(Hypertension. 1999;34:315-319.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Levels of Mineralocorticoids in Whites and Blacks
From the Department of Medicine, Indiana University School of Medicine (J.H.P., J.F.R., L.Z., W.T.A., S.A.N.), and VA Medical Center (J.H.P., J.F.R.), Indianapolis, Ind; Harry S. Truman Veterans Hospital (C.E.G.-S.), Columbia, Mo; and Endocrine Sciences (D.F.M.), Calabasas Hills, Calif.
Correspondence to J. Howard Pratt, MD, 541 Clinical Dr, Indianapolis, IN 46202-5111. E-mail johpratt{at}iupui.edu
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Abstract |
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Abstract—Blacks appear, on average, to retain more Na than whites. A higher production rate of mineralocorticoids could explain the greater Na retention in blacks. Although production of aldosterone has been shown to be lower in blacks, the level of another mineralocorticoid may be increased. Plasma levels of deoxycorticosterone and cortisol were measured in young whites (n=23; age=16.4±3.1[SD] years) and young blacks (n=25; age=13.8±1.3 years). Blacks had lower plasma levels of renin activity and aldosterone and lower urinary aldosterone excretion rates; thus, they appeared to be representative of blacks that retain additional Na. Plasma deoxycorticosterone levels were lower in blacks than in whites both at baseline (247±161 versus 381±270 pmol/L, P=0.048) and after stimulation with adrenocorticotropic hormone (822±294 versus 1127±628 pmol/L at 30 minutes, P=0.047; 925±366 versus 1440±834 pmol/L at 60 minutes, P=0.013). Cortisol levels were also lower in blacks at baseline (P=0.014) but were not significantly different from levels in whites after stimulation with adrenocorticotropic hormone. In a larger cohort of 407 whites (age=12.0±2.9 years) and 247 blacks (age=12.9±3.1 years), 18-hydroxycortisol excretion rates were also lower in blacks (P=0.021). In conclusion, increased Na retention in blacks does not appear to be secondary to increased production of either aldosterone, deoxycorticosterone, cortisol, or 18-hydroxycortisol. A primary renal mechanism may mediate the increase in Na reabsorption in blacks.
Key Words: deoxycorticosterone • cortisol • 18-hydroxycortisol • aldosterone • race • renin
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Introduction |
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Fluid homeostasis and blood pressure are integrally related to Na reabsorption by the kidneys. Blacks appear to retain more Na than whites, because blood pressure is typically more "salt-sensitive"1 2 and plasma renin activity (PRA) is usually lower in blacks than in whites.3 4 5 The greater Na reabsorption may underlie the increased susceptibility to hypertension of blacks.6 7 Why blacks might retain Na more than whites is unknown. Aldosterone does not appear to mediate the increased Na retention, because in studies that we performed in children, plasma aldosterone levels and urinary aldosterone excretion rates were actually lower in blacks than in whites.8 9 In the present study, we addressed the question of whether another mineralocorticoid might be produced in excess in blacks to account for the increase in Na reabsorption. We chose to study deoxycorticosterone (DOC) because, although it is less potent than aldosterone,10 an increase in DOC secretion, such as occurs with adrenal deficiency of 11-hydroxylase11 or 17-hydroxylase,12 can result in hypertension. There is also evidence that a partial deficiency of 11-hydroxylase contributes to common forms of hypertension.13 Cortisol was also measured because it, too, has mineralocorticoid activity14 and because an increase in the plasma cortisol level15 as well as urinary excretion of cortisol16 has been associated with higher blood pressure. Levels of DOC and cortisol were measured in whites and blacks before and after stimulation with adrenocorticotropic hormone (ACTH). Finally, we also measured urinary excretion of 18-hydroxycortisol, which reflects production of 18-oxocortisol,17 a mineralocorticoid with activity in the range of that of DOC.18 19 Levels of 18-hydroxycortisol and 18-oxocortisol are elevated in glucocorticoid-remediable aldosteronism20 21 22 and with adrenal tumors that result in primary aldosteronism.23
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Methods |
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Subjects
Subjects were recruited from a young cohort that is followed longitudinally in a study of blood pressure regulation.24 We randomly selected subjects by sending them letters requesting their participation in the study; there was no selection based on previously observed levels of renin activity, aldosterone, or blood pressure. Of those who were sent letters,
30% agreed to
participate. Their characteristics are described in Table 1. All subjects were in good health, and
none were taking medication, including oral contraceptives. All female
subjects had a negative result on a pregnancy test before starting the
study. In these subjects, the renin-aldosterone axis was
assessed and plasma levels of DOC and cortisol were measured. In a much
larger, additional group of subjects, consisting of most of the members
of the original cohort, the level of 18-hydroxycortisol in overnight
urine samples was measured. The studies were approved by the
institutional review board of Indiana University–Purdue University
of Indianapolis.
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Procedure
The first group of subjects was admitted to the General Clinical
Research Center in the afternoon. The renin-aldosterone
axis in each subject was studied by first collecting a 12-hour
overnight urine sample (from 7 PM to 7 AM) for
measurement of the aldosterone excretion rate. Blood
samples were collected the next morning (at 7 AM) while
subjects were supine and again after 2 hours of standing (at 9
AM) for measurement of the levels of renin activity and
aldosterone. Plasma samples were also collected at 9
AM (baseline) and 30 and 60 minutes after an
intravenous bolus injection of ACTH (Cortrosyn, 25 U) for
measurement of cortisol and DOC.
An assay for 18-hydroxycortisol was available for urine but not plasma. Therefore, overnight urine samples were collected on an outpatient basis from the larger cohort for measurement of 18-hydroxycortisol excretion rate. Aldosterone excretion rate was determined from the same samples to assess the relationship of 18-hydroxycortisol excretion to aldosterone excretion. Results were expressed per unit of excreted creatinine.
Assay Procedures
Aldosterone in blood was measured by radioimmunoassay
(RIA) with antiserum from Diagnostic Products
Corporation. Aldosterone excretion was assessed by
hydrolyzing aldosterone-18-glucuronide overnight at pH 1 to
generate free aldosterone, which was measured by RIA. PRA
was measured with the Clinical Assays GammaCoat RIA kit. DOC and
cortisol were determined in the laboratory at Endocrine Sciences. DOC
was measured by RIA after extraction and purification by paper
chromatography. Recovery through the procedure ranged
from 70% to 85% and was monitored in all samples with a
3H DOC tracer. Cortisol was measure by RIA
in diluted serum with a specific antibody and
I125 cortisol label. The interassay coefficients
of variation for aldosterone, PRA, DOC, and cortisol were
10%, 10%, 9%, and 5%, respectively.
Urinary 18-hydroxycortisol was measured with an ELISA25 modified from a previously published direct RIA17 that uses 0.5 µL of urine. The polyclonal antibody used was stripped of cross-reacting antibodies by incubation with aminosilane controlled-pore glass beads, to which cortisol-3-carboxymethoxime had been conjugated. The antibody showed very little cross-reactivity with cortisol (<0.0034%), corticosterone (0.0079%), cortisone (<0.003%), 18-hydroxycorticosterone (0.013%), and tetrahydrocortisol (<0.003%).17 The assay had an intraassay coefficient of variation of 8% and an interassay coefficient of variation of 12%.
Statistical Analyses
Means and SDs of the variables of interest were calculated and
are presented in Table 1. All descriptive statistics for
continuous data are reported as mean±SD. Comparisons of the
variables, unadjusted for the other covariates, were made by
2-sample t tests. Fisher's exact test was used to compare
the proportion of female subjects in the black and white samples.
Plasma levels of cortisol and DOC were modeled with ANCOVA. Included as
predictors were age and race. Pearson's correlation was used to
describe the relationships among PRA, plasma aldosterone,
plasma cortisol, and plasma DOC levels. Excretion rates of
18-hydroxycortisol were also examined by use of ANCOVA with race,
gender, age, and body mass index (BMI) (weight divided by height
squared) as predictors. Because the data were not normally distributed,
we used a log transformation of the data. Adjusted means were
calculated on the log scale and back-transformed to the original scale.
The correlation of the log of 18-hydroxycortisol excretion and the log
of aldosterone excretion was also calculated.
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Results |
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Characteristics of Subjects
Characteristics of the subjects are presented in Table 1. Whites were, on average, 3.2 years older than blacks (P=0.0007), whereas BMI and blood pressure were not significantly different in the 2 groups. PRA was lower in blacks, a difference that was significant when subjects were supine (P=0.026) but only marginally significant after they had been standing for 2 hours (P=0.074). Although plasma aldosterone levels were lower in blacks than in whites, this racial difference was only marginally significant both in the supine position (P=0.099) and after being upright (P=0.049). Levels of PRA and plasma aldosterone were significantly related both when subjects were supine (P=0.0012) and after they were standing (P=0.035). The overnight urinary excretion rate of aldosterone in blacks was about half the value observed in whites (P=0.012). Thus, the blacks who participated in the study had a suppressed renin-aldosterone axis when compared with the whites.
Plasma Cortisol and DOC Levels
Plasma levels of cortisol and DOC before and 30 and 60 minutes
after administration of ACTH are shown in Figure 1. Cortisol increased by 2-fold and
DOC by 4-fold in response to ACTH. At baseline, the mean cortisol
level was significantly higher in whites than in blacks (580±178
[SD] versus 457±146 nmol/L, P=0.014). The mean baseline
DOC level was also significantly higher in whites (381±270 versus
247±161 pmol/L, P=0.048). After treatment with ACTH,
cortisol levels were no longer significantly different in the 2 groups:
mean cortisol levels were 840±150 versus 782±137 nmol/L
(P=0.18) at 30 minutes and 933±172 versus 877±158 nmol/L
(P=0.26) at 60 minutes in whites and blacks, respectively.
Conversely, after ACTH treatment, DOC levels remained higher in whites
at 30 minutes (1127±628 versus 822±294 pmol/L, P=0.047)
and at 60 minutes (1440±834 versus 925±366 pmol/L,
P=0.013). Because the blacks were older, the data
were also examined with linear regression analysis with age and
race in the model. The results were similar. Race was a significant
predictor of the cortisol level at baseline (P=0.037),
whereas age was not (P=0.88); neither race nor age was a
significant predictor of the cortisol level at either time point after
administration of ACTH. Race was a significant predictor of the DOC
level both before and after treatment with ACTH, with P
values of 0.015, 0.0031, and 0.0019 at baseline and 30 and 60 minutes
after ACTH treatment, respectively. When age was used as a predictor of
DOC level, the P values were 0.14, 0.017, and 0.071,
respectively.
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) and blacks
(
).
18-Hydroxycortisol Excretion Rates
Excretion rates of 18-hydroxycortisol were also measured in the
larger cohort of whites and blacks. Aldosterone excretion
was also determined to examine its relation to 18-hydroxycortisol
excretion. By use of ANCOVA, race (P<0.0001), gender
(P=0.026), age (P<0.0001), and BMI
(P=0.015) were significant predictors of the
18-hydroxycortisol excretion rate, with lower levels occurring in
blacks than in whites (0.154 versus 0.189 nmol/mmol
creatinine) and lower levels in the female subjects than in
the male subjects (0.162 versus 0.180 nmol/mmol
creatinine). As BMI and age increased, excretion of
18-hydroxycortisol increased and decreased, respectively (slopes were
0.013 and -0.085 using a log scale). The t test, which used
unadjusted values, produced similar results (Table 2): for race, P=0.017, and for
gender, P=0.065. Aldosterone excretion rates
were significantly related only to race (P<0.0001), again
with lower levels in blacks. A similar result for a racial difference
in aldosterone excretion rate was observed when the
t test was used (Table 2). 18-Hydroxycortisol and
aldosterone excretion rates were highly related, with a
correlation coefficient of 0.36 (P<0.0001).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Blacks appear to retain more Na than whites, a condition that may predispose blacks more than whites to hypertension. We showed previously that production of aldosterone was lower in blacks than whites and thus that an increase in aldosterone did not explain the increase in Na reabsorption in blacks. In this study, we showed that the blood level of DOC, a mineralocorticoid with less activity than aldosterone10 but with the potential to produce hypertension,11 12 13 was also not increased in blacks, and in fact, like aldosterone, DOC production appeared to be lower in blacks. The level of cortisol was also not higher in blacks. Urinary excretion of 18-hydroxycortisol, which is reflective of 18-oxocortisol,17 another mineralocorticoid,18 19 was also lower in blacks. Our results are consistent with a primary renal mechanisms for Na reabsorption that functions at a higher level in blacks or, alternatively, with overproduction in blacks of still another mineralocorticoid.
Why blood levels of DOC were lower in blacks is unclear. Although DOC secretion appears to be driven primarily by ACTH,26 there may be partial regulation by angiotensin II. Bledsoe et al27 showed that the DOC secretion rate was higher when dietary Na was restricted. Therefore, DOC levels in blacks, like aldosterone levels, may be responding to suppression of the renin-angiotensin system. To explore this potential mechanism, we examined the relation of the 2-hour upright PRA to the DOC level (Table 3). For purposes of comparison, the relationships of PRA to the aldosterone and cortisol levels were also studied. Similar to aldosterone, DOC (but not cortisol) showed at the least a trend for a significant association with PRA (at 30 and 60 minutes after ACTH; P values for the DOC/PRA relationship were 0.027 and 0.097, respectively). The lower 18-hydroxycortisol excretion rate in blacks may also reflect less stimulation by the renin-angiotensin system. Although 18-hydroxycortisol production is known to respond to ACTH, as occurs in glucocorticoid-suppressible aldosteronism,28 29 Na restriction also increases it.30
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An increase in the normal production of cortisol has been associated with a higher blood pressure in several studies. Litchfield et al16 found higher urinary free cortisol excretion rates in hypertensive than in normotensive subjects, and, by use of the "four corners" model for identifying factors that contribute to development of hypertension, Watt et al15 found the highest plasma cortisol levels in subjects who were normotensive but had the highest blood pressures and in a parent who was hypertensive. A higher cortisol level was not observed in the blacks in our study; thus, we believe that a role of cortisol in increasing the risk of hypertension in blacks is unlikely.
In summary, plasma levels of DOC and cortisol, both at baseline and after stimulation with ACTH, were not higher, and in the case of DOC were actually lower, in blacks than in whites. 18-Hydroxycortisol excretion rates were also lower in blacks. These findings, in conjunction with previous observations that aldosterone production is lower in blacks, suggest that greater Na reabsorption in blacks is not mediated by higher levels of these mineralocorticoids but rather may result from a more active primary renal mechanism.
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Acknowledgments |
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This study was supported by National Institutes of Health grants R01-HL-35795 (J.H.P.), HL-27255 (C.E.G.-S.), and M01-RR00750, and by Merit Review grants from the US Veterans Affairs Office (J.H.P., C.E.G.-S.).
Received February 9, 1999; first decision March 4, 1999; accepted April 13, 1999.
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