Inhibitory effect of efonidipine on aldosterone synthesis and secretion in human adrenocarcinoma (H295R) cells.
Targeting aldosterone synthesis and/or release represents a potentially useful approach to the prevention of cardiovascular disease. Aldosterone production is stimulated by angiotensin II (Ang II) or extracellular K+ and is mediated mainly by Ca2+ influx into adrenal glomerulosa cells through T-type calcium channels. We therefore examined the effects of efonidipine, a dual T-type/L-type Ca2+ channel blocker, on aldosterone secretion in the H295R human adrenocarcinoma cell line; 100 nmol/L Ang II and 10 mmol/L K+ respectively increased aldosterone secretion from H295R cells 12-fold and 9-fold over baseline. Efonidipine dose-dependently inhibited both Ang II- and K+-induced aldosterone secretion, and nifedipine, an L-type Ca2+ channel blocker, and mibefradil, a relatively selective T-type channel blocker, similarly inhibited Ang II- and K+-induced aldosterone secretion, but were much less potent than efonidipine. Efonidipine also lowered cortisol secretion most potently among these drugs. Notably, efonidipine and mibefradil also significantly suppressed Ang II- and K+-induced mRNA expression of 11-beta-hydroxylase and aldosterone synthase, which catalyze the final two steps in the aldosterone synthesis, whereas nifedipine reduced only K+-induced enzyme expression. These findings suggest that efonidipine acts via T-type Ca2+ channel blockade to significantly reduce aldosterone secretion, and that this effect is mediated, at least in part, by suppression of 11-beta-hydroxylase and aldosterone synthase expression.
Imagawa
Keiichi
K
First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
Okayama
Satoshi
S
Takaoka
Minoru
M
Kawata
Hiroyuki
H
Naya
Noriyuki
N
Nakajima
Tamio
T
Horii
Manabu
M
Uemura
Shiro
S
Saito
Yoshihiko
Y
D000310:Adrenal Gland Neoplasms / Q000378:metabolism*; D000450:Aldosterone / Q000096:biosynthesis* / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000235:genetics; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors / Q000235:genetics; D004095:Dihydropyridines / Q000494:pharmacology*; D006801:Humans; D009596:Nitrophenols / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D004095:Dihydropyridines; D009596:Nitrophenols; D009943:Organophosphorus Compounds; D012333:RNA, Messenger; C066425:efonidipine; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2