A Functional Role for Nicotinic Acid Adenine Dinucleotide Phosphate in Oxytocin-Mediated Contraction of Uterine Smooth Muscle from Rat

Aley, Parvinder K.; Noh, Hyun Ji; Gào, Xīn; Tica, Andrei Adrian; Brǎiloiu, Eugen; Churchill, Grant C.

doi:10.1124/jpet.110.165837

Cited by 27 publications

(37 citation statements)

References 41 publications

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“…The uterus has been described as 'the poor sister among isolated tissues in the pharmacologist's armamentarium' because it is difficult to work with 1 . This difficulty has created gaps in our current understanding of uterine function and associated pathologies (e.g.…”

Section: Introductionmentioning

confidence: 99%

Toward Understanding Myometrial Regulation: Metabolomic Investigation Reveals New Pathways of Oxytocin and Ritodrine Activity on the Myometrium

2017

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This version is available at https://strathprints.strath.ac.uk/59989/ Strathprints is designed to allow users to access the research output of the University of Strathclyde. Unless otherwise explicitly stated on the manuscript, Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Please check the manuscript for details of any other licences that may have been applied. You may not engage in further distribution of the material for any profitmaking activities or any commercial gain. You may freely distribute both the url (https://strathprints.strath.ac.uk/) and the content of this paper for research or private study, educational, or not-for-profit purposes without prior permission or charge.Any correspondence concerning this service should be sent to the Strathprints administrator: strathprints@strath.ac.ukThe Strathprints institutional repository (https://strathprints.strath.ac.uk) is a digital archive of University of Strathclyde research outputs. It has been developed to disseminate open access research outputs, expose data about those outputs, and enable the management and persistent access to Strathclyde's intellectual output. ABSTRACTIn recent times, additional pathways involved in myometrial regulation and also in the action of oxytocin and -adrenergic agonists on the myometrium, other than what has been known previously has been suggested. Knowledge of other pathways will prove useful in designing better therapies for myometrial pathologies. This study was therefore aimed at investigating the possibility of other pathways involved in the activity of either oxytocin or a -adrenergic agonists (ritodrine was used in this study) in myometrial activity with the aid of metabolomics and bioinformatics. High resolution Fourier transform mass spectrometry (HRFTMS), and nuclear magnetic resonance (NMR) spectroscopy coupled with functional uterine assays were combined for an innovative assessment. In vitro pharmacological assay of oxytocin (1 nM) and ritodrine (0.1 nM) on isolated mice uteri mounted in 3 ml organ baths were performed. Mice uteri, treated with oxytocin (OT) or ritodrine (RIT), as well as the physiological buffer in which the uterine tissues were immersed, were rapidly collected and analysed using HRFTMS, 1 HNMR and bioinformatics. Resulting data were analyzed via pair-wise chemometric comparison models with p ≤ 0.05 considered statistically significant. In addition to previously known metabolites, anandamide, nicotinamide adenine dinucleotide, gamma aminobutyric acid and sphingosine were significantly associated with OT's activity while a downstream involvement of prostaglandin F1 and phosphatidylinositol signalling was observed with RIT's activity. These findings adds evidence to the reports on additional regulation of myometrial activity by these drugs and also offers newer pathways for therapeutic manipulation.

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Section: Introductionmentioning

confidence: 99%

Toward Understanding Myometrial Regulation: Metabolomic Investigation Reveals New Pathways of Oxytocin and Ritodrine Activity on the Myometrium

2017

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“…Given emerging evidence implicating NAADP in Ca 2ϩ signaling pathways attributed to more traditional messengers (24,25), we examined the role of NAADP in the endothelium. By combining Ca 2ϩ , voltage, and NO imaging of single cultured endothelial cells with measurement of contractility ex vivo and blood pressure in vivo, we show that NAADP-sensitive Ca 2ϩ stores are present in the endothelium, that they are recruited in an agonist-specific manner, and that their mobilization is sufficient to regulate contractility and blood pressure.…”

mentioning

confidence: 99%

Acidic NAADP-sensitive Calcium Stores in the Endothelium

Brailoiu

Gurzu

Gào

et al. 2010

Journal of Biological Chemistry

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Accumulating evidence implicates nicotinic acid adenine dinucleotide phosphate (NAADP) in the control of Ca2؉ -dependent functions. Little, however, is known concerning its role in the vascular endothelium, a major regulator of blood pressure. Here, we show that NAADP acetoxymethyl ester (NAADP-AM), a cell-permeant NAADP analog, increases cytosolic Ca 2؉ concentration in aortic endothelial cells. We demonstrate that these signals and those evoked by acetylcholine are blocked by disrupting acidic organelles with bafilomycin A1. In contrast, Ca 2؉ signals in response to thrombin are only partially inhibited by bafilomycin A1 treatment, and those to ATP were insensitive, suggesting that recruitment of acidic stores is agonist-specific. We further show that NAADP-evoked Ca 2؉ signals hyperpolarize endothelial cells and generate NO. Additionally, we demonstrate that NAADP dilates aortic rings in an endothelium-and NO-dependent manner. Finally, we show that intravenous administration of NAADP-AM into anesthetized rats decreases mean arterial pressure. Our data extend the actions of NAADP to the endothelium both in vitro and in vivo, pointing to a previously unrecognized role for this messenger in controlling blood pressure.Nicotinic acid adenine dinucleotide phosphate (NAADP) 4 is a potent and widespread Ca 2ϩ -mobilizing messenger first described in sea urchin eggs (1, 2). Although its mechanism of action is subject to debate, much evidence indicates that NAADP mobilizes Ca 2ϩ from acidic, lysosome-like organelles (3) through activation of novel Ca 2ϩ -permeable channels (1, 4). These channels have recently been identified as members of the two-pore channel family (5-9). Importantly, mobilization of so-called "acidic Ca 2ϩ stores" (10) by NAADP is often linked to mobilization of the well established endoplasmic reticulum Ca 2ϩ stores through the process of Ca 2ϩ -induced Ca 2ϩ release (11). NAADP is thus thought to act as trigger during agonistevoked Ca 2ϩ signaling (2). The functional positioning of NAADP-sensitive Ca 2ϩ stores upstream of those targeted by the messengers, inositol 1,4,5-trisphosphate (IP 3 ) and cyclic ADP-ribose, raises the possibility that agonist-evoked Ca 2ϩ signals previously ascribed to endoplasmic reticulum Ca 2ϩ release might also involve NAADP and acidic organelles.Using isolated cells or tissues, NAADP-induced Ca 2ϩ signaling has been implicated in the regulation of several physiological functions such as egg fertilization (12, 13), T lymphocyte activation (14), muscle contraction (15), and neuronal differentiation (16). The role of NAADP in vivo, however is not known, although a recent study demonstrated that a newly described NAADP antagonist could prevent T cell motility in an animal model of multiple sclerosis (17).In the cardiovascular system, a role for NAADP has been demonstrated in agonist-evoked Ca 2ϩ signaling in pulmonary (15, 18) and coronary arteries (19,20), cardiac myocytes (21), and the renal microcirculation (22). Direct measurements of NAADP have confirmed its messenge...

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“…These increases were significantly smaller than those seen in the presence of extracellular calcium. References [15,39] also showed that removal of external Ca 2+ caused a significant decrease in the oxytocininduced rise in calcium and force production.…”

Section: Discussionmentioning

confidence: 99%

“…During subsequent years, great progress was made in understanding the mechanisms of action of calcium leading to this contraction. It is now well established that a rise in intracellular calcium in uterine smooth muscle causes activation of myosin light chain kinase and phosphorylation of myosin light, leading to contraction [39] . The rise in calcium, as in many different cell types, is traditionally believed to be from two sources: extracellular calcium entry through plasma membrane calcium channels and release of calcium from the sarcoplasmic reticulum.…”

Section: Discussionmentioning

confidence: 99%

Effects of Sesamum Radiatum Aqueous Leaf Extract on Rhythmic Contractions of Uterine Smooth Muscle Bundles From Pregnant Rats

Konan¹,

Bouafou²,

Kouakou³

et al. 2012

LSMR

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Abstract-Sesamum radiatum is employed in traditional medicine for parturient women to facilitate deliveries. In this study, the effects of the aqueous leaf extract were examined on the contractile activity of uterine smooth muscle isolated from pregnant Wistar rats (19-21 days). The isometric contractile force of the uterine smooth muscle bundles was recorded by using a strain gauge. S. radiatum aqueous leaf extracts (ESera, 1×10 -4 µg/ml -100µg/ml) showed uterotonic properties. These uterotonic effects were characterized by the increase of the amplitude, the frequency and the basal tone of the uterine smooth muscle strips in normal Mac Ewen solution and by the development of contracture in depolarizing solution and in solution without calcium. Similar effects were observed with Oxytocin (OT, 2.5×10 -14 µg/ml -2.5×10 -9 µg/ml) and misoprostol (Miso, 1×10 -3 µg/ml -0.08µg/ml). In Ca 2+-free solution, the addition of the ESera (10 µg / ml) elicited the development of contracture in the presence of EGTA (0.1 mM). This result suggests that ESera could act on the double calcium flux (intracellular and extracellular) like misoprostol, a synthetic analogue of prostaglandin E 1 . In conclusion, the aqueous leaf extract of S. radiatum (ESera) had uterotonic effects (prostaglandin-like activity) on uterine contraction in pregnant rats.

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A Functional Role for Nicotinic Acid Adenine Dinucleotide Phosphate in Oxytocin-Mediated Contraction of Uterine Smooth Muscle from Rat

Cited by 27 publications

References 41 publications

Toward Understanding Myometrial Regulation: Metabolomic Investigation Reveals New Pathways of Oxytocin and Ritodrine Activity on the Myometrium

Toward Understanding Myometrial Regulation: Metabolomic Investigation Reveals New Pathways of Oxytocin and Ritodrine Activity on the Myometrium

Acidic NAADP-sensitive Calcium Stores in the Endothelium

Effects of Sesamum Radiatum Aqueous Leaf Extract on Rhythmic Contractions of Uterine Smooth Muscle Bundles From Pregnant Rats

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