Download Sodium-Accelerated Platelet Aggregation in Men Predisposed to

Clinical Science (1982) 63,3919-393s
391s
Sodium-accelerated platelet aggregation in men predisposed to
essential hypertension
Y. N A R A * , M. K I H A R A * , T. K A N B E , R . H O R I E * , J. E N D 0 A N D
Y. Y A M O R I *
Department of Pathology, Shimane Medical University, and *Japan Stroke Prevention Center, Izumo, Japan
Summary
1. Men with a genetic predisposition to essential hypertension had a significantly higher blood
pressure during salt restriction and a greater
elevation of blood pressure in response to salt
loading than men without such a genetic predisposition.
2. The activity of platelet aggregation was
significantly greater in men with a genetic
predisposition to essential hypertension.
3. Platelet aggregation was activated directly
or indirectly by an increased sodium intake.
4. This activation by an increased sodium
intake was more pronounced in men predisposed
to essential hypertension.
Key words: essential hypertension,
aggregation, sodium.
platelet
of their genetic predisposition may also be
suppressed by environmental factors, such as a
reduction in the dietary sodium/potassium ratio
and an increased intake of protein [61. We have
also succeded in selecting animals from the strain
of stroke-prone spontaneously hypertensive rats
in which the high incidence of thrombosis has
been shown to be affected by dietary factors;
these observations indicate that the predisposition to thrombosis may be related partly to
the genetic predisposition to hypertension and
that it is also influenced by dietary factors [71.
We therefore investigated, in the present study,
the activity of platelet aggregation in men with or
without a genetic predisposition to hypertension
under strictly controlled dietary conditions of
high or low salt intake.
Materials and methods
Introduction
Hypertension is an important underlying factor in
the aetiology of those cardiovascular diseases
which result in cerebrovascular accidents and
myocardial infarction. The development of essential hypertension and stroke appears to be the
complicated product of an interaction between
genetic and environmental factors [l-31. In
stroke-prone spontaneously hypertensive rats,
genetic factors predominantly contribute to the
development of hypertension and stroke (4, 51.
Even when such rats are fed on a normal
laboratory diet, 100% of them develop hypertension and over 90% of them die of stroke.
However, the development of hypertension and
stroke in these animals is markedly accelerated
by salt loading, and the phenotypic development
Correspondence: Professor Yukio Yamori, Depart'
ment of Pathology, Shimane Medical University,
Izumo 693, Japan.
Twenty-two healthy male volunteers aged 24-34
years were divided into two groups, one with a
predisposition to essential hypertension whose
members had at least one parent with clinically
defined essential hypertension and the other
control group without such a predisposition.
They were placed for 4 weeks on a 2500 kcal
diet containing either 6.1 or 25 g of sodium
chloride per day under strictly controlled dietary
conditions. Neither smoking nor alcoholic drinks
were allowed for 1 week before and during the
experimental period. The subjects received the
low and high salt diets for 1 week each, after
which the diets were repeated to confirm the
reproducibility of the results. Blood pressure was
measured three times in each subject with a
self-recording sphygmomanometer which records
Korotkoff sounds on thermopaper (Ueda
Electronic Co. Ltd). After the measurements the
recording papers were checked for phases I and
V independently by two doctors observer-blind
Y.Nara et al.
392s
and the mean of the three readings was determined as the blood pressure value of the day for
each individual. The measurement was carried
out between 16.00 and 18.00 hours before supper
on days 3 and 6 of the week, in the sitting
position after at least 20 min rest. Twenty-four
hour urine collections were made daily to check
sodium, potassium and protein intakes, and blood
samples were collected every other day. Platelet
aggregation in response to various concentrations of adenosine diphosphate (ADP) was
studied in citrated platelet-rich plasma (200 PI)
with an aggregometer (Nikko Bioscience Co.
Ltd) on the last day of each weekly dietary
regimen. Sodium and potassium in urine and
plasma were measured by flame photometry.
Results
The initial mean systolic blood pressures of the
group with a predisposition to essential hypertension and of the control group were both
normal, 120 f 3 mmHg and 111 f 2 mmHg
respectively. The blood pressures of both groups
rose by 10 mmHg on the third day of the high
salt diet. Thereafter, the blood pressure of the
control group decreased to its original value,
whereas that of the group with a predisposition to
essential hypertension remained at the higher
level on day 6 of the high salt diet (131 f 4
mmHg), 9 mmHg higher than the blood pressure
on the low salt diet (122 f 2 mmHg).
In both groups packed cell volume decreased
slightly by about 2% on the third day of high salt
diet, increasing towards the original values on the
last day of the diet. There was no difference in the
values between the two groups.
The urinary sodium/potassium ratio was significantly increased in both groups (6.10 k 0.24)
on the last day of the high salt diet compared with
that during the low salt diet (1.52 f 0.1). There
was no difference in the ratio between the two
groups. The plasma levels of sodium and
potassium did not change in either group after the
high salt diet.
The activity of platelet aggregation with
various concentrations of ADP is shown in Table
1. The group with a predisposition to essential
hypertension showed a higher activity of platelet
aggregation in response to the concentration of
ADP used than did the control group on the last
day of the low salt diet. In particular, the activity
in response to ADP at 5 ,umol/l was significantly
greater in the group with a predisposition to
essential hypertension than in the control group.
After the high salt diet the activity of platelet
aggregation was remarkably increased in both
groups compared with the activity observed
during the low salt diet. Platelet aggregation was
not mediated in most subjects by ADP at 1
pmolll after the low salt diet, although the
aggregation was mediated in most subjects by the
same concentration after the high salt diet. The
aggregation with ADP at 2 pmol/l was also
significantly more activated in the group with a
predisposition to essential hypertension than in
the control group.
Discussion
The present experiments indicate that (1)
genetically predisposed men show a long lasting
elevation of blood pressure in response to salt
loading, (2) increased sodium intake activates
platelet aggregation directly or indirectly and (3)
the activation of platelet aggregation is more
pronounced in men predisposed to hypertension.
Thus the activity of platelet aggregation is partly
related to the genetic disposition to hypertension
and partly to environmental factors such as salt
intake.
ADP has been widely used as an inducer to
TABLI1. Eflect of a high salt diet on platelet aggregation by dflerent ADP concentrations in
men with or without a genetic predisposition to essential hypertension
SE are shown with the numbers of samples in parentheses;
not detected.
-.
Mean results
Concn. of
ADP
(wnol/l)
Aggregation rate (%)
Low sodium diet
Predisposed
group
High sodium diet
Non-predisposed
group
Predisposed
group
Non-predisposed
group
13.5 f 2.7 (11)
52.7 f 10.0t ( I I )
70.2 f 5.1 ( 1 1 )
8 . 9 f 2 . 1 (11)
24.8 2 3 . 0 ( I 1)
63.3 f 6.8 ( I I )
I
-
-
2
5
13.1 + 2 . 5 ' ( l l )
39.7 f 8 . 5 * t ( I I )
9.4 ? 2.2' (9)
18.8 f 2.7. (9)
* Significantly JiNerent from the high sodium diet.
t Significantly different from the non-predisposedgroup.
Sodium-accelerated platelet aggregation
measure the activity of platelet aggregation.
However, the mechanism of the aggregation has
not been clarified. Sandler et al. [81 have reported
that sodium played an important role in platelet
aggregation induced by ADP. The platelet
aggregation was activated by ouabain treatment.
As ouabain inhibits Na+, K+dependent ATPase,
the sodium content of the platelets was increased
by the treatment.
We and other researchers have previously
reported an abnormality of the cell membrane
with regard to ion permeability which affects
erythrocytes, the walls of blood vessels and
cultured smooth muscle cells from spontaneously hypertensive rats 19-1 11. A similar
abnormality has been found in the erythrocytes
of essential hypertensive patients [ 12-14]. We
have also found that blood pressure was significantly related to the urinary sodium/
potassium ratio in an epidemiological study.
We suggest that the activation of platelet
aggregation induced by an increased salt intake
may result from the accumulation of sodium in
platelets, which is facilitated by a membrane
abnormality present in men with a genetic
disposition to essential hypertension. An excessive intake of salt is not only a risk factor for
hypertension, especially in genetically predisposed individuals, but also generally accelerates
thrombosis, particularly in people with a genetic
predisposition to hypertension.
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