title: Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade.
abstract: 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 Ca2+-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 Ca2+-induced responses. Tonic contraction was equipotently inhibited by 4APDPMe and rolipram (IC50= 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.
authors.affiliation: Centro de Investigación en Biología de la Reproducción, Área Académica de Medicina del Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Pachuca 42090, Hidalgo, México. tomedyfm@hotmail.com.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fernández-Martínez
authors.affiliation: Centro de Investigación en Biología de la Reproducción, Área Académica de Medicina del Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Pachuca 42090, Hidalgo, México. poncemonterh@gmail.com.
authors.forename: Héctor
authors.initials: H
authors.lastname: Ponce-Monter
authors.affiliation: Centro de Investigación en Biología de la Reproducción, Área Académica de Medicina del Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Pachuca 42090, Hidalgo, México. soriajasso@gmail.com.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Soria-Jasso
authors.affiliation: Centro de Investigación en Biología de la Reproducción, Área Académica de Medicina del Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Pachuca 42090, Hidalgo, México. mario_i_ortiz@hotmail.com.
authors.forename: Mario I
authors.initials: MI
authors.lastname: Ortiz
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Apdo. Postal 14-740, México City 07360, México. jaarias@fisio.cinvestav.mx.
authors.forename: José-Antonio
authors.initials: JA
authors.lastname: Arias-Montaño
authors.affiliation: Hospital General de los SSH, Pachuca 42070, Hidalgo, México. gmobarragan@hotmail.com.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Barragán-Ramírez
authors.affiliation: Centro de Investigación en Biología de la Reproducción, Área Académica de Medicina del Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Pachuca 42090, Hidalgo, México. mayen_09@hotmail.com.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Mayén-García
mesh_terms: D000293:Adolescent; D000328:Adult; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects*; D009215:Myometrium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011247:Pregnancy; D020889:Rolipram / Q000494:pharmacology; D013792:Thalidomide / Q000031:analogs & derivatives*; D055815:Young Adult
chemical_list: D002121:Calcium Channel Blockers; D058988:Phosphodiesterase 4 Inhibitors; D013792:Thalidomide; D000242:Cyclic AMP; D020889:Rolipram; D011188:Potassium; D002118:Calcium
keywords: cAMP; calcium blockers; human myometrium; phosphodiesterase-4; preterm labor; relaxation; thalidomide analogs; tocolytics