0021-972X/78/4704-0829$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1978 by The Endocrine Society
Vol. 47, No. 4 Printed in U.S.A.
Diurnal 18-Hydroxy-ll-Deoxycorticosterone Pattern in Human Stable Hypertension* FRANCESCO SPARANO, FRANCESCO SCIARRA, JOSEF SULON, GIOVANNI GIAQUINTO, MARIA A. MERCURI, ALESSANDRA ODOARDI, CARLO TOSTICROCE, PIERRE GENARD, AND CARLO CONTI Istituto di Patologia Speciale Medica II, dell'Universita' di Roma, Italia; and Departement de Clinique et de Pathologie Medicates, Universite' de Liege, Belgium ABSTRACT. Diurnal 18 - hydroxy -11 - deoxycorticosterone (18-0H-D0C) pattern was studied with RIA technique in 33 hypertensive patients in supine position and on normal sodium diet. The compound was evaluated every 2 h from 0800-2000 h. Simultaneously, plasma aldosterone and cortisol were measured. Abnormal 18-OH-DOC behavior was observed in only 2 out of 4 patients with Cushing's disease, while sporadic and slight elevations, synchronous with F, were seen in 5 out of 24 stable essential hypertensive patients [1 with nor-
A
STEROID product of the zona fasciculata of the adrenal gland, 18-hydroxy11-deoxycorticosterone (18-OH-DOC), has been implicated by some authors in essential hypertension (EH). Melby et al. (1) demonstrated an increased secretion of urinary tetrahydro-18-OH-DOC in some EH patients with low plasma renin activity (PRA), and Genest et al. (2) found an increased secretion rate of 18-OH-DOC in about 65% of patients • affected by labile and stable EH with low or normal PRA. More recently, Williams et al. (3), evaluating the plasma levels of 18-OH-DOC with an RIA technique, demonstrated high concentrations of the steroid in some cases of EH with •low or normal PRA. Ulick (4), on the contrary, found normal production of 18-OH-DOC in EH with low PRA. On the basis of these controversial results and the earlier finding of a circadian rhythm >of the steroid (5, 6) with a marked pulsatile Received February 6, 1978. Address requests for reprints to: Dr. Francesco Sparano, Istituto di Patologia Speciale Medica II, Universita di Roma, Policlinico Umberto I, Roma, Italy. * This work was supported in part by a grant from the Consiglio Nazionale delle Ricerche, Roma, Italia.
mal plasma renin activity (PRA), 1 with low PRA, and 3 with high PRA]. 18-OH-DOC was normal in 2 cases of hypertension due to renal artery stenosis, in 1 patient with nephrosclerosis, and in 1 patient with horseshoe kidney. From these results, 18-OH-DOC does not seem to play an important pathogenetic role in stable essential hypertension, considering also the low mineralocorticoid activity of the compound. (J Clin Endocrinol 29, 1978)
activity in normal subjects (7), studies were performed on the behavior of 18-OH-DOC in various types of hypertensive patients while in the supine position and on a normal sodium diet. The compound was evaluated every 2 h from 0800-2000 h. Simultaneously, plasma aldosterone (PA) and cortisol (F) were measured to establish a possible correlation with 18-OH-DOC. Materials and Methods Studies were carried out on 1) 11 normal volunteers (5 females and 6 males, aged 20-37 yr); 2) 24 EH patients (12 males and 12 females, aged 25-43 yr); 3) 3 patients (2 males and 1 female, aged 18-27 yr) with hypertension due to renal artery stenosis, 1 female (32 yr) with nephrosclerosis and 1 male (22 yr) with horseshoe kidney; 4) 4 patients (3 males and 1 female, aged 20-43 yr) with Cushing's disease (2 with bilateral hyperplasia, 1 with a right adenoma and 1 with a left adrenal carcinoma) presenting a diastolic blood pressure of more than 95 mm Hg. In the remaining 29 hypertensive patients, stable diastolic blood pressure of more than 100 mm Hg had been present for at least 3 yr. Diagnosis was based upon physical examination, urinalysis, renal function tests, serum electrolyte balance, urinary catecholamine excretion, pyelography, renography, renal scintigraphy, and renal and adrenal arteriography.
829
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 November 2015. at 21:02 For personal use only. No other uses without permission. . All rights reserved.
830
JCE & M • 1978 Vol47 • No 4
SPARANO ET AL.
After overnight recumbency, plasma samples were collected in the supine position at 2-h intervals from 0800-2000 h. A normal sodium diet [120 milliequivalents (meq) Na+ and 70 meq K + ] was given for the 10 days before the investigation. The method described by Sulon and Sparano (8) was used to measure plasma 18-OH-DOC. Briefly, 1 ml plasma is extracted with 6 ml dichloromethane, 2 ml of which are dried in glass tubes in duplicate. Incubation medium is prepared by adding 0.1 ml tracer solution (3000 cpm [1,2-3H]18-OHDOC, 45 Ci/mmol SA; Radiochemical Centre, Amersham), 0.1 ml antibody solution [18-OH-DOC3-carboxymethoxime-bovine serum albumin (BSA) in lyophilized form, with a titre of 1/4000 at 50% binding], and phosphate buffer. Overall volume is 0.5 ml. Tubes are kept at 37 C for 1 h, incubated at 4 C overnight, and placed in an icewater bath, then 0.5 ml dextran-coated charcoal suspension is added. After brief stirring and a 10-min wait, the tubes are centrifuged at 2000 X g for 10 min. The supernatant is transferred to a counting vial and 10 ml Instagel are added. A standard curve from 0-800 pg 18-OH-DOC (Searle, Mexico) is simultaneously prepared. To assess the accuracy and precision of the method, known amounts of 18-OH-DOC were added to steroid-free plasma. The relationship between the amount of 18-OH-DOC evaluated vs. added shows a coefficient of correlation of 0.99 (P < 0.0001). Multiple measurements of 18-OH-DOC in a pool of plasma (10 samples with normal and high 18-OH-DOC concentrations) present mean values of 8.2 ± 0.9 and 30.7 ± 1.2 (SD) ng/100 ml, respectively. The specificity of the antibody obtained evaluated by interference of competitive steroids is very high. In particular, F shows a cross-reaction of 100 ml), and PRA (nanograms per ml/h) determined thus demonstrating the high sensitivity of the every 2 h from 0800-2000 h in three hypertensive patients with renal artery stenosis, in one patient with nephroscle- adrenal cortex to secrete 18-OH-DOC in rerosis, and in one patient with horseshoe kidney. Shaded areas represent normal range.
episodes synchronous with those of F (7). The highest values were recorded during the early morning hours; however, sharp elevations of short duration can be seen during the 24-h study. The study of plasma 18-OH-DOC in various pathological conditions, thus, cannot be limited to a single sample, but as for F, should be evaluated in various samples collected throughout the day. The results obtained in patients with primary and secondary arterial hypertension showed that 18-OH-DOC was significantly elevated only in two patients with Cushing's disease, who also presented modifications in the circadian rhythm. This finding is in agreement with the results of Melby et al. (13), suggesting the contribution of the compound together with deoxycorticosterone in maintaining high blood pressure. In the other forms of stable arterial hyper-
30
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30 20 10
.
8.rr
10.m
11
Hr ^F ^ff "Tfr Spin
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l»m
I,*,
FIG. 5. Plasma levels of F (micrograms per 100 ml), 18OH-DOC (nanograms per 100 ml), and PA (nanograms per 100 ml) determined every 2 h from 0800-2000 h in four patients affected by Cushing's disease. Shaded areas represent normal range.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 November 2015. at 21:02 For personal use only. No other uses without permission. . All rights reserved.
18-OH-DOC IN HYPERTENSION sponse to various exogenous stimuli. In our stable EH patients, 18-OH-DOC does not seem, therefore, to play a primary pathogenetical role, especially taking into consideration the low mineralocorticoid activity of the v compound (15). Nevertheless, it cannot be excluded, in agreement with Fraser et al. (16), that an intermittent rise in 18-OH-DOC and/or other minor mineralocorticoids over a long time period in response to stress may induce in some A cases labile hypertension, which eventually becomes self-sustaining.
833
levels in normal subjects, J Clin Endocrinol Metab 45: 893, 1977. 7. SULON, J., F. SPARANO, F. SCIARRA, G. GIAQUINTO, AND P.
GENARD, 24 Hours pattern of 18-hydroxy-ll-deoxycorticosterone in normal supine man. Relationship with cortisol and aldosterone, Clin Endocrinol 8: 367,1978. 8. SULON, J., AND F. SPARANO, A non chromatographic radioim-
munoassay of 18-hydroxy-ll-deoxycorticosterone in human plasma, J Steroid Biochem 9: 253,1978. 9. MURPHY, B. E. P., Some studies on the protein binding of steroids and their application to the routine micro and ultramicro measurements of various steroids in body fluids by competitive protein binding radioassay, J Clin Endocrinol Metab 27: 973, 1967. 10. MALVANO, R., C. GANDOLFI, D. GIANNESSI, P. GIANNOTTI,
AND P. GRASSO, Radioimmunoassay of aldosterone and of plasma extracts, J Nucl Biol Med 20: 37,1976. 11. SPARANO, F., C. TOSTI-CROCE, AND F. SCIARRA, The use of
radioimmunoassay for aldosterone determination in plasma, Folia Endocrinol 5: 423, 1974. 12. HABER, F., T. KOERNER, L. B. PAGE, B. KLIMAN, AND A.
References 1. MELBY, J. C, S. L. DALE, AND T. E. WILSON, 18-Hydroxyy
deoxycorticosterone in human hypertension, Cir Res (Suppl 2) 28, 29: 143, 1971. 2. GENEST, J., W. NOWACZYNSKI, 0. KUCHEL, AND C. SASAKI,
Plasma progesterone levels and 18-hydroxy-deoxycorticosterone secretion rate in benign essential hypertension in human. Genest, J., and E. Koiw (eds.), Hypertension 72, Berlin, Heidelberg, New York, Springer Verlag, 1972, p. 293. 3. WILLIAMS, G. H., L. M. BRALEY, AND R. H. UNDERWOOD,
The regulation of plasma 18-hydroxy-ll-deoxy-corticosterone in man, J Clin Invest 58: 221, 1976. _ 4. ULICK, S., Andrenocortical factors in hypertension. I. Significance of 18-hydroxy-ll-deoxy-corticosterone, Am J Cardiol 38: 814, 1976. 5. DALE, S. L., P. KOMANICKY, J. H. PRATT, AND J. C. MELBY,
Radioimmunoassay of 18-hydroxy-ll-deoxycorticosterone in plasma, J Clin Endocrinol Metab 43: 803, 1976. 6. TUCK, M. L., D. W. CHANDLER, AND D. M. MAYES, The
influences of ACTH, dietary sodium, upright posture and angiotensin II on plasma 18-hydroxy-ll-deoxycorticosterone
PURNODE, Application of a radioimmunoassay for angiotensin I to the physiological measurement of plasma renin activity in normal human subjects, J Clin Endocrinol Metab 29:1349, 1969. 13. MELBY, J. C, S. L. DALE, R. J. GREKIN, R. GAUNT, AND T. E.
WILSON, 18-Hydroxy-ll-deoxycorticosterone (18-OH-DOC) Secretion in experimental and human hypertension, Recent Prog Horm Res 28: 287, 1972. 14. SPARANO, F., M. A. MERCURI, G. GIAQUINTO, A. ODOARDI, F. SCIARRA, AND C. CONTI, 18-Hydroxy-ll-deoxycorticosterone
response to insulin in normal man, J Steroid Biochem, in press. 15. GENEST, J., W. NOWACZYNSKI, O. KUCHEL, R. BOUCHER, J. M. ROJO-ORTEGA, G. CONSTANTOPOULOS, D. GANTEN, AND
F. MESSERLI, The adrenal cortex and essential hypertension, Recent Prog Horm Res 32: 377, 1976. 16. FRASER, R., J. J. BROWN, W. C. BROWN, J. B. FERRISS, A. KENNEDY, A. F. LEVER, P. A. MASON, J. J. MORTON, M. G. NICHOLLS, L. E. RAMSAY, J. J. S. ROBERTSON, M. A. 0.
SCHALEKAMP, AND A. WILSON, The adrenal cortex and hy-
pertension. Some observations on a possible role for mineralocorticoids other than aldosterone, J Steroid Biochem 7: 963, 1976.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 November 2015. at 21:02 For personal use only. No other uses without permission. . All rights reserved.
Vol. 47, No. 4 Printed in U.S.A.
Diurnal 18-Hydroxy-ll-Deoxycorticosterone Pattern in Human Stable Hypertension* FRANCESCO SPARANO, FRANCESCO SCIARRA, JOSEF SULON, GIOVANNI GIAQUINTO, MARIA A. MERCURI, ALESSANDRA ODOARDI, CARLO TOSTICROCE, PIERRE GENARD, AND CARLO CONTI Istituto di Patologia Speciale Medica II, dell'Universita' di Roma, Italia; and Departement de Clinique et de Pathologie Medicates, Universite' de Liege, Belgium ABSTRACT. Diurnal 18 - hydroxy -11 - deoxycorticosterone (18-0H-D0C) pattern was studied with RIA technique in 33 hypertensive patients in supine position and on normal sodium diet. The compound was evaluated every 2 h from 0800-2000 h. Simultaneously, plasma aldosterone and cortisol were measured. Abnormal 18-OH-DOC behavior was observed in only 2 out of 4 patients with Cushing's disease, while sporadic and slight elevations, synchronous with F, were seen in 5 out of 24 stable essential hypertensive patients [1 with nor-
A
STEROID product of the zona fasciculata of the adrenal gland, 18-hydroxy11-deoxycorticosterone (18-OH-DOC), has been implicated by some authors in essential hypertension (EH). Melby et al. (1) demonstrated an increased secretion of urinary tetrahydro-18-OH-DOC in some EH patients with low plasma renin activity (PRA), and Genest et al. (2) found an increased secretion rate of 18-OH-DOC in about 65% of patients • affected by labile and stable EH with low or normal PRA. More recently, Williams et al. (3), evaluating the plasma levels of 18-OH-DOC with an RIA technique, demonstrated high concentrations of the steroid in some cases of EH with •low or normal PRA. Ulick (4), on the contrary, found normal production of 18-OH-DOC in EH with low PRA. On the basis of these controversial results and the earlier finding of a circadian rhythm >of the steroid (5, 6) with a marked pulsatile Received February 6, 1978. Address requests for reprints to: Dr. Francesco Sparano, Istituto di Patologia Speciale Medica II, Universita di Roma, Policlinico Umberto I, Roma, Italy. * This work was supported in part by a grant from the Consiglio Nazionale delle Ricerche, Roma, Italia.
mal plasma renin activity (PRA), 1 with low PRA, and 3 with high PRA]. 18-OH-DOC was normal in 2 cases of hypertension due to renal artery stenosis, in 1 patient with nephrosclerosis, and in 1 patient with horseshoe kidney. From these results, 18-OH-DOC does not seem to play an important pathogenetic role in stable essential hypertension, considering also the low mineralocorticoid activity of the compound. (J Clin Endocrinol 29, 1978)
activity in normal subjects (7), studies were performed on the behavior of 18-OH-DOC in various types of hypertensive patients while in the supine position and on a normal sodium diet. The compound was evaluated every 2 h from 0800-2000 h. Simultaneously, plasma aldosterone (PA) and cortisol (F) were measured to establish a possible correlation with 18-OH-DOC. Materials and Methods Studies were carried out on 1) 11 normal volunteers (5 females and 6 males, aged 20-37 yr); 2) 24 EH patients (12 males and 12 females, aged 25-43 yr); 3) 3 patients (2 males and 1 female, aged 18-27 yr) with hypertension due to renal artery stenosis, 1 female (32 yr) with nephrosclerosis and 1 male (22 yr) with horseshoe kidney; 4) 4 patients (3 males and 1 female, aged 20-43 yr) with Cushing's disease (2 with bilateral hyperplasia, 1 with a right adenoma and 1 with a left adrenal carcinoma) presenting a diastolic blood pressure of more than 95 mm Hg. In the remaining 29 hypertensive patients, stable diastolic blood pressure of more than 100 mm Hg had been present for at least 3 yr. Diagnosis was based upon physical examination, urinalysis, renal function tests, serum electrolyte balance, urinary catecholamine excretion, pyelography, renography, renal scintigraphy, and renal and adrenal arteriography.
829
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 November 2015. at 21:02 For personal use only. No other uses without permission. . All rights reserved.
830
JCE & M • 1978 Vol47 • No 4
SPARANO ET AL.
After overnight recumbency, plasma samples were collected in the supine position at 2-h intervals from 0800-2000 h. A normal sodium diet [120 milliequivalents (meq) Na+ and 70 meq K + ] was given for the 10 days before the investigation. The method described by Sulon and Sparano (8) was used to measure plasma 18-OH-DOC. Briefly, 1 ml plasma is extracted with 6 ml dichloromethane, 2 ml of which are dried in glass tubes in duplicate. Incubation medium is prepared by adding 0.1 ml tracer solution (3000 cpm [1,2-3H]18-OHDOC, 45 Ci/mmol SA; Radiochemical Centre, Amersham), 0.1 ml antibody solution [18-OH-DOC3-carboxymethoxime-bovine serum albumin (BSA) in lyophilized form, with a titre of 1/4000 at 50% binding], and phosphate buffer. Overall volume is 0.5 ml. Tubes are kept at 37 C for 1 h, incubated at 4 C overnight, and placed in an icewater bath, then 0.5 ml dextran-coated charcoal suspension is added. After brief stirring and a 10-min wait, the tubes are centrifuged at 2000 X g for 10 min. The supernatant is transferred to a counting vial and 10 ml Instagel are added. A standard curve from 0-800 pg 18-OH-DOC (Searle, Mexico) is simultaneously prepared. To assess the accuracy and precision of the method, known amounts of 18-OH-DOC were added to steroid-free plasma. The relationship between the amount of 18-OH-DOC evaluated vs. added shows a coefficient of correlation of 0.99 (P < 0.0001). Multiple measurements of 18-OH-DOC in a pool of plasma (10 samples with normal and high 18-OH-DOC concentrations) present mean values of 8.2 ± 0.9 and 30.7 ± 1.2 (SD) ng/100 ml, respectively. The specificity of the antibody obtained evaluated by interference of competitive steroids is very high. In particular, F shows a cross-reaction of 100 ml), and PRA (nanograms per ml/h) determined thus demonstrating the high sensitivity of the every 2 h from 0800-2000 h in three hypertensive patients with renal artery stenosis, in one patient with nephroscle- adrenal cortex to secrete 18-OH-DOC in rerosis, and in one patient with horseshoe kidney. Shaded areas represent normal range.
episodes synchronous with those of F (7). The highest values were recorded during the early morning hours; however, sharp elevations of short duration can be seen during the 24-h study. The study of plasma 18-OH-DOC in various pathological conditions, thus, cannot be limited to a single sample, but as for F, should be evaluated in various samples collected throughout the day. The results obtained in patients with primary and secondary arterial hypertension showed that 18-OH-DOC was significantly elevated only in two patients with Cushing's disease, who also presented modifications in the circadian rhythm. This finding is in agreement with the results of Melby et al. (13), suggesting the contribution of the compound together with deoxycorticosterone in maintaining high blood pressure. In the other forms of stable arterial hyper-
30
eo
w Iff W IF
30 20 10
.
8.rr
10.m
11
Hr ^F ^ff "Tfr Spin
4»»
l»m
I,*,
FIG. 5. Plasma levels of F (micrograms per 100 ml), 18OH-DOC (nanograms per 100 ml), and PA (nanograms per 100 ml) determined every 2 h from 0800-2000 h in four patients affected by Cushing's disease. Shaded areas represent normal range.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 November 2015. at 21:02 For personal use only. No other uses without permission. . All rights reserved.
18-OH-DOC IN HYPERTENSION sponse to various exogenous stimuli. In our stable EH patients, 18-OH-DOC does not seem, therefore, to play a primary pathogenetical role, especially taking into consideration the low mineralocorticoid activity of the v compound (15). Nevertheless, it cannot be excluded, in agreement with Fraser et al. (16), that an intermittent rise in 18-OH-DOC and/or other minor mineralocorticoids over a long time period in response to stress may induce in some A cases labile hypertension, which eventually becomes self-sustaining.
833
levels in normal subjects, J Clin Endocrinol Metab 45: 893, 1977. 7. SULON, J., F. SPARANO, F. SCIARRA, G. GIAQUINTO, AND P.
GENARD, 24 Hours pattern of 18-hydroxy-ll-deoxycorticosterone in normal supine man. Relationship with cortisol and aldosterone, Clin Endocrinol 8: 367,1978. 8. SULON, J., AND F. SPARANO, A non chromatographic radioim-
munoassay of 18-hydroxy-ll-deoxycorticosterone in human plasma, J Steroid Biochem 9: 253,1978. 9. MURPHY, B. E. P., Some studies on the protein binding of steroids and their application to the routine micro and ultramicro measurements of various steroids in body fluids by competitive protein binding radioassay, J Clin Endocrinol Metab 27: 973, 1967. 10. MALVANO, R., C. GANDOLFI, D. GIANNESSI, P. GIANNOTTI,
AND P. GRASSO, Radioimmunoassay of aldosterone and of plasma extracts, J Nucl Biol Med 20: 37,1976. 11. SPARANO, F., C. TOSTI-CROCE, AND F. SCIARRA, The use of
radioimmunoassay for aldosterone determination in plasma, Folia Endocrinol 5: 423, 1974. 12. HABER, F., T. KOERNER, L. B. PAGE, B. KLIMAN, AND A.
References 1. MELBY, J. C, S. L. DALE, AND T. E. WILSON, 18-Hydroxyy
deoxycorticosterone in human hypertension, Cir Res (Suppl 2) 28, 29: 143, 1971. 2. GENEST, J., W. NOWACZYNSKI, 0. KUCHEL, AND C. SASAKI,
Plasma progesterone levels and 18-hydroxy-deoxycorticosterone secretion rate in benign essential hypertension in human. Genest, J., and E. Koiw (eds.), Hypertension 72, Berlin, Heidelberg, New York, Springer Verlag, 1972, p. 293. 3. WILLIAMS, G. H., L. M. BRALEY, AND R. H. UNDERWOOD,
The regulation of plasma 18-hydroxy-ll-deoxy-corticosterone in man, J Clin Invest 58: 221, 1976. _ 4. ULICK, S., Andrenocortical factors in hypertension. I. Significance of 18-hydroxy-ll-deoxy-corticosterone, Am J Cardiol 38: 814, 1976. 5. DALE, S. L., P. KOMANICKY, J. H. PRATT, AND J. C. MELBY,
Radioimmunoassay of 18-hydroxy-ll-deoxycorticosterone in plasma, J Clin Endocrinol Metab 43: 803, 1976. 6. TUCK, M. L., D. W. CHANDLER, AND D. M. MAYES, The
influences of ACTH, dietary sodium, upright posture and angiotensin II on plasma 18-hydroxy-ll-deoxycorticosterone
PURNODE, Application of a radioimmunoassay for angiotensin I to the physiological measurement of plasma renin activity in normal human subjects, J Clin Endocrinol Metab 29:1349, 1969. 13. MELBY, J. C, S. L. DALE, R. J. GREKIN, R. GAUNT, AND T. E.
WILSON, 18-Hydroxy-ll-deoxycorticosterone (18-OH-DOC) Secretion in experimental and human hypertension, Recent Prog Horm Res 28: 287, 1972. 14. SPARANO, F., M. A. MERCURI, G. GIAQUINTO, A. ODOARDI, F. SCIARRA, AND C. CONTI, 18-Hydroxy-ll-deoxycorticosterone
response to insulin in normal man, J Steroid Biochem, in press. 15. GENEST, J., W. NOWACZYNSKI, O. KUCHEL, R. BOUCHER, J. M. ROJO-ORTEGA, G. CONSTANTOPOULOS, D. GANTEN, AND
F. MESSERLI, The adrenal cortex and essential hypertension, Recent Prog Horm Res 32: 377, 1976. 16. FRASER, R., J. J. BROWN, W. C. BROWN, J. B. FERRISS, A. KENNEDY, A. F. LEVER, P. A. MASON, J. J. MORTON, M. G. NICHOLLS, L. E. RAMSAY, J. J. S. ROBERTSON, M. A. 0.
SCHALEKAMP, AND A. WILSON, The adrenal cortex and hy-
pertension. Some observations on a possible role for mineralocorticoids other than aldosterone, J Steroid Biochem 7: 963, 1976.
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