PT  - JOURNAL ARTICLE
AU  - Michel F. Rossier
AU  - Eric A. Ertel
AU  - Michel B. Vallotton
AU  - Alessandro M. Capponi
TI  - Inhibitory Action of Mibefradil on Calcium Signaling and Aldosterone Synthesis in Bovine Adrenal Glomerulosa Cells
DP  - 1998 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 824--831
VI  - 287
IP  - 3
4099  - http://jpet.aspetjournals.org/content/287/3/824.short
4100  - http://jpet.aspetjournals.org/content/287/3/824.full
SO  - J Pharmacol Exp Ther1998 Dec 01; 287
AB  - Mibefradil is a new cardiovascular drug with peculiar Ca++antagonistic properties. The most remarkable feature of mibefradil is its unique relative selectivity for T type calcium channels, a property that has been proposed to explain in part the beneficial pharmacological and clinical profiles of this drug. In adrenal glomerulosa cells, aldosterone biosynthesis and secretion in response to angiotensin II or extracellular potassium is dependent on a sustained influx of Ca++ through T type Ca++channels. The effect of mibefradil on the steroidogenic function of glomerulosa cells was therefore investigated. Using the patch clamp technique, we found that mibefradil inhibits selectively and in a concentration-dependent manner (IC50 = 3 μM) Ba++ T type currents in bovine glomerulosa cells. In addition to this tonic (voltage independent) inhibition, the drug also induced a shift of the steady-state inactivation curve of these channels toward hyperpolarized voltages, contributing to its efficacy to prevent Ca++ influx into the cell through T type channels. Concomitantly, mibefradil reduced the cytosolic calcium responses to potassium and angiotensin II (as assessed with fluorescent probes), without affecting the capacitative Ca++ influx, and inhibited pregnenolone and aldosterone formation. This inhibition of steroidogenesis was not exclusively due to mibefradil action on voltage-operated Ca++ channels, because this agent also partially reduced steroid synthesis induced by adrenocorticotropic hormone or forskolin, two activators of the cyclic AMP pathway. In conclusion, mibefradil is highly effective in adrenal glomerulosa cells in reducing T type channel activity and aldosterone biosynthesis, two actions that should contribute to the beneficial effect of the drug in the treatment of hypertension. The American Society for Pharmacology and Experimental Therapeutics