Blockade by calmodulin inhibitors of Ca²⁺ channels in smooth muscle from rat vas deferens

Abstract

• 1

  Effects of three compounds which are used as calmodulin inhibitors (trifluoperazine, W-7 and calmidazolium) on Ca²⁺ channels were investigated in smooth muscle from rat vas deferens.

• 2

  All three calmodulin inhibitors relaxed the smooth muscle precontracted by a high concentration of KCl (63.7 mm). The order of potency for the relaxation was trifluoperazine > W-7 > calmidazolium.

• 3

  In binding studies using a microsomal fraction of vas deferens, all these calmodulin inhibitors displaced specific [³H]-nimodipine binding. Trifluoperazine and W-7 inhibited the binding at concentrations that relaxed the smooth muscle whereas calmidazolium inhibited at concentrations much lower than those necessary for muscle relaxation.

• 4

  Ba²⁺ current flowing through voltage-gated Ca²⁺ channels was measured under whole-cell voltage-clamp conditions in isolated smooth muscle cells. The Ba²⁺ current was suppressed by the three calmodulin inhibitors in the concentration-range where inhibition of [³H]-nimodipine binding was observed. Neither voltage-dependence nor the inactivation time course of Ba²⁺ current were affected by these compounds.

• 5

  The results suggest that the calmodulin inhibitors directly block Ca²⁺ channels in the smooth muscle cells. The channel inhibition by trifluoperazine and W-7, but perhaps not that by calmidazolium, may be responsible for the muscle relaxation observed with these compounds.