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Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade
Uterine relaxation is crucial during preterm labor. Phosphodiesterase-4 (PDE-4) inhibitors have been proposed as tocolytics. Some thalidomide analogs are PDE-4 inhibitors. The aim of this study was to assess the uterus-relaxant properties of two thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273742/ https://www.ncbi.nlm.nih.gov/pubmed/27739411 http://dx.doi.org/10.3390/molecules21101332 |
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author | Fernández-Martínez, Eduardo Ponce-Monter, Héctor Soria-Jasso, Luis E. Ortiz, Mario I. Arias-Montaño, José-Antonio Barragán-Ramírez, Guillermo Mayén-García, Cynthia |
author_facet | Fernández-Martínez, Eduardo Ponce-Monter, Héctor Soria-Jasso, Luis E. Ortiz, Mario I. Arias-Montaño, José-Antonio Barragán-Ramírez, Guillermo Mayén-García, Cynthia |
author_sort | Fernández-Martínez, Eduardo |
collection | PubMed |
description | Uterine relaxation is crucial during preterm labor. Phosphodiesterase-4 (PDE-4) inhibitors have been proposed as tocolytics. Some thalidomide analogs are PDE-4 inhibitors. The aim of this study was to assess the uterus-relaxant properties of two thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe) and were compared to rolipram in functional studies of spontaneous phasic, K(+)-induced tonic, and Ca(2+)-induced contractions in isolated pregnant human myometrial tissues. The accumulation of cAMP was quantified in HeLa cells. The presence of PDE-4B2 and phosphorylated myosin light-chain (pMLC), in addition to the effect of thalidomide analogs on oxytocin-induced pMLC, were assessed in human uterine myometrial cells (UtSMCs). Thalidomide analogs had concentration-dependent inhibitory effects on spontaneous and tonic contractions and inhibited Ca(2+)-induced responses. Tonic contraction was equipotently inhibited by 4APDPMe and rolipram (IC(50) = 125 ± 13.72 and 98.45 ± 8.86 µM, respectively). Rolipram and the thalidomide analogs inhibited spontaneous and tonic contractions equieffectively. Both analogs increased cAMP accumulation in a concentration-dependent manner (p < 0.05) and induced changes in the subcellular localization of oxytocin-induced pMLC in UtSMCs. The inhibitory effects of thalidomide analogs on the contractions of pregnant human myometrium tissue may be due to their PDE-4 inhibitory effect and novel mechanism as calcium-channel blockers. |
format | Online Article Text |
id | pubmed-6273742 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-62737422018-12-28 Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade Fernández-Martínez, Eduardo Ponce-Monter, Héctor Soria-Jasso, Luis E. Ortiz, Mario I. Arias-Montaño, José-Antonio Barragán-Ramírez, Guillermo Mayén-García, Cynthia Molecules Article Uterine relaxation is crucial during preterm labor. Phosphodiesterase-4 (PDE-4) inhibitors have been proposed as tocolytics. Some thalidomide analogs are PDE-4 inhibitors. The aim of this study was to assess the uterus-relaxant properties of two thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe) and were compared to rolipram in functional studies of spontaneous phasic, K(+)-induced tonic, and Ca(2+)-induced contractions in isolated pregnant human myometrial tissues. The accumulation of cAMP was quantified in HeLa cells. The presence of PDE-4B2 and phosphorylated myosin light-chain (pMLC), in addition to the effect of thalidomide analogs on oxytocin-induced pMLC, were assessed in human uterine myometrial cells (UtSMCs). Thalidomide analogs had concentration-dependent inhibitory effects on spontaneous and tonic contractions and inhibited Ca(2+)-induced responses. Tonic contraction was equipotently inhibited by 4APDPMe and rolipram (IC(50) = 125 ± 13.72 and 98.45 ± 8.86 µM, respectively). Rolipram and the thalidomide analogs inhibited spontaneous and tonic contractions equieffectively. Both analogs increased cAMP accumulation in a concentration-dependent manner (p < 0.05) and induced changes in the subcellular localization of oxytocin-induced pMLC in UtSMCs. The inhibitory effects of thalidomide analogs on the contractions of pregnant human myometrium tissue may be due to their PDE-4 inhibitory effect and novel mechanism as calcium-channel blockers. MDPI 2016-10-07 /pmc/articles/PMC6273742/ /pubmed/27739411 http://dx.doi.org/10.3390/molecules21101332 Text en © 2016 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Fernández-Martínez, Eduardo Ponce-Monter, Héctor Soria-Jasso, Luis E. Ortiz, Mario I. Arias-Montaño, José-Antonio Barragán-Ramírez, Guillermo Mayén-García, Cynthia Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade |
title | Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade |
title_full | Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade |
title_fullStr | Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade |
title_full_unstemmed | Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade |
title_short | Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade |
title_sort | inhibition of uterine contractility by thalidomide analogs via phosphodiesterase-4 inhibition and calcium entry blockade |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273742/ https://www.ncbi.nlm.nih.gov/pubmed/27739411 http://dx.doi.org/10.3390/molecules21101332 |
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