Trifluoperazine inhibits the contraction of cultured rat cardiac cells and the phosphorylation of myosin light chain.

Cultured, spontaneously beating heart cells were used to study the role of calmodulin in regulating cardiac contraction. Trifluoperazine (TFP), an antipsychotic drug that binds to calmodulin, reversibly inhibited myocardial contraction. This effect occurred over a TFP concentration range of 5-100 muM with half maximal activity at approximately 15 muM TFP. When the phosphoprotein profile of TFP-treated cells was compared with control cultures, there was a significant decrease in (32)P content of the 20,000-D myosin light chain. As measured by two-dimensional gel electrophoresis, the fraction of phosphorylated myosin light chain decreased from 0.31+/-0.06 in control to 0.16+/-0.05 in TFP-treated cells (P < 0.05). This inhibition of protein phosphorylation was relatively selective, as two other phosphoproteins ( approximately 41,000 and 36,000 D) were unaffected, and a third protein ( approximately 28,000 D) showed an increase in (32)P activity. In contrast, the cessation of spontaneous beating by 50 mM KCl did not reproduce these changes. This inhibition of contraction mediated by TFP associated with alterations in the phosphorylation of certain cardiac phosphoproteins suggests a role for calmodulin and for the myosin light chain in the regulation of cardiac cell contraction.