Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade
AbstractUterine 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. View Full-Text
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Fernández-Martínez, E.; Ponce-Monter, H.; Soria-Jasso, L.E.; Ortiz, M.I.; Arias-Montaño, J.-A.; Barragán-Ramírez, G.; Mayén-García, C. Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade. Molecules 2016, 21, 1332.
Fernández-Martínez E, Ponce-Monter H, Soria-Jasso LE, Ortiz MI, Arias-Montaño J-A, Barragán-Ramírez G, Mayén-García C. Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade. Molecules. 2016; 21(10):1332.Chicago/Turabian Style
Fernández-Martínez, Eduardo; Ponce-Monter, Héctor; Soria-Jasso, Luis E.; Ortiz, Mario I.; Arias-Montaño, José-Antonio; Barragán-Ramírez, Guillermo; Mayén-García, Cynthia. 2016. "Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade." Molecules 21, no. 10: 1332.
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