Effects of verapamil on the response of the guinea‐pig tracheal muscle to carbachol

Abstract

The effects of verapamil on the contraction of the guinea‐pig tracheal smooth muscle induced by calcium (Ca²⁺) or barium (Ba²⁺) were investigated in three different conditions: (a) in excess K solution, (b) in the presence of carbachol, and (c) in excess K solution containing carbachol. In order to clarify the contractions, the effects of removal and readdition of the divalent cations were also investigated. In Ca²⁺‐loaded tissues, application of carbachol in Ca‐free medium produced a transient contraction, the magnitude of which decreased the longer the duration of exposure to Ca²⁺‐free solution. In Ca²⁺‐depleted, Ba²⁺‐loaded tissues, application of carbachol in a Ba²⁺‐ and Ca²⁺‐free medium produced a transient contraction the magnitude of which decreased the longer the duration of exposure to the Ba²⁺‐ and Ca²⁺‐free solution. After exposure to Ca²⁺‐free solution for 40 min, the sensitivity of the tissue to Ca²⁺ was greater in the presence of 30 μM carbachol (ED₅₀ = 0.06 mM) than in the presence of 40 mM K⁺ (ED50 = 0.3 mM). The Ca²⁺‐sensitivity in the presence of 30 μM carbachol plus K⁺ (40 mM) was not different from that in the presence of 30 μM carbachol alone. In Ca²⁺‐free solution, the sensitivity of the tissue to Ba²⁺ in the presence of 40 mM K⁺ (ED₅₀ = 1.4 mM) was not different from that observed in the presence of 30 μM carbachol (ED₅₀ = 1.3 mM). After exposure to Ca²⁺‐free solution, verapamil produced a parallel rightward shift in the concentration‐response curves to added Ca²⁺ and Ba²⁺ in the presence of either 40 mM K⁺, 30 μM carbachol or 40 mM K⁺ plus 30 μM carbachol. The pA₂ values of verapamil against Ca²⁺ responses in the presence of 40 mM K⁺, 30 μM carbachol and 40 mM K⁺ plus 30 μM carbachol were 7.0, 6.5 and 6.5, respectively. The pA₂ values of verapamil against Ba²⁺ responses under these conditions were 7.1, 7.0 and 7.1, respectively. It is concluded that the sustained contraction produced by carbachol requires the influx of Ca²⁺ and that Ba²⁺ can substitute for Ca²⁺ in this process. Furthermore, the ionic channels which admit Ca²⁺ may be modified by carbachol to different degrees depending on the presence of Ca²⁺ or Ba²⁺. Such changes alter the affinity of the channel to verapamil.