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Vol. 287, Issue 3, 824-831, December 1998
Division of Endocrinology and Diabetology, 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.
0022-3565/98/2873-0824$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics
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