Oxytocin: Its Mechanism of Action and Receptor Signalling in the Myometrium

Arrowsmith, Sarah; Wray, Susan

doi:10.1111/jne.12154

Cited by 235 publications

(203 citation statements)

References 187 publications

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“…Because oxytocin is a powerful stimulator of uterine contractions, it was important to determine if HIFI can be demonstrated on top of oxytocin stimulation, and if oxytocin is required for HIFI. Addition of oxytocin to the perfusate increased uterine activity as expected (14). Compared with spontaneous activity, in the presence of oxytocin the effects of transient hypoxia on the amplitude of uterine contractions were more pronounced, as shown in Fig.…”

Section: Significancesupporting

confidence: 76%

Hypoxia-induced force increase (HIFI) is a novel mechanism underlying the strengthening of labor contractions, produced by hypoxic stresses

Alotaibi

Arrowsmith

Wray

2015

Proc. Natl. Acad. Sci. U.S.A.

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For successful birth, contractions need to become progressively stronger. The underlying mechanisms are unknown, however. We have found that a novel mechanism, hypoxia-induced force increase (HIFI), is switched on selectively, at term, and is essential to strengthening contractions. HIFI is initiated as contractions cyclically reduce blood flow and produce repeated hypoxic stresses, with associated metabolic and transcriptomic changes. The increases in contractility are a long-lasting, oxytocin-independent, intrinsic mechanism present only in the full-term pregnant uterus. HIFI is inhibited by adenosine receptor antagonism and blockade of cyclooxygenase-2 signaling, and partially reproduced by brief episodes of acidic (but not alkalotic) pH. HIFI explains how labor can progress despite paradoxical metabolic challenge, and provides a new mechanistic target for the 1 in 10 women suffering dysfunctional labor because of poor contractions. myometrium | smooth muscle | pH | hypoxia | hypoxic preconditioning P ulsatile releases of oxytocin are important for labor, but as oxytocin knockout mice deliver normally (1), other mechanisms for increasing contractile strength must occur. A puzzling feature of labor is that contractions become progressively stronger as the myometrium (uterine muscle) experiences repetitive metabolic stress from hypoxia. This reaction occurs because as contractions develop they briefly compress the uterine blood vessels (2, 3). Transient decreases of oxygenation, pH, and ATP, all of which if sustained can decrease contractile activity, occur in vivo with each contraction (3-5). Hypoxia regulates a large number of genes, including those governing metabolism and function in many tissues, and changes in genes associated with hypoxia have been identified as key findings in transcriptomic studies of poorly laboring women (6, 7). Chaemsaithong et al. and Mittal et al. confirmed changes in hypoxia-inducible factor 1a (HIF1a) using RT-PCR, as well as overexpression of cyclooxygenase-2 (COX2) in myometrium and endothelial NOS, which is important for blood vessel dilation. There is, however, no empirical evidence showing how such changes could be important to successful labors, and no existing mechanism linking hypoxia to an increase in contractions. In contrast, studies of hypoxia in myometrium and other smooth muscles show it to decrease contractility (8, 9).Of note, however, are studies demonstrating ischemic tolerance as an adaptive response initiated by several exposures to a stressor of mild severity, from which resistance to ischemia is markedly increased. This is known as hypoxic or ischemic preconditioning, and has been best investigated in cardiac muscle (10) and brain (11), where it is considered to be a powerful mechanism for limiting ischemic damage. Given that physiological decreases in oxygenation are part of the normal process of labor (4, 12), this finding therefore raised some important questions: What is the effect of brief but repetitive periods of hypoxia on uterine contractility? And...

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Section: Significancesupporting

confidence: 76%

Hypoxia-induced force increase (HIFI) is a novel mechanism underlying the strengthening of labor contractions, produced by hypoxic stresses

Alotaibi

Arrowsmith

Wray

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The fact that there are many oxytocin unresponsive cases may suggest some relationship between sterility and oxytocin/oxytocin receptors, which may be worth researching [38].…”

Section: Discussionmentioning

confidence: 99%

In Vitro Fertilization Pregnancy is One of the Risk Factor for Atonic Bleeding in Problem-Free Pregnancy

Yanaihara¹,

Ohgi²,

Motomura³

et al. 2017

J Preg Child Health

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“…Oxytocin is not strictly essential, seeing as other mechanisms can generally compensate for its absence, but it is secreted in very large amounts during labour; it also acts on the uterus, which expresses greatly increased levels of oxytocin receptor at term, by either acutely blocking oxytocin release or slowing parturition (Blanks & Thornton 2003, Russell et al 2003. The trigger for initiating parturition varies between species, but it seems that oxytocin is commonly a driver for uterine contractions once parturition has begun (Russell et al 2003, Arrowsmith & Wray 2014. Oxytocin may also play some part in the initiation of labour, but in women, other paracrine mechanisms are more important for this (Kamel 2010).…”

Section: Parturitionmentioning

confidence: 99%

60 YEARS OF NEUROENDOCRINOLOGY: The posterior pituitary, from Geoffrey Harris to our present understanding

Leng¹,

Pineda²,

Sabatier³

et al. 2015

Journal of Endocrinology

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Geoffrey Harris pioneered our understanding of the posterior pituitary, mainly with experiments that involved the electrical stimulation of the supraoptico-hypophysial tract. In the present essay, we explain how his observations included clues to the pulsatile nature of the oxytocin signal -clues that were followed up by subsequent workers, including his students and their students. These studies ultimately led to our present understanding of the milk-ejection reflex and of the role of oxytocin in parturition. Discoveries of wide significance followed, including: the recognition of the importance of pulsatile hormone secretion; the recognition of the importance of stimulus-secretion coupling mechanisms in interpreting the patterned electrical activity of neurons; the physiological importance of peptide release in the brain; the recognition that peptide release comes substantially from dendrites and can be regulated independently of nerve terminal secretion; and the importance of dynamic morphological changes to neuronal function in the hypothalamus. All of these discoveries followed from the drive to understand the milk-ejection reflex. We also reflect on Harris's observations on vasopressin secretion, on the effects of stress, and on oxytocin secretion during sexual activity.

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Oxytocin: Its Mechanism of Action and Receptor Signalling in the Myometrium

Cited by 235 publications

References 187 publications

Hypoxia-induced force increase (HIFI) is a novel mechanism underlying the strengthening of labor contractions, produced by hypoxic stresses

Hypoxia-induced force increase (HIFI) is a novel mechanism underlying the strengthening of labor contractions, produced by hypoxic stresses

In Vitro Fertilization Pregnancy is One of the Risk Factor for Atonic Bleeding in Problem-Free Pregnancy

60 YEARS OF NEUROENDOCRINOLOGY: The posterior pituitary, from Geoffrey Harris to our present understanding

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