Transepithelial Sodium Absorption Is Increased in
People of African Origin
Emma H. Baker, Nicola J. Ireson, Christine Carney, Nirmala D. Markandu, Graham A. MacGregor
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
Abstract—Salt-sensitive hypertension is more common and has more severe consequences in urban black populations than
in white populations. Increased renal sodium reabsorption through epithelial sodium channels may underlie the
development of high blood pressure in black people. Increased sodium channel activity has been detected in subjects
with Liddle’s syndrome by nasal potential difference measurements. Nasal potential difference measurements were
made in 39 black normotensive, 106 black hypertensive, 51 white normotensive, and 61 white hypertensive subjects.
Blood pressure, body mass index, and 24-hour urinary sodium excretion were also measured. Maximum potential
difference was significantly higher in black subjects than in white subjects (P⫽0.009) but was not significantly different
between normotensive and hypertensive subjects after adjustment for age, gender, current smoking status, body mass
index, and 24-hour urinary sodium excretion (black normotensive, ⫺21.6⫾1.0 mV; black hypertensive, ⫺21.5⫾0.7
mV; white normotensive, ⫺18.5⫾1.0 mV; and white hypertensive subjects, ⫺18.9⫾0.9 mV). Nasal potential difference
did not correlate with blood pressure or biochemical variables within ethnic and blood pressure groups. Nasal potential
difference, an index of nasal sodium channel activity, is greater in black than in white people but does not differ between
normotensive and hypertensive groups. Increased nasal potential difference measurements may reflect generalized
upregulation of sodium transport in black people compared with white people, which may help to explain the high
prevalence of hypertension in black people but would not explain differences in blood pressure within separate ethnic
groups. (Hypertension. 2001;38:76-80.)
Key Words: blacks 䡲 whites 䡲 membrane potentials 䡲 nasal mucosa 䡲 sodium channels 䡲 hypertension, genetic
H
sodium channel function and regulation are also implicated in
other “secondary” forms of hypertension. For example, increased levels or activity of mineralocorticoid and glucocorticoid hormones increase blood pressure at least in part by
increasing sodium absorption through activation of renal
epithelial sodium channels. It is possible, therefore, that
activation of epithelial sodium channels, either due to structural variants of the channel subunits or to altered activity of
regulatory processes, could underlie the rise in blood pressure
in black people.
Renal sodium channel activity is inaccessible to clinical
assessment. However, sodium channels with structural and
physiological properties similar to renal channels are present
in the nasal epithelium.9,10 Sodium absorption through epithelial sodium channels can be quantified in the nose by
transmucosal electrical potential difference (PD) measurements before and after amiloride, a drug that blocks sodium
channels. Recent studies have shown that nasal PD measurements are increased in Liddle’s syndrome11 and decreased in
pseudohypoaldosteronism type 1, a syndrome of low blood
pressure caused by inactivating mutations of the epithelial
sodium channel.12 We therefore used measurement of nasal
transmucosal PD to compare epithelial sodium channel ac-
igh blood pressure is common in black people living in
urban societies, affecting nearly half of black adults
between 40 and 59 years of age.1 Hypertensive end-organ
damage is particularly severe in black subjects; prevalence of
end-stage renal disease and stroke are 400% and 60% to 70%
higher, respectively, in black than in white populations.2
Many clinical and biochemical features suggest that abnormalities of renal sodium handling may relate to the development of high blood pressure in black people. Black people
with hypertension have suppressed plasma renin activity and
angiotensin II levels, consistent with sodium retention and
“corrected” volume expansion.3 Black people excrete a sodium load more slowly and less completely than white
people,4 and in the majority, blood pressure is more salt
sensitive.5,6 However, mechanisms underlying altered sodium
handling in black people are incompletely understood.
The epithelial sodium channel is the final determinant of
sodium reabsorption in the distal nephron. The importance of
this channel in the control of blood pressure is illustrated by
Liddle’s syndrome, a rare monogenic form of hypertension in
which mutations in the sodium channel cause an increase in
sodium reabsorption, resulting in sodium retention and
thereby high blood pressure.7,8 Abnormalities of epithelial
Received October 5, 2000; first decision October 30, 2000; revision accepted January 17, 2001.
From the Department of Physiological Medicine, St George’s Hospital Medical School, Cranmer Terrace, London, United Kingdom.
Correspondence to Dr Emma Baker, Department of Physiological Medicine, St George’s Hospital and Medical School, Cranmer Terrace, London
SW17 0RE, United Kingdom. E-mail [email protected]
© 2001 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
76
Baker et al
tivity in black and white subjects with and without high blood
pressure.
Methods
Subjects
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Black and white hypertensive (HT) subjects were recruited from
unselected referrals to the hypertension clinic by local general
practitioners. Black and white normotensive (NT) controls were
volunteers from the local population in the same area.
All subjects had their blood pressure measured with a semiautomated ultrasound sphygmomanometer (Arteriosonde)13 on at least 2
separate occasions. On the day of the study, subjects rested for 5
minutes, after which blood pressure recordings were done in triplicate with the appropriate cuff size determined by upper midarm
circumference. Blood pressure values given are the mean of these 3
recordings. HT subjects had systolic blood pressure ⬎140 mm Hg,
diastolic blood pressure ⬎90 mm Hg, or both. NT subjects had
systolic blood pressure ⱕ140 mm Hg and diastolic blood pressure
ⱕ90 mm Hg. HT subjects had not received previous treatment or had
not taken drug treatment for at least 2 weeks and had not taken
diuretics for 4 weeks. People with ischemic heart disease, cerebrovascular disease, renal impairment, or other concurrent illness, acute
or chronic rhinitis, asthma, or atopy or people on nasal or other drugs
were excluded from the study. Ethnicity was defined by skin color,
place of birth, or parents’ birth and cultural identity. Where individuals were classified as “black,” African or Caribbean ancestry was
also noted.
Written informed consent was obtained from all individuals before
entry into the study, which was approved by the Local Research
Ethics Committee of Merton, Sutton and Wandsworth. Procedures
followed were in accordance with institutional guidelines.
Clinical Measurements
Subjects collected all urine for the 24 hours before nasal PD
measurement, and this was analyzed for 24-hour urinary sodium and
creatinine excretion. On the day of measurement, subjects attended
the Blood Pressure Unit having had water but no food or other
beverages from midnight onward. Blood pressure, weight, and height
were recorded. Smoking history was taken to determine whether the
subject had never smoked, was an ex-smoker, or was a current
smoker. Serum sodium, potassium, creatinine, and urea were measured. Plasma was analyzed for plasma renin activity and aldosterone
concentrations by radioimmunoassay.14,15
Measurement of Nasal PD
All nasal PD measurements were made by one of 2 operators using
the same set of equipment. Operators were not blinded to the blood
pressure status of the subjects. Transmucosal nasal PD was measured
by a technique previously established in our laboratory.11 In brief,
transnasal PD was measured with a high-impedance voltmeter
connected between an exploring electrode, inserted under the inferior
surface of the inferior turbinate of the right nostril, and a reference
electrode, sited in the subcutaneous tissue of the forearm. Two
baseline measurements of PD were made, and the mean of these 2
values was taken as the maximum PD for analysis. Amiloride (10⫺4
mol/L in Ringer’s solution) was then perfused onto the nasal mucosa,
and after 4 minutes, nasal PD was remeasured during continued
application of 10⫺4 mol/L amiloride in Ringer’s solution (residual
PD). The change in potential in response to amiloride (amiloridesensitive PD) was determined by calculation of the difference
between maximum PD and residual PD and was expressed both in
millivolts and as a percentage of the maximum PD.
Statistical Analysis
Group values are given as mean⫾SEM for normally distributed data
and as median and interquartile range for plasma renin activity and
aldosterone concentration, which are not normally distributed. Differences between groups were tested by 2-sample t tests for normally
distributed variables and ␹2 tests for categorical variables. Two-way
Increased Sodium Absorption in Black People
77
ANOVA was used to compare PD measurements between black and
white and between NT and HT subjects before and after adjustment
for age, gender, body mass index, smoking status, and 24-hour
urinary sodium excretion. Pearson correlation coefficients were
calculated to examine relationships between PD measurements and
biochemical variables within black and white NT and HT groups.
Two-tailed probability values of ⬍0.05 were considered significant.
Results
Thirty-nine black NT subjects, 106 black HT subjects, 51
white NT subjects, and 61 white HT subjects were studied.
Demographic characteristics of subjects are shown in Table 1,
and biochemical measurements are shown in Table 2.
Nasal PD Measurements in Black and White NT
and HT Subjects
Maximum PD was greater in black than in white subjects
(black NT, ⫺21.6⫾1.0 mV; black HT, ⫺21.5⫾0.7 mV;
white NT, ⫺18.5⫾1.0 mV; white HT, ⫺18.9⫾0.9 mV).
Two-way ANOVA showed that maximum PD was significantly higher in black than in white subjects (P⫽0.002) but
was not significantly different between NT and HT subjects
(P⫽0.848). The difference in maximum PD between black
and white subjects remained significant after adjustment for
age, gender, current smoking status, body mass index, and
24-hour urinary sodium excretion (P⫽0.009). (See Table 3.)
Residual PD after amiloride application was greater in
black than in white subjects but did not differ between HT
and NT subjects (black NT, ⫺14.7⫾0.9; black HT,
⫺13.7⫾0.5; white NT, ⫺10.9⫾0.6; white HT, ⫺12.1⫾0.6).
Two-way ANOVA showed that residual PD was significantly
higher in black than in white subjects (P⬍0.0001) but was not
significantly different between NT and HT subjects
(P⫽0.844). The difference in residual PD between black and
white subjects remained significant after adjustment for age,
gender, smoking status, body mass index, and 24-hour
urinary sodium excretion (P⫽0.009). The absolute and percentage changes in PD after amiloride application were not
different between black and white or between NT and HT
subjects (Table 3).
Nasal PD and Smoking Status
Smoking status differed between ethnic groups. Significantly
more black than white subjects had never smoked (nonsmokers:
black, 74.5%; white, 42.0%; P⬍0.0001). Similar proportions of
black and white subjects were current smokers (Table 1).
Observed differences between black and white subjects
were not accounted for by differences in smoking status.
Maximum potential was higher in black than in white
subjects when grouped by smoking history (Figure). Maximum PD remained significantly greater in black than in white
subjects after adjustment for current smoking status, as well
as for age, gender, body mass index, and 24-hour urinary
sodium excretion (P⫽0.009; Table 3).
Nasal PD in Black People of African and
Caribbean Origin
Maximum PD was similar in black subjects of African and
Caribbean origin (maximum PD: African, ⫺22.6⫾1.1 mV,
n⫽49; Caribbean, ⫺21.6⫾0.7 mV, n⫽83; P⫽0.439). Two-
78
Hypertension
July 2001
TABLE 1. Clinical Characteristics of Black and White Subjects With Normal and
High Blood Pressure
Black Ethnicity
White Ethnicity
Variable
NT (n⫽39)
HT (n⫽106)
NT (n⫽51)
HT (n⫽61)
Gender, M:F, (%
female)
18:21 (53.8)
45:61 (57.5)
34:17 (33.3)
51:10 (16.4)
Age, y
43.1⫾2.1
46.7⫾1.1
49.9⫾1.9
47.9⫾1.9
BMI, kg/m2
26.97⫾0.65
28.67⫾0.42
24.31⫾0.40
29.33⫾0.57
Systolic BP, mm Hg
121.0⫾1.6
159.1⫾1.5
125.0⫾1.3
158.1⫾2.1
Diastolic BP, mm Hg
77.4⫾1.1
100.5⫾1.0
76.1⫾1.1
99.6⫾1.5
76.9
73.6
41.2
42.6
2.6
15.1
35.3
41.0
20.5
10.4
19.6
16.4
0
0.9
3.9
0
Smoking status, %
Never
Ex
Current
Unknown
Ethnicity, %
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Caribbean
61.5
55.7
NA
NA
African
25.6
35.8
NA
NA
Other
12.8
6.6
NA
NA
0
1.9
NA
NA
Unknown
BMI indicates body mass index; BP, blood pressure; and NA, not applicable.
way ANOVA showed that maximum PD was not significantly different in African and Caribbean subjects before or
after adjustment for blood pressure status (NT or HT), age,
gender, current smoking status, body mass index, and 24-hour
urinary sodium excretion.
Discussion
We investigated the hypothesis that activity of epithelial
sodium channels is greater in black than in white people by
the measurement of nasal PD. In the present study, maximum
nasal PD was significantly higher in black than in white
subjects. Nasal PD is generated by active absorption of
sodium ions from airway surface liquid across nasal epithelium. Na-K-ATPase pumps in the basolateral membrane of
epithelial cells generate a sodium gradient by pumping sodium
out of the cell in exchange for potassium. Sodium ions enter
epithelial cells down this gradient through epithelial sodium
channels in the apical cell membrane. The greater the sodium
Relationship Between Maximum PD and
Biochemical Variables
Within each of the 4 groups of black and white NT and HT
subjects, maximum PD did not correlate with blood pressure,
serum biochemistry, 24-hour urinary sodium excretion, or
plasma hormone activity or concentration.
TABLE 2. Biochemical Characteristics of Black and White Subjects With Normal and High
Blood Pressure
Black Ethnicity
Variable
Serum Na, mmol/L
NT
White Ethnicity
HT
NT
HT
139.2⫾0.3
139.4⫾0.2
140.2⫾0.3
(n⫽34)
(n⫽100)
(n⫽49)
(n⫽60)
Serum K, mmol/L
4.25⫾0.06
4.17⫾0.06
4.16⫾0.04
4.18⫾0.04
(n⫽32)
(n⫽98)
(n⫽47)
(n⫽59)
Urine creatinine, nmol/24 h
14.5⫾0.8
14.5⫾0.5
13.5⫾0.4
16.6⫾1.1
(n⫽29)
(n⫽94)
(n⫽47)
129.1⫾6.0
156.1⫾7.8
139.5⫾0.3
(n⫽57)
Urine Na, mmol/24 h
135.8⫾11.1
(n⫽29)
(n⫽95)
(n⫽47)
(n⫽59)
Plasma renin activity,
0.39 (0.19–0.78)
0.25 (0.10–0.48)
0.65 (0.44–1.62)
0.88 (0.45–1.48)
ng 䡠 mL⫺1 䡠 h⫺1 (range)
Aldosterone, pmol/L (range)
166.0⫾7.4
(n⫽19)
(n⫽83)
(n⫽42)
(n⫽56)
281 (180–347.3)
347.0 (221–532)
309 (191–461)
423 (295–592.8)
(n⫽22)
(n⫽87)
(n⫽47)
(n⫽58)
Baker et al
TABLE 3.
Increased Sodium Absorption in Black People
79
Nasal PD Measurements in Black and White Subjects With Normal and High Blood Pressure
Black Ethnicity
White Ethnicity
Two-Way ANOVA, P for Adjusted
Differences Between
NT
HT
NT
HT
Ethnic Groups
Blood Pressure
Status Groups
Max PD, mV
⫺21.6⫾1.0
⫺21.5⫾0.7
⫺18.5⫾1.0
⫺18.9⫾0.9
0.002*
0.813
Residual PD, mV
Variable
⫺14.7⫾0.9
⫺13.7⫾0.5
⫺10.9⫾0.6
⫺12.1⫾0.6
0.025*
0.578
Amiloride-sensitive PD, mV
7.0⫾0.6
7.9⫾0.5
7.5⫾0.6
6.8⫾0.6
0.260
0.474
Amiloride-sensitive PD, %
32.8⫾2.4
35.9⫾1.7
39.7⫾1.9
34.3⫾1.9
0.868
0.309
*Significant difference.
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absorption through epithelial sodium channels, the higher the
transepithelial PD. Increased maximum PD in black compared
with white subjects suggests that transnasal sodium absorption
through epithelial sodium channels is greater in black subjects.
The interpretation of nasal PD measurements after the application of amiloride is more complicated. Amiloride blocks sodium
absorption through sodium channels, causing the epithelium to
depolarize. However, this change in PD induces secretion of
chloride ions through the cystic fibrosis transmembrane regulator (CFTR) chloride channels. Residual PD, but not amiloridesensitive PD, was greater in black than in white subjects, perhaps
reflecting a greater induction of chloride secretion generated by
a greater amiloride-induced inhibition of sodium channel activity. Alternatively, increased maximum but not amiloridesensitive PD could be explained either by increased activity of
Na-K-ATPase pumps or by increased amiloride-insensitive
transepithelial sodium absorption in black people. The lack of
amiloride-resistant sodium absorption in human airway in ion
flux studies suggests that the latter explanation is unlikely.16 –18
Nasal PD can only be generated by active ion transport
across the epithelium if the epithelium has resistance as stated
by Ohm’s law (V⫽IR). Epithelial resistance is maintained by
tight junctions between cells and can be lost where the
epithelium is abraded19 or damaged, eg, by colds19 or cigarette smoke.20,21 It is important to consider whether observed
differences in nasal PD between ethnic groups could be due
Maximum potential difference in black and white subjects with
different smoking histories.
to differences in epithelial resistance. A standard nasal PD
measurement protocol was used for both ethnic groups that
caused little or no epithelial trauma and excluded subjects
with recent rhinitis, asthma, or atopy. Although black subjects
were far less likely to have smoked cigarettes than white
subjects, differences in smoking history did not account for
ethnic differences in nasal PD. Maximum potential was
higher in black than in white nonsmokers, ex-smokers, and
current smokers (Figure), and the difference in PD between
ethnic groups remained highly statistically significant after
adjustment for current smoking status.
Although sodium channel activity as measured by nasal PD
was greater in black than in white people, there was no
difference in nasal PD between HT and NT people within
ethnic groups and no correlation between nasal PD and blood
pressure. The lack of relationship between the apparent
upregulation of sodium absorption and blood pressure status
in black people may be explained if the majority of black
people are predisposed to hypertension. In a study of systolic
hypertension in the elderly,22 76% of black Americans
between the ages of 65 and 74 years were found to have high
blood pressure. Observed differences in blood pressure in
people predisposed to hypertension may be accounted for by
individual differences in exposure to environmental factors
that increase blood pressure, such as high dietary sodium and
increased body mass index. In the present study, the black HT
group did not appear to eat more salt than the NT group,
because black NT and HT subjects had similar measured
24-hour urinary sodium excretion (Table 2). Black HT
subjects had a significantly greater body mass index
(P⫽0.035) and were older than black NT subjects.
The lack of relationship between increased nasal sodium
absorption and blood pressure status in black people could
also be explained if increased nasal sodium absorption does
not reflect sodium channel activity in the renal tubules. In the
present study, we made the assumption that nasal epithelial
sodium channels can be used as a model for renal sodium
channels, because previous studies found altered nasal PD
measurements in patients with sodium channel mutations that
increase or decrease blood pressure. Nasal PD measurements
were increased in 3 brothers with Liddle’s syndrome, who
had activating mutations of the sodium channel ␤-subunit,
compared with their unaffected sister and unrelated NT
controls.11 Nasal PD was very low in a patient with pseudohypoaldosteronism type 1 who had inactivating sodium channel
mutations.12 These findings suggest that nasal PD measure-
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Hypertension
July 2001
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ments can detect abnormalities of sodium channel activity
that affect blood pressure levels, at least when these are
caused by structural changes in channel subunits. However,
nasal and renal channels are regulated differently. For example, renal channels are activated by aldosterone, which has no
effect on nasal sodium channels.23 Sodium channel activity in
respiratory epithelium is downregulated (decreased) by interactions with CFTR,24 but it is not clear whether CFTR has
any influence on sodium channels in the renal tubule. Alteration of sodium channel regulation in the respiratory epithelium could lead to changes in sodium channel activity and
nasal PD without altering renal sodium channel function.
Ethnic variation in nasal PD may be of direct relevance in
the pathogenesis of airway disease. Black adults are 37%
more likely than white adults to have active asthma and are
nearly 3 times more likely to die of their asthma.25,26 The
composition of liquid at airway surfaces has an important
influence on bronchial reactivity. Hypotonic and hypertonic
aerosols are thought to precipitate bronchospasm by altering
the osmolarity of the periciliary fluid, invoking an intermediate event, possibly release of mediators from mast cells.27
Altered ion transport across airway epithelium in black
people could predispose them to asthma by altering osmolarity of airway surface liquid.
We have shown that epithelial sodium channel activity is
greater in black than in white people as assessed by nasal PD
measurements. Generalized upregulation of sodium channel
activity may account for the high prevalence of salt-sensitive
hypertension in the black population.
Acknowledgments
Measurements were made during a study funded by the British Heart
Foundation. We thank Rosemary Coltart and Monique Wood for
recruitment of individuals and clinical measurements, Alison Blackwood and Michelle Miller for measurement of plasma renin activity
and plasma aldosterone concentration, Franco Cappuccio for assistance in identifying black normotensive individuals, and Feng He for
assistance with statistical analysis.
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Transepithelial Sodium Absorption Is Increased in People of African Origin
Emma H. Baker, Nicola J. Ireson, Christine Carney, Nirmala D. Markandu and Graham A.
MacGregor
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Hypertension. 2001;38:76-80
doi: 10.1161/01.HYP.38.1.76
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2001 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
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