(Hypertension. 1995;26:156-163.)
© 1995 American Heart Association, Inc.
Articles |
Calcium Supplementation Attenuates an Enhanced Platelet Function in Salt-Loaded Mildly Hypertensive Patients
From The First Department of Internal Medicine, Kobe (Japan) University School of Medicine.
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Abstract |
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Abstract We designed this study to evaluate the effect of low versus high calcium intake on platelet function in salt-loaded patients with mild hypertension. After a 7-day period of dietary salt restriction, 19 patients were placed on a high salt (300 mmol/d), low calcium (6.25 mmol/d) diet for 7 days; 10 of these patients were given 54 mmol/d of supplementary calcium, and 9 patients were given placebo. At the end of the low and high salt regimens, we evaluated changes in blood pressure, platelet aggregation, and the platelet release reaction measured as plasma ß-thromboglobulin and platelet factor 4 levels. With high salt intake, significant increases in mean blood pressure (P<.02), red blood cell sodium (P<.01), and platelet aggregation induced by 3 µmol/L ADP (P<.01) and by 3.0 mg/L epinephrine (P<.05) were observed in the placebo-treated patients but not in the calcium-supplemented ones. Compared with the placebo-treated patients, calcium-supplemented patients had a smaller weight gain (P<.05) but excreted more sodium and calcium (P<.01) at the end of the high salt regimen. Calcium supplementation resulted in decreases in ß-thromboglobulin (P<.05), platelet factor 4 (P<.01), and plasma and urinary excretions of norepinephrine (P<.02) during the high salt, low calcium regimen. The decrease in plasma norepinephrine correlated positively with the decreases in ß-thromboglobulin (r=.72, P<.02) and platelet factor 4 (r=.85, P<.01). These results indicate that calcium supplementation prevents salt-induced high blood pressure and platelet hyperaggregability, with a suppression of the platelet release reaction. The beneficial effects of oral calcium for reducing thrombotic cardiovascular risk during high salt intake may partly be attributed to an attenuation of intracellular sodium retention and a decrease in sympathetic nervous activity.
Key Words: hypertension, essential • sodium • calcium • erythrocyte • platelet aggregation • ß-thromboglobulin • platelet factor 4
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Introduction |
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Platelet dysfunction, especially an increase in platelet aggregability, may lead to impeded blood flow and contribute to the development of myocardial infarction1 and cerebrovascular accidents,2 which are the major cardiovascular thrombotic complications associated with hypertension. Although some investigators3 4 have demonstrated enhanced in vitro platelet aggregatory responses to ADP or epinephrine in hypertensive compared with normotensive individuals, others have not shown any differences.5 6 7 8 In recent years, plasma levels of ß-thromboglobulin (ß-TG) and platelet factor 4 (PF4) secreted from
-granules during the platelet release
reaction are known to provide a better index of in vivo platelet
activation in atherosclerotic and hypertensive vascular
diseases.9 Clinical studies5 7 10 11 12 have
indicated that ß-TG and PF4 levels are elevated in essential
hypertension, closely related to the stage of hypertension, and are
better indicators than aggregation of in vivo platelet activation
in hypertensive patients.
Platelet function, ie, in vitro aggregation to ADP or
epinephrine and the in vivo release reaction, are known to be
affected by various dietary factors, including a high-fat,
high-cholesterol diet,13 14 15 fish oil
diet,16 or high salt6 13 and excess alcohol
intake.15 Among these, excess salt intake is known to
induce blood pressure elevation in a subset of patients with essential
hypertension17 18 19 20 and is reported to increase stroke
incidence within a short period in spontaneously hypertensive
rats.21 Clinical reports6 13 22 indicate that
platelet aggregation is accelerated by excessive salt intake,
possibly through modification of the characteristics of platelet
2-adrenergic receptors by sodium and calcium ions and/or
changes in sympathetic nervous activity. On the other hand,
epidemiological studies23 24 have suggested an inverse
relationship between the level of calcium intake and incidence of
cardiovascular disease and high blood pressure.
Increasing evidence indicates that oral calcium supplementation has a
blood pressure–lowering effect in salt-loaded hypertensive
patients25 and also in volume-expanded hypertensive
rats.26 27 28 However, to date it remains unclear how a low
versus high calcium intake can affect platelet function and how it
modifies cardiovascular thrombotic risk in salt-loaded
hypertensive patients. Therefore, we designed the present study to
evaluate the effects of oral calcium supplementation on both in vivo
and in vitro platelet activation during high salt but low calcium
intake in patients with mild essential hypertension.
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Methods |
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Patients
Nineteen patients with mild essential hypertension (14 men and 5 women, 43 to 62 years old) were studied. For at least 4 weeks before the study, antihypertensive medications were withheld. Patients were considered to have mild hypertension if during three subsequent visits to the outpatient clinic, their diastolic pressure, determined after the patient had sat quietly for 5 minutes, exceeded 90 mm Hg (fifth phase Korotkoff sound). All patients gave informed consent. None of the patients had abnormal renal function or secondary causes of hypertension, which were ruled out by the usual screening examinations (history, physical examination, urinalysis, blood chemistry, and when appropriate, radiological examination).
Protocol
Usual diets were designed by a dietician to provide
approximately 70 g/d protein, 40 g/d fat, and 260 g/d carbohydrates
throughout the study period. Subjects were studied for 1 week with
their usual diet containing 150 mmol/d sodium, then for 1 week with a
low salt diet (50 mmol/d sodium), and finally for 1 week with a high
salt diet (300 mmol/d sodium). Except for sodium intake, the
composition of the dietary electrolytes remained constant, containing
60 mmol potassium, 6.25 mmol/d (250 mg/d) calcium, and 25.8 mmol/d (800
mg/d) phosphate. The level of calcium intake selected was purposely low
to facilitate a definite comparison between the effect of low calcium
intake and that of sufficient calcium supplementation on blood pressure
and platelet function. Calcium restriction was achieved by
eliminating from the diet food rich in calcium and by not using milk
for cooking or drinking.
During the high sodium period, patients were randomly assigned to two treatment groups; treatment assignment was made in a double-blind fashion. Calcium-supplemented patients (Ca group, n=10) received two tablets of 1.0 g calcium glubionate (Calcium-Sandoz) three times per day. Each tablet contained 9.0 mmol (360 mg) elemental calcium; therefore, patients were prescribed 54.0 mmol/d (2160 mg/d) calcium as a supplement to the low calcium, high salt diet. Placebo-treated patients (non-Ca group, n=9) received the same amount of placebo tablets. Before administration, the tablets were dissolved in 100 mL water; the placebo solution was identical in appearance to the calcium solution so that patients and medical staff were unaware of the type of medication administered.
Blood pressure and pulse rate were recorded early in the morning on the seventh day of each period by an autonomic sphygmomanometer (Nippon Colin, Inc) every 5 minutes while the patients were supine for 30 minutes. Blood samples then were taken for determination of serum concentrations of electrolytes (sodium, potassium, calcium, and phosphate) together with measurement of platelet aggregation, plasma levels of two secreted platelet proteins (ß-TG and PF4), catecholamines (norepinephrine and epinephrine), and red blood cell sodium concentration.
On the last day of each dietary period, body weight and 24-hour urinary excretions of sodium, calcium, and catecholamines were determined. Since 4 women of the 19 patients (2 in the Ca group and 2 in the non-Ca group) refused urine sampling, data on the 24-hour urinary samples were available on 8 patients of the Ca group and 7 of the non-Ca group.
Platelet Aggregation and Plasma ß-TG and PF4 Levels
Platelet aggregation in response to ADP and
epinephrine was determined by the method previously described
by Yamanishi et al7 with slight modifications. Venous
blood was drawn into plastic tubes containing 3.8% sodium citrate
(1:9, citrate blood) by careful venipuncture without stasis
and was centrifuged at 160g for 10 minutes to obtain
platelet-rich plasma. The pellet was further centrifuged at
2000g for 10 minutes to obtain platelet poor plasma.
Platelet aggregation in response to ADP (1 and 3 µmol/L) and
epinephrine (0.1 and 3.0 mg/L) was studied in platelet-rich
plasma with the use of an aggregometer (PA-3210, Kyoto Daiichi Kagaku
Co) by the turbidimetric method described originally by
Born.29 Aggregating agents were added after 1 minute of
incubation at 30°C with constant stirring in siliconized cuvettes
placed in the aggregation module. Percent aggregation was calculated as
the percent increase of light transmission observed from the graphic
record 5 minutes after ADP or epinephrine was added.
Platelet-rich and platelet-poor plasmas were used as 0% and
100% light transmission, respectively.
Venous blood samples for ß-TG and PF4 were collected from an antecubital vein by clean venipuncture, immediately transferred to a cooled plastic tube containing powdered EDTA and theophylline, placed in ice water for 30 minutes, and centrifuged at 2000g and 4°C for 30 minutes. Plasma concentration of ß-TG was measured by radioimmunoassay with a test kit (Amersham) according to the method of Ludlam et al.30 PF4 in EDTA-theophylline plasma was measured with a test kit (Dainabot) in the same way as for ß-TG.
Intraerythrocyte Sodium and Serum and Urinary Electrolyte
Concentrations
Intraerythrocyte sodium concentration was determined by a
previously reported method.19 25 31 An aliquot of venous
blood (50 µL) was injected into a microhematocrit capillary tube (75
mm length) and centrifuged at 11 000 rpm for 5 minutes at room
temperature. After determination of hematocrit, the tube was cut at the
boundary between packed cells and plasma. The packed erythrocytes were
then diluted in 1 mL of diluted lithium solution, and sodium
concentration of the hemolysate was determined by flame photometry (FLM
3, Radiometer, Copenhagen, Inc). Trapped intercellular plasma was 3%,
as determined by 131I radioactive human serum
albumin, and a correction was made for this value in
calculating intraerythrocyte sodium contents. Measurements were
performed in duplicate, and the accuracy of this technique was
confirmed by previous studies.19 25 31 The interassay
reproducibility in the present study was 4.6% as determined by the
coefficient of variation.
Serum and urinary electrolytes were measured by an autoanalyzer (System E4A, Beckman Instruments, Inc), and ionized calcium levels were measured with the use of a specific calcium ion electrode (SS20, Orion Research, Inc). Plasma and urinary concentrations of norepinephrine and epinephrine were determined with high-performance liquid chromatography.
Statistical Analysis
Values are expressed as mean±SEM. Data analysis was
performed by Student's paired or unpaired t test as
appropriate when the data were normally distributed. Regression
coefficients were calculated by the least-squares method. The null
hypothesis was rejected at a value of P<.05.
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Results |
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Table 1 shows clinical characteristics and laboratory findings on the last day of the low and high salt diets for 10 patients in the Ca group and 9 in the non-Ca group. Age and sex ratios did not differ between the groups. At the end of the low sodium period, blood pressure, pulse rate, body weight, serum concentration of electrolytes, ionized calcium level, hematocrit, and platelet count also did not differ between groups.
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When the diet was changed from low to high salt, systolic and mean pressures increased significantly in the non-Ca group (+13.2±4.3 and +6.9±2.3 mm Hg, respectively, P<.02) but did not increase significantly in the Ca group (+6.0±3.0 and +2.8±1.5 mm Hg, respectively, P=NS). The change in diastolic pressure was not statistically significant in either group. Pulse rate did not show any change. A significant increase in body weight was observed for both the Ca (P<.02) and non-Ca (P<.01) groups, and weight gain was significantly greater in the non-Ca than the Ca group (+0.87±0.22 versus +0.31±0.10 kg, respectively, P<.05). On the last day of the high salt regimen, serum sodium was increased (P<.05) and calcium was decreased (P<.05) in the non-Ca group but not in the Ca group. Serum potassium, phosphate, and plasma ionized calcium did not show any changes throughout the two dietary periods. Hematocrit decreased with the high salt intake (P<.01) in both groups. Mean platelet count tended to decrease (P<.1) during the high salt regimen in both groups.
Table 2 shows 24-hour urinary excretions of sodium, calcium, and catecholamines for 8 calcium-supplemented and 7 placebo-treated patients. Although 4 women (2 in each group) were excluded from the urinalysis, clinical and laboratory findings for these 15 patients (data not shown) were not different from those for the 19 patients shown in Table 1. On the last day of the high sodium period, urinary sodium and calcium excretions were greater (P<.01) in the Ca group than in the non-Ca group, whereas they were not different on the last day of the low sodium period. When the dietary salt intake was changed from low to high, the increases in urinary sodium and calcium excretions for the Ca group were significantly greater (P<.01 and P<.001, respectively) than those for the non-Ca group. The Ca group showed a significant decrease (P<.02) in 24-hour urinary excretion of norepinephrine with salt loading, whereas the non-Ca group did not. However, the degree of change in urinary norepinephrine was not different between the two groups. Mean urinary epinephrine remained unchanged during the high salt regimen in both groups.
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Table 3 summarizes the results of platelet function on the last day of the low and high salt regimens for the Ca group (n=10) and non-Ca group (n=9). Platelet aggregation induced by 3 µmol/L ADP and 3.0 mg/L epinephrine for the non-Ca group was significantly higher (P<.01 and P<.05, respectively) during the high salt period than the low salt period, but these values for the Ca group showed no difference between the two dietary regimens. The changes in platelet aggregation induced by 1 µmol/L ADP and 0.1 mg/L epinephrine for both groups were not statistically significant.
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Plasma ß-TG and PF4 levels decreased significantly (P<.05 and P<.01, respectively) in the Ca group but tended to increase (P<.1) in the non-Ca group when the diet was changed from low to high salt. The degree of changes in ß-TG and PF4 was significantly different (P<.01) between both groups, and their mean values at the end of the high sodium period were significantly lower (P<.05) in the Ca group than in the non-Ca group.
Fig 1 shows the mean values of intraerythrocyte sodium concentration and plasma norepinephrine and epinephrine concentrations for the Ca and non-Ca groups at the end of low and high dietary sodium intake. When the diet was changed from low to high salt, a significant increase in intraerythrocyte sodium concentration was observed in the non-Ca group (10.11±0.48 versus 10.53±0.42 mmol/L cells, P<.01) but not in the Ca group (10.11±0.36 versus 10.31±0.51 mmol/L cells, P=NS). The high salt diet resulted in a significant decrease in plasma norepinephrine in the Ca group (1.21±0.16 versus 0.70±0.12 nmol/L, P<.02) but not in the non-Ca group (1.16±0.18 versus 0.89±0.18 nmol/L, P=NS). Plasma epinephrine showed no change in both groups throughout the two dietary periods.
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In the Ca group, the change in plasma norepinephrine during the high salt regimen correlated positively with the percent changes in ß-TG (r=.72, P<.02) and PF4 (r=.85, P<.01), as shown in Fig 2. These correlations were also noted even if data from three women were excluded (r=.76, P<.05 and r=.88, P<.01, respectively; n=7). Such relations were not observed in the non-Ca group. In all 19 subjects, correlation analyses revealed that the change in mean blood pressure and that in platelet aggregation induced by 3.0 mg/L epinephrine related positively with the change in plasma norepinephrine concentration (r=.59, P<.01 and r=.48, P<.05, respectively) when dietary sodium intake was changed from low to high.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study we evaluated the effects of low and high salt intake on platelet function because high salt consumption is one of the main dietary factors involved in the pathogenesis of essential hypertension and the development of cardiovascular thrombotic complications. The results demonstrate that under the dietary condition of low calcium intake, platelet aggregatory responses to 3 µmol/L ADP and 3.0 mg/L epinephrine were significantly enhanced along with blood pressure elevation during the high salt period. This is consistent with the finding of Nara et al13 that indicated increased platelet aggregation induced by 5 µmol/L ADP in healthy male subjects on a high cholesterol, high salt diet. In patients with essential hypertension, Ashida et al6 have also demonstrated increased ADP- and epinephrine-induced platelet aggregation during high dietary sodium intake but no change in collagen-induced aggregation and platelet adhesion.
In addition to the increases in in vitro platelet aggregation, the present study showed that during a low calcium intake (6.25 mmol/d), plasma levels of ß-TG and PF4 tended to increase during the high salt regimen, suggesting a possible role of calcium deficiency in the salt-induced acceleration of the in vivo platelet release reaction. During normal calcium intake (17.5 mmol/d), however, we have previously noted decreases in plasma levels of these platelet-specific proteins during a high dietary salt period.32 Although the precise reason for the different results remains unclear, it is possible that the different levels of calcium intake in our previous and the present study may be responsible. The present results suggest that during high salt intake, an extremely low calcium intake accelerates in vivo platelet activation, but conversely, a sufficient calcium supplementation can lower platelet-specific protein levels significantly.
The mechanism of platelet hyperaggregability during high sodium
intake may in part be related to intracellular sodium accumulation. The
platelet aggregatory response to ADP and epinephrine is
known to be enhanced by intraplatelet sodium accumulation and
ouabain inhibition of Na+,K+-ATPase
activity.33 In vitro study34 demonstrated
that epinephrine-induced platelet aggregation was increased
by the addition of monensin, an Na+-selective ionophore,
and of ouabain through an increase in the Kd of
epinephrine for 2-adrenergic receptors on intact
platelets. Kang et al35 have reported an enhanced
ADP-induced platelet aggregation together with an increase in red
blood cell sodium content in Dahl salt-sensitive rats fed a
sodium-enriched diet. The present results in patients with
essential hypertension showed a significant increase in
intraerythrocyte sodium content during high sodium intake in the non-Ca
group but not in the Ca group. This is consistent with reports
from us19 and other investigators36 37 that
an excessive sodium intake increases blood pressure, partly through the
reduction in cell membrane Na+,K+-ATPase
activity, with the resultant increase in intracellular sodium.
Therefore, the increase in intraplatelet sodium through a possible
inhibition in cell membrane
Na+,K+-ATPase might be one explanation
for the platelet hyperaggregability during the high salt regimen in
the non-Ca group.
Although sodium appears to play a role in enhanced platelet activation during a high salt intake, intracellular sodium accumulation alone may not have a predominant role. Platelet shape change, aggregation, and release reactions are known to result from increasing the concentration of cytosolic free calcium, one of the most important intracellular transmitters. Unfortunately, we did not evaluate an alteration in intracellular calcium in this study. There is increasing evidence,38 39 including our recent study,40 that indicate an increased intraplatelet basal free calcium concentration in patients with essential hypertension. A high salt–induced elevation in cytosolic free calcium of erythrocytes,41 lymphocytes,42 and platelets43 has also been suggested to be involved in the hypertensive mechanism of salt-sensitive hypertension. Intraplatelet free calcium level is known to be regulated and determined by calcium influx and efflux across the plasma membrane and by its pooling in dense tubular systems. Resink et al44 have found a calmodulin-stimulated Ca2+-ATPase in human platelet membranes and showed defective calcium efflux pump activity of platelets in essential hypertension. Other researchers have demonstrated increased agonist-mediated calcium influx in platelets39 and enhanced voltage-dependent calcium influx in lymphocytes from hypertensive subjects.42 It is possible that these membrane defects for calcium handling with the resultant elevation in intraplatelet free calcium may account for the enhanced agonist sensitivity in platelets from the salt-loaded subjects.
To our knowledge, the present study is the first report in humans indicating that oral calcium supplementation prevents the salt-induced acceleration in platelet aggregation in vitro with the suppression of its release reaction in vivo. In rabbits fed a diet rich in saturated fat, Renaud et al45 have reported a markedly prolonged clotting time and reduced platelet aggregation to thrombin with increasing dietary calcium, suggesting an inhibitory effect of calcium on high platelet activity induced by saturated fats. In an epidemiological study,15 multivariate analysis revealed an inverse relationship between calcium intake and platelet aggregatory responses to thrombin, ADP, and epinephrine in nine groups of European farmers, showing the known protective effect of hard water on coronary heart disease.46 A random population-based study of three areas with different stroke motality rates has demonstrated a negative association of calcium intake with blood pressure, suggesting an increased risk of stroke in humans consuming low dietary calcium.24 The present interventional trial provides additional evidence for the beneficial effect of oral calcium for reducing salt-induced thrombotic risk.
The present results confirm our previous findings25 26 that oral calcium supplementation prevents a rise in blood pressure in mildly hypertensive patients on a high salt diet. The different salt-induced changes in intra-arterial pressure and those in intravascular shear stress seem to be responsible for the different platelet function between the Ca and non-Ca groups. In vitro study47 revealed increases in plasma ß-TG and PF4 levels and sensitivity to ADP aggregation when platelet-rich plasma was exposed to pressures varying from 100 to 200 mm Hg above 1 atm. However, the pressure excursion alone cannot fully explain the different manner of the platelet release reaction in vivo, because arterial pressure remained unchanged in the Ca group, whereas ß-TG and PF4 levels were actually decreased by oral calcium loading during high salt intake.
Using the same dietary intervention protocol, we25 have previously studied sodium metabolism during high calcium intake and suggested that the attenuation of salt-induced high blood pressure in calcium-supplemented patients might partly be due to calcium-induced natriuresis, with the resultant prevention of volume expansion. In deoxycorticosterone acetate (DOCA)–salt hypertensive rats,26 we have also noted that high calcium diet moderates intraerythrocyte and total body sodium accumulation and attenuates extracellular volume expansion through calcium-induced natriuresis. The present results are consistent with these findings, showing that on the last day of the high salt regimen, the Ca group excreted more sodium and had a smaller increase in body weight and intraerythrocyte sodium than did the non-Ca group. These findings suggest the possibility that calcium supplementation may suppress volume expansion through an acceleration of urinary sodium excretion and may attenuate intracellular sodium elevation through less excretion of Na+,K+-ATPase inhibitor.36 37 48
Calcium supplementation has also been proposed to reduce intracellular free calcium concentration as well as sodium through alterations of transmembrane sodium and calcium transport mechanisms or a direct effect on cell membrane. Webb and Bohr49 observed relaxation in the helical strip of rat tail artery by high concentrations of calcium and referred to this as the "membrane-stabilizing effect" of calcium, suggesting that this action of calcium depends on the activity of Na+,K+-ATPase. In spontaneously hypertensive rats, a high calcium diet has been suggested to induce an increased activity of red blood cell Ca2+-ATPase50 and vascular Na+,K+-ATPase,51 with a concomitant reduction in intraplatelet free calcium concentration. More recently, we28 have demonstrated that a high calcium diet normalizes the augmented mobilization of calcium from cellular stores by both inositol triphosphate–induced Ca2+ release and Ca2+ influx–induced Ca2+ release in aortic rings of DOCA-salt hypertensive rats. An improvement of cellular calcium regulation with the resultant reduction in intracellular free calcium by calcium supplementation may have contributed to the decreased agonist sensitivity in platelets and to the protection of platelet hyperaggregability during high salt intake.
Another possible mechanism for the decreased platelet release reaction during a high salt, high calcium regimen is the decreased sympathetic nervous activity caused by calcium supplementation. Reports consistently indicate that provision of supplemental calcium reverses high salt–induced blood pressure increase through normalization of circulating and central nervous system changes in catecholamines.26 52 53 54 A high calcium diet attenuates an enhanced sympathetic nervous system outflow in salt-loaded spontaneously hypertensive rats52 and Dahl salt-sensitive rats.53 A normalization in catecholamine contents of the heart26 and a high plasma ß-endorphin level54 during high calcium intake in DOCA-salt hypertensive rats suggest a reduced catecholamine turnover rate and enhanced central opioidergic activity by calcium loading.
As is well established, norepinephrine levels in plasma and urine are decreased after salt loading because of the reflex suppression of sympathetic nervous function.17 18 20 The present results indicate that calcium-supplemented patients excreted sodium normally in response to oral NaCl loading and showed decreases in plasma and urinary norepinephrine by 42% and 38%, respectively. They might exhibit reflexive declines in circulating norepinephrine and achieve a normal homeostatic adjustment, maintaining adequate natriuresis in response to sodium loading. Conversely, placebo-treated patients retained more sodium than normal and had circulating norepinephrine levels inappropriately high for their level of sodium intake. These findings suggest that under the dietary condition of low calcium intake, sympathetic activity may not be adequately suppressed during high sodium intake, which may elevate blood pressure directly through vasoconstriction and indirectly through stimulation of the renal sympathetic nerve. Consistent with this possibility, salt-sensitive patients are reported to lose more calcium in the urine and to have impaired suppressibility of sympathetic nerve activity during high salt intake, with the resultant increase in renal tubular reabsorption of sodium and water.18 20
It is well recognized that catecholamines can potentiate
the platelet responses to aggregating compounds.55
Clinical studies have indicated positive relations between plasma
ß-TG and circulating epinephrine levels56 and
between an increased platelet 2-adrenergic receptor
density and a high mean arterial pressure.4
Skrabal et al22 have reported an enhanced upregulation of
the ratio of 2- to ß2-adrenoceptors in
platelets of salt-sensitive subjects consuming a high salt diet.
These findings suggest that an enhanced sympathetic nervous activity is
involved in possible explanations for the increased platelet
function in patients with a high salt but low calcium diet. In the
present study, circulating norepinephrine decreased
significantly in the Ca group but not in the non-Ca group. The high
salt–induced changes in mean blood pressure and in platelet
aggregation induced by 3.0 mg/L epinephrine were related to the
change in plasma norepinephrine in all the patients.
Moreover, in the Ca group the decrease in norepinephrine
levels correlated positively with the percent decrease in ß-TG and
with that in PF4. Therefore, the reduced sympathetic nervous activity
caused by calcium supplementation may in part be responsible for the
attenuation of receptor-mediated platelet hyperreactivity during a
high salt regimen.
In conclusion, the present study indicates that under the dietary condition of high sodium intake, oral calcium supplementation attenuates salt-induced acceleration in the platelet aggregatory response in vitro, together with a suppression of the platelet release reaction in vivo in patients with mild essential hypertension. These changes in platelet function caused by high calcium intake may partly be caused by an attenuation of intracellular sodium retention, with altered cellular calcium regulation and decreased sympathetic nervous activity. This study suggests a protective effect of calcium supplementation against hypertension-related thrombotic cardiovascular diseases under high salt dietary conditions.
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Acknowledgments |
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We wish to express our thanks to Dr Hisashi Hirouchi for his invaluable advice and to the support staff of the department of internal medicine, Hidaka Hospital.
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Footnotes |
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Reprint requests to Komei Saito, MD, The First Department of Internal Medicine, Kobe University School of Medicine 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650, Japan.
Received July 11, 1994; first decision October 19, 1994; accepted April 3, 1995.
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