0021-972X/90/7106-1454$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1990 by The Endocrine Society
Vol. 71, No. 6 Printed in U.S.A.
Alterations in Aldosterone Secretion and Metabolism in Low Renin Hypertension* G. T. GRIFFING, T. E. WILSON, AND J. C. MELBY Evans Memorial Department of Clinical Research and the Department of Medicine, University Hospital, Boston University Medical Center, Boston, Massachusetts 02118
ABSTRACT. Low renin essential hypertensives (LRH) have normal plasma aldosterone levels which are inappropriately high
4 h of upright posture was not different in the four groups. The ratio of A plasma aldosterone/A PRA, however, was elevated in
in relation to their PRA. Posture is the major determinant for
both IHA and LRH compared to that in NRH and normals.
plasma aldosterone and PRA levels, but it is not known whether postural increments (A) of plasma aldosterone and (A) PRA are also abnormal in LRH. To evaluate this, LRH (n = 8), normal renin hypertensives (NRH; n = 9), normotensive controls (n = 18), and subjects with idiopathic hyperaldosteronism (IHA; n = 5) were studied in a metabolic unit on a controlled diet over 7 days. Overnight supine and 4-h upright PRA, plasma aldosterone, and 24-h urinary tetrahydroaldosterone (THA) and aldosterone secretion rates (ASR) were measured. The A in plasma aldosterone after
THA excretion was also elevated in IHA and LRH, but LRH had a normal ASR. This resulted in a higher fractional THA excretion (THA/ASR) in LRH compared to the other three groups. These data further support enhanced adrenal angiotensin-II sensitivity in LRH. Aldosterone was preferentially metabolized to THA in LRH. Since THA has reduced biological activity, this may be a compensatory mechanism to reduce mineralocorticoid activity in LRH. (J Clin Endocrinol Metab 71:1454-1460,1990)
L
OW PLASMA renin levels occur relatively frequently in essential hypertension (LRH) (1,2). The significance and mechanism for the low renin levels found in hypertension are controversial. It has been argued that low renin levels are not abnormal, but a statistical artifact produced by a skewed distribution of plasma renin in the hypertensive population (3). This does not account for the fact that aldosterone levels in this population are relatively high compared to aldosterone levels in normotensives with comparably low renin levels (4, 5). The inappropriately high aldosterone levels in low renin hypertensives (LRH) are believed to reflect enhanced zona glomerulosa angiotensin-II sensitivity (6, 7). In other low renin normotensive states or in LRH from exogenous mineralocorticoids, aldosterone levels are low, and zona glomerulosa angiotensin-II sensitivity is depressed (5, 8). The cause of this increased aldosterone responsiveness in LRH is unknown, and a number of questions regarding the control of the renin-angiotensin-aldosterone axis and the metabolism of aldosterone Received February 1, 1990. Address requests for reprints to: Dr. George T. Griffing, Boston University Medical School, Section of Endocrinology and Metabolism, University Hospital, 75 East Newton Street, Boston, Massachusetts 02118-2393. * This work was supported by Grants-In-Aid 1-R01-HL-31051, 5-P50-HL-18318, DDK-32455, M01-RR-00533-21, and HL-40123-01A1.
need to be answered. The primary determinants of the activity of the reninangiotensin-aldosterone axis are dietary sodium intake and posture (9, 10). The purpose of this study was to assess the effect of upright posture on PRA and plasma aldosterone levels and to measure the fractional excretion of the principal aldosterone metabolite, tetrahydroaldosterone (THA), in LRH. The findings of this study provide additional documentation of the increased angiotensin-II sensitivity in LRH and also provide evidence that the metabolism of aldosterone is altered to favor excretion of THA.
Subjects and Methods Subjects Four groups of subjects were studied (1) normals, normal reninemic hypertensives (NRH), LRH, and idiopathic hyperaldosteronism (IHA; see Table 1). Protocol
All subjects were admitted to the Clinical Research Center for a 5-day protocol after they had given informed consent and the study was approved by the institutional review board. Medications influencing the renin-aldosterone or pituitaryadrenal system, including, diuretics, adrenergic blockers, vasodilators, and estrogens, were discontinued for at least 4-6 weeks preceding admission. Where required, prazosin (1-10 mg/day)
1454
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ALDO IN HYPERTENSION was the primary antihypertensive therapy (11). A fixed isocaloric diet containing 128 meq sodium and 80 meq potassium/ day was given. Daily 24-h urine samples were collected for measurement of electrolytes and creatinine. Urinary THA and aldosterone secretion rates (ASR) were measured on day 5. After 8 h of recumbancy plasma was collected at 0800 h while the patient was supine and again at 1200 h after 4 h of upright posture. Diagnosis
The diagnosis of hypertension had been previously established by two or more diastolic blood pressures greater than 95 mm Hg, or systolic blood pressures greater than 160 mm Hg (12). Low renin was defined as an upright PRA less than 0.42 ng/mL • s. The diagnosis of IHA was established by the following criteria: hypertension, spontaneous hypokalemia, low PRA, elevated ASR (>405 nmol/day), postural aldosterone increment 25% above the supine level, plasma 18-hydroxycorticosterone level below 2774 pmol/L at 0800 h, nonlateralizing selective adrenal venous aldosterone sampling, symmetrical adrenal morphology on abdominal computed tomography or magnetic resonance imaging, bilateral radioiodinated cholesterol uptake by adrenal scintigraphy. Analytical methods Plasma urinary electrolytes and PRA were measured by usual techniques. Plasma aldosterone was derivitized to the 7-lactone and measured using a 7-lactone aldosterone antisera (13). Tetrahydroaldosterone-3-glucosiduronate (THA-3-G) was measured directly without prior hydrolysis using antisera to the steroidal conjugate provided by Dr. Mattox (14). The ASR was measured by quantitating the specific activity of [3H]THA3-G after injection of [3H]aldosterone (15). The inter-a and intraassay variations of both of these RIAs is less than 10%. Statistical analysis was performed on data obtained on days 1-5. The fractional THA excretion of aldosterone was defined as the THA-3-GA excretion divided by the simultaneous ASR. The postural plasma aldosterone/PRA ratio is defined as the difference in the upright and supine daily values. The data were analyzed by a two-way analysis of variance, and if significant, a Scheffe multiple comparison procedure was used to detect differences between groups or between days of the study (16). Significance is reported as a rejection of the null hypothesis at P < 0.05. TABLE 1. Study population characteristics No
Age
Wt
Groups Women Total yr Normals NRH LRH IHA
10 4 4 3
18 9 8 5
SD Kg SD
30 11 71 10 47 9 77 14 57 11 84 11 49 11 88 18
Mean blood pressure (mm Hg) Supine
SD
Upright
SD
79 114 103 113
7 14 15 13
79 110 112 116
7 16 21 11
1455
Results The metabolic balance data are depicted in Fig. 1 below. Over the 5 days a small but significant weight loss occurred, which was greater in LRH [4.0 ± 1.7 lb (± SD)] than in NRH (2.2 ± 2.7) and normals (2.0 ± 2.3), but was not different from that in IHA (3.0 ± 0.6). No changes in urinary sodium, potassium, chloride, or plasma sodium occurred in the four study groups, but an elevated urinary sodium was seen on day 1 compared to days 2-5 in LRH and IHA. Plasma potassium was lower, despite oral supplementation, in IHA (range of mean daily levels, 3.6-3.3 meq/L) Supine plasma aldosterone was elevated in IHA on days 1-3 compared to levels in the other groups. Upright aldosterone, however, was not different. Supine and upright PRA values were lower in both LRH and IHA than in NRH and normals (see Fig. 2). The postural increment (upright minus supine; A) in plasma aldosterone was not significantly different between the groups, whereas the A PRA was decreased and the ratio of the A plasma aldosterone to A PRA was increased in both LRH and IHA (see Table 2). The postural increment of PRA significantly correlated with that of aldosterone in all four groups (see Fig. 3). The slope of the regression line was nearly eaqual for normals and NRH, it was greater for LRH, and IHA had the steepest slope (P < 0.05). THA excretion was elevated in both LRH and IHA, but the aldosterone secretion rate was normal in LRH. Fractional THA excretion (THA/ASR on day 5) was increased in LRH compared to that in the other three groups (see Table 3). Discussion The results of this study demonstrate alterations of aldosterone secretion and metabolism in a group of LRH. In LRH plasma aldosterone levels were high relative to PRA, and fractional THA excretion was increased. These observations confirm and extend previous reports of aldosterone abnormalities in LRH. It has been previously observed that plasma aldosterone levels are inappropriately normal in essential hypertensives with low PRA (4,8). The relatively high aldosterone levels are probably due to enhanced adrenal glomerulosa sensitivity to angiotensin-II (6, 7). Since upright posture is a good stimulus for angiotensin-II, the increased postural (uprightsupine) aldosterone to PRA ratio reflects this enhanced adrenal glomerulosa sensitivity. LRH aldosterone responses, however, are in contradistinction to those in normal subjects, who have suppressed responses and low levels of aldosterone after renin suppression with dietary sodium intake or exogenous mineralocorticoids (5, 17). Enhanced adrenal glomerulosa responsiveness is also
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 November 2015. at 23:13 For personal use only. No other uses without permission. . All rights reserved.
1456
GRIFFING, WILSON, AND MELBY
JCE & M • 1990 Vol 71 • No 6
FIG. 1. The urinary electrolyte and body weight loss in the four study groups over 5 days. Urinary sodium was not different between groups, but it was significantly elevated on day 1 for IHA and LRH compared to days 2-5. Body weight loss was elevated for LRH but did not differ between days 1-5. Values are the mean ±SD. *, P
Vol. 71, No. 6 Printed in U.S.A.
Alterations in Aldosterone Secretion and Metabolism in Low Renin Hypertension* G. T. GRIFFING, T. E. WILSON, AND J. C. MELBY Evans Memorial Department of Clinical Research and the Department of Medicine, University Hospital, Boston University Medical Center, Boston, Massachusetts 02118
ABSTRACT. Low renin essential hypertensives (LRH) have normal plasma aldosterone levels which are inappropriately high
4 h of upright posture was not different in the four groups. The ratio of A plasma aldosterone/A PRA, however, was elevated in
in relation to their PRA. Posture is the major determinant for
both IHA and LRH compared to that in NRH and normals.
plasma aldosterone and PRA levels, but it is not known whether postural increments (A) of plasma aldosterone and (A) PRA are also abnormal in LRH. To evaluate this, LRH (n = 8), normal renin hypertensives (NRH; n = 9), normotensive controls (n = 18), and subjects with idiopathic hyperaldosteronism (IHA; n = 5) were studied in a metabolic unit on a controlled diet over 7 days. Overnight supine and 4-h upright PRA, plasma aldosterone, and 24-h urinary tetrahydroaldosterone (THA) and aldosterone secretion rates (ASR) were measured. The A in plasma aldosterone after
THA excretion was also elevated in IHA and LRH, but LRH had a normal ASR. This resulted in a higher fractional THA excretion (THA/ASR) in LRH compared to the other three groups. These data further support enhanced adrenal angiotensin-II sensitivity in LRH. Aldosterone was preferentially metabolized to THA in LRH. Since THA has reduced biological activity, this may be a compensatory mechanism to reduce mineralocorticoid activity in LRH. (J Clin Endocrinol Metab 71:1454-1460,1990)
L
OW PLASMA renin levels occur relatively frequently in essential hypertension (LRH) (1,2). The significance and mechanism for the low renin levels found in hypertension are controversial. It has been argued that low renin levels are not abnormal, but a statistical artifact produced by a skewed distribution of plasma renin in the hypertensive population (3). This does not account for the fact that aldosterone levels in this population are relatively high compared to aldosterone levels in normotensives with comparably low renin levels (4, 5). The inappropriately high aldosterone levels in low renin hypertensives (LRH) are believed to reflect enhanced zona glomerulosa angiotensin-II sensitivity (6, 7). In other low renin normotensive states or in LRH from exogenous mineralocorticoids, aldosterone levels are low, and zona glomerulosa angiotensin-II sensitivity is depressed (5, 8). The cause of this increased aldosterone responsiveness in LRH is unknown, and a number of questions regarding the control of the renin-angiotensin-aldosterone axis and the metabolism of aldosterone Received February 1, 1990. Address requests for reprints to: Dr. George T. Griffing, Boston University Medical School, Section of Endocrinology and Metabolism, University Hospital, 75 East Newton Street, Boston, Massachusetts 02118-2393. * This work was supported by Grants-In-Aid 1-R01-HL-31051, 5-P50-HL-18318, DDK-32455, M01-RR-00533-21, and HL-40123-01A1.
need to be answered. The primary determinants of the activity of the reninangiotensin-aldosterone axis are dietary sodium intake and posture (9, 10). The purpose of this study was to assess the effect of upright posture on PRA and plasma aldosterone levels and to measure the fractional excretion of the principal aldosterone metabolite, tetrahydroaldosterone (THA), in LRH. The findings of this study provide additional documentation of the increased angiotensin-II sensitivity in LRH and also provide evidence that the metabolism of aldosterone is altered to favor excretion of THA.
Subjects and Methods Subjects Four groups of subjects were studied (1) normals, normal reninemic hypertensives (NRH), LRH, and idiopathic hyperaldosteronism (IHA; see Table 1). Protocol
All subjects were admitted to the Clinical Research Center for a 5-day protocol after they had given informed consent and the study was approved by the institutional review board. Medications influencing the renin-aldosterone or pituitaryadrenal system, including, diuretics, adrenergic blockers, vasodilators, and estrogens, were discontinued for at least 4-6 weeks preceding admission. Where required, prazosin (1-10 mg/day)
1454
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 November 2015. at 23:13 For personal use only. No other uses without permission. . All rights reserved.
ALDO IN HYPERTENSION was the primary antihypertensive therapy (11). A fixed isocaloric diet containing 128 meq sodium and 80 meq potassium/ day was given. Daily 24-h urine samples were collected for measurement of electrolytes and creatinine. Urinary THA and aldosterone secretion rates (ASR) were measured on day 5. After 8 h of recumbancy plasma was collected at 0800 h while the patient was supine and again at 1200 h after 4 h of upright posture. Diagnosis
The diagnosis of hypertension had been previously established by two or more diastolic blood pressures greater than 95 mm Hg, or systolic blood pressures greater than 160 mm Hg (12). Low renin was defined as an upright PRA less than 0.42 ng/mL • s. The diagnosis of IHA was established by the following criteria: hypertension, spontaneous hypokalemia, low PRA, elevated ASR (>405 nmol/day), postural aldosterone increment 25% above the supine level, plasma 18-hydroxycorticosterone level below 2774 pmol/L at 0800 h, nonlateralizing selective adrenal venous aldosterone sampling, symmetrical adrenal morphology on abdominal computed tomography or magnetic resonance imaging, bilateral radioiodinated cholesterol uptake by adrenal scintigraphy. Analytical methods Plasma urinary electrolytes and PRA were measured by usual techniques. Plasma aldosterone was derivitized to the 7-lactone and measured using a 7-lactone aldosterone antisera (13). Tetrahydroaldosterone-3-glucosiduronate (THA-3-G) was measured directly without prior hydrolysis using antisera to the steroidal conjugate provided by Dr. Mattox (14). The ASR was measured by quantitating the specific activity of [3H]THA3-G after injection of [3H]aldosterone (15). The inter-a and intraassay variations of both of these RIAs is less than 10%. Statistical analysis was performed on data obtained on days 1-5. The fractional THA excretion of aldosterone was defined as the THA-3-GA excretion divided by the simultaneous ASR. The postural plasma aldosterone/PRA ratio is defined as the difference in the upright and supine daily values. The data were analyzed by a two-way analysis of variance, and if significant, a Scheffe multiple comparison procedure was used to detect differences between groups or between days of the study (16). Significance is reported as a rejection of the null hypothesis at P < 0.05. TABLE 1. Study population characteristics No
Age
Wt
Groups Women Total yr Normals NRH LRH IHA
10 4 4 3
18 9 8 5
SD Kg SD
30 11 71 10 47 9 77 14 57 11 84 11 49 11 88 18
Mean blood pressure (mm Hg) Supine
SD
Upright
SD
79 114 103 113
7 14 15 13
79 110 112 116
7 16 21 11
1455
Results The metabolic balance data are depicted in Fig. 1 below. Over the 5 days a small but significant weight loss occurred, which was greater in LRH [4.0 ± 1.7 lb (± SD)] than in NRH (2.2 ± 2.7) and normals (2.0 ± 2.3), but was not different from that in IHA (3.0 ± 0.6). No changes in urinary sodium, potassium, chloride, or plasma sodium occurred in the four study groups, but an elevated urinary sodium was seen on day 1 compared to days 2-5 in LRH and IHA. Plasma potassium was lower, despite oral supplementation, in IHA (range of mean daily levels, 3.6-3.3 meq/L) Supine plasma aldosterone was elevated in IHA on days 1-3 compared to levels in the other groups. Upright aldosterone, however, was not different. Supine and upright PRA values were lower in both LRH and IHA than in NRH and normals (see Fig. 2). The postural increment (upright minus supine; A) in plasma aldosterone was not significantly different between the groups, whereas the A PRA was decreased and the ratio of the A plasma aldosterone to A PRA was increased in both LRH and IHA (see Table 2). The postural increment of PRA significantly correlated with that of aldosterone in all four groups (see Fig. 3). The slope of the regression line was nearly eaqual for normals and NRH, it was greater for LRH, and IHA had the steepest slope (P < 0.05). THA excretion was elevated in both LRH and IHA, but the aldosterone secretion rate was normal in LRH. Fractional THA excretion (THA/ASR on day 5) was increased in LRH compared to that in the other three groups (see Table 3). Discussion The results of this study demonstrate alterations of aldosterone secretion and metabolism in a group of LRH. In LRH plasma aldosterone levels were high relative to PRA, and fractional THA excretion was increased. These observations confirm and extend previous reports of aldosterone abnormalities in LRH. It has been previously observed that plasma aldosterone levels are inappropriately normal in essential hypertensives with low PRA (4,8). The relatively high aldosterone levels are probably due to enhanced adrenal glomerulosa sensitivity to angiotensin-II (6, 7). Since upright posture is a good stimulus for angiotensin-II, the increased postural (uprightsupine) aldosterone to PRA ratio reflects this enhanced adrenal glomerulosa sensitivity. LRH aldosterone responses, however, are in contradistinction to those in normal subjects, who have suppressed responses and low levels of aldosterone after renin suppression with dietary sodium intake or exogenous mineralocorticoids (5, 17). Enhanced adrenal glomerulosa responsiveness is also
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 November 2015. at 23:13 For personal use only. No other uses without permission. . All rights reserved.
1456
GRIFFING, WILSON, AND MELBY
JCE & M • 1990 Vol 71 • No 6
FIG. 1. The urinary electrolyte and body weight loss in the four study groups over 5 days. Urinary sodium was not different between groups, but it was significantly elevated on day 1 for IHA and LRH compared to days 2-5. Body weight loss was elevated for LRH but did not differ between days 1-5. Values are the mean ±SD. *, P
