Increase by trifluoperazine in calcium sensitivity of myofibrils in a skinned fibre from frog skeletal muscle.

1. Since it has been demonstrated that trifluoperazine (TFP) increases the affinity for Ca2+ of troponin C as well as calmodulin, the effect of TFP was examined on the Ca2+-induced tension in mechanically skinned fibres isolated from frog skeletal muscle and on Ca2+-dependent ATPase activity of myofibrils from similar frog skeletal muscle. 2. Lower concentrations of TFP increased the Ca2+ sensitivity of myofibrils without a change in the maximum tension, giving rise to a less steep tension-pCa relationship. This effect was reversible although thorough washes were necessary. The drug also enhanced myofibrillar ATPase activity, not only at low Ca2+ concentrations but also at saturating high Ca2+ concentrations. The increased affinity of troponin C for Ca2+ is difficult to accept as the sole explanation for the stimulatory effect of TFP. 3. Half of the maximum stimulating effect was obtained between 10 and 30 microM-TFP, which is similar to the reported apparent inhibition constant (Ki) for calmodulin-dependent enzyme reactions. However, the stimulating effect of TFP cannot be attributed to its inhibition of calmodulin because of the finding that this effect was independent of Ca2+. Earlier published results (e.g. Klee & Vanaman, 1982) also support this conclusion. 4. Studies on myofibrillar ATPase activity suggest that the stimulating effect of TFP is not identical in its underlying action with those of caffeine and quercetin, which are also known as Ca2+-sensitizing drugs, having a similar eventual effect on tension development. 5. Higher concentrations of TFP decreased the maximum tension induced by high concentrations of Ca2+, while enhancing the tension in the presence of low concentrations of Ca2+. Analogous findings for ATPase activity were also made. TFP concentration for half the maximum depression was about 10 times higher than that for half the maximum stimulation. This suggests that different site(s) are involved in the stimulatory and inhibitory effects of TFP, although there may be some sites in common. 6. Discussion favours the stimulating effects of TFP as being caused considerably by the affected molecular interactions among myosin, actin, tropomyosin and troponin.