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

Oct 31, 2003Biology of reproduction

How beta-adrenergic receptors control uterine muscle activity and contraction in mid-pregnant rats

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Abstract

Three myometrial phospholipase C beta isoforms are down-regulated at midpregnancy.

PLCbeta1, PLCbeta3, and PLCbeta4 are expressed in rat myometrium, with PLCbeta4 increasing at midpregnancy.
Isoproterenol significantly reduces basal and stimulated inositol phosphate production in midpregnant rat myometrium.
Inhibition of potassium channels with tetraethylammonium and 4-aminopyridine prevents the reduction of inositol phosphate production by isoproterenol.
Isoproterenol decreases both spontaneous and agonist-induced contractions of the longitudinal layer of midpregnant rat myometrium.
Beta-adrenergic receptors may mediate uterine relaxation through both potassium channels and cyclic AMP pathways.

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We investigated whether beta-adrenergic receptors (beta-AR) regulate the phospholipase C (PLC) system in midpregnant rat myometrium. PLCbeta 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 PLCbeta1, PLCbeta3, and PLCbeta4, and to a lesser degree PLCbeta2. Quantitative analysis revealed that PLCbeta isoforms are differentially expressed during pregnancy. Indeed, the amount of PLCbeta4 is increased at midpregnancy, whereas PLCbeta1, PLCbeta2, and PLCbeta3 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 PLCbeta isoforms (PLCbeta1, PLCbeta2, and PLCbeta3) are down-regulated at midpregnancy. At this period, beta-AR reduce basal and agonist-stimulated InsP production through activation of K+ channels. Altogether, these mechanisms could act to decrease responsiveness of the longitudinal layer of myometrium to contractant factors.

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

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