Research Article
Functional characterisation of the volume-sensitive anion channel in rat pancreatic β-cells
- L. Best, T. Speake, P. D. Brown
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- 31 July 2001, pp. 145-150
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The whole-cell and perforated patch configurations of the patch-clamp technique were used to characterise the volume-sensitive anion channel in rat pancreatic β-cells. The channel showed high permeability (P ) relative to Cl- to extracellular monovalent organic anions (PSCN/PCll = 1.73, Pacetate/PCll = 0.39, Plactate/PCll = 0.38, Pacetoacetate/PCll = 0.32, Pglutamate/PCll = 0.28) but was less permeable to the divalent anion malate (Pmalate/PCll = 0.14). Channel activity was inhibited by a number of putative anion channel inhibitors, including extracellular ATP (10 mM), 1,9-dideoxyforskolin (100 µM) and 4-OH tamoxifen (10 µM). Inclusion of the catalytic subunit of protein kinase A in the pipette solution did not activate the volume-sensitive anion channel in non-swollen cells. Furthermore, addition of 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) or forskolin failed to activate the channel in intact cells under perforated patch conditions. Addition of phorbol 12,13-dibutyrate (200 nM), either before or after cell swelling, also failed to affect channel activation. Our findings do not support the suggestion that the volume-sensitive anion channel in pancreatic β-cells can be activated by protein kinase A. Furthermore, the β-cell channel does not appear to be subject to regulation via protein kinase C. Experimental Physiology (2001) 86.2, 145-150.
Role of Ca2+-activated Cl- current in ventricular action potentials of sheep during adrenoceptor stimulation
- Arie O. Verkerk, Cees A. Schumacher, Antoni C. G. van Ginneken, Marieke W. Veldkamp, Jan H. Ravesloot
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- 31 July 2001, pp. 151-159
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Adrenoceptor stimulation enhances repolarising and depolarising membrane currents to different extents in cardiac myocytes. We investigated the opposing effects of the repolarising Ca2+-activated Cl- current (ICl(Ca)) and depolarising L-type Ca2+ current (ICa,L) on the action potential configuration of sheep ventricular myocytes stimulated with noradrenaline. Whole-cell current-clamp recordings revealed that noradrenaline accelerated and prolonged phase-1 repolarisation. We define the minimal potential at the end of phase-1 repolarisation as 'notch level'. Noradrenaline (1 µM) caused the notch level to fall from 14 ± 2.6 to 7.8 ± 2.8 mV (n = 24), but left action potential duration, resting membrane potential or action potential amplitude unaffected. Whole-cell voltage-clamp recordings showed that 1 µM noradrenaline increased both ICa,L and ICl(Ca), but it had no significant effect on the principal K+ currents. Blockage of ICl(Ca) by 0.5 mM 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) in both the absence and the presence of noradrenaline abolished phase-1 repolarisation. In the presence of noradrenaline, DIDS caused elevation of the plateau phase amplitude and an increase in the action potential duration. In conclusion, elevation of the plateau phase amplitude and action potential prolongation associated with an increased ICa,L upon adrenoceptor stimulation is prevented by an increased ICl(Ca) in sheep ventricular myocytes. Experimental Physiology (2001) 86.2, 151-159.
Effects of reactive oxygen species on aspects of excitation-contraction coupling in chemically skinned rabbit diaphragm muscle fibres
- G. M. Darnley, A. M. Duke, D. S. Steele, N. G. MacFarlane
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- 31 July 2001, pp. 161-168
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Oxidants have been suggested to enhance contractile function in unfatigued muscle. In this study we aimed to determine the effect of oxidants on 'chemically skinned' diaphragm muscle fibre bundles. The sarcoplasmic reticulum and contractile proteins were exposed to superoxide anions (O2-) and hydrogen peroxide (H2O2) under controlled conditions. Application of O2- initially increased maximum Ca2+-activated force but subsequently reduced maximum Ca2+-activated force without altering myofilament Ca2+ sensitivity. Unlike myocardium, caffeine-induced Ca2+ release from the sarcoplasmic reticulum was also inhibited by O2- exposure in diaphragm fibre bundles. Application of H2O2 also increased maximum Ca2+-activated force but had additional effects on resting tension (which increased to 25 % of the control maximum Ca2+-activated force). H2O2 was without effect on myofilament Ca2+ sensitivity or caffeine-induced Ca2+ release from the sarcoplasmic reticulum. These data demonstrate that oxidants can potentiate contractile force in the diaphragm through a direct action on the contractile proteins. The potentiation of force is not sustained, however, and under these conditions the detrimental effects of O2- on Ca2+ release from the sarcoplasmic reticulum combined with the effects of oxidants on the contractile proteins will ultimately compromise excitation-contraction coupling in the diaphragm. Experimental Physiology (2001) 86.2, 161-168.
Effects of T-lymphocyte-dependent and -independent immunity on cholinergic enzyme activity in mouse lacrimal gland
- Kakali Sinha, H. Kathleen Dannelly, Swapan K. Ghosh
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- 31 July 2001, pp. 169-176
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The nature of the immune response following ocular immunization with a protein and a polysaccharide and the effects such immunization have on the activities of cholinergic enzymes in the lacrimal glands of BALB/c mice were examined. Lacrimal glands are highly innervated by sympathetic and parasympathetic nerve fibres and are involved in mucosal immunity and therefore are excellent sites to study neuro-immune interactions. In this report, a T-lymphocyte-dependent protein antigen, keyhole limpet haemocyanin (KLH) and a T-lymphocyte-independent polysaccharide antigen, dextran (DEX) were administered topically to the eyes or intraperitoneally injected. Both routes of immunization produced a strong serum antibody response when KLH was the antigen. DEX, however, evoked a serum antibody response only after intraperitoneal administration. Eosin-haematoxylin staining indicated no histological abnormality or inflammatory changes in any immunized lacrimal glands, but immuno-staining revealed that only in the KLH-treated tissues were IgG-producing plasma cells discernible. Furthermore, KLH-specific antibody was also detectable using an immuno-blot assay in lacrimal glands. Polymerase chain reaction analysis with cytokine-specific primers revealed induction of interleukin-4 (lL-4) in KLH-treated lacrimal glands, but not in DEX or unimmunized tissues. Thus, the nature of the antigen seems important in the induction of the immune response in lacrimal glands. To delineate the effects that immunogenic differences might have on the activities of the cholinergic enzymes, choline acetyl-transferase (ChAT) and acetylcholinesterase (AChE) were assayed using radiolabelled substrates and measuring labelled products. Both ChAT and AChE activities were influenced following KLH immunization, while DEX had only transient effects on ChAT. This is possibly due to the fact that KLH, a protein antigen, is the effective inducer of the specific immune response in the lacrimal gland, while DEX is not. Experimental Physiology (2001) 86.2, 169-176.
Pacemaker shift in the rabbit sinoatrial node in response to vagal nerve stimulation
- Nitaro Shibata, Shin Inada, Kazuyuki Mitsui, Haruo Honjo, Mitsuru Yamamoto, Ryoko Niwa, Mark R. Boyett, Itsuo Kodama
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- 31 July 2001, pp. 177-184
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Effects of brief postganglionic vagal nerve stimulation on the activation sequence of the rabbit sinoatrial (SA) node were investigated. Activation sequences in a small area (7 mm × 7 mm) on the epicardial surface were measured in a beat-to-beat manner using an extracellular potential mapping system composed of 64 modified bipolar electrodes with high-gain and low-frequency band-pass filtering. The leading pacemaker site was recognised clearly from both the activation sequence and the characteristic morphology of the potentials. Vagal stimulation resulted in a short-lasting initial slowing of spontaneous rate followed by a long-lasting secondary slowing; a brief period of relative or absolute acceleration was interposed between the two slowing phases. During these changes of spontaneous rate, the leading pacemaker site shifted in a complex beat-to-beat manner by 1-6 mm alongside the crista terminalis in the superior or inferior direction. For the first spontaneous excitation following stimulation, the greater the slowing, the larger the distance of the pacemaker shift. There was no such linear relationship between the extent of slowing and the distance of pacemaker shift for the subsequent beats. These changes in the leading pacemaker site in response to vagal stimulation may be the result of the functional and morphological heterogeneity of the mammalian SA node in terms of innervation, receptor distribution and ion channel densities. Experimental Physiology (2001) 86.2, 177-184.
The effects of dietary creatine supplements on the contractile properties of rat soleus and extensor digitorum longus muscles
- M. McGuire, A. Bradford, M. MacDermott
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- 31 July 2001, pp. 185-190
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Daily creatine supplements (0.258 g kg-1 ) were administered to adult male Wistar rats (n = 7) in the drinking water. Age matched rats (n = 6) acted as controls. After 5-6 days, contractile properties were examined in soleus and extensor digitorum longus (EDL) muscle strips in vitro at 30 °C. In soleus muscles, creatine supplements decreased the half-relaxation time of the isometric twitch from 53.6 ± 4.3 ms in control muscles to 48.4 ± 5.5 ms but had no effect on twitch or tetanic tension or on twitch contraction time. In EDL muscles twitch tension, tetanic tension, twitch contraction and half-relaxation times were all unaffected by creatine supplements. Creatine supplements increased the fatigue resistance of the soleus muscles but had no effect on that of the EDL muscles. After a 5 min low-frequency fatigue test, tension (expressed as a percentage of initial tension) was 56 ± 3 % in control soleus muscles, whereas that in the creatine-supplemented muscles was 78 ± 6 % (P < 0.01). In the EDL muscles, the corresponding values were 40 ± 2 % and 41 ± 9 %, respectively. The force potentiation which occurred in the EDL muscles during the initial 20-30 s of the fatigue test was 170 ± 10 % of initial tension in the control muscles 24 s after the initial stimulus train but was reduced (P < 0.01) to 130 ± 20 % in the creatine-supplemented muscles. In conclusion, soleus muscle endurance was increased by creatine supplements. EDL endurance was unaffected but force potentiation during repetitive stimulation was decreased. Experimental Physiology (2001) 86.2, 185-190.
Expression of constitutive but not inducible cyclooxygenase maintains articular perfusion in the rat knee
- Colin G. Egan, John C. Lockhart, John S. McLean, William R. Ferrell
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- 31 July 2001, pp. 191-197
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Experiments were performed in the normal rat knee joint to investigate the role of different isoforms of cyclooxygenase (COX) in the regulation of basal joint blood flow. Laser Doppler imaging (LDI) was used to measure articular perfusion, and reverse transcriptase polymerase chain reaction (RT-PCR) for the detection of COX-1 and COX-2 mRNA in joint tissue. Intravenous infusion of indomethacin (a non-selective inhibitor of COX; 0.34 nmol min-1) over 40 min produced a time dependent increase in articular vascular resistance (maximum 22.5 % at 40 min; P < 0.0001, one-way ANOVA) whereas vehicle over a similar time period had no effect in a control group. An equimolar concentration of a highly selective inhibitor for COX-2, SC-236, was administered in a further group of rats but this did not increase articular vascular resistance. While there was no significant difference between the response to vehicle and SC-236 (two-way ANOVA; P = 0.686, n = 6) the response to indomethacin was significantly greater than vehicle or SC-236 (two-way Anova; P < 0.0001, n = 6). COX-1, but not COX-2, was detectable by RT-PCR in all joint tissue samples examined (n = 4). The results of this study indicate that prostaglandins (PGs) play an important role in the maintenance of basal perfusion in the rat knee joint, with COX-1 being the physiologically relevant isoform. Experimental Physiology (2001) 86.2, 191-197.
Feto-maternal relationships in goats during heat and cold exposure
- A. S. Faurie, D. Mitchell, H. P. Laburn
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- 31 July 2001, pp. 199-204
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Maternal and fetal body temperatures were measured in five Boer goats, of mean mass 64 ± 8 kg, using temperature-sensitive radiotelemeters implanted intra-abdominally. Body temperatures were recorded every 5 min. Throughout the last month of gestation, fetal temperature was approximately 0.6 oC higher than that of the mother, in normal laboratory conditions (ambient air temperature: 21-24 oC). This feto-maternal temperature difference between the goat fetus and its mother is similar to that found in other mammals, including sheep. When the pregnant goats were subjected to short-term heating and cooling, the difference between maternal and fetal body temperatures changed. Thus the mean difference between fetal and maternal body temperatures decreased from 0.4 to 0.2 oC during 2 h of heating, while it widened from 0.3 to 0.7 oC during 6 h of cooling. These data support the idea that the fetus is thermally protected from excursions of body temperature during changes in the mother's thermal environment. Reports of goat stock losses and abortions during cold spells in their natural habitats may be the result of more severe and/or prolonged cold exposures that not only adversely affect fetal or maternal body temperature, but also influence other aspects of metabolism. Experimental Physiology (2001) 86.2, 199-204.
Altered glycogen synthase and phosphorylase activities in skeletal muscle of tetraplegic patients
- Ying Jiao, Pavel Shashkin, Nils Hjeltnes, Harriet Wallberg-Henriksson, Abram Katz
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- 31 July 2001, pp. 205-209
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Despite marked differences in both the extent of physical activity and in muscle metabolism and structure between tetraplegic and control subjects, the glycogen content in the skeletal muscle of both groups is similar. We determined whether this similarity could be explained by the activities of key enzymes of glycogen metabolism. Muscle biopsies were analysed for glycogen synthase (GS) and glycogen phosphorylase (GP) activities, as well as for metabolites. Glycogen content did not differ significantly between the two groups. Total glycogen synthase activity was reduced by almost 60 % in tetraplegics (P < 0.01), whereas total phosphorylase activity did not differ between groups. GS fractional activity did not differ between groups, whereas phosphorylase fractional activity (-/+ AMP) was significantly higher in the tetraplegics (0.08 ± 0.01, control; 0.25 ± 0.02, tetraplegics; P < 0.001). Neither uridine diphosphate (UDP)-glucose nor glucose 6-phosphate (G-6-P) content in muscle differed significantly between groups. These data demonstrate that, in tetraplegics, muscle glycogen content is preserved despite decreases in GS activity and increases in phosphorylase fractional activity. Muscle paralysis has differential effects on the activities of GS and GP. Experimental Physiology (2001) 86.2, 205-209.
Introduction
- A. López Bernal
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- 31 July 2001, p. 211
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This issue contains a number of papers based on presentations from a Uterine Contractility Symposium held in Oxford, UK on May 3rd, 2000. They represent an overview of current knowledge on the regulation of uterine smooth muscle. Research in this area is important because disorders of parturition, notably preterm labour, remain a major cause of perinatal mortality and carry a wide range of short- and long-term morbidity in the surviving infants. Available therapies are inefficient or have undesirable side effects for the mother or the baby. A better understanding of the physiology of parturition and the cellular basis of uterine contractility will lead to the development of more efficacious and selective drugs for the management of preterm labour and other disorders of uterine function. The main presentation was the Litchfield Lecture (sponsored by the Medical School), which was given by Professor Barbara Sanborn. There were also presentations of very high standard by scientists and clinicians with a long-standing interest in this subject, and by young scientists. I am most grateful to all the contributors for their enthusiasm and for making an effort to produce quality manuscripts as a scientific record of this symposium. All the manuscripts have been fully reviewed and I am particularly indebted to Professor Lucilla Poston for coordinating the editorial work. The symposium was supported by educational grants from the Serono Pharmaceutical Research Institute, GlaxoWellcome R&D, Alliance Pharmaceuticals, Ferring Pharmaceuticals, Unipath and Aventis Pharma.
Overview of current research in parturition
- A. López Bernal
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- 31 July 2001, pp. 213-222
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The mechanism of human parturition is not understood and further research into this important physiological process is needed. Preterm labour remains a major cause of perinatal mortality and morbidity and there is controversy about the effectiveness of current tocolytic agents. In some species, notably the sheep, parturition is preceded by an activation of the fetal hypothalamic-pituitary-adrenal axis. However, in primates this axis has a supportive, rather than essential, role. A fall in maternal progesterone levels is a prerequisite for parturition in most mammals and this takes place either through increased conversion of progesterone to oestrogens in the placenta, or through the demise of the corpus luteum of pregnancy, depending on the species. In primates and guinea-pigs parturition occurs without an apparent fall in maternal progesterone levels. Gene targeting experiments in mice have demonstrated the critical role of prostaglandin FP receptors, necessary to mediate the luteolytic effect of PGF2α before parturition. Prostaglandin synthesis is required for the onset and progress of labour as demonstrated by experiments with cPLA2- and PGHS-1-deficient mice. The importance of local tissue conversion of progesterone to reduced androgens in the regulation of cervical ripening has been demonstrated in 5α-reductase-deficient mice. The chronic and ubiquitous gene inactivation obtained with conventional methods has disadvantages, in that it may allow the activation of compensating pathways, making the interpretation of results difficult. This problem may be overcome by using pulsed and tissue-selective gene knockout strategies. The study of human parturition is complicated by the lack of access to direct experimentation, whereas the endocrine differences between species make it difficult to extrapolate animal data to humans. However, the development of genomic/proteomic technologies that allow the simultaneous screening of thousands of genes and gene products in small samples of tissue, and new methods to study the biochemistry of receptors and proteins involved in smooth muscle physiology promise new insights into the control of human labour. Nevertheless, the integration of rapidly expanding knowledge into a complete understanding of the roles of the mother and the fetus in the initiation of parturition, and the development of selective medication for the effective management of preterm labour remain an arduous challenge for the next decade. Experimental Physiology (2001) 86.2, 213-222.
Hormones and calcium: mechanisms controlling uterine smooth muscle contractile activity
- Barbara M. Sanborn
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- 31 July 2001, pp. 223-237
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The regulation of myometrial contraction is of paramount importance for the maintenance of pregnancy and for parturition. Understanding this regulation involves delineating the pathways that control myometrial contraction and relaxation and defining the regulation of these pathways. The pathways can be broken down further into those signalling cascades controlling the concentration of intracellular free calcium (Ca2+i) and those controlling the contractile apparatus itself. This discussion focuses primarily on the former and their regulation during pregnancy. In particular, cross-talk between the contractant and relaxant signalling pathways mediated through cyclic AMP is markedly changed at the end of pregnancy. Experimental Physiology (2001) 86.2, 223-237.
The physiological basis of uterine contractility: a short review
- S. Wray, S. Kupittayanant, A. Shmygol, R. D. Smith, T. Burdyga
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- 31 July 2001, pp. 239-246
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In this review we discuss our current understanding of the cellular basis of uterine contractility, highlighting those areas requiring further study. It is clear that the basic processes of excitation-contraction coupling lie within the myometrial cell, and that these may be modified by agonists. Pacemaker acitivity, however, remains a mystery. The contribution of extracellular calcium entry to contraction is shown to be vital, whilst the role of the sarcoplasmic reticulum remains controversial. Much current experimental focus is on pathways controlling and regulating contraction, and we discuss sensitisation mechanisms and question their role in intact uterine preparations. Experimental Physiology (2001) 86.2, 239-246.
Regulation of human myometrial contractility during pregnancy and labour: are calcium homeostatic pathways important?
- Rachel M. Tribe
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- 31 July 2001, pp. 247-254
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If we are to develop new strategies for the treatment and management of preterm and dysfunctional term labour, it is imperative that we improve current understanding of the control of human uterine activity. Despite many studies of animal pregnancy, there is a paucity of knowledge relating to the complex control of human myometrium during pregnancy. It is hypothesized that human myometrium is relatively quiescent during the majority of pregnancy and that as term approaches there is cascade of molecular events that prepare the uterus for labour. This review will consider the cellular mechanisms involved in the regulation of human myometrial activity and the modulation of these by hormonal and mechanical signals. In particular, the contribution of calcium homeostatic pathways to the control of human myometrial contractility during gestation will be discussed. Experimental Physiology (2001) 86.2, 247-254.
Potassium channels in the human myometrium
- Raheela N. Khan, Balwir Matharoo-Ball, Sabaratnam Arulkumaran, Michael L. J. Ashford
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- 31 July 2001, pp. 255-264
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The contractility of the human uterus is under the fine control of a variety of interacting bioactive agents. During labour, the excitability of the uterus is drastically transformed in comparison with the non-labour state and is manifest at the membrane level via the acivity of uterine ion channels. This article reviews the contribution of potassium (K+) channels to human uterine excitability. Experimental Physiology (2001) 86.2, 255-264.
Uterine quiescence: the role of cyclic AMP
- Sarah A. Price, Andrés López Bernal
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- 31 July 2001, pp. 265-272
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It is accepted that whilst hormones such as oxytocin, vasopressin and prostaglandin F2α induce myometrial contractions, essentially via an elevation of intracellular calcium, other ligands, such as β-adrenoceptor agonists, calcitonin gene-related peptide, and prostaglandin E2, promote uterine quiescence via their ability to increase intracellular cyclic AMP levels. At present, the exact factors initiating human parturition remain unknown, and labour may occur due to a loss of uterine quiescence, an increase in uterine contractility, or a combination of both. Whilst many studies have aimed to understand the mechanisms underlying uterine contractility there is a relative paucity of data regarding myometrial relaxation. We have verified the presence of mRNA encoding adenylyl cyclase (AC) isoforms I, II, III, V, VI, VII, VIII and IX in both non-pregnant and pregnant human myometrium, and in isolated myometrial cells maintained in cell culture. Furthermore, by means of immunoblotting and immunocytochemistry, we have demonstrated the expression of these isoforms as membrane-associated AC proteins, and identified changes in individual AC isoform expression during gestation. These findings illustrate the diversity of potential cAMP generating pathways in human myometrium, and the complexity of the signal transduction systems underlying uterine quiescence. Experimental Physiology (2001) 86.2, 265-272.
Corticotrophin releasing hormone: its potential for a role in human myometrium
- E. A. Linton, J. R. Woodman, G. Asboth, B. P. Glynn, C. P. Plested, A. López Bernal
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- 31 July 2001, pp. 273-281
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Aside from its role as a hypothalamic stress hormone, corticotrophin releasing hormone (CRH) is also a placental hormone, at least in primates. Although the function of placentally derived CRH remains to be fully elucidated, elevated CRH levels have been associated with premature labour, suggesting that the hormone may be involved in regulating the duration of pregnancy. Indeed, pregnant human myometrium expresses functional CRH receptors (CRH R1 and CRH R2 subtypes) thought to signal predominantly via the second messenger cAMP. Thus, like other cAMP-producing hormones in the myometrium such as β2 agonists, CRH may play a part in maintaining uterine quiescence. However, several of the CRH receptor isoforms identified to date have a reduced ability to activate adenylate cyclase, raising the question as to whether they are linked to other signal transduction pathways. Here, we discuss critically the evidence for the peptide's role in regulating contractility, both directly at the myometrium and indirectly via the fetal membranes and decidua. The possibility of a role in myometrial growth modulation is also described. Experimental Physiology (2001) 86.2, 273-281.
Receptor-coupled contractility of uterine smooth muscle: from membrane to myofilaments
- Y.-H. Lee, M.-K. Hwang, K. G. Morgan, Michael J. Taggart
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- 31 July 2001, pp. 283-288
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A comprehensive understanding of the mechanisms by which agonists control uterine contraction is essential for the successful clinical management of parturition and for the timely treatment of situations involving inappropriate uterine performance. In this review we discuss some of the key stimulatory mechanisms linking receptor occupation at the myometrial plasma membrane with alteration of myofilament activation. We focus on evidence that receptor-induced membranous recruitment of the small G-protein rhoA, and its downstream effector rho-associated kinase (ROK) is crucial to agonist-induced Ca2+-sensitisation of uterine contraction and that co-ordination of this signal transduction pathway may be mediated by the actions of caveolins, proteins integral to specialised membranous regions termed caveolae. Experimental Physiology (2001) 86.2, 283-288.
The structure and regulation of the oxytocin receptor
- Richard Ivell, Tadashi Kimura, Dieter Müller, Kai Augustin, Nicole Abend, Ross Bathgate, Ralph Telgmann, Marga Balvers, Gina Tillmann, Anna-Riitta Fuchs
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- 31 July 2001, pp. 289-296
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The oxytocin receptor (OTR) is part of an ancient hormone system expressed in diverse phyla in relation to acute reproductive smooth muscle responses, such as egg-laying, birth, or milk letdown. The regulation of the OTR gene, while correlating with steroid levels in vivo, remains elusive. There appear to be both inhibitory and stimulatory influences acting upon a constitutive pattern of basal expression. We have found no evidence, however, for an effect of the sex steroids either directly on gene transcription, or on the receptor itself at the protein level. In the prostatic carcinoma cell line Du145, we have shown that up-regulation of the OTR gene transcription can be effected by cAMP. In an attempt to characterize the expression of the OTR protein in vivo, we have shown, using ligand-blotting, that the OTR can be expressed at different sizes in transfected cells and in myometrium. Also, in the myometrium at term, immunohistochemistry suggests that there is both an increase in OTR protein per cell, as well as in the number of smooth muscle cells expressing OTR, emphasizing that perinatal changes are the results of both individual gene activation events and gross cellular differentiation. The OTR is a valuable model system reflecting molecular changes in the perinatal period. When we understand how this important molecule is regulated, we will also be a long way towards understanding the mechanisms controlling myometrial contractility at birth. Experimental Physiology (2001) 86.2, 289-296.
Oxytocin antagonists: clinical and scientific considerations
- Steven Thornton, Manu Vatish, Donna Slater
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- 31 July 2001, pp. 297-302
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Preterm delivery is the largest cause of perinatal mortality and morbidity, yet the treatment of preterm labour has not been demonstrated to improve outcome. The reasons are numerous and complex, but they include a failure to understand the mechanism(s) of preterm labour, the multitude of different causes, the difficulty in diagnosis and the problems of outcome measurement in clinical trials. Recently, an oxytocin antagonist (atosiban) has been introduced into clinical practice in Europe. Although it may be an effective tocolytic, a beneficial effect on perinatal outcome has not been demonstrated. Atosiban has an effect at both oxytocin and vasopressin (V1a) receptors, which (assuming efficacy) raises the question as to whether oxytocin or vasopressin V1a antagonism is required for tocolysis. This review examines the rationale for tocolysis in preterm labour, the evidence for administration of atosiban and the role for oxytocin, vasopressin and their receptors in the onset of labour. Experimental Physiology (2001) 86.2, 297-302.