European journal of pharmacology · 2025
Relaxing effect of ramelteon on the uterus of non-pregnant and pregnant rats: Importance of melatonin receptors and BKCa.
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Alasaad Kármen Mirella, Ducza Eszter, Bódi Nikolett, Bagyánszki Mária, Szűcs Kálmán F, Schaffer Annamária, Barna Tamara, Gáspár Róbert
Аннотация
AIMS: Our objective was to measure the effect and mechanism of action of the melatonin agonist ramelteon in rat uteri from non-pregnant and pregnant rats in vitro.
MAIN METHODS: KCl-induced contractions of non-pregnant and pregnant uterine rings samples (whole or endometrium-denuded) were investigated in an organ bath in the presence of ramelteon alone or with melatonin (MT) receptor antagonist luzindole or with the high-conductance calcium-dependent potassium channel (BKCa) blocker paxilline. The changes in melatonin receptor expressions were followed by RT-PCR, Western blot, and fluorescent immunohistochemistry.
KEY FINDINGS: Ramelteon inhibited uterine contractions, with the degree of inhibition being greater towards the end of pregnancy. Both MT1 and MT2 receptors were identified in all uteri (except gestational day 5); they do not participate in the relaxing effect of ramelteon in non-pregnant and 5-day pregnant samples. The activation of BKCa appears to be a constitutive component of the uterorelaxant action of ramelteon throughout the gestational period. Endometrial melatonin receptors have a significant impact in mediating relaxation in mid- and late pregnancy.
SIGNIFICANCE: Ramelteon has a relaxing effect on mid- and late-pregnant uteri through at least a dual mechanism of action. The alteration of melatonin receptors during the gestational period raises the possibility that melatonin receptors might be potential drug targets for the treatment of premature labour.
MAIN METHODS: KCl-induced contractions of non-pregnant and pregnant uterine rings samples (whole or endometrium-denuded) were investigated in an organ bath in the presence of ramelteon alone or with melatonin (MT) receptor antagonist luzindole or with the high-conductance calcium-dependent potassium channel (BKCa) blocker paxilline. The changes in melatonin receptor expressions were followed by RT-PCR, Western blot, and fluorescent immunohistochemistry.
KEY FINDINGS: Ramelteon inhibited uterine contractions, with the degree of inhibition being greater towards the end of pregnancy. Both MT1 and MT2 receptors were identified in all uteri (except gestational day 5); they do not participate in the relaxing effect of ramelteon in non-pregnant and 5-day pregnant samples. The activation of BKCa appears to be a constitutive component of the uterorelaxant action of ramelteon throughout the gestational period. Endometrial melatonin receptors have a significant impact in mediating relaxation in mid- and late pregnancy.
SIGNIFICANCE: Ramelteon has a relaxing effect on mid- and late-pregnant uteri through at least a dual mechanism of action. The alteration of melatonin receptors during the gestational period raises the possibility that melatonin receptors might be potential drug targets for the treatment of premature labour.