Guy Germain

Uterine electromyography: A critical review

On the basis of a literature review, this work summarizes uterine animal and human electromyographic information obtained at cellular, myometrial, and abdominal levels during gestation and parturition. We show that both internal and external electromyograms occur in phase with intrauterine pressure increase and exhibit similar spectra, including a slow wave (0.01 < frequency < 0.03 Hz) probably because of mechanical artifacts and a fast wave whose frequency content can be subdivided into a low-frequency band always present in every contraction and a high-frequency band related to efficient parturition contractions. Application of classic spectral techniques to electromyogram envelopes has identified group propagation but not pacemaker areas. However, no time delay or classic propagation has been demonstrated by applying the same spectral techniques to the electromyogram itself, probably because of the nonlinearity and three-dimensional nature of the propagating process.

Endothelin ETA receptors mediate human uterine smooth muscle contraction

Receptors mediating endothelin-induced contraction of myometrium were investigated in the human uterus. Endothelin-1 and endothelin-3 (10 pM to 0.3 microM) caused concentration-dependent contraction of myometrial strips. Endothelin-1 was approximately ten times more potent than endothelin-3, with pD2 values of 8.24 and 7.20, respectively. By contrast, two endothelin ETB receptor selective agonist, BQ 3020 (N-acetyl-[Ala11,15]endothelin-1-(6-21) and sarafotoxin 6c (up to 0.3 microM), did not induce contraction of human myometrium. The endothelin ETA receptor selective antagonist, FR139317 (1-hexahydroazepino-CO-Leu-D-Trp(CH3)-D-(2-pyridyl)alanine) (0.1, 0.3 and 1 microM), competitively antagonized the endothelin-1-elicited contraction, with a pA2 value of 7.10, whereas another endothelin ETA receptor-selective blocking drug, BQ 123 [cyclo(-D-Trp-D-Asp-Pro-D-Val-Leu)], behaved as a non-competitive antagonist. Pretreatment of myometrial strips with an endothelin ETB receptor selective antagonist, IRL 1038 ([Cys11-Cys15]endothelin-1-(11-21)), had no effect on contractions induced by endothelin-1. All these data indicate that only endothelin ETA receptors mediate endothelin-1-induced contractions of human myometrium.

Uterine EMG spectral analysis and relationship to mechanical activity in pregnant monkeys

The objective is to analyse internal and external recordings of uterine EMG in order to reveal common features and to assess the relationship between electrical activity and intra-uterine pressure modification. Three monkeys participated in the study, one as a reference and the others for data. EMGs are recorded simultaneously, internally by unipolar wire electrodes and externally by bipolar Ag/AgCl electrodes. Intra-uterine pressure is recorded as a mechanical index. Except for delay measurements, parameters are derived from spectral analysis and relationships between recordings are assessed by studying the coherence. Spectral analysis exhibits two basic activities in the analysed frequency band, and frequency limits are defined as relevant parameters for electrical activity description. Parameter values do not depend on the internal electrode location. Internal and external EMGs present a similar spectral shape, despite differences in electrode configuration and tissue filtering. It is deduced that external uterine EMG is a good image of the genuine uterine electrical activity. To some extent, it can be related to an average cellular electrical activity.

In Vitro and in Vivo Pharmacological Characterization of Ethyl-4-{trans-4-[((2S)-2-hydroxy-3-{4-hydroxy-3[(methylsulfonyl)amino]-phenoxy}propyl) Amino]cyclohexyl}benzoate Hydrochloride (SAR150640), a New Potent and Selective Human β3-Adrenoceptor Agonist for the Treatment of Preterm Labor

Ethyl-4-{trans-4-[((2S)-2-hydroxy-3-{4-hydroxy-3[(methylsulfonyl)amino] phenoxy}propyl) amino]cyclohexyl}benzoate hydrochloride (SAR150640) was characterized as a new potent and selective β3-adrenoceptor agonist for the treatment of preterm labor. SAR150640 and its major metabolite, the corresponding acid 4-{trans-4-[((2S)-2-hydroxy-3-{4-hydroxy-3[(methylsulfonyl) amino] phenoxy}propyl)amino]cyclohexyl}benzoic acid (SSR500400), showed high affinity for β3-adrenoceptors (Ki = 73 and 358 nM) and greater potency than (-)-isoproterenol in increasing cAMP production in membrane preparations from human neuroblastoma cells (SKNMC), which express native β3-adrenoceptors (pEC50 = 6.5, 6.2, and 5.1, respectively). SAR150640 and SSR500400 also increased cAMP production in membrane preparations from human uterine smooth muscle cells (UtSMC), which also express native β3-adrenoceptors (pEC50 = 7.7 and 7.7, respectively). In these cells, SAR150640 dose-dependently inhibited oxytocin-induced intracellular Ca2+ mobilization and extracellular signal-regulated kinase 1/2 phosphorylation. SAR150640 and SSR500400 had no β1- or β2-agonist or antagonist activity in guinea pig atrium and trachea, or in human isolated atrium and bronchus preparations. Both compounds concentration-dependently inhibited spontaneous contractions in human near-term myometrial strips, with greater potency than salbutamol and 4-[3-[(1,1-dimethylethyl)-amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (CGP12177) (pIC50 = 6.4, 6.8, 5.9, and 5.8, respectively), but with similar potency to (-)-isoproterenol and atosiban (oxytocin/vasopressin V1a receptor antagonist). SAR150640 also inhibited the contractions induced by oxytocin and prostaglandin F2α. In vivo, after intravenous administration, SAR150640 (1 and 6 mg/kg), but not atosiban (6 mg/kg), dose-dependently inhibited myometrial contractions in conscious unrestrained female cynomolgus monkeys, with no significant effects on heart rate or blood pressure. In contrast, salbutamol (50 and 250 μg/kg) had no inhibitory effect on uterine contractions, but it dose-dependently increased heart rate. These findings indicate a potential for the therapeutic use of SAR150640 in mammals during preterm labor.

Heterogeneity of oxytocin receptors in the pregnant rat myometrium near parturition

The contractile response of longitudinal and circular strips of rat myometrium to oxytocin (OT), [Arg8]vasotocin (AVT) and [Arg8]vasopressin (AVP) was examined in vitro in late pregnancy (controls at day 20, day 21, day 22) and 24 h after treatment with the antiprogestin, RU 486 (or mifepristone, given on day 20 or day 21 of gestation). In controls, the maximal effect (Emax) of OT in longitudinal strips increased with gestation, but there was no change in OT sensitivity in either myometrial layer. The pA2 values for the OT/AVP V1 antagonist, d(CH2)5[Tyr(Me)2]OVT, against OT, AVT and AVP on longitudinal strips and against AVT and AVP on circular strips were not different. However, the antagonist did not inhibit the effect of OT in circular strips, indicating that the receptor activated by OT is different from that in longitudinal strips. RU 486 treatment did not modify the characteristics of responses to AVT and AVP. RU 486 improved the response to OT in circular strips from rats treated at day 20, however the sensitivity to OT in longitudinal strips was decreased compared to that in the controls.

Electromyographical Study of Uterine Activity in the Human during Labour Induced by Prostaglandin F2 Alpha

In full-term pregnant women, electrical and mechanical activity of the uterus was monitored throughout the course of labour promoted by intravenous infusion of Pg F2 alpha. The recorded potentials were mostly biphasic and characterized by their long duration ranging from 1 to 2s. A wide range of potential amplitudes (100 microV to 1.8 mV) was observed according to the various patients. Early at the beginning of labour induction, the electrical complexes firing at various uterine sites were proved to be in close relationship and also well correlated with the mechanical events. This feature remained unchanged during labour. Potential amplitudes also remained unchanged during the same period of time. Under these conditions, improvement of uterine coordination does not appear to be the mechanism by which the increase of uterine contractile strength, necessary to expel the fetus, is obtained at the end of gestation.

Effects of nomegestrol acetate on spontaneous and sulprostone-induced uterine contractions in pregnant cynomolgus monkeys monitored by telemetry.

OBJECTIVEnOur purpose was to study the effects of the progestomimetic compound nomegestrol acetate on spontaneous and sulprostone-induced uterine contractility in pregnant cynomolgus monkeys.nnnSTUDY DESIGNnIntrauterine pressure was continuously monitored with use of an implanted intraamniotic catheter and a telemetric pressure transmitter from day 115 to 135 of gestation (term = 165 days). After surgery the animals received either nomegestrol acetate (5 mg per day orally, n = 3) or vehicle only (controls, n = 3). The intramuscular prostaglandin E2 analog sulprostone (25 micrograms) was administered as a single injection 10 days after amniotic catheter implantation. Spontaneous and sulprostone-induced uterine contractions were compared between nomegestrol acetate- and vehicle-treated animals.nnnRESULTSnThe frequency of spontaneous uterine contractions in control animals demonstrated a 24-hour pattern with a minimum at 12 hours and a maximum at 0 hours. The frequency of spontaneous contractions did not differ between nomegestrol acetate- and vehicle-treated animals. Sulprostone induced an increase in both the frequency and amplitude of contractions, reaching a maximum 12 hours after injection and fading out after 24 hours in vehicle-treated animals. In animals receiving nomegestrol acetate, the frequency of contractions increased moderately and transiently for a total duration of 6 hours only and returned to control levels thereafter.nnnCONCLUSIONnNomegestrol acetate significantly decreases the contractile response of the pregnant uterus induced by the prostaglandin E2 analog sulprostone.

Nonlinearity testing in the case of non Gaussian surrogates, applied to improving analysis of synchronicity in uterine contraction

Surrogates are commonly used to test a particular hypothesis on time series. The parameter commonly used in the literature to test these hypotheses is the z score. The z score assumes that the distribution of the statistics obtained on the surrogates is Gaussian. In this paper, we propose the use of a more general parameter than the z score that will also work in the case of non-Gaussian distribution of the statistics. We also derive a statistical test, based on the fitting of the distribution of the surrogate measure profile, in order to test the initial hypothesis. We validate the proposed approach on both synthetic signals and real uterine EMG signals by using the nonlinear correlation coefficient as initial statistic. We further show that this corrected nonlinear correlation coefficient can discriminate between pregnancy contractions and labor in a monkey, but the uncorrected nonlinear correlation coefficient cannot. This makes the corrected nonlinear correlation coefficient a promising candidate in a future application for preterm labor prediction in humans.

Bivariate piecewise stationary segmentation; improved pre-treatment for synchronization measures used on non-stationary biological signals

Analysis of synchronization between biological signals can be helpful in characterization of biological functions. Many commonly used measures of synchronicity assume that the signal is stationary. Biomedical signals are however often strongly non stationary. We propose to use a bivariate piecewise stationary pre-segmentation (bPSP) of the signals of interest, before the computation of synchronization measures on biomedical signals to improve the performance of standard synchronization measures. In prior work we have shown how this can be achieved by using the auto-spectrum of either one of the signals under investigation. In this work we show how major improvements of the performance of synchronization measures can be achieved using the cross-spectrum of the signals to detect stationary changes which occur independently in either signal. We show on synthetic as well as on real biological signals (epileptic EEG and uterine EMG) that the proposed bPSP approach increases the accuracy of the measures by making a good tradeoff between the stationarity assumption and the length of the analyzed segments, when compared to the classical windowing method.

A multiscale model of the electrohysterogram the BioModUE_PTL project

The electrohysterogram (EHG) is a promising means of monitoring pregnancy and of detecting a risk of preterm labor. To improve our understanding of the EHG as well as its relationship with the physiologic phenomena involved in uterine contractility, we plan to model these phenomena in terms of generation and propagation of uterine electrical activity. This activity can be realistically modeled by representing the principal ionic dynamics at the cell level, the propagation of electrical activity at the tissue level and then the way it is reflected on the skin surface through the intervening tissue. We present in this paper the different steps leading to the development and validation of a biophysics based multiscale model of the EHG, going from the cell to the electrical signal measured on the abdomen.