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 F2 alpha (PGF2 alpha) and inositol 1,4,5-trisphosphate (IP3) on 45Ca2+ mobilization in permeabilized rat myometrial cells and to examine the activation of the inositol lipid cycle in intact myocytes. Cells were isolated from late pregnant rat myometrium and used as confluent monolayers after a single passage. All four agonists caused a biphasic release of 45Ca2+ from non-mitochondrial pool(s), with the rank order of potency: oxytocin > PGF2 alpha > ET-1 > IP3. Inhibitors of phospholipase C blocked ET-1- and oxytocin-promoted but not PGF2 alpha-promoted 45Ca2+ efflux. Similarly, heparin, an IP3 receptor blocker, failed to inhibit PGF2 alpha-induced 45Ca2+ release while inhibiting the action of the other agonists. Endothelin-1 and oxytocin stimulated inositol phosphate accumulation at concentrations similar to those that promoted 45Ca2+ efflux, whereas about 100 times higher concentrations of PGF2 alpha were needed to activate this signaling pathway in intact cells. It is concluded that the primary action of PGF2 alpha in myometrial cells is to enhance Ca2+ influx, whereas oxytocin and ET-1 receptors are coupled to phospholipase C, generating IP3 and raising the intracellular concentration of free Ca2+ from intracellular as well as extracellular sources.