title: Role of voltage-gated calcium channels in potassium-stimulated aldosterone secretion from rat adrenal zona glomerulosa cells.
abstract: The mineralocorticoid aldosterone plays an important role in the regulation of plasma electrolyte homeostasis. Exposure of acutely isolated rat adrenal zona glomerulosa cells to elevated K(+) activates voltage-gated calcium channels and initiates a calcium-dependent increase in aldosterone synthesis. We developed a novel 96-well format aldosterone secretion assay to rapidly evaluate the effect of known T- and L-type calcium channel antagonists on K(+)-stimulated aldosterone secretion and better define the role of voltage-gated calcium channels in this process. Reported T-type antagonists, mibefradil and Ni(2+), and selected L-type antagonist dihydropyridines, inhibited K(+)-stimulated aldosterone synthesis. Dihydropyridine-mediated inhibition occurred at concentrations which had no effect on rat alpha1H T-type Ca(2+) currents. In contrast, below 10 microM, the L-type antagonists verapamil and diltiazem showed only minimal inhibitory effects. To examine the selectivity of the calcium channel antagonist-mediated inhibition, we established an aldosterone secretion assay in which 8Br-cAMP stimulates aldosterone secretion independent of extracellular calcium. Mibefradil remained inhibitory in this assay, while the dihydropyridines had only limited effects. Taken together, these data demonstrate a role for the L-type calcium channel in K(+)-stimulated aldosterone secretion. Further, they confirm the need for selective T-type calcium channel antagonists to better address the role of T-type channels in K(+)-stimulated aldosterone secretion.
authors.affiliation: Merck Research Labs, Sumneytown and West Point Pikes, Department of Molecular Neurology, WP26-265, West Point, PA 194486, USA. victor_uebele@merck.com
authors.forename: Victor N
authors.initials: VN
authors.lastname: Uebele
authors.forename: Cindy E
authors.initials: CE
authors.lastname: Nuss
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Connolly
mesh_terms: D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D001681:Biological Assay; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*; D051381:Rats; D015384:Zona Glomerulosa / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020747:Calcium Channels, T-Type; D000450:Aldosterone; D011188:Potassium; D002118:Calcium