Investigation of the role of the serotonergic activity of certain subtype‐selective α1A antagonists in the relaxant effect on the pregnant rat uterus in vitro

Results from recent studies have shown that α1A‐adrenergic receptor (α1A‐AR) antagonists could offer a new alternative in the treatment of preterm delivery. However, members of this group [2‐(2,6‐dimethoxyphenoxyethyl)aminomethyl‐1,4‐benzodioxane hydrochloride (WB4101), 5‐methylurapidil (5‐MU)] are known to influence serotonin (5‐hydroxy‐tryptamine) (5‐HT1A) receptors, too. Our objective was to clarify the role of their 5‐HT1A activities in the uterus relaxant effect. RT–PCR was used to determine mRNA expression of the receptor subtypes in 22 day pregnant rat uteri. Isolated uteri were stimulated by 5‐HT or electrical field to investigate the contraction‐inhibiting effect and the 5‐HT1A activity of the α1A antagonists. Both receptor subtypes are present in rat myometrium. 5‐HT induced contractions were inhibited by the α1A antagonists. Besides shifting the dose–response curve of 5‐HT to the right, 5‐MU decreased its maximal effect. The α1A antagonists inhibited electrical field stimulation‐induced contractions. 5‐HT1A blockade increased the maximal effect of 5‐MU but did not change that of WB4101. These results suggest that the contraction increase caused by 5‐HT is mediated by α1A receptors. Serotonergic activity of α1 antagonists and especially α1A antagonists should be investigated as it may alter their efficacy and could interfere with their side‐effects. It is proposed that novel α1A antagonists should be designed with no 5‐HT1A activity to achieve maximal relaxant effect.