Hormonal Interactions in the Uterus: Inhibition of Isoproterenol-Induced Accumulation of Adenosine 3′:5′-Cyclic Monophosphate by Oxytocin and Prostaglandins

Abstract

Interactions of hormones stimulating and inhibiting uterine contraction were studied in vitro in uteri from oophorectomized rats. The ,3-adrenergic effector, isoproterenol, a potent inhibitor of contraction, produced a dose-related increase of adenylate cyclase and accumulation of adenosine 3' :5'-cyclic monophosphate (cAMP) that was inhibitable by propranolol. Oxytocin, which stimulates contraction, effectively inhibited accumulation of uterine cAMP induced by isoproterenol in the presence or absence of theophylline. Prostaglandins E2 and F2a, each at a maximum effective concentration of 0.5 AMM, also inhibited accumulation of cAMP induced by isoproterenol, consistent with their effect in stimulation of uterine contraction. Prostaglandin E2, but not prostaglandin F2a, stimulated cAMP accumulation in a dose-related manner at concentrations in excess of 0.5 MM. Neither propranolol nor oxytocin inhibited that response. Bovine endometrial adenylate cyclase failed to respond to isoproterenol but was stimulated by prostaglandins El and E2. When myometrial preparations were studied, isoproterenol stimulation and prostaglandin effects were observed as for whole castrate uterus. The competitive physiological actions of ,B-adrenergic effectors on the one hand, and oxytocin and prostaglandins on the other hand, are based on their influences on a myometrial adenylate cyclase. Stimulation of uterine cAMP accumulation by prostaglandin Ea is due to action at a different and unrelated site.Uterine tissue is designed to respond specifically to hormonal influences in order to provide the appropriate environment for implantation, fetal growth and development, and parturition. It appears to be ideal for study of the relationship between steroid-mediated and cAMP-mediated responses. Recently, it was shown that smooth muscle, particularly uterus, has an adenylate cyclase system whose activation by ,B-adrenergic effectors resulted in inhibition of contractility (1-4). It was further demonstrated that contractions produced by oxytocin, acetylcholine, and calcium were inhibited by fl-adrenergic effectors, theophylline, and dibutyryl-cAMP (3, 4) in association with an increase in adenylate cyclase activity (5-7). Prostaglandins, particularly those of the E series, are potent stimulators of uterine contraction despite the fact that they stimulate uterine adenylate cyclase activity (7,8).In these studies, we show that the stimulatory effects of oxytocin and prostaglandins E2

Specific inhibition by prostaglandins E2 and I2 of histamine-stimulated [14C]aminopyrine accumulation and cyclic adenosine monophosphate generation by isolated canine parietal cells.

“…There are other examples in the literature of inhibition of hormone-stimulated cyclic AMP function by prostaglandins (31,32). However, in certain cell types, such as platelets (33,34) and heart tissue (35), prostaglandins in concentrations in the nanomolar range may also stimulate adenylate cyclase, whereas in other cell types, this action is only found at 1,000-fold higher concentrations (36,37).…”

Chronic Oxytocin Pretreatment Inhibits Adenylyl Cyclase Activity in Cultured Rat Myometrial Cells1

“…During pregnancy, the uterus becomes more sensitive to oxytocin, primarily because of increased concentrations of oxytocin receptors [4]. Myometrial oxytocin receptors couple to the G proteins G q [5] and G i [6,7]. Increases in uterine contractility by activation of these G proteins occur acutely, during occupation of the oxytocin receptor by oxytocin.…”

Relation of c-AMP to Relaxation of Pulmonary Artery

“…Other workers have found, under various cir cumstances, that relaxation could occur without any increase in c-AMP; e.g., in Ca++-deficient solutions [Andersson et al, 1972], with papaverine [Triner et al, 1970;, etc. Furthermore, prostaglandin E2 increases c-AMP in rat myometrium associated with contraction [Bhalla et al, 1972;H arbon and Clausen, 1971; Vesin and Harbon, 1974], and angiotensin contracts myometrium despite elevated c-AMP levels [Angles d'AuRiAC and M eyer, 1972].…”