Endocrinology, Vol 132, 1489-1496, Copyright © 1993 by Endocrine Society

ARTICLES

Peripheral-type benzodiazepines inhibit calcium channels and aldosterone production in adrenal glomerulosa cells

CP Python, MF Rossier, MB Vallotton and AM Capponi
Division of Endocrinology, University Hospital, Geneva, Switzerland.

Angiotensin-II (Ang-II), K+, and ACTH are important stimulators of aldosterone secretion that require Ca2+ influx to be active. However, Ang-II and K+ are linked to the Ca2+ messenger system, while ACTH is coupled to the cAMP pathway. Peripheral-type binding sites for benzodiazepines are particularly abundant in steroidogenic tissues and have been proposed to be involved in the steroidogenic action of ACTH in Y-1 adrenocortical cells. We report here that in adrenal glomerulosa cells, peripheral-type [4'-chlor-diazepam (CDZ), 1-(2-chlorophenyl)N- methyl-N-(1-methylpropyl)3-isoquinolinecarboxamid e (RP 52028), and flunitrazepam], but not a central-type (flumazenil) benzodiazepine reversibly abolished the stimulation of aldosterone output induced by Ang-II or K+, while they had no significant effect on basal aldosterone secretion. This inhibitory effect depended upon drug concentration (IC50 30 microM for CDZ) and affected the potencies of both stimulators, without altering their respective EC50 values. Similar results were obtained when aldosterone production was stimulated with ACTH, forskolin, or (Bu)2cAMP. Aldosterone production from exogenous 25- hydroxycholesterol or progesterone was partially inhibited by CDZ. In glomerulosa cells loaded with a fluorescent Ca2+ probe, benzodiazepines blocked Ca2+ influx triggered by K+ or Ang-II without affecting the release of Ca2+ from intracellular stores induced by Ang-II. T- and L- type Ca2+ channel activities, monitored with the patch-clamp technique, were both inhibited within the same range of concentrations as aldosterone synthesis and Ca2+ influx. These results indicate that in adrenal zona glomerulosa cells, peripheral-type benzodiazepines block Ca2+ influx through voltage-activated channels. The combined action of peripheral-type benzodiazepines on calcium influx and precursor conversion may be responsible for the observed inhibition of Ang-II-, K(+)-, or ACTH-induced aldosterone secretion.

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