Relaxing effect of ramelteon on the uterus of non-pregnant and pregnant rats: Importance of melatonin receptors and BKCa.

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.

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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.