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(-4) M) or a depolarizing concentration of [K+] (56 mM KCl) in a dose-related fashion. The ID50s of this effect were 2 x 10(-7) M and 2.2 x 10(-6) M for acetylcholine and high [K+], respectively. A decrease in external [Ca2+] 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 [Ca2+] concentrations tested with the exception of 4.4 mM [Ca2+]. Trifluoperazine, unlike the [Ca2+] channel blocker Ni2+, 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 of 2.5 x 10(-5) M was found to produce a small decrease in the 45Ca efflux curve and a decrease in the [K+]-evoked 45Ca uptake of 30 +/- 14% (n = 6). In addition, 2.5 x 10(-6) M trifluoperazine, a concentration which was found to suppress high [K+]-induced amine release by 64 +/- 5%, did not inhibit the 45Ca2+-Ca2+ 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.
D000109:Acetylcholine / Q000494:pharmacology; D000313:Adrenal Medulla / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors*; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000502:physiology; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D046508:Culture Techniques; D007473:Ion Channels / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism; D012636:Secretory Rate / Q000187:drug effects; D014268:Trifluoperazine / Q000494:pharmacology*
D002135:Calcium-Binding Proteins; D002147:Calmodulin; D002395:Catecholamines; D007473:Ion Channels; D014268:Trifluoperazine; D000109:Acetylcholine; D002118:Calcium; D009638:Norepinephrine