Endothelin-1 and Its Receptors A and B in Human Aldosterone-Producing Adenomas

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Abstract
Abstract Endothelin-1 stimulates aldosterone secretion by interacting with specific receptors. Accordingly, we wished to investigate endothelin-1, endothelin-A (ET A ) receptor, and endothelin-B (ET B ) receptor gene expression, localization, and properties in aldosterone-producing adenomas and in the normal human adrenal cortex. We carried out 125 I–endothelin-1 displacement studies with cold endothelin-1, endothelin-3, the specific ET A antagonist BQ-123, and the specific ET B weak agonist sarafotoxin 6 C and coanalyzed data with the nonlinear iterative curve-fitting program ligand . We also studied gene expression with reverse transcription–polymerase chain reaction with specific primers for endothelin-1, ET A , and ET B complementary DNA. Normal adrenal cortices from consenting kidney cancer patients (n=2) and aldosterone-producing adenomas (n=4) were studied; for the latter, surrounding normal cortex and kidney biopsy tissue served as controls. To further localize the receptor subtypes, tissue sections were studied by autoradiography in the presence and absence of 500 nmol/L BQ-123, 100 nmol/L sarafotoxin 6 C, and 1 μmol/L cold endothelin-1. In all tissues examined, endothelin-1, ET A , and ET B messenger RNAs were easily detected. However, in aldosterone-producing adenomas, both receptors’ genes were expressed at a higher level than in the kidney. In aldosterone-producing adenomas (F=9.49, P <.01) as well as in the normal adrenal cortex (F=8.57, P <.01), but not in adrenocortical tissue surrounding aldosterone-producing adenomas (F=5.08, P =NS), the significantly best fitting of binding data was provided by a two-site model indicating the presence of two receptor subtypes with density ( B max ) and affinity ( K d ) similar to those previously found in other tissues. Autoradiography confirmed the presence of both ET A and ET B receptors on normal zona glomerulosa cells as well as on aldosterone-producing adenoma cells. Thus, the genes of endothelin-1 and of its receptors, ET A and ET B , are actively transcribed in the human adrenal cortex, and both receptor subtypes are translated into proteins in zona glomerulosa and aldosterone-producing adenoma cells. These data are consistent with an autocrine-paracrine role of endothelin-1 in the regulation of aldosterone secretion, both under normal conditions and in aldosterone-producing adenomas.