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Dopamine Receptor Expression and Function in Human Normal Adrenal Gland and Adrenal Tumors

Departments of Internal Medicine (R.P., D.F., W.W.d.H., M.W., D.M.M., P.M.v.K., S.W.J.L., L.J.H.) and Pathology (R.R.d.K.) Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands; Departments of Molecular and Clinical Endocrinology and Oncology (R.P., G.L., A.C.) and Pathology (M.L.D.B.D.C.), "Federico II" University of Naples, 80131 Naples, Italy; and Department of Endocrinological and Metabolic Sciences and Centre for Excellence for Biomedical Research (D.F., A.B.), University of Genova, 16132 Genova, Italy

Address all correspondence and requests for reprints to: Rosario Pivonello, M.D., Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University, Via Sergio Pansini, 5, 80131 Naples, Italy. E-mail: rpivone{at}tin.it.

Dopamine is known to play a role in the modulation of aldosterone and catecholamine secretion from the adrenal gland, where dopamine receptors (DR), in particular the DR type 2 (D₂), have been found to be expressed. DR expression has also been demonstrated in some types of benign adrenal tumors.

The aims of the current study were to evaluate DR expression and D₂ localization in the normal adrenal gland and in different types of benign and malignant adrenal tumors, as well as to evaluate the in vitro effects of the dopamine agonists bromocriptine and cabergoline on hormone secretion in nontumoral adrenal cells.

Adrenal tissues from 25 patients, subjected to adrenal surgery for different diseases, were studied. These included three normal adrenals; five adrenal hyperplasias; four aldosterone-secreting, two cortisol-secreting, and two clinically nonfunctioning adrenal adenomas; two aldosterone-secreting, two cortisol-secreting, and two androgen-secreting adrenal carcinomas; and three pheochromocytomas. In all tissues, DR and D₂ isoform (D_2long and D_2short) expression was evaluated by RT-PCR. D₂ localization was also evaluated by immunohistochemistry using a specific polyclonal antibody, whereas D₂-like receptor expression was evaluated by receptor-ligand binding study, using the radiolabeled D₂ analog ¹²⁵I-epidepride. The effects of bromocriptine and cabergoline on baseline and ACTH and/or angiotensin II-stimulated aldosterone, cortisol, and androstenedione secretion were evaluated in cell cultures derived from five different adrenal hyperplasia.

At RT-PCR, both D₁-like and D₂-like receptors were expressed in all normal and hyperplastic adrenals. D₂ and D₄ were expressed in aldosterone- and cortisol-secreting adenomas, cortisol-secreting carcinomas, and clinically nonfunctioning adenomas, whereas no DR was expressed in aldosterone- and androgen-secreting carcinomas. D₂, D₄, and D₅ were expressed in pheochromocytomas. In all D₂-positive tissues, both D₂ isoforms were expressed, with the exception of one case of aldosterone-secreting adenoma and the cortisolsecreting carcinomas, in which only the D_2long isoform was expressed. D₂-like receptor expression was confirmed at receptor-ligand binding study. At immunohistochemistry, D₂ was mainly localized in the zona glomerulosa and reticularis of the adrenal cortex and, to a lesser extent, in the zona fasciculata and medulla of normal and hyperplastic adrenal tissue. In the positive tumors, D₂ was localized in the tumoral cells. At the in vitro study, a significant inhibition of both baseline and ACTH-stimulated aldosterone secretion was found after high-dose cabergoline, but not bromocriptine, administration; and a significant inhibition of angiotensin-II-stimulated aldosterone secretion was found after both bromocriptine and cabergoline administration in the adrenal hyperplasias.

In conclusion, the current study demonstrated that both D₁-like and D₂-like receptors are expressed in the normal adrenal gland and in a percentage of adrenal adenomas or carcinomas. Bromocriptine and cabergoline induce only a minor inhibition of the secretion of adrenal hormones in the nontumoral adrenal gland in vitro, not excluding, however, the possible effective use of dopamine agonists in vivo in the treatment of adrenal tumors.

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