PMID- 30962532
OWN - NLM
STAT- MEDLINE
DCOM- 20201006
LR  - 20210109
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 9
IP  - 1
DP  - 2019 Apr 8
TI  - Oxytocin Receptor Antagonists, Atosiban and Nolasiban, Inhibit Prostaglandin 
      F(2alpha)-induced Contractions and Inflammatory Responses in Human Myometrium.
PG  - 5792
LID - 10.1038/s41598-019-42181-2 [doi]
LID - 5792
AB  - Oxytocin receptor antagonists (OTR-A) have been developed as tocolytics for the 
      management of preterm labour due to the significant role of oxytocin (OT) in the 
      onset of both term and preterm labour. Similar to OT, prostaglandins (PGs) play 
      key roles in myometrial contractility and cervical ripening. Inhibition of PG 
      synthesis/activity is used to delay preterm birth. Thus, targeting the PG pathway 
      in combination with an OTR-A may be an effective strategy for delaying preterm 
      delivery. In this study, we examined the effects of atosiban and nolasiban on 
      PGF(2alpha)-induced contractions and pro-inflammatory responses in human pregnant 
      myometrium. Both OTR-As, atosiban and nolasiban, inhibited PGF(2alpha)-induced 
      contractions in a dose-dependent manner (p < 0.001 and p < 0.01, respectively). 
      These inhibitory effects involved the suppression of PGF(2alpha)-mediated increase in 
      intracellular calcium levels. In addition, the OTR-As significantly suppressed 
      PGF(2alpha)-induced activation of pro-inflammatory pathways such as NF-kappaB and mitogen 
      activated protein kinases (MAPKs), and the subsequent expression of 
      contraction-associated-protein, COX-2. We have demonstrated that atosiban and 
      nolasiban not only inhibit contractions elicited by OT, but also inhibit 
      contractions and inflammation induced by PGF(2alpha). This suggests a possible 
      crosstalk between OTR and PG receptor signalling and highlights the importance of 
      understanding G protein-coupled receptor interactions/crosstalk in the 
      development of future tocolytics.
FAU - Kim, Sung Hye
AU  - Kim SH
AD  - Imperial College London, Parturition Research Group, IRDB, Du Cane Road, London, 
      W12 0NN, UK.
FAU - Riaposova, Lucia
AU  - Riaposova L
AD  - Imperial College London, Parturition Research Group, IRDB, Du Cane Road, London, 
      W12 0NN, UK.
FAU - Ahmed, Hauwa
AU  - Ahmed H
AD  - Imperial College London, Parturition Research Group, IRDB, Du Cane Road, London, 
      W12 0NN, UK.
FAU - Pohl, Oliver
AU  - Pohl O
AD  - ObsEva SA, R&D, Chemin des Aulx 12, CH-1228, Plan-les-Ouates, Geneva, 
      Switzerland.
FAU - Chollet, Andre
AU  - Chollet A
AD  - ObsEva SA, R&D, Chemin des Aulx 12, CH-1228, Plan-les-Ouates, Geneva, 
      Switzerland.
AD  - Andre Chollet Consulting, CH-1295, Tannay, Switzerland.
FAU - Gotteland, Jean-Pierre
AU  - Gotteland JP
AD  - ObsEva SA, R&D, Chemin des Aulx 12, CH-1228, Plan-les-Ouates, Geneva, 
      Switzerland.
FAU - Hanyaloglu, Aylin
AU  - Hanyaloglu A
AUID- ORCID: 0000-0003-4206-737X
AD  - Imperial College London, Parturition Research Group, IRDB, Du Cane Road, London, 
      W12 0NN, UK.
FAU - Bennett, Phillip R
AU  - Bennett PR
AD  - Imperial College London, Parturition Research Group, IRDB, Du Cane Road, London, 
      W12 0NN, UK.
FAU - Terzidou, Vasso
AU  - Terzidou V
AUID- ORCID: 0000-0002-7579-4947
AD  - Imperial College London, Parturition Research Group, IRDB, Du Cane Road, London, 
      W12 0NN, UK. v.terzidou@imperial.ac.uk.
LA  - eng
GR  - P45272/DH_/Department of Health/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190408
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (NF-kappa B)
RN  - 0 (Oximes)
RN  - 0 (Pyrrolidines)
RN  - 0 (Tocolytic Agents)
RN  - 081D12SI0Z (atosiban)
RN  - 3765U8A1EC (nolasiban)
RN  - 50-56-6 (Oxytocin)
RN  - B7IN85G1HY (Dinoprost)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - SY7Q814VUP (Calcium)
RN  - W6S6URY8OF (Vasotocin)
SB  - IM
MH  - Adult
MH  - Anti-Inflammatory Agents/*pharmacology
MH  - Calcium/metabolism
MH  - Cells, Cultured
MH  - Cyclooxygenase 2/metabolism
MH  - Dinoprost/pharmacology
MH  - Female
MH  - Humans
MH  - MAP Kinase Signaling System
MH  - *Muscle Contraction
MH  - Myometrium/*drug effects/metabolism/physiology
MH  - NF-kappa B/metabolism
MH  - Oximes/*pharmacology
MH  - Oxytocin/pharmacology
MH  - Pregnancy
MH  - Pyrrolidines/*pharmacology
MH  - Tocolytic Agents/*pharmacology
MH  - Vasotocin/*analogs & derivatives/pharmacology
PMC - PMC6453954
COIS- V.T. has worked as a consultant to GlaxoSmithKline. P.B. has worked as a 
      consultant to Boehringer Ingelheim, GlaxoSmithKline, Merck Serono, ObsEva SA and 
      Tokyo Tanabe Pharmaceuticals, drug companies with an interest in the 
      pharmacological effects of oxytocin and oxytocin antagonists. P.B. holds shares 
      of ObsEva SA. J.P.G. and O.P. are salaried employees of ObsEva SA. A.C. is a 
      consultant to ObsEva SA.
EDAT- 2019/04/10 06:00
MHDA- 2020/10/07 06:00
PMCR- 2019/04/08
CRDT- 2019/04/10 06:00
PHST- 2018/11/22 00:00 [received]
PHST- 2019/03/19 00:00 [accepted]
PHST- 2019/04/10 06:00 [entrez]
PHST- 2019/04/10 06:00 [pubmed]
PHST- 2020/10/07 06:00 [medline]
PHST- 2019/04/08 00:00 [pmc-release]
AID - 10.1038/s41598-019-42181-2 [pii]
AID - 42181 [pii]
AID - 10.1038/s41598-019-42181-2 [doi]
PST - epublish
SO  - Sci Rep. 2019 Apr 8;9(1):5792. doi: 10.1038/s41598-019-42181-2.