Voltage-gated calcium currents have two opposing effects on the secretion of aldosterone.
Using Ca2+ channel blockers with different specificities for L- and T-type Ca2+ channels, we have investigated the roles of these two channel types in K(+)-induced aldosterone secretion. In whole cell voltage-clamp experiments, the spider toxin omega-agatoxin-IIIA (omega-Aga-IIIA) completely blocks L-type Ca2+ channels but has no effect on T-type Ca2+ channels. In contrast, Ni2+ and 1,4-dihydropyridines block both L- and T-type Ca2+ channels. Secretion induced by 7 mM extracellular K+ concentration ([K+]o) is unaffected by omega-Aga-IIIA but is strongly inhibited by Ni2+ or the 1,4-dihydropyridine, nitrendipine. This suggests that physiological increases in [K+]o stimulate aldosterone secretion primarily by enhancing Ca2+ entry through T-type Ca2+ channels. Surprisingly, secretion induced by 60 mM [K+]o is enhanced by omega-Aga-IIIA or Ni2+ and is inhibited by the L-type Ca2+ channel activator BAY K 8644. Nitrendipine (1 nM) also stimulates such secretion, although higher concentrations are inhibitory (concentration inhibiting 50% of maximal response approximately 30 nM). If extracellular Ca2+ concentration is reduced from 1.25 to 0.5 mM, secretion induced by 60 mM [K+]o is enhanced, and Ni2+ or low nitrendipine become inhibitory. Together, these results that L-type Ca2+ currents can reduce steroidogenesis and that the role of these currents was previously misconstrued because 1,4-dihydropyridines modify secretion by multiple mechanisms. Thus Ca2+ entry can function as a negative modulator of steroid secretion.
Barrett
P Q
PQ
Department of Pharmacology, University of Virginia, Charlottesville 22908, USA.
Ertel
E A
EA
Smith
M M
MM
Nee
J J
JJ
Cohen
C J
CJ
D060848:Agatoxins; D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D002417:Cattle; D004095:Dihydropyridines / Q000494:pharmacology; D004553:Electric Conductivity; D004594:Electrophysiology; D009532:Nickel / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D013111:Spider Venoms / Q000494:pharmacology; D015384:Zona Glomerulosa / Q000166:cytology / Q000378:metabolism
D060848:Agatoxins; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D013111:Spider Venoms; C070132:omega-agatoxin III; D000450:Aldosterone; D009532:Nickel; D011188:Potassium