Stress stimulates the adrenal medulla to rapidly secrete catecholamines (CAs), and the adrenal cortex to release progesterone (PROG), which may locally regulate stress-induced CA release. We used bovine chromaffin cells to investigate the effects of PROG on CA secretion. PROG dose-dependently inhibited CA secretion induced by nicotinic acetylcholine receptor (nAChR) agonist 1,1-dimethyl-4-phenlypiperazinium iodide (DMPP) up to 77%. Pre-incubation with PROG up to 1 h increased this inhibition. 3α,5α-
Tetrahydroprogesterone (3α,5α-THP) and dexamethasone were less potent inhibitors. Patch-clamp techniques revealed that PROG co-applied with DMPP inhibited peak DMPP-induced current up to 68%and with 3 min pre-incubation inhibited both peak and integrated current up to
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95%. Monitoring of FURA-2 showed that PROG similarly inhibited parallel changes in intracellular-free Ca
++ concentration. PROG also inhibited CA secretion elicited by elevated K
+ (38%), and, in single cells, suppressed Ca
++ current evoked by step depolarization, inhibiting amplitude by 15%, and reducing the time constant of current decay during depolarization by 57%. In contrast to the immediate inhibition of nicotinic current, inhibition of Ca
++ current became statistically significant only after 1 min exposure to PROG. PROG did not inhibit secretion stimulated by high Ca
++ perfusion of permeabilized cells. These data suggest that PROG inhibits CA secretion from chromaffin cells predominantly by rapidly inhibiting nAChRs, and by gradually enhancing the inactivation of voltage-dependent Ca
++ channels (VDCCs), but not by affecting secretory processes downstream of Ca
++ influx. This study supports a role for adrenocortical PROG in the regulation of CA secretion during stress.