Calix[4]arene С-956 as a selective inhibitor of Ca2+-pump of the plasma membrane and a modulator of the contractile function in the myometrium

Abstract

Background. At present, creating and testing pharmacological instruments for selective inhibition of Са2+-pump of the plasma membrane, which would become the foundation for medical preparations, for instance, for the treatment of the impaired excitability of the cardiac and smooth muscles, remains critically significant. We have demon­strated in our previous experiments that calix[4]arene С-956 is effective in inhibi­ting Са2+, Mg2+-ATPase activity of the plasma membrane of myometrium cells. The aim of this study was to investigate the regularities and mechanisms of the impact of calix[4]arene С-956 on Са2+-transporting activity of Са2+, Mg2+-ATPase of the plasma membrane (PM) and the contractile function of rat myometrium. Materials and Methods. The experiments were conducted using outbred white non-pregnant rats. Ca2+-transporting activity of myocytes PM preparations loaded with Ca2+-sensitive fluorescent probe fluo-4 AM was investigated. The registration of the contractile activity in the preparations of longitudinal smooth muscles of uterine horns with preserved endothelium was done in the isometric mode. Results. It was determined that calix[4]arene C-956 causes blocking of the transport function of the calcium pump of preparations of plasma membranes of uterine myocytes. The C-956 compound causes an increase in the amplitude of spontaneous contractions and a change in their mechanokinetic parameters during a short-term effect on multicellular preparations of rat myometrium. Calix[4]arene C-956 also significantly affects the contractions caused by high-potassium depolarization of the PM and oxytocin, increa­sing their amplitude and decreasing the rate of relaxation. Blocking the synthesis of nitric oxide significantly enhances the effects of C-956 on spontaneous and high-potassium- and oxytocin-induced contractions of the myometrium. Conclusions. The results of our research indicate that the main target of the action of calix[4]arene C-956 on myocytes is the calcium pump of the PM. With the preliminary inhibition of nitric oxide synthases followed by the use of C-956, we were able to fully demonstrate the contribution of the calcium pump of the PM to the regulation of uterine contractions.