THG113.31, a specific PGF2alpha receptor antagonist, induces human myometrial relaxation and BKCa channel activation

Single and whole-cell electrophysiological BKCa channel recordings from freshly dispersed myocytes, were investigated in the presence and absence of THG113.31. Functional studies investigated the effects of THG113.31 on isolated spontaneous myometrial contractions, in the presence and absence of the BKCa channel blocker, iberiotoxin.Single channel recordings identified the BKCa channel as a target of THG113.31. THG113.31 significantly increased the open state probability of these channels [control 0.023+/-0.006; 10 microM THG113.31 0.087+/-0.012 (P = 0.009); and 50 microM THG113.31 0.1356+/-0.018 (P = 0.001)]. In addition, THG113.31 increased whole-cell BKCa currents over a range of membrane potentials, and this effect was reversed by 100 nanoM IbTX. Isometric tension studies demonstrated that THG113.31 exerted a significant concentration-dependent relaxant effect on human myometrial tissue and pre-incubation of strips with IbTX abolished this effect on spontaneously occurring contractions.These data suggests that activation of the BKCa channel may contribute, at least partially, to the uterorelaxant effect of THG113.31.The mechanisms underlying the onset and maintenance of human parturition are poorly understood [1,2]. During pregnancy and labour the uterus undergoes dramatic changes in its contractile activity when it is transformed from a relatively quiescent state during pregnancy to a state of maximal contractile activity at labour onset. The exact regulatory mechanisms for this process are unclear [3,4], but what is well established, is that abnormalities of this process have major clinical implications. Preterm labour is the single largest cause of perinatal mortality in developed countries and is a major contributor to neonatal morbidity and childhood developmental problems [1,5,6]. In addition, these problems constitute an immense cost to healthcare resources.PGF2α plays a pivotal role in parturition [7-9]. It is the most effective smooth muscle contractile