Increase of the uterus-relaxant effect of nifedipine by the Abcg2 efflux protein inhibitor KO134 in the rat in vivo

Norbert Lovasz, Eszter Ducza, I. Zupkó, G. Falkay

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)363-369
Number of pages7
JournalIn Vivo
Volume27
Issue number3
Publication statusPublished - May 2013

Fingerprint

Nifedipine
Uterus
Rats
Tocolytic Agents
Pregnancy
Proteins
Animal Pregnancy
Adrenergic Agonists
ATP-Binding Cassette Transporters
Tocolysis
Polymerase chain reaction
Substrates
Substrate Specificity
Animals
Placenta
Pumps
Real-Time Polymerase Chain Reaction
Personnel
Tissue
Western Blotting

Keywords

  • Abcg2 inhibition
  • Nifedipine
  • Ontogeny of Abcg2
  • Premature labour
  • Rat uterus
  • Tocolysis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology

Cite this

Increase of the uterus-relaxant effect of nifedipine by the Abcg2 efflux protein inhibitor KO134 in the rat in vivo. / Lovasz, Norbert; Ducza, Eszter; Zupkó, I.; Falkay, G.

In: In Vivo, Vol. 27, No. 3, 05.2013, p. 363-369.

Research output: Contribution to journalArticle

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abstract = "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.",
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