Abstract
Objective
The uterus and the bladder have striking physiologic and anatomic similarities. Anticholinergic medications are commonly used to treat “overactive bladder” by targeting M2 and M3 muscarinic receptors. The uterus also contains M2 and M3 muscarinic receptors; however, current management of preterm labor does not target these receptors. We assessed whether muscarinic blockade with oxybutynin reduces both spontaneous and oxytocin‐induced uterine muscle contractions.
Study Design
Longitudinal strips of uterine tissue from pregnant rats (17–19 days gestation) were mounted on an isometric test apparatus to directly measure uterine muscle contractions. The effect of cumulatively higher concentrations of oxybutynin (100 nM to 100 uM) on both spontaneous and on oxytocin‐induced (1 nM) uterine muscle contractility was tested. We measured both the area under the curve (AUC) and the frequency of the uterine muscle contractions compared to water vehicle control. Measurements are presented as a percentage of baseline. Two‐Way ANOVA with Dunnett's post hoc test was performed.
Results
Uterine muscle strips harvested from pregnant rats consistently showed spontaneous muscle contractions. Oxybutynin resulted in a statistically significant decrease in both spontaneous uterine muscle strength (AUC) and contraction frequency compared to vehicle controls at concentrations ≥10 µM. Oxytocin‐induced uterine muscle contractions were also affected by oxybutynin. At concentrations ≥10 µM, uterine muscle strength (AUC) was reduced (p < 0.01), but no difference was observed in contraction frequency compared to controls.
Conclusions
Oxybutynin significantly reduces spontaneous uterine muscle contraction strength (AUC) and contraction frequency in our animal ex vivo model. It reduces oxytocin‐induced uterine muscle contraction strength (AUC) but not contraction frequency. Antimuscarinic agents warrant future clinical investigation and may represent a novel treatment of preterm labor and “overactive uterus.”
Keywords: anticholinergic medication, antimuscarinic medication, oxybutynin, prematurity, preterm labor
1. INTRODUCTION
Despite considerable clinical and research efforts directed toward the prevention of preterm birth, it complicates an estimated 11.2% of pregnancies in North America [1]. Preterm labor (PTL) is a major public health burden, given its high prevalence, substantial economic costs, and major neonatal morbidity and mortality [2]. Long‐term sequelae include severe neuromuscular disorders, learning disabilities, blindness, and chronic respiratory disease [3]. There are a variety of proposed etiologies of PTL, but the underlying pathophysiologic trigger for PTL remains unknown. Therefore, clinicians depend on symptomatic treatments to decrease and delay contractions. Multiple tocolytic agents such as nonsteroidal anti‐inflammatory agents, magnesium sulfate, and progesterone have been used in an attempt to treat or prevent preterm uterine contractions [2, 4, 5]. These treatments are often ineffective and can be associated with maternal and fetal harm [5]. There is an urgent need for innovative and novel approaches that provide safe, rapid, and effective treatment options for PTL.
The uterus and bladder are two seemingly disparate organs, yet they share a surprising overlap from their embryologic origins to their anatomic structure and physiologic function. The uterus and the bladder both originate from the same embryologic origin (intermediate mesoderm), they have similar blood supply (internal iliac), they are structurally similar (hollow, smooth muscle pelvic organs, two proximal inlets, and one distal outlet), and they have similar autonomic innervation [6]. The uterus and the bladder are generally in a flaccid, noncontractile state throughout most of their biologic cycles. They each receive parasympathetic nervous system (PNS) innervation which controls excretory function including bladder detrusor muscle contraction for voiding and uterine muscle contraction for parturition. The primary neurotransmitter of the PNS, acetylcholine, binds to muscarinic receptors on smooth muscle cells. There are five well‐characterized muscarinic receptors, M1–M5, which are found throughout the body. The bladder and uterus each contain M2 and M3 muscarinic receptors [7, 8].
Previous work has identified the M2 and M3 receptors as key targets to regulate overactive contractions of the bladder [8]. Overactive bladder (OAB), also described as urge urinary incontinence, is characterized by premature bladder contractions resulting in large volume unpredictable urine leakage due to untimely bladder contractions. OAB is effectively treated with anticholinergic agents that target and block M2 and M3 muscarinic receptors, with onabotulinumtoxinA that inhibits the release of acetylcholine, or with neuromodulation that reduces OAB contractions.
Magnesium sulfate and progesterone have been used to treat and reduce the risk of preterm delivery, but their efficacy was limited, and their mechanism of action was poorly understood [2, 4, 5]. In unrelated studies, magnesium sulfate has been shown to inhibit the release of acetylcholine, the neurotransmitter that activates muscarinic receptors [9]. Progesterone has been shown to relax smooth muscle by blocking muscarinic receptors [10]. We hypothesize that the underlying mechanism by which both magnesium sulfate and progesterone work to reduce preterm uterine contractions, albeit inconsistently, may be through the muscarinic pathway. The unreliable nature of their effectiveness may be because their inhibition of uterine muscarinic activity is secondary, off‐target effects. Therefore, it is prudent to test compounds that primarily target the muscarinic pathways in uterine muscle.
The primary treatment for OAB typically includes antimuscarinic agents, such as oxybutynin. We therefore sought to understand the effect of oxybutynin on uterine muscle given the striking similarities between the bladder and uterus. We hypothesized that the same approach of treating premature bladder contractions by blocking muscarinic receptors on the detrusor muscle could be used on the uterus to effectively treat PTL and “overactive uterus.”
2. METHODS
The study aimed to investigate the effects of oxybutynin, an anticholinergic compound, on spontaneous and oxytocin‐induced uterine muscle contractility in pregnant rats. The experiments were conducted ex vivo using gravid rat uterine tissue strips between January and July 2024.
2.1. Animals
Sprague‐Dawley (SD) rats were bred at Taconic Biosciences (Rensselaer, NY). All animal work was reviewed and approved by the Taconic Biosciences Institutional Animal Care and Use Committee (IACUC) IC0055. The average gestation period of these animals is 22 days. We used uterine muscle tissue extracted between day 17 and 19 gestation to study the impact of anticholinergic treatment in a preterm environment. The “donor animals” were humanely euthanized. Uterine tissue was collected immediately following euthanasia and pups were euthanized. Uterine horns were then shipped in nutrient‐rich media overnight to Reprocell, Inc. (Beltsville, MD).
2.2. Tissue and solution preparation
Upon arrival at Reprocell, Inc., each uterine horn was cut into longitudinal strips of equal size (approximately 1 cm length, 2–4 strips per horn). Strips were mounted on an isometric test apparatus in 25 mL organ baths (Panlab 8 channel automated organ baths with thermostatic controllers) containing a physiologic solution (composition: 119.0 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO4, 24.9 mM NaHCO3, 1.2 mM KH2PO4, 2.5 mM CaCl2, and 11.1 mM glucose), aerated with 95% O2 /5% CO2 gas mix, warmed and maintained at approximately 37°C throughout the experiment. This setup allowed for the direct measurement of uterine muscle contractions, providing an accurate assessment of contractility parameters. Uterine strips were allowed to equilibrate to 37°C and tension was preset at 1.0 ± 0.2 g. Contractions were recorded continuously and data were collected using ADInstruments Powerlab and ADInstruments LabChart 7 software.
All compounds and stock solutions were prepared in deionized water. Stock solutions of respective treatments were added to the organ bath to yield intended treatment concentrations. Deionized water was used as a vehicle control.
2.3. Experimental design
Uterine strips were suspended in the tissue organ bath at 1 g of tension, allowed to equilibrate, and confirmed to have spontaneous contractions. Throughout the experiments, contractions were continuously recorded. After the addition of each compound treatment, strips were incubated for approximately 15 min or until the response had plateaued or stabilized before the next treatment concentration or compound was added. The contraction parameters were determined by averaging the values over a 5‐min interval.
An initial pilot experiment was performed to confirm viability and responsiveness of the tissue in our ex vivo model. We used 1–100 uM carbachol, a known muscarinic agonist, to confirm that muscarinic receptor pathways are involved in rat uterine muscle contractility in a dose‐dependent manner. We then assessed the effect of oxybutynin, a known competitive muscarinic receptor blocker, on carbachol‐induced contractility. Uterine strips were pretreated with 10 µM carbachol to stimulate contractility, and subsequently, strips were treated with serially increasing concentrations of oxybutynin (100 nM, 300 nM, 1 uM, 3 uM, 10 uM, 30 uM) and the responses were recorded.
Next, we studied the effect of oxybutynin on spontaneous uterine contractions. The pregnant uterine muscle strips were suspended in the tissue organ bath and spontaneous contractions were monitored and recorded. After confirming a spontaneous contraction pattern, uterine strips were treated with increasing concentrations of oxybutynin (100 nM, 300 nM, 1 uM, 3 uM, 10 uM, 30 uM, 100 uM) or with vehicle only (water).
Finally, we assessed the effect of oxybutynin on oxytocin‐induced uterine muscle contractions. Pregnant uterine strips were suspended in the tissue organ baths, spontaneous contraction patterns were confirmed and then oxytocin (1 nM) was added to the bath and the contractions were monitored for approximately 15 min or until the response had plateaued or stabilized. Then, oxybutynin was added serially in increasing concentrations (100 nM, 300 nM, 1 uM, 3 uM, 10 uM, 30 uM, 100 uM) and responses continued to be recorded.
2.4. Data collection and statistical analysis
Contractions were monitored and recorded continuously. Contractility parameters such as area under the curve (AUC) and frequency of contractions were determined by averaging the values of multiple contractions over a fixed, 5‐min monitoring interval (before and after each compound addition) using LabChart Version 7 (ADI Instruments). For experiments evaluating effects on spontaneous muscle contractions, the baseline values were calculated over a 5‐min interval before the addition of oxybutynin. For experiments that evaluated uterine muscle strips pretreated with carbachol or oxytocin, the pretreatment baseline values were similarly calculated over a 5‐min interval before the addition of oxybutynin. Treatment effects were assessed over 5‐min time periods after the addition of each increasing concentration of oxybutynin. The vehicle controls were time‐matched with compound treatment. The person performing the data analysis was not masked to the exposure. The measurement and analysis of both the contraction frequency and AUC were performed by the software program.
As this was a novel study, no a priori sample size calculation or power analysis was performed. Each donor animal counted as one biological replicate (statistical unit). Measurements for a given treatment condition for each donor animal were calculated by averaging technical replicates (individual uterine muscle strips from a given donor animal). Numbers of biological and technical replicates are indicated in each figure. Data are plotted in figures as the mean of all biological replicates and the standard error of the mean (SEM) relative to baseline values. Calculations were performed using GraphPad Prism version 10. GraphPad Prism nonlinear regression (curve fit) analysis was used to draw sigmoidal dose–response curves for each data set. Data were analyzed to assess the concentration‐related effects of oxybutynin as compared to vehicle controls. All results were analyzed using ANOVA followed by Dunnett's post hoc test. A p‐value less than 0.05 was considered statistically significant.
3. RESULTS
3.1. Spontaneous contractility
Uterine strips from pregnant rats (17–19 days of gestation) consistently exhibited spontaneous contractile activity, which was present in all donor animals. Contractility parameters, including AUC and frequency were calculated for spontaneous contractions before the administration of oxybutynin.
3.2. Effects of oxybutynin on carbachol‐induced contractility
We performed initial pilot experiments to confirm that oxybutynin is effective in our uterine tissue ex vivo model. Thus, we administered carbachol, a known muscarinic agonist, which was expected to stimulate contractions in the rat uterine muscle strips. We then tested if oxybutynin, a muscarinic antagonist, could reduce this effect. Our confirmatory pilot experiment using two uterine muscle strips confirmed that the uterine muscle tissues were viable and showed a dose‐dependent increase in uterine muscle contraction parameters with increasing doses of carbachol (Figure 1). Based on those results, we pretreated two uterine muscle strips with carbachol (10 µM) to induce uterine muscle contractions followed by treatment with increasing doses of oxybutynin. Oxybutynin decreased uterine muscle contractility (AUC) in the muscle strips pretreated with carbachol in a dose‐dependent manner (Figure 2).
FIGURE 1.
Pilot experiment to evaluate cumulative concentration response curve to carbachol in pregnant rat isolated uterine muscle strips. Results are expressed as the percentage of maximum response of contractile area under the curve (± SEM). n = donor animal; replicates = individual uterine strips.
FIGURE 2.
Cumulative concentration response curve to oxybutynin treatment in pregnant rat isolated uterine muscle strips after pretreatment with 10 uM carbachol. Results are expressed as the percentage of the pretreatment baseline contractile area under the curve area (± SEM). n = donor animal; replicates = individual uterine strips.
3.3. Effects of oxybutynin on spontaneous contractility
In gravid rat isolated uterine muscle strips, oxybutynin resulted in a dose‐dependent inhibition of spontaneous uterine muscle contractions (AUC and frequency). A modest time‐related reduction in contractility parameters was also observed in the vehicle control (deionized water) group. However, the decrease was much more pronounced in uterine muscle strips treated with oxybutynin. At concentration of oxybutynin ≥10 uM, there was a statistically significant decrease compared to vehicle in the AUC and frequency of contractions. At the highest concentration tested (100 µM), spontaneous contractility was almost completely abated in all uterine strips (Figures 3 and 4). Representative tracings show the reduction in contraction parameters with increasing concentrations of oxybutynin (Figure 5).
FIGURE 3.
Cumulative concentration response curve to oxybutynin or vehicle (water) in pregnant rat isolated uterine muscle strips on spontaneous contractions (in the absence of oxytocin). Results are expressed as the percentage of the baseline contractile area under the curve area (± SEM). Nonlinear regression of each data set is displayed. Two‐Way ANOVA with Dunnett's post hoc test was performed, **p < 0.01, **p < 0.001. n = donor animal; replicates = individual uterine strips.
FIGURE 4.
Cumulative concentration response curve to oxybutynin or vehicle (water) in pregnant rat isolated uterine muscle strips on spontaneous contractions (in the absence of oxytocin). Results are expressed as the percentage of baseline contractile frequency (± SEM). Nonlinear regression of each data set is displayed. Two‐Way ANOVA with Dunnett's post hoc test was performed, *p < 0.05, **p < 0.01, ***p < 0.001. n = donor animal; replicates = individual uterine strips.
FIGURE 5.
Representative tracings from pregnant rat uterine muscle strips showing spontaneous contractions before and after treatment with water vehicle (top) or serially increasing concentrations of oxybutynin (bottom).
3.4. Effects of oxybutynin on oxytocin‐induced contractility
Pretreatment with oxytocin (1 nM) was used to induce uterine muscle contractions. The contraction parameters in both oxybutynin‐treated and vehicle‐control strips decreased in a time‐dependent manner. Contraction frequency was not significantly different between controls and oxybutynin‐treated strips. However, a dose‐dependent reduction of the AUC was observed, which was significantly reduced compared to vehicle controls at concentrations of oxybutynin ≥10 uM (10 µM p < 0.01; 30 and 100 µM p < 0.001) (Figures 6 and 7). Representative tracings show the effect of treatment with serially increasing oxybutynin concentrations on uterine muscle contractions pretreated with oxytocin (Figure 8).
FIGURE 6.
Cumulative concentration response curve to oxybutynin or vehicle (deionized water) in pregnant rat isolated uterine muscle strips in the presence of 1 nM oxytocin. Results are expressed as the percentage of the pretreatment baseline contractile area under the curve (± SEM). Nonlinear regression of each data set is displayed. Two‐Way ANOVA with Dunnett's post hoc test was performed, **p < 0.01, ***p < 0.001. n = donor animal, replicates = individual uterine strips.
FIGURE 7.
Cumulative concentration response curve to oxybutynin or vehicle (deionized water) in pregnant rat isolated uterine muscle strips in the presence of 1 nM oxytocin. Results are expressed as the percentage of the pretreatment baseline contractile frequency (± SEM). Nonlinear regression of each data set is displayed. Two‐Way ANOVA with Dunnett's post hoc test was performed with all p‐values > 0.05. n = donor animal; replicates = individual uterine strips.
FIGURE 8.
Representative tracings from pregnant rat uterine muscle strips that were pretreated with oxytocin and showing contractions after treatment with water vehicle (top) or serially increasing concentrations of oxybutynin (bottom).
4. CONCLUSIONS
Our data provide strong evidence that antimuscarinic agents can indeed reduce contraction parameters in gravid rat uterine tissue. The lessons learned from treating OAB may lead us to better treat PTL and potentially prevent preterm birth. As with the bladder, overactivity of the uterus is not equivalent to the complex pathophysiological changes that occur in the uterus, cervix, placenta, and likely fetus during preterm birth. OAB is commonly treated with antimuscarinic medications, including oxybutynin. Given the similarities between the bladder and the uterus, including embryologic origin, anatomy, and the presence of muscarinic receptors, we investigated whether oxybutynin would have a similar relaxing effect on uterine muscle as it does on the detrusor muscle. We found that oxybutynin significantly reduces spontaneous uterine muscle strength (AUC) and contraction frequency. Since oxytocin is a well‐established uterine muscle stimulant, we were interested to learn if oxybutynin had an effect on the oxytocin pathway. We found that oxybutynin reduces oxytocin‐induced uterine muscle strength (AUC). The effects of oxybutynin on spontaneous contractions were more pronounced than on oxytocin‐induced contractions. Our study does not address the mechanism of action of oxybutynin on either spontaneous or oxytocin‐induced uterine muscle contractions. Future studies will need to address this more specifically. However, it is likely that activity of muscarinic receptors or elements downstream of those receptors is involved.
The U.S. Food and Drug Administration monograph package insert for oxybutynin has shown no definitive evidence of fetal harm in animal models. Its safety in pregnant women has not been established [11]. Similarly, Welk et al. studied the association between anticholinergic medication during pregnancy and adverse outcomes and found no association with congenital malformations [12]. Welk et al. found a significant association between anticholinergic use and preterm birth and low birth weight. The most common anticholinergic medication in that cohort was oxybutynin (84%) and of the anticholinergic exposure during pregnancy, 95.4% was in the first trimester. The authors postulate that anticholinergic use during the first trimester could potentially result in preterm birth by interfering with placental development. Conversely, we suggest that the use of anticholinergic medications is a confounding factor and that patients with OAB may be predisposed to PTL due to inherent muscarinic overactivity.
Since the bladder and uterus have similar neurologic innervation and muscarinic receptors, it is possible that women taking anticholinergic medications possess an innate overactivity of both the bladder and the uterus. Patients treated for OAB in the first trimester may be at increased risk of developing PTL simply due to underlying muscarinic overactivity. Future investigation of this hypothesis could potentially identify patients at future risk for preterm labor and birth based on the development of OAB symptoms early in their pregnancy. Identification of an at‐risk population would provide opportunities for focused prevention strategies.
Over the last several years, several investigators have reported an association between anticholinergic use and cognitive decline [11, 13]. These reports of associated dementia pose serious concerns about the potential effects on brain health, in particular the potential impact of anticholinergic medications on neurodevelopment [13, 14]. Conversely, a 2021 Cochrane review reported that no firm conclusions can be drawn for risk of accelerated cognitive decline, neuropsychiatric disturbances, decline in physical function, or institutionalization related to anticholinergic burden [15]. These potential risks would need to be carefully studied and balanced with the well‐known risks of extreme prematurity on neurodevelopment.
This manuscript reports the effects of oxybutynin on uterine muscle tissue from pregnant rats. Oxybutynin decreased muscle contraction strength and frequency. Additional studies are necessary to explore other anticholinergics given their different affinities for M2 and M3 receptors and their ability to cross the blood–brain barrier [16, 17, 18]. Trospium, a quaternary amine, does not easily cross the blood–brain barrier but seems to cross the uteroplacental barrier [18, 19]. Whether it would cross into the developing neonate's central nervous system is an area of exciting exploration. We are actively investigating additional anticholinergic drugs and beta‐3 agonists and their effect at reducing uterine muscle contractions. The simple fact that the uterus contains muscarinic and beta‐3 agonist receptors suggests that they may have a purpose in uterine muscle function including labor.
Our research has many strengths. First, the hypothesis is novel and could potentially unlock a completely new method for the treatment of PTL. The laboratories that performed the research study are very experienced and the data showed consistent, dose–response relationships. The uterine muscle used for the experiments were extracted from near‐term pregnant rats to more closely approximate the clinical condition of interest. The uterine tissues remained viable during transport and during the experiments consistently showing spontaneous muscle contractions. This ex vivo rat model is a powerful model to test many different candidates within a reasonable time frame.
There were also some limitations. This was an ex vivo experiment in pregnant rats that may not be representative of the effect of oxybutynin on human pregnant uterine muscle. However, experiments using rat models have led to many other insights that could be translated to human. In our ex vivo animal model, the effects of oxybutynin on both spontaneous and oxytocin‐induced uterine muscle contractions were observed at concentrations between 10 and 100 uM. While these concentrations correlate with supratherapeutic plasma concentrations in humans, this study provides strong proof of principle evidence. As compared to in vivo human efficacy, the experiments were done in an ex vivo animal model and active oxybutynin metabolites are likely not generated. Responsiveness in the present experiments may also have been reduced as the pregnant uterine tissue was harvested the day prior to experimentation. Using fresh tissue immediately after removal from the animal, may show effects at lower dosages. The safe and effective dosages for anticholinergic medications for the potential treatment of PTL would need to be determined. Future in vivo studies are needed to determine more definitively whether desired effects are achievable within the established therapeutic ranges.
Muscarinic receptor blockade in the bladder effectively reduces OAB contractions. Despite extensive research, effective treatment for PTL remains elusive. Our preliminary research suggests that muscarinic blockade has the potential to decrease uterine contractility. Further research is needed to see if this mechanism can be used as a treatment for PTL. Antimuscarinic agents warrant further investigation as therapeutic targets and may offer a promising new approach to managing PTL and preventing preterm birth.
CONFLICT OF INTEREST STATEMENT
Dr. Anthony Visco is the founder and owner of NinoMed, LLC. US Patent: US 11,179,393, PCT: WO2015171753A1. Additional US and International Patents Pending.
ETHICS STATEMENT
This study was reviewed and approved by Taconic's Animal Care and Use Committee (IACUC), IC0055.
ACKNOWLEDGMENTS
The authors thank Taconic Biosciences (Rensselaer, NY) for animal breeding and tissue extraction. The research was soley funded by NinoMed, LLC, Chapel Hill, NC.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from NinoMed, LLC. Restrictions apply to the availability of these data.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from NinoMed, LLC. Restrictions apply to the availability of these data.