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Synergism between β2-adrenoceptor agonists and subtype-selective α1A-adrenoceptor antagonists in the tocolytic effect on pregnant rat uterus in vitro

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1. Despite great efforts in recent decades, premature birth is still a leading cause of perinatal morbidity and mortality. β2-Adrenoceptor agonists are frequently used as tocolytics, although their use is rather controversial. Previous animal studies have revealed that blockade of α1A-adrenoceptors results in relaxation of the pregnant rat myometrium.

2. The aim of the present study was to investigate the uterus relaxant effect of the β2-adrenoceptor agonists (terbutaline, ritodrin) applied together with the subtype-selective α1A-adrenoceptor antagonists (WB 4101, 5-methylurapidil) in an in vitro rat model. The main objective of the experiments was to clarify whether there was an additive or a potentiating synergism between the two drug classes.

3. Myometrial rings were taken from female, 22-day pregnant (end-term) Sprague-Dawley rats. Electrical field stimulation (EFS) was used to elicit rhythmical contractions. Non-cumulative concentration–response curves were constructed to the β2-adrenoceptor agonists and the α1A-adrenoceptor antagonists alone and to β2-adrenoceptor agonists co-administered with the α1A-adrenoceptor antagonists.

4. Both groups of drugs inhibited EFS-induced contractions in a dose-dependent way. Administering the β2-adrenoceptor agonists in combination with the α1A-adrenoceptor antagonists resulted in a significant decrease in the EC50 and an increase in the maximal contraction inhibiting effect.

5. The potentiating synergism that has been revealed between β2-adrenoceptor agonists and α1A-adrenoceptor antagonists in the uterus relaxant effect may be of great clinical importance because it could improve the efficacy of therapy of preterm delivery.
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Keywords: combination; electric field stimulation; rat; tocolysis; α1A-adrenoceptor antagonists; β2-adrenoceptor agonists

Document Type: Research Article

Affiliations: University of Szeged, Faculty of Pharmacy, Department of Pharmacodynamics and Biopharmacy, Szeged, Eötvös, Hungary

Publication date: March 1, 2003

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