Effects of trifluoperazine on the contraction kinetics of the isolated intact tracheal and pulmonary artery smooth muscle.

Abstract

We studied the effect of the calmodulin antagonist trifluoperazine (TFP) on isolated intact rat tracheal and pulmonary artery smooth muscle contractile behaviour. Experimental series: 1) TFP-dose-response curves for TFP's effect on force generation were constructed using rat tracheal smooth muscles and rat pulmonary artery preparations (n = 8). A concentration of 1 micromol/l TFP was chosen for the subsequent experimental series. 2) Tracheas and pulmonary arteries (n = 14) were dissected in three segments. One of them was used immediately for experiments ("native"), the other two were treated for 12 h in 4 degrees C Tyrode solution without ("12 h cold storage") or with 1 micromol/l TFP ("12 h cold storage + TFP"). These preparations contracted after supramaximal effective electrical field stimulation. The force-clamping technique was used to analyse kinetic and mechanical parameters of smooth-muscle contraction in both types of preparation (measurement conditions: resting tension 2 mN, 37 degrees C, modified Krebs-Henseleit solution). 1) TFP decreased developed force dose-dependently in pulmonary artery and tracheal smooth muscle. 2) During sustained tonic activation, the contraction kinetics become slower both with and without TFP treatment (p < 0.0001). 3) TFP caused a dramatic retardation of the velocity of force generation in both types of preparation for any given time interval during the course of a tonic activation (p < 0.0005). 4) The dramatic effects of TFP on the contraction kinetics were not associated with effects on the extent of force generation. These results support the assumption that tracheal and pulmonary artery smooth muscle cross-bridge rates are controlled by a calcium-calmodulin-dependent myosin light chain kinase. This finding suggests the involvement of a calmodulin-independent regulator process responsible for the changes observed in the cross-bridge cycling rates during sustained tonic activation. A direct intervention on the contractile apparatus level is a measure for reduction of smooth-muscle tone without negative inotropic side effects.