Effects of oestradiol and tamoxifen on oxytocin-induced phospholipase C activation in human myometrial cells

Abstract

The role of oestradiol in the control of uterine responsiveness to oxytocin was investigated by measuring oxytocin-induced phospholipase C activation in [3H]inositol-labelled cultured human myometrial cells. Addition of oestradiol to steroid-free culture medium (10% (v/v) fetal calf serum treated with dextran-coated charcoal in phenol red-free medium) enhanced formation of inositol phosphates and this effect was completely abolished by the anti-oestrogen tamoxifen. The inhibitory effect of tamoxifen on oxytocin-induced phospholipase C activation occurred in both steroid-free and complete culture medium; it was time- and concentration-dependent and was only partly reversed by oestradiol. When phospholipase C was activated with PGF2 alpha or fluoroaluminate instead of oxytocin, oestradiol and tamoxifen had the same stimulatory and inhibitory effects, respectively. The inhibitory effect of tamoxifen could not be prevented by treating the cells with pertussis toxin. Moreover, the effect of tamoxifen was not mediated by inhibition of protein kinase C, since the use of staurosporine (a protein kinase inhibitor) resulted in potentiation of phospholipase C activation by oxytocin. Both oestradiol and tamoxifen increased [3H]inositol incorporation into cellular lipids and cell proliferation. These results suggest that oestradiol enhances myometrial responsiveness to oxytocin and other agonists by facilitating phospholipase C activation at a post-receptor level. This effect is antagonized by tamoxifen; however, tamoxifen also has oestrogen-independent inhibitory effects.

Up-regulation of rat myometrial phospholipases Cβ1 and Cβ3 correlates with increased term sensitivity to carbachol and oxytocin

“…Indeed, up to date, only corticoids were reported to regulate the expression of PLC enzymes (Dwivedi & Pandey 1999, Cueille et al 2003. Furthermore, although oestradiol was suggested to facilitate norepinephrine-, CCh-and OTinduced PLC activation at a post-receptor level in the myometrium (Riemer et al 1987, Phaneuf et al 1995, Abdalla et al 2000, no studies have addressed its direct effect on PLC expression. Our findings indicated that administration of oestradiol to rats triggers the expression of myometrial PLC 1 and PLC 3 to a level normally observed between day 21 of pregnancy and term.…”

The Oxytocin‐induced Inward Current in Vagal Neurons of the Rat is Mediated by G Protein Activation but not by an Increase in the lntracellular Calcium Concentration

“…Thus, neuronal oxytocin receptors, like oxytocin receptors in uterine smooth muscle cells, belong to the Gprotein-coupled family. In the uterus, oxytocin receptors are linked to a G protein possessing aq/ll subunits (Arnaudeau et al, 1994;Ku et al, 1995;Phaneuf et al, 1995). The identity of the G protein coupled to neuronal oxytocin receptors is not yet known.…”

Inositol supplementation in pregnancies at risk of apparently folate‐resistant NTDs

“…Patients were particularly instructed to note any possible adverse pregnancy events, in particular myometral contractions, which might be associated with inositol therapy (Phaneuf et al, 1995).…”