The Synergic In Vitro Tocolytic Effect of Nifedipine Plus Ritodrine on Human Myometrial Contractility

Abstract

Many pharmacological agents have been investigated to manage preterm labor; we postulate that a combination of tocolytic drugs may achieve a better effect in the prevention of uterine contractions without dose-dependent adverse effects. The aim of this study was to evaluate the inhibitory effect of dual combinations of tocolytics in vitro. Human myometrium was obtained during elective cesarean sections (term without labor; n = 40). Myometrial strips were placed in organ baths for the measurement of isometric tension. Contractile activity was induced by oxytocin (10 mol/L), then a concentration-response curve to single or dual combinations of tocolytics was started. All studied tocolytics (nifedipine, ritodrine, nitroglycerin, atosiban, and NS-1619), when used alone, significantly inhibited myometrial contractions. When combined, nifedipine plus ritodrine produced a significantly greater inhibition of contractility than each drug alone in the midrange of concentrations. The combination of nifedipine plus nitroglycerin or nifedipine plus atosiban produced a significantly greater inhibition than nitroglycerin or atosiban alone but not greater than nifedipine. The combination of nifedipine plus NS-1619 (Ca-activated K [BK] channel opener) reduced the inhibitory effect of each drug. We concluded that a selected combination of tocolytics (nifedipine plus ritodrine) produced a significantly greater inhibitory effect on contractility than each drug alone at intermediate concentrations. Thus, specific combinations of tocolytics with different intracellular signaling pathways may have a synergic effect constituting a provocative new option for preterm labor treatment.

Effect of dual tocolysis with fenoterol and atosiban in human myometrium

“…Test substances were applied on spontaneously contracting human myometrial samples. This was contrary to methods of other investigators using a model of oxytocin-induced contractions to analyse tocolytic effects [12][13][14]. In preliminary experiments, however, we found that this approach was not feasible for a study design including atosiban as oxytocin-induced contractions were already maximally supressed by the oxytocin receptor antagonist atosiban (data not shown).…”

“…The in vitro model is well established at our institute and internationally accepted in the literature as a means to evaluate the effect of single or dual tocolysis [6,7,[11][12][13][14].…”

“…The authors could demonstrate that in rat myometrium the combinations of either rofecoxib or atosiban with ritodrine had a synergistic effect while other combi nations resulted in an additive effect [6,22]. Two more recent in vitro studies on human myometrium demonstrated that atosiban and nifedipine resulted in an additive tocolytic effect and nifedipine with ritodrine produced a significantly greater inhibition of contractility than each drug alone [11,14]. In conclusion, there were two promising combinations that exhibited a synergistic inhibition for myometrial activity: ritodrine with rofecoxib and ritodrine with atosiban.…”

Oxytocin receptor antagonists and their clinical application

“…Результаты этого исследования указывали на перспективность применения блокаторов ОР при ПР. На изолированном миометрии беременных также было показано, что атозибан снижает утеростимулирующий эффект окситоцина [19,32,37,38], в том числе совместно с нифедипином [38] или с сульфатом магния [37]. В опытах с беременными крысами показано [39], что под влиянием атозибана уменьшается содержание ОР в миометрии, что трактуется как проявление десенситизации.…”

“…Ряд авторов [37,38,51]признают целесообразность применения атозибана в комплексе с другими токолитиками, в том числе с нифедипином, с агонистами β 2 -АР, например, с ритодрином, с нитроглицерином или с сульфатом магния. Преимущество такой комбинированной токолитической терапии было продемонстрировано в опытах с изолированным миометрием беременных женщин в отношении окситоцинвызванных сокращений [37,38]. Полагают [53], что после успешного лечения угрожающих ПР с помощью атозибана рационально применение прогестерона.…”