Hydrogen peroxide and superoxide anion modulate pregnant human myometrial contractility

Reactive oxygen species (ROS) have the propensity to cause macromolecular damage with consequent modification of cellular function. We investigated the effects of two particular oxidants, superoxide (O2−) anions and hydrogen peroxide (H2O2), on oxytocin-induced myometrial contractility using biopsies from women undergoing Caesarean section at term gestation. Isometric tension recordings were performed and concentration–response curves derived after addition of test agents. A maximal reduction in myometrial contractility to 27.2 ± 4.5% of control was observed followed application of H2O2. The enzyme scavenger catalase (CAT) reduced the inhibitory effect of H2O2but had little effect at 10-fold lower concentrations. Addition of dialysed xanthine oxidase ± hypoxanthine significantly inhibited contractility to 23.8.0 ± 4.2% compared with control. Pre-incubation with superoxide dismutase and CAT diminished this effect. The non-specific potassium channel blocker, tetraethylammonium chloride (1 mM), had no effect on myometrial contractility. We conclude that human myometrium is susceptible to the effects of ROS, which may be produced by reperfusion–ischaemic episodes during labour. Our findings could, in part, explain the weak or prolonged depression of contractions characteristic of myometrial dysfunction culminating in difficult labours.

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Effects of abnormal cannabidiol on oxytocin-induced myometrial contractility

Reproduction ◽

10.1530/rep-09-0496 ◽

2010 ◽

Vol 139 (4) ◽

pp. 783-788 ◽

Cited By ~ 5

Author(s):

Diarmaid D Houlihan ◽

Michael C Dennedy ◽

John J Morrison

Keyword(s):

Methylene Blue ◽

Guanylate Cyclase ◽

Inhibitory Effect ◽

Isometric Tension ◽

Tissue Type ◽

Elective Cesarean Section ◽

Uterine Contractility ◽

Response Curves ◽

Myometrial Contractility

The objective of this study was to investigate the effects of abnormal cannabidiol (abn-cbd) on oxytocin-induced myometrial contractility occurring during pregnancy. Isometric tension recordings were performed in isolated myometrial strips from biopsies obtained at elective cesarean section. The effects of cumulative doses of abn-cbd (10−9–10−5 M) on oxytocin-induced myometrial contractions alone, and on those following pre-incubation with SR 144528, AM 251, methylene blue, and iberiotoxin were measured, and dose–response curves were constructed. The pD2(−log EC50) values and the maximal inhibitory (MMI) values that were achieved were compared for each tissue type. Abn-cbd exerted a potent relaxant effect on oxytocin-induced myometrial contractionsin vitro. Pre-incubation with the guanylate cyclase inhibitor, methylene blue, and the BKCachannel antagonist, iberiotoxin, significantly attenuated this effect (for pD2,P<0.01; for MMI,P<0.01). Abn-cbd exerts a potent inhibitory effect on human uterine contractility. This effect is partially mediated through modulation of guanylate cyclase and activation of BKCachannel activity. These findings have implications for physiologic regulation of myometrial quiescence.

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Isoproterenol attenuates myosin phosphorylation and contraction of tracheal muscle

Journal of Applied Physiology ◽

10.1152/jappl.1989.66.5.2017 ◽

1989 ◽

Vol 66 (5) ◽

pp. 2017-2022 ◽

Cited By ~ 21

Author(s):

K. Obara ◽

P. de Lanerolle

Keyword(s):

Light Chain ◽

Myosin Light Chain ◽

Isometric Force ◽

Smooth Muscles ◽

Inhibitory Effect ◽

Isometric Tension ◽

Myosin Light Chain Phosphorylation ◽

Response Curves ◽

Shortening Velocity ◽

Myosin Phosphorylation

The effects of isoproterenol on isometric force, unloaded shortening velocity, and myosin phosphorylation were examined in thin muscle bundles (0.1–0.2 mm diam) dissected from lamb tracheal smooth muscle. Methacholine (10(-6) M) induced rapid increases in isometric force and in phosphorylation of the 20,000-Da myosin light chain. Myosin phosphorylation remained elevated during steady-state maintenance of isometric force. The shortening velocity peaked at 15 s after stimulation with methacholine and then declined to approximately 45% of the maximal value by 3 min. Isoproterenol pretreatment inhibited methacholine-stimulated myosin light chain phosphorylation, shortening velocity, and force during the early stages of force generation. However, the inhibitory effect of isoproterenol on force and myosin phosphorylation is proportionally greater than that on shortening velocity. Isoproterenol pretreatment also caused a rightward non-parallel shift in the methacholine dose-response curves for both isometric tension and myosin light chain phosphorylation. These data demonstrate that isoproterenol attenuates the contractile properties of airway smooth muscles by affecting the rate and extent of myosin light chain phosphorylation, perhaps through a mechanism that involves the synergistic interaction of myosin light chain kinase phosphorylation and Ca2+ metabolism.

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The Effect of an Oxytocin Receptor Antagonist (Retosiban, GSK221149A) on the Response of Human Myometrial Explants to Prolonged Mechanical Stretch

Endocrinology ◽

10.1210/en.2015-1378 ◽

2015 ◽

Vol 156 (10) ◽

pp. 3511-3516 ◽

Cited By ~ 6

Author(s):

Alexandros A. Moraitis ◽

Yolande Cordeaux ◽

D. Stephen Charnock-Jones ◽

Gordon C. S. Smith

Keyword(s):

Preterm Birth ◽

Receptor Antagonist ◽

Multiple Pregnancy ◽

Mechanical Stretch ◽

Inhibitory Effect ◽

Oxytocin Receptor ◽

Human Myometrium ◽

Spontaneous Preterm Birth ◽

Myometrial Contractility ◽

Stimulation Of

Multiple pregnancy is a major cause of spontaneous preterm birth, which is related to uterine overdistention. The objective of this study was to determine whether an oxytocin receptor antagonist, retosiban (GSK221149A), inhibited the procontractile effect of stretch on human myometrium. Myometrial biopsies were obtained at term planned cesarean delivery (n = 12). Each biopsy specimen was dissected into 8 strips that were exposed in pairs to low or high stretch (0.6 or 2.4 g) in the presence of retosiban (1 μM) or vehicle (dimethylsulfoxide) for 24 hours. Subsequently, we analyzed the contractile responses to KCl and oxytocin in the absence of retosiban. We found that incubation under high stretch in vehicle alone increased the response of myometrial explants to both KCl (P = .007) and oxytocin (P = .01). However, there was no statistically significant effect of stretch when explants were incubated with retosiban (P = .3 and .2, respectively). Incubation with retosiban in low stretch had no statistically significant effect on the response to either KCl or oxytocin (P = .8 and >.9, respectively). Incubation with retosiban in high stretch resulted in a statistically significant reduction (median fold change, interquartile range, P) in the response to both KCl (0.74, 0.60–1.03, P = .046) and oxytocin (0.71, 0.53–0.91, P = .008). The greater the effect of stretch on explants from a given patient, the greater was the inhibitory effect of retosiban (r = −0.65, P = .02 for KCl and r= −0.73, P = .007 for oxytocin). These results suggest that retosiban prevented stretch-induced stimulation of human myometrial contractility. Retosiban treatment is a potential approach for preventing preterm birth in multiple pregnancy.

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Regional heterogeneity in acetylcholine-induced relaxation in rat vascular bed: role of calcium-activated K+ channels

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01383.2005 ◽

2006 ◽

Vol 291 (1) ◽

pp. H216-H222 ◽

Cited By ~ 52

Author(s):

Rob H. P. Hilgers ◽

Joseph Todd ◽

R. Clinton Webb

Keyword(s):

Mesenteric Artery ◽

Channel Blocker ◽

Inhibitory Effect ◽

Vasomotor Tone ◽

Response Curves ◽

Regional Heterogeneity ◽

Relative Contribution ◽

Vascular Bed ◽

Relative Mrna Expression

Ca+-activated K+-channels (KCa) regulate vasomotor tone via smooth muscle hyperpolarization and relaxation. The relative contribution of the endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation differs depending on vessel type and size. It is unknown whether these KCa channels are differentially distributed along the same vascular bed and hence have different roles in mediating the EDHF response. We therefore assessed the role of small- (SKCa), intermediate- (IKCa), and large-conductance (BKCa) channels in mediating acetylcholine-induced relaxations in both first- and fourth-order side branches of the rat superior mesenteric artery (MA1 and MA4, respectively). Two-millimeter segments of each MA were mounted in the wire myograph, incubated with Nω-nitro-l-arginine methyl ester (l-NAME, 100 μmol/l) and indomethacin (10 μmol/l), and precontracted with phenylephrine (10 μmol/l). Cumulative concentration-response curves to ACh (0.001–10 μmol/l) were performed in the absence or presence of selective KCa channel antagonists. Apamin almost completely abolished these relaxations in MA4 but only partially blocked relaxations in MA1. The selective IKCa channel blocker 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) caused a significantly greater inhibition of the ACh-induced relaxation in MA4 compared with MA1. Iberiotoxin had no inhibitory effect in MA4 but blunted relaxation in MA1. Relative mRNA expression levels of SKCa (rSK1, rSK3, and rSK4 = rIK1) were significantly higher in MA4 compared with MA1. BKCa (rBKα1 and rBKβ1) genes were similar in both MA1 and MA4. Our data demonstrate regional heterogeneity in SKCa and IKCa function and gene expression and stress the importance of these channels in smaller resistance-sized arteries, where the role of EDHF is more pronounced.

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Halothane Attenuates Endothelium-dependent Pulmonary Vasorelaxant Response to Lemakalim, an Adenosine Triphosphate (ATP)-sensitive Potassium Channel Agonist

Anesthesiology ◽

10.1097/00000542-199709000-00024 ◽

1997 ◽

Vol 87 (3) ◽

pp. 625-634 ◽

Cited By ~ 10

Author(s):

Sumihiko Seki ◽

Mayumi Horibe ◽

Paul A. Murray

Keyword(s):

Adenosine Triphosphate ◽

Inhibitory Effect ◽

Isometric Tension ◽

Maximal Response ◽

Response Curves ◽

Nitric Oxide Synthase Inhibitor ◽

Pulmonary Vasodilation ◽

Synthase Inhibitor ◽

Oxide Synthase ◽

Channel Agonist

Background Lemakalim, an adenosine triphosphate (ATP)-sensitive potassium (K+(ATP)) channel agonist, causes profound pulmonary vasodilation in conscious dogs, which is attenuated during halothane anesthesia. The goal of the present study was to investigate the mechanism responsible for this attenuating effect of halothane. Methods Isolated canine pulmonary arterial rings were suspended for isometric tension recording in 25 ml organ baths. Rings with and without endothelium were contracted to 50% of their maximal response to phenylephrine, followed by the cumulative administration of lemakalim with or without exposure to halothane (0.5-1.5 minimum alveolar concentration [MAC] in dogs). Lemakalim dose-response curves were also generated in rings pretreated with the nitric oxide synthase inhibitor, Nw-nitro-L-arginine methyl ester (L-NAME); the cyclooxygenase inhibitor, indomethacin; or the K+(ATP) channel antagonist, glybenclamide. Results Compared with intact rings, the pulmonary vasorelaxant response to lemakalim was attenuated (P < 0.05) in endothelium-denuded rings. Halothane at 0.5 MAC had no effect on the vasorelaxant response to lemakalim. Halothane at 1 MAC attenuated (P < 0.05) the vasorelaxant response to lemakalim in intact rings, but not in endothelium-denuded rings. Halothane at 1.5 MAC attenuated (P < 0.05) the vasorelaxant response to lemakalim in both intact and endothelium-denuded rings. In endothelium-intact rings, indomethacin attenuated (P < 0.05) the vasorelaxant response to lemakalim, whereas L-NAME had no effect. Further, indomethacin, but not L-NAME, abolished the endothelium-dependent, halothane-induced attenuation of the lemakalim vasorelaxation response. Glybenclamide markedly attenuated (P < 0.05) lemakalim vasorelaxation at lemakalim doses less than 10(-6) M. Conclusions Lemakalim-induced pulmonary vasorelaxation involves an endothelium-dependent and vascular smooth muscle component. Further, halothane attenuates the endothelium-dependent pulmonary vasorelaxant response to lemakalim via an inhibitory effect on vasodilator metabolites of the cyclooxygenase pathway.

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Bryophyllum pinnatum enhances the inhibitory effect of atosiban and nifedipine on human myometrial contractility: an in vitro study

BMC Complementary and Alternative Medicine ◽

10.1186/s12906-019-2711-5 ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

S. Santos ◽

C. Haslinger ◽

M. Mennet ◽

U. von Mandach ◽

M. Hamburger ◽

...

Keyword(s):

Cell Viability ◽

Therapeutic Potential ◽

Inhibitory Effect ◽

Human Myometrium ◽

Anthroposophic Medicine ◽

Organ Bath ◽

Amplitude Data ◽

Myometrial Contractility ◽

Bryophyllum Pinnatum

Abstract Background The herbal medicine Bryophyllum pinnatum has been used as a tocolytic agent in anthroposophic medicine and, recently, in conventional settings alone or as an add-on medication with tocolytic agents such as atosiban or nifedipine. We wanted to compare the inhibitory effect of atosiban and nifedipine on human myometrial contractility in vitro in the absence and in the presence of B. pinnatum press juice (BPJ). Methods Myometrium biopsies were collected during elective Caesarean sections. Myometrial strips were placed under tension into an organ bath and allowed to contract spontaneously. Test substances alone and at concentrations known to moderately affect contractility in this setup, or in combination, were added to the organ bath, and contractility was recorded throughout the experiments. Changes in the strength (measured as area under the curve (AUC) and amplitude) and frequency of contractions after the addition of all test substances were determined. Cell viability assays were performed with the human myometrium hTERT-C3 and PHM1–41 cell lines. Results BPJ (2.5 μg/mL), atosiban (0.27 μg/mL), and nifedipine (3 ng/mL), moderately reduced the strength of spontaneous myometrium contractions. When BPJ was added together with atosiban or nifedipine, inhibition of contraction strength was significantly higher than with the tocolytics alone (p = 0.03 and p < 0.001, respectively). In the case of AUC, BPJ plus atosiban promoted a decrease to 48.8 ± 6.3% of initial, whereas BPJ and atosiban alone lowered it to 70.9 ± 4.7% and to 80.9 ± 4.1% of initial, respectively. Also in the case of AUC, BPJ plus nifedipine promoted a decrease to 39.9 ± 4.6% of initial, at the same time that BPJ and nifedipine alone lowered it to 78.9 ± 3.8% and 71.0 ± 3.4% of initial. Amplitude data supported those AUC data. The inhibitory effects of BPJ plus atosiban and of BPJ plus nifedipine on contractions strength were concentration-dependent. None of the test substances, alone or in combination, decreased myometrial cell viability. Conclusions BPJ enhances the inhibitory effect of atosiban and nifedipine on the strength of myometrial contractions, without affecting myometrium tissue or cell viability. The combination treatment of BPJ with atosiban or nifedipine has therapeutic potential.

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Vasorelaxant Action of N-p-Nitrophenylmaleimide in the Isolated Rat Mesenteric Artery

Zeitschrift für Naturforschung C ◽

10.1515/znc-2010-7-806 ◽

2010 ◽

Vol 65 (7-8) ◽

pp. 451-457 ◽

Cited By ~ 1

Author(s):

Eurica Ribeiro ◽

Fabíola F. Furtado ◽

Vânia F. Noldin ◽

Rogério Corrêa ◽

Valtir Cechinel-Filho ◽

...

Keyword(s):

Mesenteric Artery ◽

Inhibitory Effect ◽

Isometric Tension ◽

Free Medium ◽

Response Curves ◽

Tetraethylammonium Bromide ◽

Relaxant Effect ◽

Vasorelaxant Effect ◽

Resting Tension ◽

Rat Mesenteric Artery

The vasorelaxant response of N-p-nitrophenylmaleimide (4-NO2-NPM) was evaluated. The mesenteric rings (1 - 2 mm i.d.) were suspended by cotton thread for isometric tension recordings in a Tyrode’s solution at 37 °C and gassed with a mixture of 95% O2 and 5% CO2, under a resting tension of 0.75 g. 4-NO2-NPM induced relaxation in mesenteric rings pre-contracted with phenylephrine (Phe; 10 μM, pD2 = 6.7 ± 0.3) or KCl (80 mM, pD2 = 3.9 ± 0.2). This effect was significantly attenuated after removal of the vascular endothelium, NG-nitro L-arginine methyl ester (L-NAME; 100 μM), atropine (1 μM), indomethacin (10 μM), L-NAME + indomethacin or 1H-[1,2,3]oxadiazolo[4,3-α]quinoxalin-1-one (ODQ; 10 μM). LArginine (1 mM) reversed the inhibitory effect of L-NAME. In endothelium-intact preparations pre-incubated with 20 mM KCl, tetraethylammonium bromide (TEA; 1 mM) or glibenclamide (Glib; 10 μM), the vasorelaxant effect was significantly attenuated when compared to controls (endothelium intact). In denuded rings, separate incubation with 20 mM KCl, TEA or Glib did not change the relaxation when compared with that obtained in denuded rings. 4-NO2-NPM inhibited in a concentration-dependent and non-competitive manner the concentration-response curves induced by CaCl2. In calcium-free medium, the transient contractions induced by Phe (10 μM) or caffeine (20 mM) were inhibited. The relaxant effect induced by 4-NO2 -NPM appeared to be due to endothelial muscarinic receptors activation, NO and prostacyclin release and KATP and BKCa (Ca2+-activated K+ channels) endotheliumdependent activation. Inhibition of the Ca2+ influx and inhibition of the Ca2+ release from intracellular IP3- and caffeine-sensitive stores are also involved in the vasorelaxation

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Role of beta-adrenergic receptor subtypes in pig uterus contractility with inflammation

Scientific Reports ◽

10.1038/s41598-021-91184-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Barbara Jana ◽

Jarosław Całka

Keyword(s):

Adrenergic Receptors ◽

Adrenergic Receptor ◽

Domestic Animals ◽

Inhibitory Effect ◽

Receptor Subtypes ◽

Beta Adrenergic Receptor ◽

Pharmacological Modulation ◽

Uterine Inflammation ◽

Myometrial Contractility

AbstractUterine inflammation is a very common and serious condition in domestic animals. To development and progression of this pathology often lead disturbances in myometrial contractility. Participation of β1-, β2- and β3-adrenergic receptors (ARs) in noradrenaline (NA)-influenced contractility of the pig inflamed uterus was studied. The gilts of SAL- and E.coli-treated groups were administered saline or E.coli suspension into the uterine horns, respectively. Laparotomy was only done in the CON group. Compared to the period before NA administration, this neurotransmitter reduced the tension, amplitude and frequency in uterine strips of the CON and SAL groups. In the E.coli group, NA decreased the amplitude and frequency, and these parameters were lower than in other groups. In the CON, SAL and E.coli groups, β1- and β3-ARs antagonists in more cases did not significantly change and partly eliminated NA inhibitory effect on amplitude and frequency, as compared to NA action alone. In turn, β2-ARs antagonist completely abolished NA relaxatory effect on these parameters in three groups. Summarizing, NA decreases the contractile amplitude and frequency of pig inflamed uterus via all β-ARs subtypes, however, β2-ARs have the greatest importance. Given this, pharmacological modulation of particular β-ARs subtypes can be used to increase inflamed uterus contractility.

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Enhanced role of K+ channels in relaxations of hypercholesterolemic rabbit carotid artery to NO

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.269.3.h805 ◽

1995 ◽

Vol 269 (3) ◽

pp. H805-H811 ◽

Cited By ~ 16

Author(s):

S. Najibi ◽

R. A. Cohen

Keyword(s):

Carotid Artery ◽

Sodium Nitroprusside ◽

Channel Blocker ◽

Isometric Tension ◽

K Channel ◽

K Channels ◽

Rabbit Carotid Artery ◽

Cyclic Monophosphate ◽

Endothelium Dependent Relaxation

Endothelium-dependent relaxations to acetylcholine remain normal in the carotid artery of hypercholesterolemic rabbits, but unlike endothelium-dependent relaxations of normal rabbits, they are inhibited by charybdotoxin, a specific blocker of Ca(2+)-dependent K+ channels. Because nitric oxide (NO) is the mediator of endothelium-dependent relaxation and can activate Ca(2+)-dependent K+ channels directly or via guanosine 3',5'-cyclic monophosphate, the present study investigated the role of Ca(2+)-dependent K+ channels in relaxations caused by NO, sodium nitroprusside, and 8-bromoguanosine 3',5'-cyclic monophosphate (8-Brc-GMP) in hypercholesterolemic rabbit carotid artery. Isometric tension was measured in rabbit carotid artery denuded of endothelium from normal and hypercholesterolemic rabbits which were fed 0.5% cholesterol for 12 wk. Under control conditions, relaxations to all agents were similar in normal and hypercholesterolemic rabbit arteries. Charybdotoxin had no significant effect on relaxations of normal arteries to NO, sodium nitroprusside, or 8-BrcGMP, but the Ca(2+)-dependent K+ channel blocker significantly inhibited the relaxations caused by each of these agents in the arteries from hypercholesterolemic rabbits. By contrast, relaxations to the calcium channel blocker nifedipine were potentiated to a similar extent by charybdotoxin in both groups. In addition, arteries from hypercholesterolemic rabbits relaxed less than normal to sodium nitroprusside when contracted with depolarizing potassium solution. These results indicate that although nitrovasodilator relaxations are normal in the hypercholesterolemic rabbit carotid artery, they are mediated differently, and to a greater extent, by Ca(2+)-dependent K+ channels. These data also suggest that K+ channel-independent mechanism(s) are impaired in hypercholesterolemia.

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Effect of Potassium Channel Modulators on Morphine Withdrawal in Mice

Substance Abuse Research and Treatment ◽

10.4137/sart.s6211 ◽

2010 ◽

Vol 4 ◽

pp. SART.S6211 ◽

Cited By ~ 1

Author(s):

Vikas Seth ◽

Mushtaq Ahmad ◽

Prerna Upadhyaya ◽

Monika Sharma ◽

Vijay Moghe

Keyword(s):

Potassium Channel ◽

Withdrawal Syndrome ◽

Channel Blocker ◽

Inhibitory Effect ◽

Morphine Withdrawal ◽

The Other ◽

Opioid Antagonist ◽

Potassium Channel Openers ◽

Potassium Channel Modulators ◽

Withdrawal Signs

The present study was conducted to investigate the effect of potassium channel openers and blockers on morphine withdrawal syndrome. Mice were rendered dependent on morphine by subcutaneous injection of morphine; four hours later, withdrawal was induced by using an opioid antagonist, naloxone. Mice were observed for 30 minutes for the withdrawal signs ie, the characteristic jumping, hyperactivity, urination and diarrhea. ATP-dependent potassium (K+ATP) channel modulators were injected intraperitoneally (i.p.) 30 minutes before the naloxone. It was found that a K+ATP channel opener, minoxidil (12.5–50 mg/kg i.p.), suppressed the morphine withdrawal significantly. On the other hand, the K+ATP channel blocker glibenclamide (12.5–50 mg/kg i.p.) caused a significant facilitation of the withdrawal. Glibenclamide was also found to abolish the minoxidil's inhibitory effect on morphine withdrawal. The study concludes that K+ATP channels play an important role in the genesis of morphine withdrawal and K+ATP channel openers could be useful in the management of opioid withdrawal. As morphine opens K+ATP channels in neurons, the channel openers possibly act by mimicking the effects of morphine on neuronal K+ currents.

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