Evaluating aminophylline and progesterone combination treatment to modulate contractility and labor-related proteins in pregnant human myometrial tissues

TY - JOUR

T1 - Evaluating aminophylline and progesterone combination treatment to modulate contractility and labor-related proteins in pregnant human myometrial tissues

AU - Lai, Pei F.

AU - Young, Roger C.

AU - Tribe, Rachel M.

AU - Johnson, Mark R.

N1 - Funding Information: The authors thank all maternity unit patients at Chelsea & Westminster Hospital (London, UK), who kindly consented to provide myometrium biopsies used in this study, and to the NHS staff who assisted their collection. This work was financially supported by charity funding from Action Medical Research (No. 208701; project grant GN2395), Borne (No. 1167073) and Tommy's Baby Charity (No. 1060508). Infrastructure support for this work was provided by the NIHR Imperial Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Funding Information: This work was financially supported by funding from Action Medical Research (No. 208701; project grant GN2395) to PFL, RMT, and MRJ, The Borne Foundation (No. 1167073) to PFL, and Tommy's Baby Charity (No. 1060508) to RMT. The authors thank all maternity unit patients at Chelsea & Westminster Hospital (London, UK), who kindly consented to provide myometrium biopsies used in this study, and to the NHS staff who assisted their collection. This work was financially supported by charity funding from Action Medical Research (No. 208701; project grant GN2395), Borne (No. 1167073) and Tommy's Baby Charity (No. 1060508). Infrastructure support for this work was provided by the NIHR Imperial Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Funding Information: This work was financially supported by funding from Action Medical Research (No. 208701; project grant GN2395) to PFL, RMT, and MRJ, The Borne Foundation (No. 1167073) to PFL, and Tommy's Baby Charity (No. 1060508) to RMT. 2 t Publisher Copyright: © 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.

PY - 2021/8/1

Y1 - 2021/8/1

N2 - Progesterone (P4) and cyclic adenosine monophosphate (cAMP) are regarded as pro-quiescent factors that suppress uterine contractions during pregnancy. We previously used human primary cells in vitro and mice in vivo to demonstrate that simultaneously enhancing myometrial P4 and cAMP levels may reduce inflammation-associated preterm labor. Here, we assessed whether aminophylline (Ami; phosphodiesterase inhibitor) and P4 can reduce myometrial contractility and contraction-associated proteins (CAPs) better together than individually; both agents are clinically used drugs. Myometrial tissues from pregnant non-laboring women were treated ex vivo with Ami acutely (while spontaneous contracting) or throughout 24-h tissue culture (±P4); isometric tension measurements, PKA assays, and Western blotting were used to assess tissue contractility, cAMP action, and inflammation. Acute (1 h) treatment with 250 and 750 μM Ami reduced contractions by 50% and 84%, respectively, which was not associated with a directly proportional increase in whole tissue PKA activity. Sustained myometrial relaxation was observed during 24-h tissue culture with 750 μM Ami, which did not require P4 nor reduce CAPs. COX-2 protein can be reduced by 300 nM P4 but this did not equate to myometrial relaxation. Ami (250 μM) and P4 (100 and 300 nM) co-treatment did not prevent oxytocin-augmented contractions nor reduce CAPs during interleukin-1β stimulation. Overall, Ami and P4 co-treatment did not suppress myometrial contractions more than either agent alone, which may be attributed to low specificity and efficacy of Ami; cAMP and P4 action at in utero neighboring reproductive tissues during pregnancy should also be considered.

AB - Progesterone (P4) and cyclic adenosine monophosphate (cAMP) are regarded as pro-quiescent factors that suppress uterine contractions during pregnancy. We previously used human primary cells in vitro and mice in vivo to demonstrate that simultaneously enhancing myometrial P4 and cAMP levels may reduce inflammation-associated preterm labor. Here, we assessed whether aminophylline (Ami; phosphodiesterase inhibitor) and P4 can reduce myometrial contractility and contraction-associated proteins (CAPs) better together than individually; both agents are clinically used drugs. Myometrial tissues from pregnant non-laboring women were treated ex vivo with Ami acutely (while spontaneous contracting) or throughout 24-h tissue culture (±P4); isometric tension measurements, PKA assays, and Western blotting were used to assess tissue contractility, cAMP action, and inflammation. Acute (1 h) treatment with 250 and 750 μM Ami reduced contractions by 50% and 84%, respectively, which was not associated with a directly proportional increase in whole tissue PKA activity. Sustained myometrial relaxation was observed during 24-h tissue culture with 750 μM Ami, which did not require P4 nor reduce CAPs. COX-2 protein can be reduced by 300 nM P4 but this did not equate to myometrial relaxation. Ami (250 μM) and P4 (100 and 300 nM) co-treatment did not prevent oxytocin-augmented contractions nor reduce CAPs during interleukin-1β stimulation. Overall, Ami and P4 co-treatment did not suppress myometrial contractions more than either agent alone, which may be attributed to low specificity and efficacy of Ami; cAMP and P4 action at in utero neighboring reproductive tissues during pregnancy should also be considered.

KW - cAMP

KW - parturition

KW - phosphodiesterase

KW - progesterone

KW - smooth muscle

KW - uterus

UR - http://www.scopus.com/inward/record.url?scp=85110864650&partnerID=8YFLogxK

U2 - 10.1002/prp2.818

DO - 10.1002/prp2.818

M3 - Article

C2 - 34223706

AN - SCOPUS:85110864650

SN - 2052-1707

VL - 9

SP - e00818

JO - Pharmacology research & perspectives

JF - Pharmacology research & perspectives

IS - 4

M1 - e00818

ER -