Role of voltage-gated calcium channels in potassium-stimulated aldosterone secretion from rat adrenal zona glomerulosa cells.
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.
Uebele
Victor N
VN
Merck Research Labs, Sumneytown and West Point Pikes, Department of Molecular Neurology, WP26-265, West Point, PA 194486, USA. victor_uebele@merck.com
Nuss
Cindy E
CE
Renger
John J
JJ
Connolly
Thomas M
TM
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*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020747:Calcium Channels, T-Type; D000450:Aldosterone; D011188:Potassium; D002118:Calcium