Inhibitory action of mibefradil on calcium signaling and aldosterone synthesis in bovine adrenal glomerulosa cells

Mibefradil is a new cardiovascular drug with peculiar Ca++ antagonistic pro perties. The most remarkable feature of mibefradil is its unique relative s electivity for T type calcium channels, a property that has been proposed t o explain in part the beneficial pharmacological and clinical profiles of t his drug. In adrenal glomerulosa cells, aldosterone biosynthesis and secret ion in response to angiotensin It or extracellular potassium is dependent o n a sustained influx of Ca++ through T type Ca++ channels. The effect of mi befradil on the steroidogenic function of glomerulosa cells was therefore i nvestigated. Using the patch clamp technique, we found that mibefradil inhi bits selectively and in a concentration-dependent manner (IC50 = 3 mu M) Ba ++ T type currents in bovine glomerulosa cells. In addition to this tonic ( voltage independent) inhibition, the drug also induced a shift of the stead y-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 r esponses to potassium and angiotensin II (as assessed with fluorescent prob es), without affecting the capacitative Ca++ influx, and inhibited pregneno lone and aldosterone formation. This inhibition of steroidogenesis was not exclusively due to mibefradil action on voltage-operated Ca++ channels, bec ause this agent also partially reduced steroid synthesis induced by adrenoc orticotropic hormone or forskolin, two activators of the cyclic AMP pathway . In conclusion, mibefradil is highly effective in adrenal glomerulosa cell s in reducing T type channel activity and aldosterone biosynthesis, two act ions that should contribute to the beneficial effect of the drug in the tre atment of hypertension.