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Autocrine-Paracrine Role of Endothelin-1 in the Regulation of Aldosterone Synthase Expression and Intracellular Ca²⁺ in Human Adrenocortical Carcinoma NCI-H295 Cells¹

Departments of Clinical and Experimental Medicine, Pharmacology (S.B., L.T.), Division of Endocrinology (F.F.), Institutes of Microbiology (G.P.) and Anatomy (A.S.B., G.G.N.), University of Padua Medical School, Padova, Italy; and Max Planck Institute of Psychiatry, Clinical Institute (U.P.), Munich, Germany

Address all correspondence and requests for reprints to: Gian Paolo Rossi, M.D., F.A.C.C., Clinica Medica 1, Dipartimento di Medicina Clinica e Sperimentale, University Hospital via Giustiniani, 2, 35126 Padova, Italy. E-mail: gprossi{at}ipdunidx.unipd.it

The role played by endothelin (ET-1) and its receptor subtypes A and B (ET_A and ET_B) in the functional regulation of human NCI-H295 adrenocortical carcinoma cells has been investigated. Reverse transcription-PCR with primers specific for prepro-ET-1, human ET-1 converting enzyme-1, ET_A, and ET_B complementary DNAs consistently demonstrated the expression of all genes in NCI-H295 cells. The presence of mature ET-1 and both its receptor subtypes was confirmed by immunocytochemistry and autoradiography, respectively. Aldosterone synthase (AS) messenger RNA was also detected in NCI-H295 cells, and AS gene expression was enhanced by both ET-1 and the specific ET_B agonist IRL-1620; this effect was not inhibited by either the ET_A antagonist BQ-123 or the ET_B antagonist BQ-788. A clear-cut increase in the intracellular Ca²⁺ concentration in NCI-H295 cells in response to ET_B, but not ET_A, activation was observed. In light of these findings, the following conclusions can be drawn: 1) NCI-H295 cells possess an active ET-1 biosynthetic pathway and are provided with ET_A and ET_B receptors; 2) ET-1 regulates in an autocrine/paracrine fashion the secretion of aldosterone by NCI-H295 cells by enhancing both AS transcription and raising the intracellular Ca²⁺ concentration; and 3) the former effect of ET-1 probably involves the activation of both receptor subtypes, whereas calcium response is exclusively mediated by the ET_B receptor.

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