Trifluoperazine, a calmodulin inhibitor, blocks secretion in cultured chromaffin cells at a step distal from calcium entry

Trifluoperazine, a calmodulin antagonist, inhibited the secretory response of cultured bovine adrenal medullary chromaffin cells to acetylcholine (10 −4M) or a depolarizing concentration of [K +] (56 mM KCl) in a dose-related fashion. The ID 50s of this effect were2 × 10 −7M and2.2 × 10 −6M for acetylcholine and high [K +], respectively. A decrease in external [Ca 2+] concentration of the incubation medium from 4.4 to 0.275 mM resulted in an increase in the percentage of inhibition produced by trifluoperazine on the acetylcholine-evoked secretory response from 20.7 to 96.5%, respectively. However, trifluoperazine inhibited the acetylcholine-evoked catecholamine output by a similar absolute magnitude for all [Ca 2+] concentrations tested with the exception of 4.4 mM [Ca 2+]. Trifluoperazine, unlike the [Ca 2+] channel blocker Ni 2+, in concentrations (10 −6−10 −5 M) that were found to inhibit significantly [K +]-induced amine output did not modify [K +]-induced 45Ca uptake or 45Ca efflux. However, trifluoperazine at a concentration of2.5 × 10 −5M was found to produce a small decrease in the 45Ca efflux curve and a decrease in the [K + ]-evoked 45Ca uptake of30 ± 14% ( n = 6). In addition,2.5 × 10 −6M trifluoperazine, a concentration which was found to suppress high [K +]-induced amine release by64 ± 5%, did not inhibit the 45Ca 2+−Ca 2+ exchange mechanism. These results demonstrate that trifluoperazine, an antipsychotic agent with anticalmodulin activity, blocks catecholamine release from cultured chromaffin cells at a step distal from calcium entry and, consequently, suggests a role for calmodulin in the secretory process of these cells.