CLINICAL STUDY Elevated plasma endothelin as an additional cardiovascular risk factor in patients with Cushing’s syndrome G Kirilov, ATomova, L Dakovska, Ph Kumanov, A Shinkov and A S Alexandrov 1 Clinical Center of Endocrinology, Medical University, Sofia, Bulgaria and 1 Institute of Biophysics, Bulgarian Academy of Sciences, Sofia, Bulgaria (Correspondence should be addressed to G Kirilov, Clinical Center of Endocrinology, 6 Blvd Damian Gruev, 1303-Sofia, Bulgaria; Email: kirilov@uheg.medicalnet-bg.org) Abstract 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 ¼ 13): 1.59^0.78 vs 0.46^0.20pmol/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 posi- tive 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 ¼þ 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 athero- sclerosis development in this disorder. European Journal of Endocrinology 149 549–553 Introduction Recently, many experimental and clinical studies have been published confirming the role of endothelin (ET) as a stimulator and modulator of hypothalamic –pitu- itary–adrenal function (1–4). The ETs are classified in the group of the neuroendocrine peptides, which is illustrated by the fact that ET-1 stimulates the hypo- thalamic release of corticotropin-releasing hormone (CRH) and pituitary secretion of adrenocorticotropic hormone (ACTH) via specific ET-A and ET-B receptors (5). On the other hand, it was found that ET is a local adrenomedullary and adrenocortical paracrine regulator. The genes of both ET and its converting enzyme and receptors are expressed by human adreno- cortical cells (6). Thus, ET stimulates cortisol and aldo- sterone secretion directly and by enhancing ACTH action. Together with nitric oxide (NO) it regulates the adrenal vascular tone and stimulates adrenal growth (7, 8). It was demonstrated that glucocortico- steroids induce ET release by vascular smooth muscle cells, suppress the activity of the NO system and thus cause vasoconstriction, endothelial dysfunction and atherosclerosis (9). From this point of view, in conditions associated with hypercortisolism, plasma ET assessment is by all means justified, insofar as it may reveal eventual pathophysio- logical implications of this vasoactive peptide. What is more, in a number of adrenal diseases, such as primary hyperaldosteronism, pheochromocytoma and adrenal insufficiency, plasma ET levels undergo significant changes (10 – 12). Proceeding from already discussed experimental and clinical data concerning the role of ET in adrenal physiology and pathology, we undertook to evaluate the levels of plasma immunoreactive ET in patients with Cushing’s syndrome. European Journal of Endocrinology (2003) 149 549–553 ISSN 0804-4643 q 2003 Society of the European Journal of Endocrinology Online version via http://www.eje.org