scholarly journals Effects of abnormal cannabidiol on oxytocin-induced myometrial contractility

Reproduction ◽  
2010 ◽  
Vol 139 (4) ◽  
pp. 783-788 ◽  
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.

Levobupivacaine-induced contraction of isolated rat aorta is calcium dependent

2011 ◽  
Vol 89 (7) ◽  
pp. 467-476 ◽  
Author(s):  
Ji Seok Baik ◽  
Ju-Tae Sohn ◽  
Seong-Ho Ok ◽  
Jae-Gak Kim ◽  
Hui-Jin Sung ◽  
...  
Keyword(s):  
Methylene Blue ◽  
Smooth Muscle ◽  
Calcium Influx ◽  
Rat Aorta ◽  
Isometric Tension ◽  
Guanosine Monophosphate ◽  
Response Curves ◽  
Calcium Dependent ◽  
Isolated Rat

Levobupivacaine is a long-acting local anesthetic that intrinsically produces vasoconstriction in isolated vessels. The goals of this study were to investigate the calcium-dependent mechanism underlying levobupivacaine-induced contraction of isolated rat aorta in vitro and to elucidate the pathway responsible for the endothelium-dependent attenuation of levobupivacaine-induced contraction. Isolated rat aortic rings were suspended to record isometric tension. Cumulative levobupivacaine concentration–response curves were generated in either the presence or absence of the antagonists verapamil, nifedipine, SKF-96365, 2-aminoethoxydiphenylborate, Gd3+, NW-nitro-l-arginine methyl ester (L-NAME), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), and methylene blue, either alone or in combination. Verapamil, nifedipine, SKF-96365, 2-aminoethoxydiphenylborate, low calcium concentrations, and calcium-free Krebs solution attenuated levobupivacaine-induced contraction. Gd3+ had no effect on levobupivacaine-induced contraction. Levobupivacaine increased intracellular calcium levels in vascular smooth muscle cells. L-NAME, ODQ, and methylene blue increased levobupivacaine-induced contraction in endothelium-intact aorta. SKF-96365 attenuated calcium-induced contraction in a previously calcium-free isotonic depolarizing solution containing 100 mmol/L KCl. Levobupivacaine-induced contraction of rat aortic smooth muscle is mediated primarily by calcium influx from the extracellular space mainly via voltage-operated calcium channels and, in part, by inositol 1,4,5-trisphosphate receptor-mediated release of calcium from the sarcoplasmic reticulum. The nitric oxide – cyclic guanosine monophosphate pathway is involved in the endothelium-dependent attenuation of levobupivacaine-induced contraction.

scholarly journals Hydrogen peroxide and superoxide anion modulate pregnant human myometrial contractility

Reproduction ◽  
2005 ◽  
Vol 130 (4) ◽  
pp. 539-544 ◽  
Author(s):  
Averil Y Warren ◽  
Balwir Matharoo-Ball ◽  
Robert W Shaw ◽  
Raheela N Khan
Keyword(s):  
Hydrogen Peroxide ◽  
Channel Blocker ◽  
Inhibitory Effect ◽  
Isometric Tension ◽  
Human Myometrium ◽  
Response Curves ◽  
Tetraethylammonium Chloride ◽  
Myometrial Contractility ◽  
Macromolecular Damage ◽  
Maximal Reduction

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.

Fibrin-specificity of a Plasminogen Activator Affects the Efficiency of Fibrinolysis and Responsiveness to Ultrasound: Comparison of Nine Plasminogen Activators In Vitro

1999 ◽  
Vol 81 (04) ◽  
pp. 605-612 ◽  
Author(s):  
Dmitry V. Sakharov ◽  
Marrie Barrett-Bergshoeff ◽  
Rob T. Hekkenberg ◽  
Dingeman C. Rijken
Keyword(s):  
Thrombolytic Therapy ◽  
Plasminogen Activator ◽  
Tissue Type ◽  
Bolus Administration ◽  
High Frequency Ultrasound ◽  
Single Chain ◽  
Response Curves ◽  
Maximal Speed ◽  
Frequency Ultrasound

SummaryIn a number of cases, thrombolytic therapy fails to re-open occluded blood vessels, possibly due to the occurrence of thrombi resistant to lysis. We investigated in vitro how the lysis of hardly lysable model thrombi depends on the choice of the plasminogen activator (PA) and is accelerated by ultrasonic irradiation. Lysis of compacted crosslinked human plasma clots was measured after addition of nine different PAs to the surrounding plasma and the effect of 3 MHz ultrasound on the speed of lysis was assessed.Fibrin-specific PAs showed bell-shaped dose-response curves of varying width and height. PAs with improved fibrin-specificity (staphylokinase, the TNK variant of tissue-type PA [tPA], and the PA from the saliva of the Desmodus rotundus bat) induced rapid lysis in concentration ranges (80-, 260-, and 3,500-fold ranges, respectively) much wider than that for tPA (a 35-fold range). However, in terms of speed of lysis, these three PAs exceeded tPA only slightly. Reteplase and single-chain urokinase were comparable to tPA, whereas two-chain urokinase, anistreplase, and streptokinase were inferior to tPA. In the case of fibrin-specific PAs, ultrasonic treatment accelerated lysis about 1.5-fold. For streptokinase no acceleration was observed. The effect of ultrasound correlated with the presence of plasminogen in the outer plasma, suggesting that it was mediated by facilitating the transport of plasminogen to the surface of the clot.In conclusion, PAs with improved fibrin-specificity induce rapid lysis of plasminogen-poor compacted plasma clots in much wider concentration ranges than tPA. This offers a possibility of using single-or double-bolus administration regimens for such PAs. However, it is not likely that administration of these PAs will directly cause a dramatic increase in the rate of re-opening of the occluded arteries since they are only moderately superior to tPA in terms of maximal speed of lysis. Application of high-frequency ultrasound as an adjunct to thrombolytic therapy may increase the treatment efficiency, particularly in conjunction with fibrin-specific PAs.

scholarly journals In Vitro Effects of Propofol on Gravid Human Myometrium

2008 ◽  
Vol 36 (6) ◽  
pp. 802-806 ◽  
Author(s):  
A. S. Thind ◽  
R. J. Turner
Keyword(s):  
Isometric Tension ◽  
Human Myometrium ◽  
Organ Bath ◽  
Dependent Manner ◽  
Uterine Contractility ◽  
Time Curve ◽  
Lower Segment Caesarean Section ◽  
Uterine Muscle ◽  
In Vitro Effects

The aim of this study was to evaluate the direct effect of propofol (di-isopropyl phenol) on the contractile properties of gravid human uterine muscle. Six specimens of uterine muscle were obtained from term parturients undergoing elective lower segment caesarean section. Small strips (1 × 2 x 12 mm) of muscle were prepared and suspended in an organ bath containing oxygenated Kreb's solution at 36.5°C. Following preparation, spontaneous regular contractions developed at a rate of one contraction every six to 10 minutes. Force of contraction was recorded continuously using an isometric tension transducer. Following baseline measurements, propofol was introduced into the bath at concentrations corresponding to 2 /μg/ml, 5 /μg/ml and 8 /μg/ml. The specimens were also exposed to intralipid in concentrations equivalent to that found in the 8 μ/ml solution of propofol to determine whether this additive influenced uterine contractility. Contractility (defined as area under the tension/time curve) was decreased to 89 ± 6.5% of control at 2 μg/ml 53±4.3% at 5 μ/ml and 45 ± 4.1% at 8 μg/ml. This decrease in contractility was statistically significant at concentrations >2 μg/ml. Intralipid did not significantly affect uterine contractility. The results of this study show that propofol decreases isolated human uterine muscle contractility in a dose-dependent manner.

Isoproterenol attenuates myosin phosphorylation and contraction of tracheal muscle

1989 ◽  
Vol 66 (5) ◽  
pp. 2017-2022 ◽  
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.

Relaxing effects of 17(18)-EpETE on arterial and airway smooth muscles in human lung

2009 ◽  
Vol 296 (1) ◽  
pp. L130-L139 ◽  
Author(s):  
Caroline Morin ◽  
Marco Sirois ◽  
Vincent Echave ◽  
Edmond Rizcallah ◽  
Eric Rousseau
Keyword(s):  
Pulmonary Artery ◽  
Mode Of Action ◽  
Smooth Muscles ◽  
Isometric Tension ◽  
Response Curves ◽  
Airway Diseases ◽  
Human Cytochrome ◽  
Exogenous Addition ◽  
Human Pulmonary Artery

Human cytochrome P-450 epoxygenase enzymes metabolize eicosapentaenoic acid (EPA), an ω-3-polyunsaturated fatty acid (PUFA), and leads to the production of 17(18)-epoxyeicosatetraenoic acid, or 17(18)-EpETE. The aim of the present study was to delineate the mode of action of 17(18)-EpETE on human pulmonary artery (HPA) and distal bronchi. Isometric tension measurements demonstrated that 17(18)-EpETE induced concentration-dependent relaxing effects in pulmonary artery and airway smooth muscles. Iberiotoxin (IbTx) and glyburide (Glyb), known BKCa and KATP channel inhibitors, respectively, reversed the relaxation induced by 17(18)-EpETE on both tissues types. Microelectrode measurements showed that exogenous addition of 17(18)-EpETE hyperpolarized the membrane potential of HPA and bronchial smooth muscle cells. These induced electrophysiological effects were reversed by the addition of 10 nM IbTx and 10 μM Glyb. Complementary experiments performed on human bronchi, using the planar lipid bilayer reconstitution technique, demonstrated that 17(18)-EpETE activated reconstituted BKCa channels at low free Ca2+ concentration. Moreover, in bronchi, the relaxing responses induced by 17(18)-EpETE were also related to reduced Ca2+ sensitivity of the myofilaments, since free Ca2+ concentration-response curves, performed on β-escin-permeabilized cultured explants, were shifted toward higher Ca2+. Together, these results provide new insight into the mode of action of 17(18)-EpETE in lung tissues and highlight this eicosanoid as a potent modulator of tone on both HPA and distal bronchi in vitro, which may be of clinical relevance in the pathophysiology of pulmonary hypertension and airway diseases.

Cigarette smoke extract contracts isolated porcine coronary arteries by superoxide anion-mediated degradation of EDRF

1994 ◽  
Vol 266 (3) ◽  
pp. H874-H880 ◽  
Author(s):  
T. Murohara ◽  
K. Kugiyama ◽  
M. Ohgushi ◽  
S. Sugiyama ◽  
H. Yasue
Keyword(s):  
Methylene Blue ◽  
Cigarette Smoke ◽  
Coronary Arteries ◽  
Cigarette Smoke Extract ◽  
Isometric Tension ◽  
Relaxing Factor ◽  
Prostaglandin F2 Alpha ◽  
Endothelium Derived Relaxing Factor ◽  
Pig Coronary Arteries

To test whether cigarette smoke extract (CSE) influences the endothelial regulation of vascular tone in vitro, pig coronary arterial rings were incubated in organ chambers and isometric tension changes were examined. CSE was prepared by bubbling mainstream smoke of one filter cigarette into phosphate-buffered saline (2 ml). Fresh CSE (3.3, 10, and 30 microliters/ml) elicited initial contraction and subsequent relaxation during stable contraction to prostaglandin F2 alpha (PGF2 alpha). Initial contraction to CSE was dependent on the presence of endothelium, whereas subsequent relaxation was endothelium independent. Initial contraction was significantly attenuated by superoxide dismutase (SOD), methylene blue, but not by catalase. Prior inhibition of the basal release of endothelium-derived relaxing factor by NG-monomethyl-L-arginine also inhibited the initial contraction, and this inhibition was reversed by coincubation with L-arginine but not D-arginine. Subsequent relaxation was significantly potentiated by SOD but was markedly attenuated by methylene blue. CSE reduced ferricytochrome c, and this reduction was significantly inhibited by SOD. In conclusion, CSE induced biphasic tension change, initial contraction, and subsequent relaxation during stable contraction to PGF2 alpha in isolated pig coronary arteries. The initial contraction may be, at least in part, mediated through the degradation of basally released endothelium-derived relaxing factor (nitric oxide) by superoxide anions derived from CSE.

scholarly journals Systematic Identification of Antiprion Drugs by High-Throughput Screening Based on Scanning for Intensely Fluorescent Targets

2005 ◽  
Vol 79 (12) ◽  
pp. 7785-7791 ◽  
Author(s):  
Uwe Bertsch ◽  
Konstanze F. Winklhofer ◽  
Thomas Hirschberger ◽  
Jan Bieschke ◽  
Petra Weber ◽  
...  
Keyword(s):  
High Throughput ◽  
Conformational Changes ◽  
High Throughput Screening ◽  
Prion Diseases ◽  
Inhibitory Effect ◽  
Helical Conformation ◽  
Response Curves ◽  
Vitro Assay ◽  
Systematic Identification

ABSTRACT Conformational changes and aggregation of specific proteins are hallmarks of a number of diseases, like Alzheimer's disease, Parkinson's disease, and prion diseases. In the case of prion diseases, the prion protein (PrP), a neuronal glycoprotein, undergoes a conformational change from the normal, mainly alpha-helical conformation to a disease-associated, mainly beta-sheeted scrapie isoform (PrPSc), which forms amyloid aggregates. This conversion, which is crucial for disease progression, depends on direct PrPC/PrPSc interaction. We developed a high-throughput assay based on scanning for intensely fluorescent targets (SIFT) for the identification of drugs which interfere with this interaction at the molecular level. Screening of a library of 10,000 drug-like compounds yielded 256 primary hits, 80 of which were confirmed by dose response curves with half-maximal inhibitory effects ranging from 0.3 to 60 μM. Among these, six compounds displayed an inhibitory effect on PrPSc propagation in scrapie-infected N2a cells. Four of these candidate drugs share an N′-benzylidene-benzohydrazide core structure. Thus, the combination of high-throughput in vitro assay with the established cell culture system provides a rapid and efficient method to identify new antiprion drugs, which corroborates that interaction of PrPC and PrPSc is a crucial molecular step in the propagation of prions. Moreover, SIFT-based screening may facilitate the search for drugs against other diseases linked to protein aggregation.

Bisphenol A decreases the spontaneous contractions of rat uterus in vitro through a nitrergic mechanism

2018 ◽  
Vol 29 (6) ◽  
pp. 593-598 ◽  
Author(s):  
Hemlata Gupta ◽  
Shripad B. Deshpande
Keyword(s):  
Methylene Blue ◽  
Bisphenol A ◽  
Estrogenic Activity ◽  
Dependent Manner ◽  
Uterine Contractility ◽  
Adult Rats ◽  
Concentration Dependent Manner ◽  
Uterine Contractions ◽  
Synthase Inhibitor

Abstract Background: Bisphenol A (BPA), a chemical used in the manufacture of plastics, has toxic effects on various systems of the human body including the reproductive system. BPA possesses estrogenic activity and is implicated in altering oogenesis, ovulation, and fertility. In addition to ovulatory changes, uterine contractility is an important factor for fertility. However, the effects of BPA on myometrial contractions are not known. Therefore, we examined the effect of BPA on rat uterine contractions. Methods: The uterus was isolated from adult rats showing estrous phase, and spontaneous in vitro contractions were recorded (35±1 °C). The effect of cumulative concentrations of BPA was determined. Further, the involvement of nitric oxide (NO) and guanylyl cyclase (GC) for the BPA-induced changes on uterine contractility was evaluated using the NO synthase inhibitor (L-NAME) or GC inhibitor (methylene blue). Results: BPA decreased the amplitude and frequency of spontaneous uterine contractions in a concentration-dependent manner. A decrease of 50% occurred at 1 and 3 μM for amplitude and frequency, respectively. L-NAME (N-ω-nitro-l-arginine methyl ester) blocked the BPA-induced decrease in amplitude at all concentrations but antagonized the frequency only at the maximum concentration (10 μM). Methylene blue (a GC inhibitor) did not block the BPA-induced responses but for the frequency at 10 μM of BPA. Conclusions: The results indicate that BPA decreased the amplitude and frequency of spontaneous uterine contractions by involving the nitrergic mechanism; however, the GC mechanism is not involved in the depression.

Propofol Potentiates Phenylephrine-induced Contraction via  Cyclooxygenase Inhibition in Pulmonary Artery Smooth Muscle

2001 ◽  
Vol 94 (5) ◽  
pp. 833-839 ◽  
Author(s):  
Koji Ogawa ◽  
Satoru Tanaka ◽  
Paul A. Murray
Keyword(s):  
Arachidonic Acid ◽  
Smooth Muscle ◽  
In Vitro Study ◽  
Isometric Tension ◽  
Relaxation Response ◽  
Response Curves ◽  
Independent Manner ◽  
Pulmonary Arterial

Background The authors previously demonstrated in vivo that the pulmonary vasoconstrictor response to the a agonist phenylephrine is potentiated during propofol anesthesia compared with the conscious state. The current in vitro study tested the hypothesis that propofol potentiates phenylephrine-induced contraction by inhibiting the synthesis and/or activity of vasodilator metabolites of the cyclooxygenase pathway. Methods Canine pulmonary arterial rings were suspended for isometric tension recording. Intracellular calcium concentration ([Ca2+]i) was measured in pulmonary arterial strips loaded with acetoxylmethyl ester of fura-2. After phenylephrine-induced contraction, propofol (10(-7) to 10(-4) M) was administered in the presence or absence of the cyclooxygenase inhibitor ibuprofen (10(-5) M). The effects of propofol on the arachidonic acid and prostacyclin relaxation-response curves were assessed. The amount of 6-keto prostaglandin F1alpha (stable metabolite of prostacyclin) released from pulmonary vascular smooth muscle in response to phenylephrine was measured with enzyme immunoassay in the presence or absence of propofol and ibuprofen. Results Propofol potentiated phenylephrine-induced contraction in pulmonary arterial rings in a concentration-dependent and endothelium-independent manner. In endothelium-denuded strips, propofol (10(-4) M) increased tension by 53+/-11%, and increased [Ca2+]i by 56+/-9%. Ibuprofen also potentiated phenylephrine-induced contraction but abolished the propofol-induced increases in tension and [Ca2+]i. Propofol had no effect on the relaxation response to prostacyclin, whereas propofol and ibuprofen attenuated the relaxation response to arachidonic acid to a similar extent. Phenylephrine markedly increased 6-keto prostaglandin F1alpha production, and this effect was virtually abolished by propofol and ibuprofen. Conclusion These results suggest that propofol potentiates alpha-adrenoreceptor-mediated pulmonary vasoconstriction by inhibiting the concomitant production of prostacyclin by cyclooxygenase.

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