The oxytocin-oxytocin receptor system and its antagonists as tocolytic agents

Abstract

Oxytocin, a hormone involved in numerous physiologic processes, plays a central role in the mechanisms of parturition and lactation. It acts through its receptor, which belongs to the G-protein-coupled receptor superfamily, while Gq/phospholipase C (PLC)/inositol 1,4,5-triphosphate (InsP3) is the main pathway via which it exerts its action in the myometrium. Changes in receptor levels, receptor desensitization, and locally produced oxytocin are factors that influence the effect of oxytocin on uterine contractility in labor. Activation of oxytocin receptor causes myometrial contractions by increasing intracellular Ca(+2) and production of prostaglandins. Since oxytocin induces contractions, the inhibition of its action has been a target in the management of preterm labor. Atosiban is today the only oxytocin receptor antagonist that is available as a tocolytic. However, the quest for oxytocin receptor antagonists with a better pharmacological profile has led to the synthesis of peptide and nonpeptide molecules such as barusiban, retosiban, L-368,899, and SSR-126768A. Many of these oxytocin receptor antagonists are used only as pharmacological tools, while others have tocolytic action. In this paper, we summarize the action of oxytocin and its receptor and we present an overview of the clinical and experimental data of oxytocin antagonists and their tocolytic action.

Figure 1

Oxytocin receptor linked signaling pathways resulting in myometrial contraction. Binding of OT to OTR activates Gα _q/11 and then PLC, which hydrolyses PIP2 to InsP3 and DAG. InsP3 causes release of Ca²⁺ from the sarcoplasmic reticulum, while DAG activates PKC. Gα _q/11 also causes activation of voltage-regulated Ca²⁺ channels and Ca²⁺ entry into the cells. Ca²⁺ binds to calmodulin, and the Ca²⁺-calmodulin complex activates MLC kinase, resulting in myometrial contraction. Both OTR and PKC activate the MAPK cascade, while OTR and MAPK result in increased cPLA2 activity. Increased cPLA2 activity and MAPK activation result in prostaglandin production, which also contributes to the contractile effect. The activation of the RhoA-ROK cascade by the OTR is another pathway that results in increased MLC phosphorylation and myometrial contraction. OT: oxytocin, OTR: oxytocin receptor, PLC: phospholipase, PIP2: phosphatidylinositol 4,5-bisphosphate, InsP3: inositol 1,4,5- triphosphate, DAG: diacylglycerol, PKC: protein kinases type C, MLC: myosin light-chain, MAPK: mitogen-activated protein kinase, cPLA2: cytosolic phospholipase A2, ROK: RhoA associated protein kinase.

Figure 2

The structure of oxytocin, arginine vasopressin, and atosiban.