High plasma levels of endothelin-1 in untreated Addison's disease Claudio Letizia, Marco Centanni, Luigi Scuro, Gianluca Canettieri, Sabrina Cerci, Anita De Ciocchis, Cecilia D'Ambrosio and Domenico Scavo Patologia Medica, and Endocrine Unit1, Department of Experimental Medicine and Pathology, University "La Sapienza", Rome, Italy Letizia C, Centanni M, Scuro L, Canettieri G, Cerci S, De Ciocchis A, D'Ambrosio C, Scavo D. High plasma levels of endothelin 1 in untreated Addison's disease. Eur J Endocrinol 1996;135:696\p=n-\9.ISSN 0804\p=n-\4643 The aim of this study has been to investigate the plasma endothelin-1 (ET-1) levels in adult patients with proven Addison's disease (AD). Plasma ET-1 levels were measured in 29 subjects (17 males and 12 females, aged between 20 and 54 years): 15 of them were patients with AD and 14 were sex- and age-matched normal subjects, used as a control group. All patients with AD have been studied under basal conditions and nine of them also after 2 weeks on oral corticosteroid therapy (individual cortisol dosage ranging from 25 to 37.5 mg/day and 0.1 mg/day 9\g=a\-fluorohydrocortisone). Extracted plasma ET-1 was determined by a specific radioimmunoassay using rabbit endothelin antisera. Mean ET-1 values in the patients with AD were three times higher than in normal subjects (21.09 \m=+-\4.38 pg/ml vs 6.72 \m=+-\1.74 pg/ml; p < 0.0001). Plasma ET-1 levels assayed in the patients with AD after 2 weeks of corticosteroid therapy were significantly decreased (14.47 \m=+-\3.7 pg/ml vs 22.8 \m=+-\5.2 pg/ml; \m=-\37%; p < 0.001) compared to values in untreated patients. However, the plasma ET-1 values obtained following corticosteroid therapy were still significantly higher (p < 0.001) than those detected in the control subjects. These results clearly indicate that patients with untreated AD have increased circulating ET-1 levels that may be reduced by short-term corticosteroid therapy. Claudio Letizia, Policlinico Umberto I, II Clinica Medica, 00185 Roma, Italy Endothelin-l (ET-1), a peptide isolated from the media of cultured vascular endothelial cells, exerts marked vasomodulatory, mainly vasoconstrictive, effects (1) and may represent a major factor in the regulation of blood pressure. Its role, however, in blood pressure homeostasis, in physiological and pathological condi¬ tions, remains to be elucidated. Recently, it has been shown that ET-1 stimulates hormone secretion from various endocrine organs and cells, such as atrial natriuretic peptide from atrial myocytes (2), catechola- mines from chromaffin cells (3) and vasopressin from the hypothalamus (4). Specific high-affinity receptors for ET-1 have been identified in the zona glomerulosa of the adrenal gland (5, 6) where ET-1 is involved in the process of aldosterone production but not in that of cortisol (7). In fact, although ET-1 is a less potent aldosterone secretagogue than angiotensin II, it enhances the effects of angiotensin II and ACTH on aldosterone biosynthesis (8,9). Impaired blood pressure control is a key feature of various pathological conditions; however, the role of the individual factors in the pathogenesis of the impaired blood pressure has not been well defined. Recently, an excessive secretion of ET-1 has been shown in some cases of pheochromo¬ cytoma (10) whereas normal levels of plasma ET-1 have been recorded in patients with primary hyperaldoster- onism (11). In untreated Addison's disease (AD), due to the chronic decrease of the circadian amplitude of blood pressure (12) and to the low mean blood pressure, all vasoactive mechanisms to maintain the blood pressure homeostasis are likely to be fully activated. However, as far as we know, no information is available concerning ET-1 levels in adult patients with primary adrenal failure. The aim of this investigation has been to study plasma levels of immunoreactive ET-1 before and after short-term corticosteroid therapy in patients with AD. Subjects and methods Subjects Plasma ET-1 levels have been measured in 29 subjects (17 males and 12 females, aged between 20 and 54 years): namely, 15 patients with AD and 14 sex- and age-matched normal subjects used as a control group. Diagnosis of Ad was made on clinical grounds (weight loss, hypotension, anorexia, cutaneous hyperpigmenta- tion) and on the basis of laboratory tests (low basal and ACTH-stimulated cortisol levels, low urinary cortisol excretion, low plasma aldosterone, high plasma renin activity, high plasma ACTH). In 11 out of 15 patients, the pathogenesis of the adrenal failure was autoim¬ mune; in the remaining four patients a previous pulmonary tuberculosis indicated an infectious origin. None of the patients showed biochemical or functional evidence of renal failure or kidney disease. All patients were studied under basal conditions and nine out of the 15 also following 2 weeks on oral corticosteroid therapy