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From the Department of Medicine (W.R.L., N.D.L.F., G.H.W.), Brigham and
Women's Hospital and Harvard Medical School, Boston, Mass; the
Department of Medicine (S.H., P.H., R.W.), University of Utah, Salt Lake City,
Utah; and the Department of Molecular Hypertension and Clinical Investigative
Center (X.J., P.C.), Hospital Broussais, Paris, France.
A recent potential addition to the list of intermediate
phenotypes in hypertension is the abnormal regulation or
metabolism of cortisol. The first study to suggest this was
the Four Corners study of normotensive subjects.9
In this population-based study, normotensive subjects were divided into
four groups according to whether none, one, or both parents had
hypertension, and a number of metabolic factors were
assessed. One of these factors was plasma cortisol. Its concentration
was significantly higher in young subjects with higher blood pressures
and hypertensive parents than in the rest of the population. In
addition, these subjects shared a consistent polymorphism
of the glucocorticoid receptor gene, as determined by RFLP. However,
these findings have not been reproduced in a hypertensive population.
Thus, the relevance of the Four Corners study report to the genetics of
hypertension remains uncertain.
The primary objective of the present study was to test the
hypothesis that cortisol regulation was abnormal in a hypertensive
population. If documented, these findings would provide the first
evidence of cortisol levels being an intermediate phenotype in
hypertension. To circumvent the difficulties of using plasma cortisol
as the measure of the activity of the ACTH-cortisol axis, we used
urinary cortisol excretion, which integrates the secretion of cortisol
over a 24-hour period. Cortisol excretion rates were determined on both
a high- and low-sodium diet for two reasons: to assess the salt
sensitivity of the blood pressure in these subjects and to pursue
scattered unconfirmed reports that cortisol metabolism may
be influenced by sodium intake.10 11 12 Finally,
data were analyzed for any gender effect because a gender
effect on cortisol excretion has been inconsistently
reported.10 13 14 15
The patients were enrolled at the Clinical Research Centers of the
Brigham and Women's Hospital in Boston, Mass; the University of Utah
in Salt Lake City, Utah; and Hospital Broussais in Paris, France. The
study was reviewed and approved by the institutional review boards of
each center, and all patients gave informed written consent before
enrollment.
Each subject consumed both high-sodium (200-mmol/d) and low-sodium
(10-mmol/d) diets, which were prepared in the metabolic
kitchens of each of the study sites and then consumed in the outpatient
setting. Dietary compliance was ensured by the measurement of urinary
sodium and creatinine in a 24-hour urine collection after
at least 3 days on the high-salt diet and 7 days on the low-salt diet.
The high-salt diet was performed first and was immediately followed by
the low-salt diet for 7 days. We obtained 24-hour urine collections in
153 consecutive white patients with essential hypertension and in 18
normotensive white subjects who met the above criteria.
Techniques
Urine was stored without preservatives or additives at -20°C until
assay. Serum was separated from venous blood and stored at -20°C
until assay. UFC, serum cortisol, and urine aldosterone
(free aldosterone plus aldosterone glucuronide)
were measured with commercial radioimmunoassay kits (Incstar Corp).
Sodium and potassium in both serum and urine were measured by direct
potentiometry with an ion-selective electrode (NOVA analyzer I,
Nova Biochemical). Creatinine was measured in both serum
and urine on a Beckman creatinine analyzer (model
II).
Statistics
After hypertensive and normotensive subjects were combined, there was a
significant effect of dietary sodium intake on UFC levels. The
difference between high- and low-salt UFC was 59.6 nmol/d
(P<.01). Gender also significantly modified urinary
cortisol levels (Fig 1
To determine the relative contributions of these various factors to the
level of UFC, ANCOVA models were developed for both high- and low-salt
UFC measurements (Table 2
Based on the results from the univariate model, a model
that uses repeated measures ANCOVA in a multivariate
model was developed. This model showed that gender, hypertension
status, and dietary sodium were significantly related to UFC. UFC was
significantly higher in men compared with women (P=.0006),
higher in hypertensive subjects than normotensive subjects
(P=.020), and higher on the high-sodium diet compared with
the low-sodium diet (P=.0001). The interactions between
gender and hypertension status, gender and dietary sodium, and
hypertension status and dietary sodium were not statistically
significant (P=.73, P=.60, and P=.86,
respectively). These results suggest that each variable was having
an independent effect on the UFC.
Bimodality of UFC
Salt Sensitivity of Blood Pressure
In an additional analysis, we analyzed age- and
sex-adjusted changes in systolic and diastolic
blood pressures after sodium restriction in the hypertensive subjects.
Hypertensive subjects were stratified into subgroups on the basis of
their UFC and compared by Student's t test. When the
low-salt UFC was considered, a significant decrease in systolic
(P=.024) and diastolic (P=.044) blood
pressure was observed in patients in the low-mode compared with that
observed in high-mode patients. A similar but nonsignificant trend was
noted for the high-salt UFC for systolic (P=.058)
and diastolic (P=.11) blood pressures.
Hypertensive subjects who were part of the high mode for UFC on a
low-salt diet were relatively salt resistant compared with
hypertensive subjects who fell into the low mode for low-salt UFC. The
blood pressure response to salt restriction of these high-mode
hypertensive patients was not significantly different from that of
normotensive subjects, who showed almost no reduction in
diastolic blood pressure after salt restriction (Fig 5
The second major observation in the present data was the
substantial influence of dietary sodium intake and gender on UFC
levels, whether the subjects were normotensive or hypertensive.
Repeated measures ANCOVA showed UFC to be significantly related to
gender (P=.0006) and dietary sodium intake
(P=.0001). As a consequence, UFC levels were substantially
higher on the high-sodium diet and in male subjects. These results may
have implications in relation to using UFC to screen for Cushing's
syndrome in patients with hypertension. Although few of the UFC levels
were substantially elevated over the normal range in our patient
population, there were some values that would have been clearly
considered consistent with mild Cushing's syndrome if one did
not take into account the dietary sodium intake or sex of the subject.
Thus, in screening for Cushing's syndrome in the hypertensive
population, care must be taken in assigning that diagnosis on the basis
of a randomly collected urinary cortisol without reference to dietary
sodium intake and gender.
Although there is a precedent for urinary cortisol being higher in
hypertensive patients than in normal subjects,17
most previous investigators18 19 failed to detect
a difference in UFC between normotensive and hypertensive subjects. The
present study provides a likely answer for why this is so. No
previous study controlled sodium intake or assessed the effect of
gender. Both could substantially obscure any differences, because the
impact of diet and gender was greater than the difference observed
between normotensive and hypertensive patients. In addition, it is not
a generalized increase in UFC levels in the hypertensive patients that
produced the statistically significant difference. Instead, a minority
subset with a higher-than-normal level of urinary cortisol was
responsible for the observed changes. Thus, if previous studies
contained only a few of this minority subset, there would have been no
observed difference in UFC, even if dietary sodium and gender had been
controlled for. Although normotensive and hypertensive patients
differed significantly with respect to age and BMI, our
analyses showed no relation between UFC and these
variables, indicating that the observed difference in cortisol is
not easily explained on this basis.
Is an elevated UFC an intermediate phenotype for a subset of
the hypertensive population? It is premature to answer "yes."
However, a number of findings in the present study, as well as the
study by Watt et al,9 suggest that elevated
urinary cortisol may be genetically determined. Our study documented
significant differences between hypertensive and normotensive patients
for this variable. It also showed urinary cortisol to be bimodally
distributed in the hypertensive population. Watt et
al9 found evidence of elevated cortisol levels in
the normotensive offspring of hypertensive subjects. In total, these
findings suggest that elevated urinary cortisol is a strong candidate
as a new intermediate phenotype of hypertension. Additional
studies assessing family history and determining whether cortisol
cosegregates with blood pressure in families will be required to firmly
establish this hypothesis.
There are a number of mechanisms that could account for the observed
elevation in UFC in this hypertensive subset. For example, a relative
deficiency of 11-ß-hydroxysteroid dehydrogenase increases the
cortisol:cortisone ratio and enables cortisol to activate the
mineralocorticoid receptor. Alternatively, cross-reactivity of
cortisone with the cortisol assay could falsely elevate urinary
cortisol levels. However, the assay used in this study is documented to
have very little cross-reactivity between cortisol and cortisone (<1%
cross-reactivity of cortisone with the assay). This fact, plus the
absence of salt-sensitive hypertension in these subjects (which would
be expected in patients with 11-ß-hydroxysteroid dehydrogenase
deficiency), makes these mechanisms unlikely explanations for our
observations.
An additional possibility could be a change in cortisol
metabolism conveyed through changes in the glucocorticoid
receptor. This possibility is supported by the Four Corners
study.9 In this scenario, a higher level of
cortisol would be required to suppress ACTH release and therefore
modify adrenal steroidogenesis. Direct data relevant to this point are
not available in the present data set or from the published
literature. Although we can safely exclude cortisone as a potential
contaminating cross-reacting substance confounding our results, we have
not excluded other substances that could cross-react with the cortisol
antibody. However, there are no data to suggest such compounds.
Finally, there is the intriguing possibility that the elevated urinary
cortisol levels in these patients with relative salt-resistant
hypertension is actually a reflection of an altered stress response.
There are several lines of evidence suggesting that some hypertensive
patients have heightened activity of the adrenergic nervous system.
Elevated cortisol levels are part of the output from a generalized
stress response that includes activation of the adrenergic nervous
system, increase in blood pressure, and an increase in pulse rate. Few
published data are available to determine whether individuals with an
activated adrenergic system are salt sensitive versus salt
resistant. However, a recent study by Brown et
al20 using tracer-labeled compartmental
analysis of norepinephrine kinetics suggests that
increased sympathetic nervous system activity is associated with a
decreased sensitivity of blood pressure to dietary sodium intake. These
findings are consistent with the report in the present
study and the overall hypothesis that the individuals included in the
higher mode of UFC may have an increased stress response with increased
activity of the adrenergic nervous system. Additional studies will be
needed to accept or reject this hypothesis.
In conclusion, we identified a subset of the hypertensive population
with increased free cortisol excretion. This subset may compose as much
as 30% of the hypertensive population. Our data suggest that if
dietary sodium intake is controlled and gender is considered, UFC may
serve as an effective intermediate phenotype for a genetic form
of hypertension. In contrast to previously defined forms of genetic
hypertension, all of which have blood pressure sensitive to salt
intake, this subset appears to be relatively salt resistant.
Whether this abnormality is associated with alterations in the activity
of the adrenergic nervous system, in stress response, and/or in the
glucocorticoid receptor remains to be determined. However, it is likely
that with better characterization of this potential new intermediate
phenotype of hypertension, a better understanding of the way in
which glucocorticoids may be involved in the pathogenesis of elevated
blood pressure will be reached.
Received July 3, 1997;
first decision July 25, 1997;
accepted September 9, 1997.
2.
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Fallo F, Gill JR Jr, Feld L, Ganguly A, Laidlaw JC, Murnaghan DJ,
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Shimkets R, Nelson-Williams C, Rossier BC, Lifton RP. A de novo
missense mutation of the beta subunit of the epithelial sodium channel
causes hypertension and Liddle's syndrome and identifies a
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8.
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Rossier BC. Liddle's disease caused by a missense mutation of beta
subunit of the epithelial sodium channel gene. J Clin
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9.
Watt GC, Harrap SB, Foy CJ, Holton DW, Edwards HV,
Davidson HR, Connor JM, Lever AF, Fraser R. Abnormalities of
glucocorticoid metabolism and the
renin-angiotensin system: a four-corners approach to the
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Hypertens. 1992;10:473–482.[Medline]
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© 1998 American Heart Association, Inc.
Scientific Contributions
Increased Urinary Free Cortisol
A Potential Intermediate Phenotype of Essential Hypertension
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Abstract—We evaluated urinary
cortisol excretion as a potential intermediate phenotype of
essential hypertension in 153 white patients with essential
hypertension and 18 normotensive white control subjects.
Analyses were controlled for dietary sodium and gender to
adjust for potential confounding effects of these variables on
cortisol excretion. Urinary cortisol excretion measured on both high-
and low-salt diets was significantly related to hypertension by
repeated measures ANCOVA (P=.02). Additional
determinants of urinary free cortisol included dietary sodium intake
and gender; cortisol excretion was significantly higher in men
(P=.0006) and during a high-sodium diet
(P=.0001). Maximum likelihood analysis showed
urinary cortisol to have a bimodal distribution on both 200-mmol
(P<.01) and 10-mmol (P<.002) sodium
diets in hypertensive subjects. On the low-salt diet, the mean urinary
cortisol in normotensive subjects (108.7±44.7 nmol/d) was similar to
the mean of hypertensive subjects in the low mode (127.2±43.0 nmol/d).
The high mode comprised 31.2% of the hypertensive population and had a
mean urinary cortisol of 224.3±93.8 nmol/d. Subjects with the highest
urinary free cortisol showed the least sensitivity of blood pressure to
dietary sodium loading (P<.05). These data suggest that
there is an association between salt-resistant hypertension and
high urine cortisol levels. This association may have a genetic
basis.
Key Words: cortisol • genetics • phenotype, intermediate • sodium • bimodality
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Essential
hypertension is a heterogeneous syndrome in which several
pathogenetic mechanisms result in an increase in blood pressure. One
approach that has been used to reduce this
heterogeneity is to group patients according to similar
pathophysiological characteristics (eg,
salt-sensitive and salt-resistant subsets). For example, three
genetic forms of salt-sensitive hypertension have been identified:
glucocorticoid-remediable aldosteronism,1 2
hypertension in patients carrying the M235T allele of
the angiotensinogen gene,3 4 and
Liddle's syndrome.5 6 7 8 Thus, substantial
progress has been made in identifying potential genetic factors
involved in salt-sensitive hypertension. In contrast, no studies have
reported genetic factors that could be responsible for
salt-resistant hypertension.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
The hypertensive patients were recruited from three communities:
Boston, Mass; Salt Lake City, Utah; and Paris, France. Subjects were
not preselected, except for their willingness to participate in the
study. Hypertension was defined as a history of hypertension with a
diastolic blood pressure 
100 mm Hg off all
medications, a diastolic blood pressure 90 mm Hg on
one antihypertensive agent, or the need for two or more
antihypertensive medications at the time of the screening visit. A
group of normotensive individuals served as control subjects. Secondary
forms of hypertension were excluded by history and physical examination
and when indicated, by biochemical testing. All antihypertensive
medications were discontinued at least 2 weeks before the study.
Exclusion criteria included diabetes mellitus, obesity (BMI >33 for
men and >31 for women), renal insufficiency, or other significant
medical problems.
Patients were admitted on the last day of each diet to enable
standardization of blood pressure measurement. Blood pressure was
measured with a Dinamap blood pressure monitor (Critikon Inc) with the
patient in the supine position after overnight recumbency and in the
fasting state. Blood pressure was reported as the mean of three
separate measurements taken at least 5 minutes apart.
Data were analyzed with repeated measures ANCOVA by the
General Linear Models procedure of SAS statistical software (SAS
Institute Inc). The repeated measures dependent variable was UFC
measured on a low- and high-sodium diet for each individual. The
independent variables included age, hypertension status, gender,
and the interaction terms of gender and hypertension status. Bimodality
analysis was performed with maximum likelihood
analysis.16 Data are reported as mean±SD
unless otherwise indicated.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Clinical Characteristics
Because preliminary data suggested that gender modified UFC,
patient characteristics are presented separately for men and
women (Table 1
). Hypertensive and
normotensive subjects differed with respect to age and blood pressure.
These patients were not different with respect to urinary sodium and
potassium levels on either high- or low-salt diets. Serum cortisol was
similar in hypertensive and normotensive men and women on both diets.
Compared with normotensive patients, hypertensive patients had higher
BMI, but this did not reach statistically significant levels.
View this table:
[in a new window]
Table 1. Patient Characteristics for 85 Men and 68 Women With
Essential Hypertension and 11 Normotensive Men and 7 Normotensive Women ). The influence of
dietary sodium was equally manifest in women and men. Finally,
hypertension also influenced the absolute levels of UFC; however, this
effect was observed predominantly in the men (Fig 2). There was no significant relation
between urinary cortisol and BMI. Urinary aldosterone was
not correlated with blood pressure status or gender. As anticipated,
there was a significant correlation between urinary
aldosterone and dietary sodium (P=.03), as well
as an inverse relation with age (decreased aldosterone
excretion rate with increasing age, P=.03).
View larger version (29K):
[in a new window]
Figure 1. Gender-specific changes in UFC with changes in
dietary sodium. UFC was higher in men (n=96) than in women (n=78) on
both high-sodium (*P=.009) and low-sodium
( 
P=.0006) diets (mean±SD).
View larger version (43K):
[in a new window]
Figure 2. UFC on high-sodium (200 mmol) and low-sodium
(10 mmol) diets in essential hypertension (HTN) and normotensive
(NBP) men and women (mean±SD). Repeated measures ANCOVA showed UFC to
be higher in men (P=.0006), hypertensive subjects
(P=.02), and those on a high-sodium diet
(P=.0001). ). With these
models, the effect of high- and low-sodium diets on UFC as related to
gender and blood pressure was determined. The level of UFC was
significantly greater in men (P=.009 and P=.0006
on high- and low-salt diets, respectively). Hypertensive patients also
had higher free cortisol levels, which were significant for the
low-salt diet (P=.081 and P=.017 on high- and
low-salt diets, respectively). The relation between urinary cortisol
and both blood pressure and gender was strongest on the low-sodium
diet. Finally, there was a strong correlation between high- and
low-salt UFC (r=.50, P<.0001; Fig 3).
View this table:
[in a new window]
Table 2. Effect of Covariates on Urinary Free Cortisol
View larger version (19K):
[in a new window]
Figure 3. UFC on high-sodium (200 mmol/d) and
low-sodium (10 mmol/d) diets. There was a strong relation between
urinary cortisol on both diets. Pearson correlation coefficient
r=.50; P<.0001.
Maximum likelihood analysis of the urinary cortisol data,
with statistical adjustment for gender, was performed for hypertensive
patients as an assessment of bimodality. In the hypertensive subjects,
both the high- and low-salt (Fig 4) UFC
fit bimodal distributions significantly better than unimodal
distributions (
2=9.8, P=.0017 and
2=6.6, P=.01, respectively). On the
high-salt diet, the modes for UFC were identified with means of
140.7±40.0 and 261.6±101.5 nmol/d. The low-salt UFC distribution had
modal means of 127.2±43.0 and 224.3±93.8 nmol/d. These
represented 68.8% and 31.2% of the hypertensive
population, with the intersection point occurring at 204.2 nmol/d.
Because the sample size in the normotensive subjects was small,
bimodality testing was not performed. However, sex-adjusted mean UFC on
high- and low-salt diets were 164.7±63.7 and 108.7±44.7 nmol/d,
respectively, for the normotensive patients. These levels are similar
to those observed in the low mode of the hypertensive population,
suggesting that the increased UFC observed in the hypertensive
population is primarily due to the presence of a subgroup of essential
hypertensive subjects who are different from the normotensive
subjects.
View larger version (31K):
[in a new window]
Figure 4. Frequency distribution plot of UFC on a low-salt
diet in hypertensive subjects. X1, mean±SD for low mode; X2, mean±SD
for high mode; proportion of population shown in parentheses.
Because the sensitivity of blood pressure to salt intake can be
influenced by age, blood pressure changes with salt restriction were
adjusted for age and sex and then correlated with UFC levels. There was
a statistically significant negative correlation between the change in
systolic blood pressure and both high-salt
(r=-0.19, P=.019) and low-salt
(r=-0.24, P=.0027) UFC levels. Similar results
were seen for the changes in diastolic blood pressure: high
salt, r=-0.16, P=.047 and low salt,
r=-0.22, P=.0056. These data suggest that the
higher the UFC on either a low- or high-salt diet, the smaller the
blood pressure change when dietary sodium intake is modified. However,
there is no correlation between the change in UFC by dietary
manipulation and dietary sodium-induced changes in either
systolic or diastolic blood pressure. ).
View larger version (35K):
[in a new window]
Figure 5. Changes in diastolic blood pressure
with sodium restriction. Normotensive subjects were compared with
hypertensive subjects stratified on the basis of UFC on a low-salt
diet. All hypertensive subjects showed a significant decrease in blood
pressure with salt restriction (P<.001), but
normotensive subjects did not. Individuals composing the low mode had
greater reductions in blood pressure than the other two groups, whereas
the individuals composing the high mode for UFC were not significantly
different from normotensive subjects. Data are mean±SEM.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The present study was designed to determine whether
abnormalities in the ACTH-cortisol axis were present in individuals
with essential hypertension. According to the Four Corners study of
normotensive subjects, if such an abnormality is present, it is
likely to be genetically determined. The results of this study provide
support for this hypothesis. This study documents that the level of UFC
is predicted by blood pressure status, with hypertensive subjects
having higher UFC levels than subjects with normal blood pressure
(P=.02). In addition, UFC levels were bimodally distributed
in the hypertensive population, with the clearest separation observed
on a low-sodium diet. Normotensive subjects on both a low- and
high-salt diet had UFC levels that were equivalent to the low mode of
the hypertensive population. Therefore, in the hypertensive population
there is a subgroup with elevated UFC levels. Furthermore, this
subgroup of the essential hypertensive population appears to be
relatively salt resistant. Thus, these data provide the first
suggestion of a potentially genetically determined subgroup of the
salt-resistant hypertensive subset. In addition, this subgroup
may comprise as much as 30% of the total hypertensive population, a
sizable fraction of the salt-resistant subset.
Selected Abbreviations and Acronyms
ACTH
=
adrenocorticotropic hormone (corticotropin)
BMI
=
body mass index
UFC
=
urinary free cortisol
Acknowledgments
This study was supported by grants from the National Center for
Research Resources (RR-02635, RR-00064) and the National Institutes of
Health (HL-5500, HL-47651, HL-97609, HL-36420, HL-45321, and HL-36568).
We gratefully acknowledge the editorial assistance of Barbara N. Smith
and the support of the Dietary, Nursing, and Laboratory staffs of the
three Clinical Research Centers. We also acknowledge the technical and
administrative assistance of the following members of the Genetics of
Human Hypertension team: Lynne M. Braley, MS, Jennifer S. Wyckoff, MD,
Jennifer Bowen, Judith Everett (Boston, Mass); Barbara Smith, LPN,
Brett Hicken, Elaine Hillas, Jan Skuppin, RN (Salt Lake City, Utah);
Anne Charru, MD, Sylvie Toulemont, Michel Azizi, and Joel Ménard
(Paris, France).
Footnotes
Reprint requests to Gordon H. Williams, MD, Endocrine-Hypertension Division, Brigham and Women's Hospital, 221 Longwood Ave, RFB-2, Boston, MA 02115.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S,
Ulick S, Lalouel JM. A chimaeric 11
beta-hydroxylase/aldosterone synthase gene causes
glucocorticoid-remediable aldosteronism and human hypertension.
Nature. 1992;355:262–265.[Medline]
[Order article via Infotrieve]
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V. F. Panoulas, K. M. J. Douglas, A. Stavropoulos-Kalinoglou, G. S. Metsios, P. Nightingale, M. D. Kita, M. S. Elisaf, and G. D. Kitas Long-term exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with rheumatoid arthritis Rheumatology, January 1, 2008; 47(1): 72 - 75. [Abstract] [Full Text] [PDF]
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 A L Markel, O E Redina, M A Gilinsky, G M Dymshits, E V Kalashnikova, Y. V Khvorostova, L A Fedoseeva, and G S Jacobson Neuroendocrine profiling in inherited stress-induced arterial hypertension rat strain with stress-sensitive arterial hypertension J. Endocrinol., December 1, 2007; 195(3): 439 - 450. [Abstract] [Full Text] [PDF]
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 F. Pecori Giraldi, A. G. Ambrogio, M. De Martin, L. M. Fatti, M. Scacchi, and F. Cavagnini Specificity of First-Line Tests for the Diagnosis of Cushing's Syndrome: Assessment in a Large Series J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4123 - 4129. [Abstract] [Full Text] [PDF]
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B. Chamarthi, N. S. Kolatkar, S. C. Hunt, J. S. Williams, E. W. Seely, N. J. Brown, L. J. Murphey, X. Jeunemaitre, and G. H. Williams Urinary Free Cortisol: An Intermediate Phenotype and a Potential Genetic Marker for a Salt-Resistant Subset of Essential Hypertension J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1340 - 1346. [Abstract] [Full Text] [PDF]
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 A. G. Bechtold and D. A. Scheuer Glucocorticoids act in the dorsal hindbrain to modulate baroreflex control of heart rate Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2006; 290(4): R1003 - R1011. [Abstract] [Full Text] [PDF]
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M. al'Absi, C. France, A. Harju, J. France, and L. Wittmers Adrenocortical and nociceptive responses to opioid blockade in hypertension-prone men and women. Psychosom Med, March 1, 2006; 68(2): 292 - 298. [Abstract] [Full Text] [PDF]
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L. M. Kurina, L. A. Weiss, S. W. Graves, R. Parry, G. H. Williams, M. Abney, and C. Ober Sex Differences in the Genetic Basis of Morning Serum Cortisol Levels: Genome-Wide Screen Identifies Two Novel Loci Specific to Women J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4747 - 4752. [Abstract] [Full Text] [PDF]
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 C. M. Masi, E. M. Rickett, L. C. Hawkley, and J. T. Cacioppo Gender and ethnic differences in urinary stress hormones: the population-based Chicago Health, Aging, and Social Relations Study J Appl Physiol, September 1, 2004; 97(3): 941 - 947. [Abstract] [Full Text] [PDF]
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 B. Bocchi, S. Kenouch, M. Lamarre-Cliche, M. Muffat-Joly, M. H. Capron, J. Fiet, G. Morineau, M. Azizi, J. P. Bonvalet, and N. Farman Impaired 11-{beta} Hydroxysteroid Dehydrogenase Type 2 Activity in Sweat Gland Ducts in Human Essential Hypertension Hypertension, April 1, 2004; 43(4): 803 - 808. [Abstract] [Full Text] [PDF]
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 C. Moreno, P. Dumas, M. L. Kaldunski, P. J. Tonellato, A. S. Greene, R. J. Roman, Q. Cheng, Z. Wang, H. J. Jacob, and A. W. Cowley Jr Genomic map of cardiovascular phenotypes of hypertension in female Dahl S rats Physiol Genomics, November 11, 2003; 15(3): 243 - 257. [Abstract] [Full Text] [PDF]
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M. N. Kerstens, F. G. H. van der Kleij, A. H. Boonstra, W. J. Sluiter, J. Koerts, G. Navis, and R. P. F. Dullaart Salt Loading Affects Cortisol Metabolism in Normotensive Subjects: Relationships with Salt Sensitivity J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4180 - 4185. [Abstract] [Full Text] [PDF]
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N. D.L. Fisher, S. Hurwitz, X. Jeunemaitre, D. A. Price, G. H. Williams, and N. K. Hollenberg Adrenal Response to Angiotensin II in Black Hypertension: Lack of Sexual Dimorphism Hypertension, September 1, 2001; 38(3): 373 - 378. [Abstract] [Full Text] [PDF]
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J. A. Whitworth, G. J. Mangos, and J. J. Kelly Cushing, Cortisol, and Cardiovascular Disease Hypertension, November 1, 2000; 36(5): 912 - 916. [Abstract] [Full Text] [PDF]
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R. C. Y. Lin, W. Y. S. Wang, and B. J. Morris Association and Linkage Analyses of Glucocorticoid Receptor Gene Markers in Essential Hypertension Hypertension, December 1, 1999; 34(6): 1186 - 1192. [Abstract] [Full Text] [PDF]
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G. C. Inglis, M. C. Ingram, C. D. Holloway, L. Swan, D. Birnie, W. S. Hillis, E. Davies, R. Fraser, and J. M. C. Connell Familial Pattern of Corticosteroids and Their Metabolism in Adult Human Subjects - the Scottish Adult Twin Study J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 4132 - 4137. [Abstract] [Full Text]
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E. Lovati, P. Ferrari, B. Dick, K. Jostarndt, B. M. Frey, F. J. Frey, U. Schorr, and A. M. Sharma Molecular Basis of Human Salt Sensitivity: The Role of the 11{beta}-Hydroxysteroid Dehydrogenase Type 2 J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3745 - 3749. [Abstract] [Full Text] [PDF]
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J. H. Pratt, J. F. Rebhun, L. Zhou, W. T. Ambrosius, S. A. Newman, C. E. Gomez-Sanchez, and D. F. Mayes Levels of Mineralocorticoids in Whites and Blacks Hypertension, August 1, 1999; 34(2): 315 - 319. [Abstract] [Full Text] [PDF]
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R. Fraser, M. C. Ingram, N. H. Anderson, C. Morrison, E. Davies, and J. M. C. Connell Cortisol Effects on Body Mass, Blood Pressure, and Cholesterol in the General Population Hypertension, June 1, 1999; 33(6): 1364 - 1368. [Abstract] [Full Text] [PDF]
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E. Davies, C. D. Holloway, M. C. Ingram, G. C. Inglis, E. C. Friel, C. Morrison, N. H. Anderson, R. Fraser, and J. M. C. Connell Aldosterone Excretion Rate and Blood Pressure in Essential Hypertension Are Related to Polymorphic Differences in the Aldosterone Synthase Gene CYP11B2 Hypertension, February 1, 1999; 33(2): 703 - 707. [Abstract] [Full Text] [PDF]
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M. Horiguchi, M. Kimura, J. Skurnick, and A. Aviv Parameters of Lymphocyte Na+-Ca2+ Regulation and Blood Pressure : The Gender Effect Hypertension, November 1, 1998; 32(5): 869 - 874. [Abstract] [Full Text] [PDF]
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