SIGNAL-TRANSDUCTION IN RAT MYOMETRIAL CELLS - COMPARISON OF THE ACTIONS OF ENDOTHELIN-1, OXYTOCIN AND PROSTAGLANDIN-F2-ALPHA

The objectives of this study were to evaluate and compare the actions of endothelin-1 (ET-1), oxytocin, prostaglandin F-2 alpha (PGF(2 alpha )) and inositol 1,4,5-trisphosphate (IP3) on Ca-45(2+) mobilization in permeabilized rat myometrial cells and to examine the activation of t he inositol lipid cycle in intact myocytes. Cells were isolated from l ate pregnant rat myometrium and used as confluent monolayers after a s ingle passage. All four agonists caused a biphasic release of Ca-45(2) from non-mitochondrial pool(s), with the rank order of potency: oxyt ocin > PGF(2 alpha) > ET-1 > IP3. Inhibitors of phospholipase C blocke d ET-1- and oxytocin-promoted but not PGF(2 alpha)-promoted Ca-45(2+) efflux. Similarly, heparin, an IP3 receptor blocker, failed to inhibit PGF(2 alpha)-induced Ca-45(2+) release while inhibiting the action of the other agonists. Endothelin-1 and oxytocin stimulated inositol pho sphate accumulation at concentrations similar to those that promoted 4 5Ca(2+) efflux, whereas about 100 times higher concentrations of PGF(2 alpha) were needed to activate this signaling pathway in intact cells . It is concluded that the primary action of PGF(2 alpha) in myometria l cells is to enhance Ca2+ influx, whereas oxytocin and ET-1 receptors are coupled to phospholipase C, generating IP3 and raising the intrac ellular concentration of free Ca2+ from intracellular as well as extra cellular sources.