BACKGROUND: Recently the pathophysiological role of endothelin (ET) has been presumed in a number of adrenal disorders such as primary hyperaldosteronism, pheochromocytoma and adrenocortical insufficiency. AIM: The aim of the present study was to evaluate circulating ET-1 levels in patients with endogenous Cushing's syndrome. METHODS AND RESULTS: Plasma ET-1 levels were determined by highly sensitive RIA. Thirteen untreated subjects with Cushing's syndrome were studied: eight women and five men of mean age 44.2+/-9.5 Years (s.d.). In ten of them, Cushing's disease had been diagnosed and three had adrenal adenomas. ET-1 was 3-fold higher in the patient group than in age-matched healthy controls (n=13): 1.59+/-0.78 vs 0.46+/-0.20 pmol/l respectively, P<0.001. In adrenal adenoma patients, ET-1 was not significantly higher than in the Cushing's disease subjects (1.84+/-0.67 vs 1.51+/-0.83 pmol/l respectively, P>0.05). In three patients who died of severe cardiovascular complications, plasma ET-1 was significantly higher than in the remaining patients (2.34+/-0.35 pmol/l, P<0.05). A positive correlation was found between the total cholesterol (6.94+/-1.75 mmol/l) and ET-1 levels in the patients with Cushing's syndrome: r=+0.73, P<0.02. No correlation was observed, however, between the levels of ET-1 and blood pressure (183+/-37/106+/-18 mmHg), plasma cortisol levels (455.2+/-74.5 nmol/l) or urinary cortisol excretion (1463+/-726 nmol/24 h). The successful treatment and correction of hypercortisolism in seven patients led to insignificant reduction in plasma ET from 1.34+/-0.69 to 0.73+/-0.53 pmol/l, P>0.05. CONCLUSION: Our results clearly demonstrate that the ET system is activated in Cushing's syndrome. Elevated plasma ET-1 levels probably play a role in the pathogenesis of accelerated and early atherosclerosis development in this disorder.