Investigation of the role of the serotonergic activity of certain subtype-selective alpha1A antagonists in the relaxant effect on the pregnant rat uterus in vitro.
Results from recent studies have shown that alpha(1A)-adrenergic receptor (alpha(1A)-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-HT(1A)) receptors, too. Our objective was to clarify the role of their 5-HT(1A) 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-HT(1A) activity of the alpha(1A) antagonists. Both receptor subtypes are present in rat myometrium. 5-HT induced contractions were inhibited by the alpha(1A) antagonists. Besides shifting the dose-response curve of 5-HT to the right, 5-MU decreased its maximal effect. The alpha(1A) antagonists inhibited electrical field stimulation-induced contractions. 5-HT(1A) 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 alpha(1A) receptors. Serotonergic activity of alpha(1) antagonists and especially alpha(1A) antagonists should be investigated as it may alter their efficacy and could interfere with their side-effects. It is proposed that novel alpha(1A) antagonists should be designed with no 5-HT(1A) activity to achieve maximal relaxant effect.
Mihályi
Attila
A
University of Szeged, Faculty of Pharmacy, Department of Pharmacodynamics and Biopharmacy, H-6720 Szeged, Eötvös u. 6, Hungary.
Ducza
Eszter
E
Gáspár
Robert
R
Falkay
George
G
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D066298:In Vitro Techniques; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009215:Myometrium / Q000187:drug effects / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D014590:Uterine Contraction / Q000187:drug effects / Q000502:physiology
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C057446:5-methylurapidil; D012701:Serotonin; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane