Effects of chlorpromazine on the electrical and mechanical properties of intact and skinned muscle cells of guinea-pig mesenteric artery.

1 Effects of chlorpromazine on the contraction evoked in intact muscles, and of chlorpromazine or calmodulin on the contraction evoked in the saponin-treated skinned muscles of the guinea-pig mesenteric artery were investigated. 2 Chlorpromazine, above 5 X 10(-7) M, depolarized the membrane and reduced the membrane resistance measured from the current-voltage relationships at the depolarized and resting membrane potential levels. 3 The contraction evoked by excess [K]o, NaCl-free Krebs and by caffeine was suppressed by application of chlorpromazine; contractions induced by the former two treatments were suppressed to a greater extent than those induced by the latter. Contractions induced by excess [K]o or NaCl-free Krebs ceased in Ca-free solution, but not those induced by caffeine, i.e. influxes of Ca across the membrane were more suppressed than was the the release of Ca from the storage sites by chlorpromazine. 4 In skinned muscles, chlorpromazine suppressed and calmodulin enhanced the Ca-induced contraction in a dose-dependent fashion. The minimum concentration of chlorpromazine required to suppress the Ca-induced contraction (10-5 M) was 10(-6) M and that of calmodulin to enhance the Ca-induced contraction was 10(-7) M. 5 After skinned muscles had been loaded with Ca, chlorpromazine or calmodulin itself did not induce the contraction by the release of stored Ca in the cell. However, calmodulin increased and chlorpromazine suppressed the accumulation of Ca into the storage site (presumably sarcoplasmic reticulum). 6 From the present results, it is suggested that chlorpromazine acts on the surface membrane and suppresses Ca-influx, thus causing a relaxation of the mesenteric artery. However, when chlorpromazine or calmodulin was applied to skinned muscles, the former suppresses and the latter enhances the Ca accumulation into the storage site and the activation of contractile proteins. Thus chlorpromazine causes the relaxation of the vascular tissue. However, a lower concentration of chlorpromazine was required to suppress the Ca influx than to suppress the Ca accumulation into the storage site or the activity of calmodulin in contractile protein. Thus vasodilatation induced by chlorpromazine in vitro, is mainly due to the suppression of Ca influx.