Synergism between beta 2-adrenoceptor agonists and subtype-selective alpha 1A-adrenoceptor antagonists in the tocolytic effect on pregnant rat uterus in vitro.
1. Despite great efforts in recent decades, premature birth is still a leading cause of perinatal morbidity and mortality. beta2-Adrenoceptor agonists are frequently used as tocolytics, although their use is rather controversial. Previous animal studies have revealed that blockade of alpha1A-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 beta2-adrenoceptor agonists (terbutaline, ritodrin) applied together with the subtype-selective alpha1A-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 beta2-adrenoceptor agonists and the alpha1A-adrenoceptor antagonists alone and to beta2-adrenoceptor agonists co-administered with the alpha1A-adrenoceptor antagonists. 4. Both groups of drugs inhibited EFS-induced contractions in a dose-dependent way. Administering the beta2-adrenoceptor agonists in combination with the alpha1A-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 beta2-adrenoceptor agonists and alpha1A-adrenoceptor antagonists in the uterus relaxant effect may be of great clinical importance because it could improve the efficacy of therapy of preterm delivery.
Mihályi
A
A
University of Szeged, Faculty of Pharmacy, Department of Pharmacodynamics and Biopharmacy, Szeged, Eötvös, Hungary.
Gáspár
R
R
Csonka
D
D
Falkay
G
G
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D004357:Drug Synergism; D005260:Female; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology; D015149:Tocolytic Agents / Q000494:pharmacology*; D014599:Uterus / Q000187:drug effects* / Q000502:physiology
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D018340:Receptors, Adrenergic, alpha-1; D018343:Receptors, Adrenergic, beta-2; D015149:Tocolytic Agents