Tyrphostin-23 is commonly used as inhibitor of tyrosine kinase (TK). We found that tyrphostin-23 concentration-dependently increased basal steroid-hormone secretion from dispersed human and rat adrenocortical cells, the maximal effective concentration being 10^-5 M. Tyrphostin-23 (10^-5 M) enhanced 10^-9 M angiotensin-II- and endothelin-1-stimulated secretion of human and rat adrenocortical cells, but not the secretory response to 10^-9 M ACTH. However, it increased the response to lower concentrations (10^-12 or 10^-11 M) of ACTH. The secretagogue effect of tyrphostin-23 on dispersed rat adrenocortical cells was abolished by either the adenylate cyclase inhibitor SQ-22536 (10^-4 M) or the protein kinase A (PKA) inhibitor H-89 (10^-5 M). Tyrphostin-23 (10^-5 M) raised basal cyclic-AMP release by dispersed rat adrenocortical cells, but in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX, 10^-3 M) it was ineffective. Both tyrphostin-23 and IBMX increased cyclic-AMP release by rat adrenocortical cells in response to 10^-10 M ACTH, and their effects were not additive. Taken together, our findings suggest that tyrphostin-23, acting as an inhibitor of phosphodiesterases in adrenocortical cells, increases the intracellular concentration of cyclic-AMP available for PKA activation thereby stimulating steroid-hormone secretion. They also stress that caution must be used in interpreting the results of studies aimed at investigating the possible cross-talk between adenylate cyclase- and TK-dependent signaling cascades.