(endo)plasmic reticulum Ca2+-ATPase, are greatly modified by removal of external Na+ and by treatment with ouabain (reviewed in Reference 2323 ). These findings support the presence of NCE in these cells.
Oshima et al20 29 have demonstrated a strong correlation between [Na+]c (measured by flame photometry) and [Ca2+]c in lymphocytes from hypertensive and normotensive subjects. Although these investigators showed higher levels of lymphocyte [Ca2+]c and [Na+]c in patients with essential hypertension than in normotensive controls, they did not find correlations for the levels of these ions with blood pressure when blood pressure was evaluated as a continuously distributed variable.19 20 29 The present study and our previous work17 have confirmed the lack of correlation between the resting [Ca2+]c in lymphocytes and blood pressure. However, we did show a strong correlation between the [Na+]c in lymphocytes and blood pressure in men but not in women. One possible explanation is that in the present work the use of SBFI facilitated a more sensitive measurement of [Na+]c and uncovered the relationship between this cellular parameter and blood pressure. It is possible that variation in Na+ intake (a parameter not evaluated in this work) accounts for some variation in lymphocyte Na+ and Ca2+ regulation. Nonetheless, the relationship among the cellular parameters and between lymphocyte Na+ and blood pressure should hold irrespective of variation in Na+ intake.
It is noteworthy that gender, presumably through the effects of ovarian steroid hormones, plays a role in modifying the relationship between blood pressure and a number of molecular, cellular, and systemic modalities, including polymorphism in the angiotensinogen locus,30 and the activities of Na+-Li+ exchange in erythrocytes31 32 and Na+-H+ exchange in platelets.33 In addition, gender modifies the expression of non-modulation34 and urinary excretion of cortisol.35 These phenotypes reflect variables involved in Na+ regulation at the cellular and systemic levels. Their dependency on gender is therefore in accordance with our findings that the relationship between lymphocyte [Na+]c and blood pressure is stronger for men than for women. The gender-dependent effect was shown in our investigations not only for the relationship between SOCE and the NCE but perhaps also for the relationship between [Na+]c and blood pressure.
The positive correlation between [Ca2+]c and [Na+]c in lymphocytes suggests that, through its effect on the NCE, [Na+]c modifies [Ca2+]c. It is noteworthy that the resting [Ca2+]c might poorly reflect the overall cellular Ca2+ load, since the bulk of the freely exchangeable Ca2+ is sequestered within the sarco(endo)plasmic reticulum. A number of investigations have demonstrated that in platelets, the resting [Ca2+]c correlates with blood pressure.7 8 12 Other studies, including a number of studies by our group, have found no statistical correlations between the resting [Ca2+]c in platelets and blood pressure when the blood pressure was evaluated as a continuously distributed variable.9 10 25 36 In our more recent work in platelets, we found that although the resting [Ca2+]c was not correlated with blood pressure, the freely exchangeable Ca2+ in the sarco(endo)plasmic reticulum (dense tubules) of platelets was strongly correlated with blood pressure, but only in men25 and not in women.37 These observations further underscore the role of gender in shaping cellular Ca2+ and Na+ regulation.
We previously reported,25 as in the present work, that serum triglycerides correlated with Ca2+ parameters in circulating cells. This conclusion is not confined to our studies on the relationship between cellular ion regulation and blood pressure. For instance, other groups have repeatedly shown that serum triglycerides correlated with the activity of the Na+-Li+ exchange in erythrocytes and therefore modified the relationship between this transport system and blood pressure.38 39 40 41 42 Our findings are relevant in that they clearly show that triglycerides do not modify the interrelationships between the various cellular Ca2+ (and Na+) parameters but the relationships between these parameters and blood pressure. In this regard, the variation in lymphocyte parameters might not be causally related to variation in triglycerides. Rather, both might be pleiotropic expressions of variant genes.
In conclusion, we report here that [Na+]c in peripheral lymphocytes of a heterogeneous human population positively correlates with resting [Ca2+]c and that [Na+]c strongly correlates with blood pressure, particularly in men. Fluctuating levels of ovarian steroid hormones in premenopausal women might account for the sexual dimorphism in the expression of hypertension43 and for the effect of gender on the relationship among cellular variables of Ca2+ and Na+ regulation and on the relationship between [Na+]c and blood pressure in humans.
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Acknowledgments |
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This work was supported by National Institutes of Health grant HL7906. Dr Horiguchi's postdoctoral fellowship was supported by the American Heart Association, New Jersey Affiliate.
Received April 21, 1998; first decision May 18, 1998; accepted July 2, 1998.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Reeves JP. Sodium-calcium exchange. In: Bronner F, ed. Intracellular Calcium Regulation. New York, NY: Alan R. Liss; 1990:305–347.
2.
Smith L, Smith B. Regulation of sodium-calcium
exchanger by glucocorticoids and growth factors in vascular smooth
muscle. J Biol Chem. 1994;269:27527–27531.
3. Smith JB, Lee H-W, Smith L. Regulation of expression of sodium-calcium exchanger and plasma membrane calcium ATPase by protein kinases, glucocorticoids, and growth factors. Ann N Y Acad Sci. 1996;779:258–271.[Medline] [Order article via Infotrieve]
4.
Kofuji P, Lederer WJ, Schulze DH. Mutually exclusive
and cassette exons underlie alternatively spliced isoforms of the Na/Ca
exchanger. J Biol Chem. 1994;269:5145–5149.
5.
Blaustein MP. Sodium ions, calcium ions, blood
pressure regulation and hypertension: a reassessment and a hypothesis.
Am J Physiol.. 1977;232:C165–C173.
6.
Blaustein MP. Physiological
effects of endogenous ouabain: control of intracellular
Ca2+ stores and cell responsiveness.
Am J Physiol. 1993;264:C1367–C1387.
7. Erne P, Bolli P, Burgisser E, Buhler FR. Correlation of platelet calcium with blood pressure. N Engl J Med. 1984;310:1084–1088.[Abstract]
8.
Touyz RM, Schiffrin EL. Effects of
angiotensin II and endothelin-1 on platelet aggregation
and cytosolic pH and free Ca2+ concentration in
essential hypertension. Hypertension. 1993;22:853–862.
9.
Cho JH, Nash F, Fekete Z, Kimura M, Reeves JP, Aviv A.
Increased calcium stores in platelets from African Americans.
Hypertension. 1995;25:377–383.
10.
Gardner JP, Cho J-H, Skurnick JH, Awad G, Gutkin M,
Byrd LH, Lasker N, Aviv A. Blood pressure inversely correlates with
thrombin-evoked calcium rise in platelets. Hypertension. 1994;23:703–709.
11. Haller H, Lenz T, Thiede M, Ludersdorf M, Kribben A, Distler A, Philipp T. Platelet intracellular free calcium and hypertension. J Clin Hypertens. 1987;3:12–19.[Medline] [Order article via Infotrieve]
12.
Brickman A, Nyby M, VonHungen K, Eggena P, Tuck M.
Parathyroid hormone platelet calcium and blood pressure in
normotensive subjects. Hypertension. 1991;18:176–182.
13.
Cooper RS, Shamsi N, Katz S. Intracellular calcium and
sodium in hypertensive patients. Hypertension. 1987;9:224–229.
14. Carr SJ, Thomas TH. Perturbations of cell membranes: perturbations of blood cells and platelet membranes in human essential hypertension. In: Swales JD, ed. Textbook of Hypertension. Boston, Mass: Blackwell Scientific Publications, Inc; 1994:160–174.
15. Weder AB. Membrane sodium transport and salt sensitivity of blood pressure. Hypertension. 1991(suppl I);17:I-74–I-80.
16. Aviv A, Lasker N. Proposed defects in membrane transport and intracellular ions as pathogenic factors in essential hypertension. In: Laragh JH, Brennen BM, eds. Hypertension: Pathophysiology, Diagnosis, and Management. New York, NY: Raven Press; 1990:923–937.
17. Fekete Z, Kimura M, Horiguchi M, Gardner JP, Nash F, Aviv A. Differences between store-dependent Ca2+ fluxes in lymphocytes from African Americans and whites. J Hypertens. 1996;14:1293–1299.[Medline] [Order article via Infotrieve]
18. Alexiewicz JM, Gaciong A, Parise M, Karubian F, Massry SE, Campese VM. Effect of dietary sodium intake on intracellular calcium in lymphocytes of salt-sensitive hypertensive patients. Am J Hypertens. 1992;5:536–541.[Medline] [Order article via Infotrieve]
19.
Oshima T, Matsuura H, Matsumoto K, Kido K, Kajyama G.
Role of cellular calcium in salt sensitivity of patients with essential
hypertension. Hypertension. 1988;11:703–707.
20.
Oshima T, Matsuura H, Kido K, Matsumoto K, Fujii H,
Masaoka S, Okamoto M, Tsuchioka Y, Kajiyama G, Tsubokura T.
Intralymphocytic sodium and free calcium and plasma renin in essential
hypertension. Hypertension. 1988;12:26–31.
21. Berridge MJ. Capacitative calcium entry. J Biol Chem. 1995;312:1–11.
22. Balasubramanyam M, Rohowsky-Kochan C, Reeves JP, Gardner JP. Na+/Ca2+ exchange-mediated calcium entry in human lymphocytes. J Clin Invest. 1994;94:2002–2008.
23. Gardner JP, Balasubramanyam M. Na-Ca exchange in circulating blood cells. Ann N Y Acad Sci. 1996;779:502–514.[Medline] [Order article via Infotrieve]
24. Kimura M, Aviv A. 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. Eur J Physiol. 1993;422:585–590.[Medline] [Order article via Infotrieve]
25.
Horiguchi M, Kimura M, Lytton J, Skurnick J, Nash F,
Awad G, Poch E, Aviv A. Ca2+ in the dense
tubules: a model of platelet Ca2+ load.
Hypertension. 1998;31:595–602.
26.
Minta A, Tsien RY. Fluorescent indicators for
cytosolic sodium. J Biol Chem. 1989;264:19449–19457.
27.
Tsien RY, Pozzan T, Rink TJ. Calcium homeostasis in
intact lymphocytes: cytoplasmic free calcium monitored with a new,
intracellularly trapped fluorescent indicator. J
Cell Biol. 1982;94:325–334.
28.
Pozzan T, Rizutto R, Meldolesi J. Molecular and
cellular physiology of calcium stores. Physiol Rev. 1994;74:595–636.
29. Oshima T, Matsuura H, Kido K, Matsumoto K, Otsuki T, Fujii H, Masaoka S, Okamoto M, Tsuchioka Y, Kajiyama G, Tsubokura T. Intralymphocytic sodium and free calcium concentration in relation to salt sensitivity in patients with essential hypertension. Jpn Circ J. 1987;51:1184–1190.[Medline] [Order article via Infotrieve]
30. Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, Williams CS, Charru A, Hunt SC, Hopkins PN, Williams RR, Lalouel JM, Corvol P. Molecular basis of human hypertension: role of angiotensinogen. Cell. 1992;71:169–180.[Medline] [Order article via Infotrieve]
31. Rebbeck TR, Turner ST, Michels VV, Moll PP. Genetic and environmental explanations for the distribution of sodium-lithium countertransport in pedigrees from Rochester, MN. Am J Hum Genet. 1991;48:1092–1104.[Medline] [Order article via Infotrieve]
32.
Ibsen KK, Jensen HA, Wieth JO, Funder JF. Essential
hypertension: sodium-lithium countertransport in erythrocytes from
patients and from children having one hypertensive parent.
Hypertension. 1982;4:703–709.
33. Stratton PD, Ritter JM. Influence of sex on sodium-proton exchange-dependent swelling of platelets from patients with essential hypertension. J Hypertens. 1997;15:1403–1406.[Medline] [Order article via Infotrieve]
34.
Fisher NDL, Ferri C, Bellini C, Santucci A, Gleason R,
Williams GH, Hollenberg NK, Seely EW. Age, gender and non-modulation: a
sexual dimorphism in essential hypertension. Hypertension. 1997;29:980–985.
35.
Litchfield WR, Hunt SC, Jeunemaitre X, Fisher NDL,
Hopkins PN, Williams RR, Corvol P, Williams GH. Increased urinary free
cortisol: a potential intermediate phenotype of essential
hypertension. Hypertension. 1998;31:569–574.
36. Miller MA, Sagnella GA, Markandu ND, MacGregor GA. Determinants of platelet intracellular free calcium in essential hypertension and effect of stimulation by arginine vasopressin. Am J Hypertens. 1993;6:209–216.[Medline] [Order article via Infotrieve]
37. Horiguchi M, Kimura M, Lytton J, Poch E, Aviv A. The relationship between Ca2+-ATPase and freely exchangeable Ca2+ in the dense tubules: a study in platelets from women. Am J Hypertens. In press.
38. Stengard JH, Zerba KE, Turner ST, Sing CF. A biometrical study of the relationship between sodium-lithium countertransport and triglycerides. Ann Hum Genet. 1997;61:121–136.[Medline] [Order article via Infotrieve]
39. Villar J, Montilla C, Muniz-Crijalvo O, Muriana FG, Stiefel P, Ruiz-Gutierrez V, Carenado J. Erythrocyte Na+/Li+ countertransport in essential hypertension: correlation with membrane lipid levels. J Hypertens. 1996;14:969–973.[Medline] [Order article via Infotrieve]
40. Strazzullo P, Cappuccio FP, Trevisan M, Siani A, Barba G, Reyne E, Pagano E, Mancini M. The relationship of erythrocyte sodium-lithium countertransport to blood pressure and metabolic abnormalities in a sample of untreated middle-age workers. J Hypertens. 1993;11:815–822.[Medline] [Order article via Infotrieve]
41. Englemann B, Duhm J, Schonthier UM, Streich S. Relation of sodium-lithium countertransport kinetics to plasma and red cell membrane phospholipids in hyperlipidemia. Atherosclerosis. 1993;99:151–163.[Medline] [Order article via Infotrieve]
42.
Turner ST, Michels VV. Sodium-lithium countertransport
and hypertension in Rochester, Minnesota. Hypertension. 1991;18:183–190.
43. Chen Y-F. Sexual dimorphism of hypertension. Curr Opin Nephrol Hypertens. 1996;5:181–185.[Medline] [Order article via Infotrieve]
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