Abstract
BackgroundCurrently available tocolytic agents are not effective treatment for preterm labor beyond 48 h. A major reason is the development of maternal side effects which preclude the maintenance of an effective steady-state drug concentration. One strategy that can mitigate these side effects is utilizing synergistic drug combinations to reduce the drug concentrations necessary to elicit a clinical effect. We have previously shown that three anoctamin 1 (ANO1) antagonists mediate potent relaxation of precontracted human uterine smooth muscle (USM). In this study, we aimed to determine whether a combination of sub-relaxatory doses of tocolytic drugs in current clinical use [the L-type voltage-gated calcium channel (VGCC) blocker, nifedipine (NIF); and the β2-adrenergic (β2AR) agonist, terbutaline (TRB)] will potentiate USM relaxation with two ANO1 antagonists [benzbromarone (BB) and MONNA (MN)].ObjectiveThis study sought to examine the synergistic potency and mechanistic basis of two ANO1 antagonists with currently available tocolytic drugs. Functional endpoints assessed included relaxation of pre-contracting pregnant human USM tissue, inhibition of intracellular calcium release, and reduction of spontaneous transient inward current (STIC) recordings in human uterine smooth muscle cells.MethodsHuman myometrial strips and primary human USM cells were used in organ bath and calcium flux experiments with different combinations of sub-threshold doses of ANO1 antagonists and terbutaline or nifedipine to determine if ANO1 antagonists potentiate tocolytic drugs.ResultsThe combination of sub-threshold doses of two ANO1 antagonists and current tocolytic drugs demonstrate a significant degree of synergy to relax human pregnant USM compared to the effects achieved when these drugs are administered individually.ConclusionA combination of sub-threshold doses of VGCC blocker and β2AR agonist with ANO1 antagonists potentiates relaxation of oxytocin-induced contractility and calcium flux in human USM ex vivo. Our findings may serve as a foundation for novel tocolytic drug combinations.
Highlights
Preterm birth (PTB) remains a major obstetric crisis affecting one in every ten births and is the leading cause of neonatal death in the US [1, 2]
The combination of sub-threshold doses of two anoctamin 1 (ANO1) antagonists and current tocolytic drugs demonstrate a significant degree of synergy to relax human pregnant uterine smooth muscle (USM) compared to the effects achieved when these drugs are administered individually
Our findings may serve as a foundation for novel tocolytic drug combinations
Summary
Preterm birth (PTB) remains a major obstetric crisis affecting one in every ten births and is the leading cause of neonatal death in the US [1, 2]. Available tocolytics [nifedipine (NIF), terbutaline (TRB), and indomethacin] are complicated by maternal side effects that preclude the maintenance of effective steady-state drug concentrations contributing to clinical inefficacy beyond 48 h [4]. These side effects include hypotension with NIF as well as tachycardia and tachyphylaxis with TRB. There is growing interest in repurposing drugs that possess synergistic effects in combination to utilize lower doses of each medication to avoid side effects known to occur after chronic, high-dose treatment [5,6,7,8,9,10]. We aimed to determine whether a combination of sub-relaxatory doses of tocolytic drugs in current clinical use [the L-type voltage-gated calcium channel (VGCC) blocker, nifedipine (NIF); and the β2-adrenergic (β2AR) agonist, terbutaline (TRB)] will potentiate USM relaxation with two ANO1 antagonists [benzbromarone (BB) and MONNA (MN)]
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