CELLULAR MECHANISMS OF OXYTOCIN ACTION

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The pituitary hormone oxytocin is thought to play an important role in parturition in mammals including humans. Although it has been and is extensively used to induce labor in women, little is known about its mechanism of action. Oxytocin concentration in the circulation changes little at the onset of labor, however, our previous studies in the rabbit indicate that myometrial oxytocin receptor levels increase tenfold just before the onset of labor in association with a marked increase in sensitivity to this hormone. In this project, we will utilize our recently developed dispersal and primary culture technique for rabbit uterus to characterize directly the myometrial and endometrial mechanisms of oxytocin action and also determine how they are regulated and how they interact with other uterotonic agents. We propose to characterize the post-receptor response to oxytocin by examining the production of inositol 1,4,5 triphosphate and 1,2, diacylglycerols, the elevation of intracellular calcium concentration, and myosin light chain phosphorylation. We have previously shown that the contractile sensitivity to oxytocin in rabbits increase sharply prior to term and is associated with a ten fold increase in specific receptor concentration. We will determine whether changes in receptor concentration completely explain increased sensitivity by comparing changes in receptor concentration induced by in vivo treatment with estrogen and progesterone to determine the sites at which the response cascade can be chronically regulated. We have also shown that eicosanoid production accompanies oxytocin action, that such production can enhance myometrial response to oxytocin, and that these changes can be mimicked by in nonpregnant animals by estrogen treatment. The role of diacylglycerol production via phospholipases C and arachidonate production via phospholipases A2 and C in the subcellular response to oxytocin receptor occupancy will also be examined in terms of the potential for eicosanoid production and acute regulation of response. The interaction of the endometrial and myometrial actions of oxytocin will be examined for effects on myometrial activation. To understand how this response mechanism is acutely regulated, we will determine whether the oxytocin receptors are subject to homologous or heterologous desensitization. Thee studies will provide a mechanistic basis for understanding the physiologic effects of oxytocin on myometrium. This information is necessary to ultimately determine why oxytocin is sometimes unable to cause labor or has only a brief effect to stimulate uterine contractions, despite the presence of receptors. It may also suggest methods which ensure successful induction of labor.