Proceedings of The Physiological Society

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCA333

Poster Communications

The effect of dual combination of Magnesium sulphate with atosiban and indomethacin on myometrial contractions of pregnant mouse

B. Osaghae1, S. Arrowsmith1, S. Wray1

1. University of Liverpool, Liverpool, United Kingdom.

Preterm birth is a major cause of neonatal morbidity. It currently accounts for approximately 10% of all births and about 51% of infant deaths in the UK. Several types of tocolytics (uterine relaxants) have been tested for the treatment of preterm labour: oxytocin receptor antagonists e.g. atosiban, calcium channel blockers, e.g. nifedipine, prostaglandin synthetase inhibitor e.g. indomethacin, β- adrenoceptor agonist e.g. ritodrine and Magnesium sulphate (MgSO4). The most commonly used tocolytics in the UK are atosiban, indomethacin and nifedipine. MgSO4 is not used as a tocolytic in the UK, but is given to women in threatened early preterm birth (before 30 weeks) as a fetal neuroprotectant to substantially reduce the risk of cerebral palsy. We hypothesized that MgSO4 in combination with other tocolytics may cause synergistic inhibition of myometrial contraction. The aim of the study is to compare the tocolytic efficacy of atosiban and indomethacin, used in combination with MgSO4, to see whether the combination of these drugs, which act via different pathways, could improve the inhibition of oxytocin augmented uterine contractility in term pregnant mouse myometrium. Longitudinal myometrial strips were obtained from term pregnant C57BL/6J mice (19 days gestation). Contractile activity was recorded using digital software (Labtrax). MgSO4 was applied in increasing concentrations between 2mM and12mM, either alone or in combination with indomethacin or atosiban at their predetermined IC50 values. Each concentration of MgSO4 was applied for 15 minutes. Control contractile activity and activity after addition of each combination were measured using the last 10 minutes of activity and the changes expressed as a percentage of control (100%). Values were compared by one way ANOVA and Bonferroni post hoc test. P<0.05 was considered to be significant. The IC50 values of atosiban and indomethacin were found to be 300nM and 30µM respectively and were taken forward for combination with MgSO4. 12mM MgSO4 alone reduced force integral to 44.31± 8.67% of control. With the addition of indomethacin, contractions reduced to 48.43±2.69% (n=6); P = not significant. MgSO4 in combination with atosiban reduced contractions to 1.35±1.05% (n=7) of control; P<0.0001. Values are expressed as mean ± SEM. Our preliminary in vitro data demonstrated that the combination of MgSO4 and atosiban exhibits a greater effect for mouse myometrial inhibition than MgSO4 alone or in combination with indomethacin. The greater inhibitory effect observed may be explained by atosiban's mechanism of action as an oxytocin receptor antagonist. This suggests that atosiban may be a more promising tocolytic when magnesium has been administered for neuroprotection.

Where applicable, experiments conform with Society ethical requirements