Plasma immunoreactive gamma melanotropin in patients with idiopathic hyperaldosteronism, aldosterone-producing adenomas, and essential hypertension. G T Griffing, … , R C Pedersen, A C Brownie J Clin Invest. 1985;76(1):163-169. https://doi.org/10.1172/JCI111941. Research Article A non-ACTH aldosterone-stimulating factor(s) has been implicated in the pathogenesis of idiopathic hyperaldosteronism (IHA). Although this factor has not been fully characterized, some evidence suggests that it may be related to a pro- gamma-melanotropin (pro-gamma-MSH), derived from the NH2-terminal region of pro-opiomelanocortin. In the present study, plasma immunoreactive (IR-) gamma-MSH levels at 0800 h in patients with IHA were evaluated (90 +/- 17 fmol/ml; range: 13-173 fmol/ml) and found to be significantly higher (P less than 0.05) than those in subjects with aldosterone- producing adenomas (33 +/- 8 fmol/ml), essential hypertension (33 +/- 6 fmol/ml), and normotensive controls (19 +/- 2 fmol/ml). Seven of nine IHA subjects had circulating IR-gamma-MSH levels above the normal range (greater than 35 fmol/ml). In plasmas sampled at 1200 h, IR-gamma-MSH was significantly higher in patients with IHA (95 +/- 26 fmol/ml) and adenomas (63 +/- 23 fmol/ml), as compared with essential hypertensives (31 +/- 6 fmol/ml) and normotensives (19 +/- 3 fmol/ml). Mean plasma IR-ACTH, plasma cortisol, and urinary cortisol levels did not differ significantly between any of these groups. In order to evaluate the effect of a pro-gamma-MSH in vitro, adrenal adenoma tissue was obtained from two patients, one with elevated IR-gamma-MSH (61 fmol/ml) and a second with low IR-gamma-MSH (12 fmol/ml). Aldosterone secretion by dispersed adenoma cells from the former, but not the latter, […] Find the latest version: https://jci.me/111941/pdf Plasma Immunoreactive Gamma Melanotropin in Patients with Idiopathic Hyperaldosteronism, Aldosterone-producing Adenomas, and Essential Hypertension George T. Griffing, Brian Berelowitz, Margo Hudson, Robert Salzman, Jo Ann E. Manson, Steven Aurrechia, and James C. Melby Section ofEndocrinology and Metabolism, Evans Memorial Department of Clinical Research and the Department ofMedicine, University Hospital and Boston University School ofMedicine, Boston, Massachusetts 02118 Robert C. Pedersen and Alexander C. Brownie Departments ofBiochemistry and Pathology, Schools ofMedicine and Dentistry, State University ofNew York at Buffalo, Buffalo, New York 14214 Abstract Major support for this hypothesis comes from investigations of idiopathic hyperaldosteronism (IHA),' a variant in primary A non-ACTH aldosterone-stimulating factor(s) has been im- aldosteronism (1, 2). Patients with IHA have increased levels plicated in the pathogenesis of idiopathic hyperaldosteronism of a circulating glycoprotein termed aldosterone-stimulating (IHA). Although this factor has not been fully characterized, factor (ASF) (3-5). This finding may explain the bilateral some evidence suggests that it may be related to a pro-y- adrenal hyperplasia and increased aldosterone production as- melanotropin (pro-'y-MSH), derived from the NH2-terminal sociated with IHA. Although the characterization of ASF is region of pro-opiomelanocortin. In the present study, plasma incomplete, it has been localized to the pituitary by immuno- immunoreactive (IR-) -y-MSH levels at 0800 h in patients with histochemical staining (6). A number of pituitary polypeptide IHA were evaluated (90±17 fmol/ml; range: 13-173 fmol/ml) candidates have been evaluated for ASF-like activity, including and found to be significantly higher (P < 0.05) than those in several that are derived from pro-opiomelanocortin (POMC): subjects with aldosterone-producing adenomas (33±8 fmol/ a-melanotropin, melanocyte-stimulating hormone (a-MSH) ml), essential hypertension (33±6 fmol/ml), and normotensive (7, 8), fl-MSH/fl-lipotropin (9-12), and fl-endorphin (13, 14). controls (19±2 fmol/ml). Seven of nine IHA subjects had Interest has also focused on the glycosylated NH2-terminal circulating IR--y-MSH levels above the normal range (>35 segment of POMC, which includes the y-MSH sequence (15), fmol/ml). In plasmas sampled at 1200 h, IR-y-MSH was and which can be cleaved at several sites to generate a small significantly higher in patients with IHA (95±26 fmol/ml) and group of pro-y-MSHs. Various of these pro-'y-MSHs have adenomas (63±23 fmol/ml), as compared with essential hyper- been shown to stimulate aldosterone secretion by dispersed tensives (31±6 fmol/ml) and normotensives (19±3 fmol/ml). aldosteronoma cells (16); to potentiate aldosterone secretion Mean plasma IR-ACIH, plasma cortisol, and urinary cortisol in vitro (17) and in vivo (18); and to exhibit hyperplastic and levels did not differ significantly between any of these groups. hypertrophic effects on the adrenal cortex (19). The present In order to evaluate the effect of a pro-'y-MSH in vitro, adrenal study was undertaken to evaluate the circulating levels of adenoma tissue was obtained from two patients, one with immunoreactive- (IR-) 'y-MSH in patients with IHA, aldoste- elevated IR-'y-MSH (61 fmol/ml) and a second with low IR- rone-producing adenomas (APA), and essential hypertension -y-MSH (12 fmol/ml). Aldosterone secretion by dispersed (EH), as compared with normotensive controls (NC). adenoma cells from the former, but not the latter, underwent a fourfold dose-dependent (10-'4-10-' M) increase in response Methods to human Lys-'y3-MSH. These data suggest that a pro-'y- MSH may be implicated as a pathogenic factor in a subset of Subjects. Four groups of subjects were studied: IHA (total/females- patients with primary aldosteronism, particularly among those 9/5; X age-51 yr, X weight- 188 Ib); APA (5/2; 49 yr; 154 lb); EH differentially diagnosed as having IHA. (9/6; 49 yr, 173 lb); NC (7/4; 32 yr, 144 lb). All hypertensive patients underwent a 7-d protocol in a metabolic Introduction unit before diagnosis. Medications influencing the renin-aldosterone or pituitary-adrenal systems, including diuretics, adrenergic-blockers, There is mounting evidence that a non-ACTH pituitary factor(s) vasodilators, and estrogens, were discontinued for at least 4 wk may be involved in the regulation of aldosterone secretion. preceding admission. Where required, prazosin (1-10 mg/d) (20) was the primary antihypertensive therapy. After admission to the metabolic This paper was presented in part at the Plenary session of the American unit, patients were given a fixed isocaloric diet containing 128 meq Society for Clinical Investigation, 1984, in Washington, DC (Clin. Res. Na' and 80 meq K+/d. After one to two days of electrolyte equilibration, 32:261A. [Abstr.]), and at the Seventh International Congress of a 24-h urine sample was collected for measurement of aldosterone Endocrinology, 1984, in Quebec City, Canada. secretion rate (ASR), cortisol, tetrahydroaldosterone, electrolytes, and Address reprint requests to Dr. Melby. Received for publication 2 November 1984 and in revised form 8 1. Abbreviations used in this paper: AI, angiotensin I; APA, aldosterone- February 1985. producing adenoma; ASF, aldosterone-stimulating factor, ASR, aldo- sterone secretion rate; EH, essential hypertension; IHA, idiopathic J. Clin. Invest. hyperaldosteronism; IR, immunoreactive; KRBGA, Krebs-Ringer bi- © The American Society for Clinical Investigation, Inc. carbonate/glucose/albumin buffer, MSH, melanotropin, melanocyte- 002 1-9738/85/07/0163/07 $ 1.00 stimulating hormone; NC, normotensive controls; POMC, pro-opi- Volume 76, July 1985, 163-169 omelanocortin; PRA, plasma renin activity. Immunoreactive Gamma Melanotropin in Hypertension 163 creatinine. After 8 h of recumbancy, plasma was collected at 0800 h vial contained 1.9 ml of suspension (6.0 X 104 cells) and 0.1 ml of while the patient was supine and again at 1200 h after 4 h of upright test solution. The latter consisted of ACTH( 1-24) (Organon of Canada, posture. On a subsequent day plasma was collected (1100 h) at 3 h Ltd., Ontario, Canada) or synthetic human Lys-y3-MSH, which was after upright posture and furosemide (80 mg, oral). Additional diagnostic reconstituted just before addition with peptide diluent (0.15 M NaCl testing included an adrenal iodocholesterol scan (NP-59), computerized containing 1 mg/ml bovine serum albumin, adjusted to pH 2.3 with axial tomography of the abdomen (21, 22), and selective adrenal vein 1 N HCI). After incubation, the cells were centrifuged and the medium catheterization, if necessary. was removed for determination of aldosterone. The diagnosis of hypertension was established by two or more Statistical analysis. Where appropriate, results are expressed as diastolic blood pressures > 90 mmHg, or systolic blood pressures x±SE. Multiple comparisons were carried out by analysis of variance > 140 mmHg (23). The diagnosis of IHA was established by the using Dunnett's modified t test (33, 34). Comparisons between two following criteria: hypertension; spontaneous hypokalemia; suppressed meaifs were performed using unpaired t test. A nonparametric Krushall- plasma renin activity (PRA) (<1.5 ng angiotensin I [AI]/ml per h); Wallis one-way analysis of variance by ranks and Mann-Whitney U elevated ASR (> 150 ml/d); postural aldosterone increment 25% above test for two independent samples was also used for statistical inferences. the supine level; plasma 18-hydroxycorticosterone level <100 ng/dl at Rejection of the null hypothesis was at a probability of P < 0.05. 0800 h (24); nonlateralizing selective adrenal