Plasma Immunoreactive Proopiolipomelanocortin- Derived Peptides in Patients with Primary Hyperaldosteronism, Idiopathic Hyperaldosteronism with Bilateral Adrenal Hyperplasia, and Dexamethasone-Suppressible Hyperaldosteronism*
HANS-GEORG GÜLLNER, WENDELL E. NICHOLSON, JOHN R. GILL, JR., AND DAVID N. ORTH
Hypertension-Endocrine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20205; and Department of Medicine, Vanderbilt University School of Medicine (W.E.N., D.N.O.), Nashville, Tennessee 37232
ABSTRACT. Immunoreactive plasma levels of the proopioli- pomelanocortin-derived peptides, ACTH, ß-endorphin-lipotro- pin, and yaMSH, were measured in patients with primary hy- peraldosteronism, idiopathic hyperaldosteronism with bilateral adrenal hyperplasia, and dexamethasone-suppressible hyperal- dosteronism. Plasma peptide concentrations in patient groups were not different from those in normal controls. Removal of aldosterone-producing adenomas in three patients and of an
aldosterone-producing adrenocortical carcinoma in one patient did not affect plasma peptide concentrations. Furthermore, in- fusion of the opiate antagonist naloxone (0.2 mg/min) in one patient with bilateral adrenal hyperplasia had no effect on either plasma aldosterone or cortisol. These results suggest that the proopiolipomelanocortin-derived peptides are not overproduced in states of hyperaldosteronism. (J Clin Endocrinol Metab 56: 853, 1983)
T HERE is considerable evidence that a pituitary factor(s) other than ACTH may be involved in the regulation of aldosterone secretion (1, 2). The nature of this factor(s) is unknown. An aldosterone-stimulating factor has also been implicated in the pathogenesis of idiopathic aldosteronism (IH) (3). Suppression of aldo- sterone with the antiserotoninergic agent cyprohepta- dine has been observed in patients with IH and has been interpreted as evidence for a serotonin-mediated pitui- tary aldosterone-stimulating system (4). Recently, Mul- row (5) has suggested that one of the proopiolipomelan- ocortin (pro-OLMC)-derived peptides may be the stim- ulus for the high plasma aldosterone concentrations in patients with the syndrome of dexamethasone-suppres- sible hyperaldosteronism (DSH). This hypothesis was based on the observation that plasma concentrations of ACTH and -lipotropin (BLPH) change in the same direction in response to a variety of stimuli, including glucocorticoid negative feedback inhibition.
Received May 19, 1982.
Address requests for reprints to: Hans-Georg Güllner, M.D., Build- ing 10, Room 8C103, National Institutes of Health, Bethesda, Maryland 20205.
* This work was supported in part by National Cancer Institute Research Grants 5-R01-CA-11685 and 5-R25-CA-19429.
To further investigate this hypothesis, we measured plasma concentrations of the pro-OLMC peptides, ACTH, ß-endorphin (SEND)/ALPH and y3MSH (the core sequence of yMSH) in patients with primary hy- peraldosteronism (PH), IH with bilateral adrenal hyper- plasia, and DSH.
Materials and Methods
Three patients with an aldosterone-producing adrenal ade- noma causing PH, one patient with an aldosterone-producing adrenocortical carcinoma causing PH, two patients with IH, and one woman with DSH were studied in the Clinical Center of the NIH. The diagnosis of IH was established by measure- ment of adrenal venous corticosteroids. In the patients with DSH and IH, plasma aldosterone levels were variable, occa- sionally falling into the upper normal range, a finding that has also been observed by others (4). The reason for this variability is unknown. The patients were maintained on a metabolic diet containing 109 meq/day sodium and 50-70 meq/day potassium for the duration of the study. Medications had been discontin- ued 2 weeks before the study. At least two early morning blood samples were drawn from each patient after overnight bedrest for the measurement of plasma peptides, cortisol, and aldoste- rone. In the patients with PH, blood was drawn before and after surgical removal of the adrenal tumors. In a separate
study, one of the patients with IH and the patient with DSH were treated with dexamethasone (1 mg in the evening and 1 mg in the morning, 3 h before blood drawing).
To study the effect of an antagonist of endogenous opioid peptides on plasma aldosterone, we infused naloxone (0.2 mg/ min for 40 min, infused at a rate of 0.5 ml/min) in one patient with aldosteronism due to bilateral adrenal hyperplasia, and compared its effect with that of infusion of a solution of 5% dextrose in water.
The peptides were measured by specific RIAs as recently described [ACTH, Y3MSH (6) and SEND/ALPH using an antibody that cross-reacts with SEND and LPH on an equi- molar basis (7)]. Plasma cortisol and aldosterone (8, 9) concen- trations were measured by RIA by Hazelton Laboratories, Inc. (Vienna, VA).
Results
The results of measurements of plasma immunoreac- tive BEND/BLPH, cortisol, and aldosterone in three patients with adrenal adenoma and one patient with adrenal carcinoma are summarized in Table 1. Plasma levels of BEND/LPH were not different from those in normal controls and did not increase or decrease con- sistently, remaining within the normal range after re- moval of the adenoma. Table 2 shows measurements of plasma immunoreactive aldosterone, cortisol, ACTH, BEND/BLPH, and Y3MSH concentrations in two pa- tients with IH and in one patient with DSH before treatment with dexamethasone and in one patient each with IH and DSH after dexamethasone treatment. Basal values for peptides in these three patients were in the low normal range. All peptides were somewhat lower after dexamethasone administration in the patients with IH and DSH, but plasma aldosterone was suppressed
| Patient | Aldosterone (ng/dl) | Cortisol (µg/dl) | BEND/BLPH (pg/ml) |
|---|---|---|---|
| R.M. | |||
| Pre-op | 63.7ª | 17b | 39€ |
| Post-op | 3.0 | 14 | 46 |
| v.S. | |||
| Pre-op | 34.1 | 8 | 38 |
| Post-op | 4.0 | 10 | 31 |
| M.R. | |||
| Pre-op | 8.7 | 7 | 28 |
| Post-op | 2 | 14 | 32 |
| H.N.ª | |||
| Pre-op | 185.0 | 9 | 20 |
| Post-op | 16.4 | 15 | 40 |
” Normal range while on a 100 meq Na+ diet, 0800-1000 h: 3-12 ng/ dl (supine).
Normal range, 0800-1000 h: 8-18 ug/dl (supine).
· Normal range, 0800-1000 h: ≤85 pg/ml.
d Adrenocortical carcinoma.
| Aldos- terone (ng/dl) | Cortisol (ug/dl) | ACTH (pg/ml) | BEND/ BLPH (pg/ml) | Y3MSH (pg/ml) | |
|---|---|---|---|---|---|
| IH | |||||
| E.H. control | 7.8 | 15 | 17ª | 21 | 25b |
| E.W. | |||||
| Control | 16.7 | 9 | 22 | 21 | 22 |
| Dexameth- | 16.5 | 2 | 8 | 20 | 19 |
| asone | |||||
| DSH | |||||
| B.M. | |||||
| Control | 8.6 | 12 | 28 | 25 | 24 |
| Dexameth- asone | 2 | 2 | 12 | 17 | 18 |
ª Normal range, 0800-100: ≤85 pg/ml.
· Normal range, 0800-1000 h: ≤85 pg/ml.
Infusion
Control
Naloxone (0.2 mg/min)
30
Plasma Aldosterone (ng/dl)
0
0
30
Plasma Cortisol (µg/dl)
0
0
20
40
60
80
100
120
Minutes
only in the patient with DSH (Table 2).
Figure 1 shows the effect of iv infusion of naloxone or 5% dextrose in water on plasma aldosterone and cortisol in a patient with IH. There was no significant change in the concentrations of either steroid.
Discussion
There is considerable experimental and clinical evi- dence suggesting that pituitary peptides other than ACTH participate in the regulation of aldosterone secre- tion. BLPH, «MSH, and ØMSH have been reported to stimulate the production of aldosterone in rat adrenal cells in vitro (10-12). A human glycopeptide representing the major immunoreactive form of the pituitary NH2- terminal segment of proopiomelanocortin (13) has been shown to stimulate aldosterone release by human adrenal adenoma cells in vitro (14). Furthermore, BEND selec-
tively stimulates aldosterone production in hypophysec- tomized nephrectomized dogs (15). A glycoprotein that produces hypertension and increases plasma aldosterone in the rat has been extracted from normal human urine (16). These reports prompted us to measure the carboxy- and amino-terminal peptide fragments of the pituitary prohormone pro-OLMC in patients with hyperaldoster- onism and to examine the responses of these peptides to removal of the adrenal tumor or to treatment with dex- amethasone, which has been shown to suppress plasma ACTH, ØLPH, and SEND.
Our data suggest that the pro-OLMC peptides are not overproduced in states of hyperaldosteronism. Since na- loxone failed to suppress plasma aldosterone, we can rule out the possibility that the increase in plasma peptide concentrations was too small to be detected by the assays used. The plasma concentrations of the pro-OLMC pep- tides were neither elevated, as might be expected if they were responsible for the hyperaldosteronism, nor sup- pressed, as would be expected if hypersecretion of adrenal steroids were exerting negative feedback inhibition of pituitary pro-OLMC peptide secretion. The BEND RIA measures BEND and LPH on an equimolar basis, so we cannot exclude the possibility that plasma BEND is increased in the absence of an increase in total immu- noreactive BEND (i.e. BEND plus BLPH). However, the fact that neither y: MSH nor ACTH concentrations was elevated is strong evidence that secretion of none of the pro-OLMC-derived peptides is increased in patients with aldosteronism. Furthermore, although dexamethasone decreased plasma concentrations of all of the measured pro-OLMC-derived peptides, it suppressed plasma aldo- sterone only in the patient with DSH. These results suggest that none of the known pro-OLMC peptides is responsible for the increase in aldosterone production in IH, and are consistent with the concept that ACTH (or possibly another unidentified pituitary factor) mediates aldosterone overproduction in DSH.
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