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Increase of the Uterus-relaxant Effect of Nifedipine by the Abcg2 Efflux Protein Inhibitor KO134 in the Rat In Vivo.

In Vivo. 2013 May-Jun;27(3):363-9

Authors: Lovasz N, Ducza E, Zupko I, Falkay G


UNLABELLED: Background/Aim: High Abcg2 (ATP-Binding Cassette Transporter Subfamily G, Member-2) levels have been found in reproductive tissues, such as the placenta and uterus. The substrate specificity of Abcg2 is very wide, including uterus-relaxant agents (e.g. nifedipine and prazosine). Through the use of a potent inhibitor (KO134), intracellular accumulation of the substrate can be increased. Nifedipine, commonly used in acute tocolytic therapy, exerts a greater tocolytic effect and has fewer side-effects than β2-adrenergic receptor agonists. The aims of the present study were to investigate the expression of Abcg2 in the rat uterus during gestation and the uterus-relaxant effect of nifedipine in the presence of the Abcg2 inhibitor KO134.

MATERIALS AND METHODS: Real-time Polymerase Chain Reaction (PCR) and western blot analyses were performed to detect the levels of Abcg2 during gestation in the rat. The uterus-relaxant effect of nifedipine in vivo was investigated by the intra-uterine pressure measuring method, described by Csapo.

RESULTS: Low levels of Abcg2 were found in non-pregnant animals and early-pregnancy (days 6, 8 and 10), but on day 15 of gestation, a sharp increase in Abcg2 levels was observed, which reached its maximum on day 18 and later decreased until the end of gestation. The post-partum levels were similar to those in non-pregnant rats. The in vivo contractility studies revealed that nifedipine had a strong uterus-relaxant effect on spontaneous contractions, and that this effect was significantly and dose-dependently increased by the Abcg2 blocker KO134.

CONCLUSION: The administration of efflux pump inhibitors in combination with tocolytic agents may be of novel therapeutic relevance in the management of pre-term labour.

PMID: 23606692 [PubMed - in process]