0021-972X/78/4702-0401$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1978 by The Endocrine Society

Vol. 47, No. 2 Printed in U.S.A.

Role of Angiotensin II in the Aldosterone Secretory Response to Adrenocorticotropin in Sodium-Restricted Normal Human Subjects* ALAN N. ELIAS, GUNNAR H. ANDERSON, JR., AND DAVID H. P. STREETEN Department of Medicine, Section of Endocrinology, SUNY Upstate Medical Center, Syracuse, New York 13210 ABSTRACT. A study was performed to determine the possible role of angiotensin II (All) in mediating the increased adrenal aldosterone response to infused a1'24ACTH, induced by sodium deprivation. Nine normal subjects, aged 18-31 yr, received 8-h infusions of 1) a'24-ACTH (0.5 U given over 8 h) while on a diet with unrestricted sodium content; 2) saralasin at 0.5 jug/kg/min or ACTH alone (0.5 U over 8 h) on the 7th day of a 10 meq sodium diet; and 3) ACTH and saralasin together on the 8th day while still on sodium restriction. All was administered for the last 2 h of infusion 3. Plasma cortisol and aldosterone concentrations were measured at hourly intervals during the infusions and plasma renin activity was measured at 2 hourly intervals.

R

EGULATION of aldosterone production seems to be effected mainly via the renin-angiotensin system (1, 2). However, independently of this system, elevation of the serum potassium concentration stimulates aldosterone secretion while hypokalemia reduces it (3). The role of ACTH in controlling aldosterone synthesis has been generally considered to be of lesser importance (4). However, in anephric individuals in whom the renin-angiotensin system is essentially inoperative, both ACTH and potassium assume importance as stimuli for the production of aldosterone (5, 6). When sodium intake is restricted, adrenal responsiveness to ACTH, as measured by aldosterone output, is greatly Received July 28, 1977. Address requests for reprints to: Dr. David H. P. Streeten, State University Hospital of the Upstate Medical Center, College of Medicine, Department of Medicine, 750 East Adams Street, Syracuse, New York 13210. * This work was supported by a Graduate Training Grant in Endocrinology (AM-07146) from the NIAMDD, a Clinical Research Center Grant (RR-00229) from the Division of Research Facilities and Resources, USPHS, and a Research Grant from Eaton Laboratories, Norwich, NY.

ACTH infusion produced an increase in the plasma aldosterone concentration which was significantly greater during sodium restriction than when sodium intake was unlimited. This increase was not associated with an ACTH-induced rise in the plasma renin activity and was not significantly altered when ACTH was administered with saralasin. The rise in plasma cortisol concentration induced by ACTH was not significantly different when the normal subjects were on liberal and restricted sodium intakes. It is concluded that All plays little if any acute role in increasing the stimulatory action of ACTH on aldosterone secretion during sodium restriction. (J Clin Endocrinol Metab 47: 401, 1978)

enhanced (7-12). The purpose of this study is to determine whether the enhancement of ACTH-induced aldosterone secretion resulting from sodium deprivation is mediated by increased production of angiotensin II. Materials and Methods Nine normal subjects (males and females, aged 18-31) were studied on the Clinical Research Center of the Upstate Medical Center. Before admission to the study, all subjects had been on unrestricted diets. On day 1, after the subjects had been recumbent for 90 min, blood (20 ml) was drawn for plasma levels of renin activity, aldosterone, and cortisol concentrations. An iv infusion of a1'24ACTH (Cortrosyn) in 5% dextrose solution was then administered with a Harvard pump, in a total dose of 0.5 U (5 /xg) infused over 8 h, starting at 0800-0900 h. Blood (15 ml) was drawn for cortisol and aldosterone determinations at hourly intervals, and for measurements of plasma renin activity (PRA; 5 ml) at 2 hourly intervals. On days 2-8, the subjects were maintained on a constant, weighed, 10-meq sodium diet prepared by the Research Dietician. On the 7th day of sodium restriction, five of the subjects received an iv infusion of the angioten-

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sin II analogue, saralasin (l-sar-8-ala-angiotensin II) at 0.5 jug/kg/min over 8 h and the remaining four subjects and one additional individual received an iv infusion of ACTH only in a dose of 0.5 U over 8 h. On the 8th day, all of the subjects received combined infusions of ACTH (0.5 U) and saralasin (0.5 jiig/kg/min) over 8 h. Two hours before the end of this combined infusion, the subjects received angiotensin II (Hypertensin) at rates ranging from 5-15 ng/kg/min while blood pressure (BP) was monitored, initially at 2-min intervals and later at 5-min intervals with an Arteriosonde 1216 (Roche). Blood for measurement of PRA, cortisol, and aldosterone concentrations was obtained as on day 1 of the study. All baseline measurements were made after an initial 90-min period of recumbency. The subjects remained recumbent throughout the period of each infusion. PRA was measured by RIA of angiotensin I at pH 7.4, using the method of Goodfriend (13). Plasma aldosterone was measured by RIA, using the NIH sheep antibody, by the method of Underwood et al. (14). The antibody used has 0.01% crossreactivity with cortisol, 0.08% cross-reactivity with corticosterone, and 0.2% cross-reactivity with deoxycorticosterone. As aldosterone was separated from these and most other steroids by a preparatory paper chromatographic step with the Bush B5 system, it is unlikely that the aldosterone determinations could have been influenced measurably by cross-reactivity of the antibody with other steroids. Cortisol concentrations were measured by RIA using an antibody purchased from Radioassay Systems Laboratories, Carson, CA. The studies were approved in advance by the Institutional Review Board for the Protection of Human Subjects. All subjects who participated did so voluntarily after reading and signing an approved consent document.

Results While on the 10-meq Na diet, the subjects had the anticipated increase in mean control level of plasma aldosterone concentration (P < 0.001) and showed a highly significantly greater rise in mean plasma aldosterone at 2, 4, 6, and 8 h during the infusion of ACTH (P < 0.001), as is shown in Fig. 1. The figure also shows that when saralasin was infused together with ACTH on the 10-meq Na diet, plasma aldosterone concentrations were not significantly different from those seen during infusion of ACTH alone and were still highly significantly greater than when ACTH was

JCE&M Vol47

1978 No 2

ACTH ALONE 10 mEq No DIET

ACTH ALONE UNRESTRICTED No DIET

FIG. 1. Plasma aldosterone concentrations (mean ± SEM) before and during ACTH infusions in normal subjects on unrestricted and 10-meq Na diets. Note that plasma aldosterone concentration was significantly higher during the low than during the unrestricted sodium intake both before the ACTH infusion (P < 0.001) and in the mean of the observations made at 2,4,6, and 8 h during the ACTH infusion (P < 0.001). Addition of saralasin to the ACTH infusion had no effect on plasma aldosterone changes. Angiotensin II, administered for the last 2 h of the ACTH and saralasin infusion, caused no significant change in plasma aldosterone concentration.

infused on the unrestricted Na diet. The addition of angiotensin II for the last 2 h of the infusion of ACTH and saralasin produced no significant rise in plasma aldosterone concentration. Infusion of saralasin alone during intake of the 10-meq Na diet was associated with a downward drift in plasma aldosterone concentrations (mean ± SEM) from 33.4 ±5.1 ng/dl before the infusion to 30.0 ± 5.5 at 2 h, 29.0 ± 4.3 at 4 h, 27.8 ± 5.5 at 6 h, and 20.5 ± 3.3 ng/dl at 8 h after the start of the saralasin infusion. Plasma cortisol concentration was unaffected by the 10-meq Na diet and rose equally during ACTH infusion on the unrestricted diet and on the 10-meq Na diet (Fig. 2). When saralasin was infused together with the ACTH on the 10-meq Na diet, plasma cortisol rose to a mean concentration of 36.6 ± 5.0 /xg/dl at 2, 4, 6, and 8 h after starting the infusion, which was significantly greater than the mean level reached during ACTH infusion alone on the

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V

ALDOSTERONE RESPONSE TO ACTH

2 30-

UNRESTRICTED DIET

403

therefore, presumably in plasma angiotensin II concentrations) during ACTH infusion in the sodium-restricted state; and secondly, saralasin, a specific competitive antagonist of angiotensin II, had no effect on the ACTHinduced increase in plasma aldosterone levels during concomitant ACTH infusion while on the 10-meq Na diet. The failure of saralasin to block the enhanced ACTH response during Na deprivation did not result from 1) inade-

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T I M E (hours)

FIG. 2. Plasma cortisol concentrations (mean ± SEM) before and during iv infusion of ACTH and/or saralasin on the unrestricted and 10-meq Na diets. ACTH produced comparable rises in plasma cortisol concentration, except for a significant difference when infused on the unrestricted diet and the 10-meq Na diet together with saralasin (P < 0.05). Saralasin alone had no significant effect on plasma cortisol concentration.

10 mEq No DIET

p< 0.001

p-* 25SARALASIN enhanced ACTH-induced rise in plasma al^»v ALONE > / / dosterone concentration during sodium dep5 20/ / rivation, confirming previous reports that soz I / X z15I / dium restriction increased the effects of r / / T SARALASIN J+ ACTH on aldosterone excretion, aldosterone I 10- / / CO 1 / ^ ACTH secretion rate, and plasma aldosterone concentration (7-12). The data provide evidence of two types that the observed enhancement 0 2 4 6 8 of the aldosterone response did not result from TIME (hours) elevated angiotensin II levels or from an in- FIG. 4. PRA (mean ± SEM) during the infusion of saracreased sensitivity to angiotensin II. First, lasin with and without ACTH on the 10-meq Na diet, there was no significant increase in PRA (and, showing comparable changes during both infusions.

i 1

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quacy of dosage, as it was shown that, at the rate of its infusion in these studies, saralasin completely prevented both the BP response to angiotensin II (15-17) and an aldosterone response which otherwise invariably occurs (18-21) during angiotensin II administration, even in Na-depleted human subjects (21); or 2) an associated agonistic response to saralasin (i.e. an angiotensin II-like rise in plasma aldosterone), because in fact saralasin produced no rise in plasma aldosterone concentration when infused alone under essentially identical conditions of sodium deprivation in these experiments. It is concluded, therefore, that the augmented aldosterone responsiveness of the adrenals during sodium deprivation is not directly dependent on the increased concentration or effectiveness of circulating angiotensin II. The possibility has not been excluded that the elevation of plasma angiotensin levels, which presumably started at the onset and increased with the continuation of sodium deprivation, might have had some relatively chronic action on the glomerulosal cells. Such an effect might not have been acutely reversible by saralasin and might have potentiated the effect of ACTH on aldosterone release during sodium restriction. The enhancement of adrenal response to ACTH during restriction of sodium intake seems to affect mainly the zona glomerulosa. Thus, plasma cortisol concentration rose equally during ACTH infusion at both levels of sodium intake. Whereas the infusion of saralasin alone did not affect the plasma cortisol concentration, it was found that plasma cortisol concentration rose further during the combined infusion of ACTH and saralasin on the low sodium diet than during ACTH infusion alone on the unrestricted sodium intake. The mechanism of this somewhat surprising result is unknown.

JCE&M Vol47

1978 No 2

2. DAVIS, J. O., C. R. AYERS, AND C. C. J. CARPENTER, Renal

origin of aldosterone-stimulating hormone in dogs with thoracic cava constriction and in sodium-depleted dogs, J Clin Invest 40: 1466, 1961. 3. DAVIS, J. 0., J. URQUHART, AND J. T. HIGGINS, The effects of

alterations of plasma sodium and potassium concentration on aldosterone secretion, J Clin Invest 42: 597, 1963. 4. MULROW, P. J., AND W. F. GANONG, The effect of hemorrhage

upon aldosterone secretion in normal and hypophysectomized dogs, J Clin Invest 40: 579, 1961. 5. BERMAN, L. B., V. VERTES, S. MITRA, AND A. B. GOULD,

Renin angiotensin system in anephric patients, N EnglJMed 286: 58, 1972. 6. MITRA, S., S. M. GENUTH, L. B. BERMAN, AND V. VERTES,

Aldosterone secretion in anephric patients, N Engl J Med 286: 61, 1972. 7. LIDDLE, G. W., L. E. DUNCAN, AND F. C. BARTTER, Dual

mechanism regulating adrenocortical function in man, Am J Med 21: 380, 1956. 8. CRABBE, J., W. J. REDDY, E. J. Ross, AND G. W. THORN, The

stimulation of aldosterone secretion by adrenocorticotropic hormone (ACTH), J Clin Endocrinol Metab 19: 1185, 1959. 9. Tucci, J. P., E. A. ESPINER, P. I. JAGGER, G. L. PAUK, AND D.

P. LAULER, ACTH stimulation of aldosterone secretion in normal subjects and in patients with chronic adrenocortical insufficiency, J Clin Endocrinol Metab 27: 568,1967. 10. RAYFIELD, E. J., L. I. ROSE, R. G. DLUHY, AND G. H. WIL-

LIAMS, Aldosterone secretory and glucocorticoid excretory responses to alpha 1-24 ACTH (Cortrosyn) in sodium depleted normal man, J Clin Endocrinol Metab 36: 30, 1973. 11. MCCAA, R. E., V. H. READ, A. W. COWLEY, JR., J. D. BOWER,

A. V. SMITH, AND C. S. MCCAA, Influence of acute stimuli on plasma aldosterone concentration in anephric man and kidney allograft recipients, Circ Res 33: 313, 1973. 12. KEM, D. C, C. GOMEZ-SANCHEZ, N. J. KRAMER, O. B. HOL-

LAND, AND J. R. HIGGINS, Plasma aldosterone and renin activity response to ACTH infusion in dexamethasone-suppressed normal and sodium-depleted man, J Clin Endocrinol Metab 40: 116, 1975. 13. GOODFRIEND, T. L., Radioimmunoassay of angiotensins and renin activity, In Berson, S. A., and R. S. Yalow (eds.), Methods in Investigative and Diagnostic Endocrinology, vol. 2B, Amsterdam, North Holland Publishing Co., 1973, p. 1158. 14. UNDERWOOD, R. H., AND G. H. WILLIAMS, The simultaneous

measurement of aldosterone, cortisol and corticosterone in human peripheral plasma by displacement analysis, J Lab Clin Med 79: 848, 1972. 15. STREETEN, D. H. P., G. H. ANDERSON, JR., J. M. FREIBERG,

AND T. G. DALAKOS, Use of an angiotensin II antagonist (saralasin) in the recognition of angiotensinogenic hypertension, N EnglJMed 292: 657, 1975. 16. STREETEN, D. H. P., G. H. ANDERSON, JR., AND T. G. DALA-

KOS, Angiotensin blockade: its clinical significance, Am J Med 60: 817, 1976. 17. STREETEN, D. H. P., J. M. FREIBERG, G. H. ANDERSON, JR.,

AND T. G. DALAKOS, Identification of angiotensinogenic hypertension in man using l-sar-8-ala angiotensin II (saralasin P-113), CirRes (Suppl) 36: 125, 1975. 18. OELKERS, W., J. J. BROWN, R. FRASER, A. F. LEVER, J. J.

MORTON, AND J. I. S. ROBERTSON, Sensitization of the adrenal

cortex to angiotensin II in sodium-depleted man, Circ Res 34: 69, 1974. 19. MEYER, P., Summary of current studies on angiotensin-induced aldosterone release, Cir Res (Suppl 2) 38: 127, 1976. 20. BOYD, G. W., A. R. ADAMSON, M. ARNOLD, V. H. T. JAMES,

References

AND W. S. PEART, The role of angiotensin II in the control of aldosterone in man, Clin Sci 42: 91, 1972.

1. LARAGH, J. H., M. ANGERS, W. G. KELLY, AND S. LIEBERMAN,

21. HOLLENBERG, N. K., W. R. CHENITZ, D. F. ADAMS, AND G. H.

Hypotensive agents and pressor substances. The effect of epinephrine, norepinephrine, angiotensin II and others on the secretory rate of aldosterone in man, JAMA 174: 234, 1960.

WILLIAMS, Reciprocal influence of salt intake on adrenal glomerulosa and renal vascular responses to angiotensin II in normal man, J Clin Invest 54: 34, 1974.

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Role of angiotensin II in the aldosterone secretory response to adrenocorticotropin in sodium-restricted normal human subjects.

0021-972X/78/4702-0401$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1978 by The Endocrine Society Vol. 47, No. 2 Printed in U...
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