The in vitro effect of dual combinations of ritodrine, nicardipine and atosiban on contractility of pregnant rat myometrium

Objective: To compare the tocolytic potency of ritodrine, nicardipine and atosiban, used alone and in dual combinations, to see whether combinations of these drugs, which act via different pathways, could improve inhibition of uterine contractility. Design: Study on myometrial contractility in vitro. Setting: Laboratory of physiology, Lyon, France. Sample: Longitudinal myometrial strips from non-labouring timed pregnant Wistar rats (18 gestational days). Methods: Strips were simultaneously exposed to EC₂₅, EC₅₀ or EC₇₅ of dual combinations of either ritodrine and nicardipine, ritodrine and atosiban or nicardipine and atosiban (n = 10/group). Basal contractile activity and contractile activity after addition of each combination was measured using the 10 min integral of activity. Changes were expressed as percentage from the basal 10 min integral activity. The observed percentage inhibition of activity was compared with the expected percentage inhibition in an additive pharmacological model. When no significant difference occurred, the combination was deemed simply to have an additive tocolytic effect. When inhibition of activity was significantly greater compared with the expected percentage inhibition, the combination was deemed to have a synergistic effect. Main outcome measure: Changes in integral contractile activity in response to tocolytic combinations. Results: Ritodrine and atosiban inhibited integral activity to a greater extent than expected [e.g. using EC₅₀: observed inhibition 88.9% (13.8%) vs expected inhibition 75%; P < 0.015]. Actual inhibition by nicardipine/ritodrine [78.55% (20.4%) vs 75%; P = n.s.] and nicardipine/atosiban [78.94% (17.8%) vs 75%; P = n.s.] was not significantly different from expected. Conclusions: A combination of ritodrine plus atosiban exhibits a synergistic inhibition for myometrial activity, thus allowing the use of lower concentrations of each drug to achieve the same effect compared with each drug used alone. Combination of nicardipine plus ritodrine and nicardipine plus atosiban achieves only an additive effect. The potential for decreasing side effects (beta-mimetics) and costs (atosiban) when using a combination in clinical practice needs to be evaluated.