Regulation of Myometrial Phospholipase C System and Uterine Contraction by (beta)-Adrenergic Receptors in Midpregnant Rat

We investigated whether (beta)-adrenergic receptors ((beta)-AR) regulate the phospholipase C (PLC) system in midpregnant rat myometrium. PLC(beta) isoforms were characterized, and the effect of isoproterenol ((beta)-adrenergic agonist) was tested on myometrial inositol phosphate (InsP) production and uterine contraction. Using specific antibodies, we showed that rat myometrium expresses PLC(beta)1, PLC(beta)3, and PLC(beta)4, and to a lesser degree PLC(beta)2. Quantitative analysis revealed that PLC(beta) isoforms are differentially expressed during pregnancy. Indeed, the amount of PLC(beta)4 is increased at midpregnancy, whereas PLC(beta)1, PLC(beta)2, and PLC(beta)3 are up-regulated at term. At midpregnancy, pretreatment of myometrial strips with isoproterenol significantly reduced basal and agonist-stimulated InsP production. Forskolin, a diterpene that increases cAMP accumulation by directly activating adenylyl cyclases, had no effect on InsP production. In contrast, two global potassium (K+) channel inhibitors, tetraethylammonium (TEA) and 4-aminopyridine (4-AP), prevented attenuation of InsP production by isoproterenol. Isoproterenol also significantly decreased spontaneous and agonist-induced contraction of the longitudinal layer of midpregnant rat myometrium. Preincubation of uterine strips with TEA plus 4-AP prior to (beta)-AR activation blocked only partial uterine relaxation, whereas Forskolin was as potent as isoproterenol. This indicates that (beta)-AR operate through both K+ channels and cAMP to induce uterine relaxation. In conclusion, we show for the first time that three myometrial PLC(beta) isoforms (PLC(beta)1, PLC(beta)2, and PLC(beta)3) are down-regulated at midpregnancy. At this period, (beta)-AR reduce basal and agoniststimulated InsP production through activation of K+ channels. Altogether, these mechanisms could act to decrease responsiveness of the longitudinal layer of myometrium to contractant factors.