Dataset Information

Phenylephrine, a common cold remedy active ingredient, suppresses uterine contractions through cAMP signalling.

ABSTRACT: Regulation of uterine contractility is an important aspect of women's health. Phenylephrine, a selective agonist of the ?₁-adrenoceptor and a potent smooth muscle constrictor, is widely used in women even during pregnancy to relieve cold-related symptoms, to treat postpartum haemorrhoid, and during routine eye exams. We performed isometric tension recordings to investigate the effect of phenylephrine on mouse uterine contractility. Phenylephrine decreased spontaneous and oxytocin-induced contractions in non-pregnant mouse uterine rings and strips with an IC₅₀ of ~1??M. Prazosin, an inhibitor of ?₁-adrenoceptor, did not prevent phenylephrine-mediated relaxations. Conversely, ICI118551, an antagonist of ?2-adrenoceptors, inhibited phenylephrine relaxation. In the presence of ICI118551, high concentrations (>30??M) of phenylephrine caused mouse uterine contractions, suggesting that ?-adrenoceptor-mediated inhibition interferes with the phenylephrine contractile potential. Phenylephrine-dependent relaxation was reduced in the uterus of pregnant mice. We used primary mouse and human uterine smooth muscle cells (M/HUSMC) to establish the underlying mechanisms. Phenylephrine stimulated large increases in intracellular cAMP in M/HUSMCs. These cAMP transients were decreased when HUSMCs were cultured in the presence of oestrogen and progesterone to mimic the pregnancy milieu. Thus, phenylephrine is a strong relaxant in the non-pregnant mouse uterus, but exhibits diminished effect in the pregnant uterus.

SUBMITTER: Chen X

PROVIDER: S-EPMC6076280 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Phenylephrine, a common cold remedy active ingredient, suppresses uterine contractions through cAMP signalling.

Chen Xingjuan X Meroueh Marya M Mazur Gabriela G Rouse Evan E Hundal Karmjot Singh KS Stamatkin Christopher W CW Obukhov Alexander G AG

Scientific reports 20180803 1

Regulation of uterine contractility is an important aspect of women's health. Phenylephrine, a selective agonist of the α<sub>1</sub>-adrenoceptor and a potent smooth muscle constrictor, is widely used in women even during pregnancy to relieve cold-related symptoms, to treat postpartum haemorrhoid, and during routine eye exams. We performed isometric tension recordings to investigate the effect of phenylephrine on mouse uterine contractility. Phenylephrine decreased spontaneous and oxytocin-indu ...[more]

PMID: 30076382

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Project description:The mechanisms used to coordinate uterine contractions are not known. We develop a new model based on the proposal that there is a maximum distance to which action potentials can propagate in the uterine wall. This establishes "regions", where one action potential burst can rapidly recruit all the tissue. Regions are recruited into an organ-level contraction via a stretch-initiated contraction mechanism (myometrial myogenic response). Each uterine contraction begins with a regional contraction, which slightly increases intrauterine pressure. Higher pressure raises tension throughout the uterine wall, which initiates contractions of more regions and further increases pressure. The positive feedback synchronizes regional contractions into an organ-level contraction. Cellular automaton (CA) simulations are performed with Mathematica. Each "cell" is a region that is assigned an action potential threshold. An anatomy sensitivity factor converts intrauterine pressure to regional tension through the Law of Laplace. A regional contraction occurs when regional tension exceeds regional threshold. Other input variables are: starting and minimum pressure, burst and refractory period durations, enhanced contractile activity during an electrical burst, and reduced activity during the refractory period. Complex patterns of pressure development are seen that mimic the contraction patterns observed in laboring women. Emergent behavior is observed, including global synchronization, multiple pace making regions, and system memory of prior conditions. The complex effects of nifedipine and oxytocin exposure are simulated. The force produced can vary as a nonlinear function of the number of regions. The simulation directly links tissue-level physiology to human labor. The concept of a uterine pacemaker is re-evaluated because pace making activity may occur well before expression of a contraction. We propose a new classification system for biological CAs that parallels the 4-class system of Wolfram. However, instead of classifying the rules, biological CAs should classify the set of input values for the rules that describe the relevant biology.

Project description:Understanding the mechanisms of uterine contractions during pregnancy is especially important in predicting the onset of labor and thus in forecasting preterm deliveries. Preterm birth can cause serious health problems in newborns, as well as large financial burdens to society. Various techniques such as electromyography (EMG) and magnetomyography (MMG) have been developed to quantify uterine contractions. However, no widely accepted method to predict labor based on electromagnetic measurement is available. Therefore, developing a biophysical model of EMG and MMG could help better understand uterine contractions, interpret real measurements, and detect labor. In this work, we propose a multiscale realistic model of uterine contractions during pregnancy. At the cellular level, building on bifurcation theory, we apply generalized FitzHugh-Nagumo (FHN) equations that produces both plateau-type and bursting-type action potentials. At the tissue level, we introduce a random fiber orientation model applicable to an arbitrary uterine shape. We also develop an analytical expression for the propagation speed of transmembrane potential. At the organ level, a realistic volume conductor geometry model is provided based on magnetic resonance images of a pregnant woman. To simulate the measurements from the SQUID Array for Reproductive Assessment (SARA) device, we propose a sensor array model. Our model is able to reproduce the characteristics of action potentials. Additionally, we investigate the sensitivity of MMG to model configuration aspects such as volume geometry, fiber orientation, and pacemaker location. Our numerical results show that fiber orientation and pacemaker location are the key aspects that greatly affect the MMG as measured by the SARA device. We conclude that sphere is appropriate as an approximation of the volume geometry. The initial step towards validating the model against real MMG measurement is also presented. Our results show that the model is flexible to mimic the limited-propagation magnetic signature during the emergence and decay of a uterine contraction.

Dataset Information

Phenylephrine, a common cold remedy active ingredient, suppresses uterine contractions through cAMP signalling.

Publications

Phenylephrine, a common cold remedy active ingredient, suppresses uterine contractions through cAMP signalling.

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