Clinical Science (1979) 57,3219-324s
Abnormal whole-body and cellular (erythrocytes) turnover
of 22Na+in normotensive relatives of probands with
established essential hypertension
N. C . H E N N I N G S E N , S. M A T T S S O N , B. N O S S L I N , D . N E L S O N A N D
0. O H L S S O N
Medical Departments 1 and 2, Department of Radiation Physics and Department of Nuclear Medicine, Universi@ of Lund. Malmo
General Hospital, Malmo. Sweden
Summary
1. Whole-body elimination rate of 22Na+was
decreased in normotensive or borderline firstdegree relatives of hypertensive probands.
2. Whole-body potassium; exchangeable sodium
and urine excretion of sodium, potassium and
creatinine were similar in relatives and controls.
3. Erythrocyte net influx of W a + was
significantly increased in normotensive relatives.
4. Abnormal whole-body and cellular handling
of sodium (22Na+) demonstrated in relatives
indicates that this abnormality may have an
important role in the development of essential
hypertension in man.
Key words: erythrocyte net influx, normotensive
relatives, sodium metabolism.
Introduction
Several studies from different populations (Prior,
Evans, Harvey, Davidson & Lindsey, 1968; Dahl,
1972; Dawber, Kannel, Kagan, Donabedian,
McNamara & Pearson, 1967) indicate a positive
relationship between sodium chloride intake and
prevalence of essential hypertension, but studies
within single populations have given discrepant
results. Rat experiments have indicated a gentic
susceptibility to normal or high intakes of sodium
chloride in some spontaneously hypertensive
strains (Dahl,Heine & Tassinari, 1962). Various
Correspondence: Dr N. C. Henningsen. Hypertension
Unit, Medical Departments 1 and 2, Malmo General
Hospital, 214 01 Sweden.
mechanism have been proposed (Postnov, Orlov,
Gulak & Shevchenko, 1976; Friedman,
Nakashima & McIndoe, 1977; Ganguli, Tobian
& Iwai, 1979). It has been proposed that there is a
genetic susceptibility to NaCl in man that
predisposes to hypertension (Fries, 1976).
Dahl, Lax, Young, Schackow & Knudsen
(1966) failed to confirm his early findings of an
abnormal whole-body turnover of 22Na+in patients
with established essential hypertension, but the
genetic background was not studied. There is an
increased net influx of 22-24Na+in erythrocytes of
hypertensive patients (Wessels, Junge-Hiilsing &
Losse, 1967) together with increased leucocyte
intracellular sodium content and a decreased
sodium efflux (Edmondson, Thomas, Hilton,
Patrick &Jones, 1975).
In this work we have investigated the wholebody turnover of 22Na+in firstdegree relatives of
hypertensive probands as well as the net influx of
22Na+in erythrocytes.
Material and metbods
Subjects
All firstdegree relatives in the present study
belonged to families with a history of established
essential hypertension for at least two generations.
Controls were normotensive, age-, sex- and weightmatched individuals without hypertension in their
families during two generations.
In study A whole-body turnover of 22Na+was
investigated in 24 firstdegree relatives (four
females, 20 males) and 15 controls (two females,
321s
N . C.Henningsen et al.
322s
13 males). In study B erythrocyte net influx of
22Na+was studied in 35 first-degree relatives (15
females, 20 males) and 24 controls (10 females, 14
males).
Both methods have been applied on 11 firstdegree relatives and 10 controls.
Study A
Whole-body potassium (40K activity) was
measured in the low-background iron room. After
background scanning with two opposite NaI(T1)detectors the individuals were injected with 20-50
kBq of 22Na+ intravenously. Total exchangeable
sodium was calculated after 24 h. The subjects
maintained their usual diet and were scanned five
times for the elimination rate over 8 days (days 08). Five urine collections (24 h) were obtained, and
also plasma samples for measurements of 22Na+
and 23Na+were taken. Twelve first-degree relatives
and 11 controls continued the study (days 8-15)
by adding NaCl (12 g daily) to their dietary sodium
intake.
Study B
Blood was drawn into heparinized vessels and
studied within 45 min. The packed erythrocytes
were washed once with 1 vol. of the incubation
solution (Dulbecco & Vogt, 1954) also containing
glucose (8-84 mmol/l) human albumin (5.0 g/l)
and 22Na+(37 MBq/l). A portion (2 ml) of the
7
5
packed erythrocytes was incubated at 37OC with 2
ml of incubation solution. Aliquots were taken after
80 and 140 min and applied on a Sephadex G 50
(fine) column (20 cm long, 1.6 cm diameter; rate 1
ml/min) (Kantura, Kurashina & Nakao, 1974).
Tris buffer, 0.15 mol/l with NaCl (153 mmol/l),
pH 7-4, was used as etlluent. Three erythrocyte
fractions from the void were counted for 22Na+
radioactivity in a Nukab Scintillator (350-1550
keV) after measurement of packed cell volume.
Intra-assay and intra-individual accuracy was 13% (SD).
In study A blood pressure and heart rate were
measured by nurses at 13.00- 15.00 hours. In study
B pressure was measured at 08.00-09.00 hours
with an automatic pressure-recording apparatus
(Bosomat, Boehringer Ingelheim) each minute for
10 min. Urine collections (24 h) were measured for
sodium, potassium and creatinine.
Results
Study A
Whole-body elimination rate (%/day) and the
biological half-life (to.5 days) of 22Na+ were
significantly (P < 0.01) different in firstdegree
relatives (5.8%/day; to,5 = 12.7 & 3.1 days)
compared with controls (7.3%/day; 9-8 & 1.5
days) during period 1 (Fig; 1). During days 8-15
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Urinary Na+ (mmo1/24 h)
FIG. 1. Study A: 22Na+half-life as a function of 24 h urinary sodium excretion: 0 , first-degree relatives,
and 0 , controls, on normal diet; 4 relatives, and A, controls, on normal diet plus 12 g of NaCl/day in
tablet form. Mean values for each period are used for daily urinary Na+ excretion.
Sodium turnover in hypertension
the elimination rate was equal in the two groups
(first-degree relatives: 1 1.O%/day; controls:
1 1*4%/day).
The mean sodium output (24 h) during period 1
was equal (firstdegree relatives: 147 f 37 mmol;
controls: 154 f 14 mmol).
Whole-body potassium (first-degree relatives:
48.3 f 7-3; controls: 49.8 f 6.3 mmol/kg) and
total exchangeable sodium (firstdegree relatives:
37.3 f 4.9; controls: 38.6 f 4.1 mmol/kg),
plasma and urine elimination rate of 22Na+,mean
age (firstdegree relatives: 33 f 5 years; controls:
32 f 5) and extrarenal excretion of 22Na+during
period 1 (11 first-degree relatives: 17.2%, 10
controls: 14.8%) were all equal in the two groups.
Blood pressure was significantly higher (P <
0.01) in first-degree relatives (140 f 14/88 f 9
mmHg) than in controls (124 k 10/77 f: 8
mmHg). Heart rate was equal. Seventeen firstdegree relatives were normotensive (< 135/90
mmHg) and seven were borderline (< 150/100
mmHg).
Study B
After 140 min of incubation the net influx of
22Na+in erythrocytes was significantly increased in
both males (P < 0.01) and females (P < 0.05).
A(Net influx) was only significantly increased
(P < 0.01) in male first-degree relatives (244 46
Bq/ml of erythrocytes) against male controls
(191 f 56 Bq/ml). Net influxes at both 80 and 140
min were significantly (P < 0.01) increased in
both male groups compared with corresponding
female groups.
Diastolic blood pressure was positively but not
significantly correlated ( r = 0.37, P < 0.1) to
A(net influx) in males.
The mean age was equal in the two groups (3 1 k
4 years).
Blood pressures in males (relatives: 124 f
10/80 ? 8; controls: 121 f 10/75 f 10) were
equal, but the diastolic pressure in female relatives
was significantly higher (P < 0.05) than in
controls (relatives: 111 f: 8/78 k 6; controls:
108 f 8/71 f 10). Heart rate was significnatly
higher (P < 0.05) in female first-degree relatives.
Urine volume, sodium, potassium and creatinine
excretion were equal in the two groups.
In the 11 firstdegree relatives and 10 controls in
whom both investigations had been carried out, the
whole-body elimination rate was significantly
decreased (P < 0.05) and the net influx of 22Na+
323s
significantly increased (P < 0.05) in firstdegree
relatives.
In both studies there were no significant
differences in weight, height and skinfold thickness.
Discussion
The biological half-life of 22Na+in controls (9.8 f
1.5 days) is exactly the same as that found by Dahl
et af. (1966) under metabolic ward conditions. The
exchangeable sodium, whole-body potassium and
NaCl intake were also closely similar. Increased
intracellular content of sodium or an abnormally
slow intracellular exchange of a fraction of the
sodium compartment (Garay, Moura, OsbornePellegrin, Papadimitriou & Worcel, 1979) could
explain the reported findings.
An increase in intracellular sodium, which is
only 20-25% of the total exchangeable sodium,
would be very difficult to determine with the
presently available methods for exchangeable
sodium measurement. The increased net influx of
22Na+in erythrocytes might indicate an abnormally
slow intracellur exchange of sodium, which may be
explained by an increased sodium content or a slow
exchange in a fraction of it. There seem to be a
marked difference in cellular handling of sodium
between the sexes; this has not been reported
before. The significantly increased 22Na+net influx
in first-degree relatives indicates that it may play an
important role in the development of essential
hypertension in man.
Acknowledgments
This work has been supported by the Hulda
Almroth’s Foundation, Ernhold Lundstrom’s
Foundation, the Swedish Heart and Lung Disease
Association and the University of Lund.
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