REGULATION OF MYOMETRIAL CYCLASE ISOTYPE EXPRESSION

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Mechanisms underlying normal changes in uterine tone are not well understood. Pathological situations of increased uterine tone lead to conditions such as preterm labor and uterine hypertonus during labor analgesia. A proposed mechanism of uterine hypertonus involves acute decreases in catecholamine levels, but the relevant myometrial signal transducing pathways have not been fully elucidated. The most important pathways producing uterine contraction and relaxation are the oxytocin (OT) and the beta adrenergic receptor (betaAR)-mediated pathways. Our goal is to understand crossregulation between these two pathways in nonpregnant myometrium, how pregnancy affects crossregulation, and how crossregulation affects responses to changes in betaAR activity. Preliminary results show that chronic OT pretreatment inhibits basal and stimulated adenylyl cyclase (AC) activity in vivo and in vitro. We hypothesize that OT-induced dysfunction of the stimulatory AG pathway, at the level of AC, leads to uterine hypertonus as betaAR input is withdrawn. We will study cultured pregnant and nonpregnant rat and human myometrial cells pretreated with OT. To identify the mechanism of crossregulation, we will measure numbers and affinities of betaAR and OT receptors, and AC activity. To identify the role of specific isoforms of AC, we will determine presence and quantities of mRNA for those isoforms involved in the down-regulation of AG. To further develop a model of in vivo responses, we will characterize cultured cells from nonpregnant and pregnant rats and human subjects. Knowledge of crossregulation as a common mechanism of uterine hyperactivity will lead to prevention of fetal distress and preterm labor, thus reducing the number of unnecessary cesarean sections. This will result in improved care of both the mother and child and to decreased costs of childbirth and prematurity.