Synergistic stimulation of aldosterone production in human adrenocortical carcinoma NCI-H295R cells by endothelin-1 and angiotensin II.
Aldosterone has recently been implicated in the pathogenesis of heart failure. The purpose of the present study was to determine the effect of endothelin-1 (ET-1) and angiotensin II (Ang II), two potent vasoconstrictors that are also involved in heart failure, on aldosterone secretion by human adrenocortical carcinoma NCIH295R cells grown in 96-well plates. Ang II stimulated the production of aldosterone dose-dependently in serum-free medium, and the presence of serum drastically decreased aldosterone secretion. In contrast, ET-1-stimulated aldosterone production absolutely required serum. Under optimal conditions, ET-1 was more effective than Ang II as an aldosterone secretagogue. In a suboptimal condition of 2.5% serum, ET-1 and Ang II at 1 microM produced 63 and 76 pmol aldosterone/mg protein, respectively, while 230 pmol aldosterone/mg protein was generated upon coincubation with ET-1 and Ang II. The effect of ET-1 was inhibited dose-dependently by the selective ETA receptor antagonist BQ-123 with an IC50 of 23 nM, but the selective ETB receptor antagonist RES-701 had no effect up to 10 microM. These results suggest that ET-1 and Ang II stimulated aldosterone secretion synergistically in NCIH295R cells and that the effect of ET-1 was mediated via the ETA receptor subtype.
Hu
Chii-Whei
CW
Cardiovascular Diseases Research, Novartis Institutes for BioMedical Research, East Hanover, New Jersey 07936-1080, USA.
Webb
Randy L
RL
Jeng
Arco Y
AY
D000306:Adrenal Cortex Neoplasms / Q000378:metabolism*; D018268:Adrenocortical Carcinoma / Q000378:metabolism*; D000450:Aldosterone / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D019333:Endothelin-2 / Q000378:metabolism; D019334:Endothelin-3 / Q000378:metabolism; D006801:Humans; D010456:Peptides, Cyclic / Q000494:pharmacology; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D044967:Serum / Q000378:metabolism; D015854:Up-Regulation
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D019333:Endothelin-2; D019334:Endothelin-3; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D000804:Angiotensin II; D000450:Aldosterone; C072247:cyclo(Trp-Asp-Pro-Val-Leu)