Comparison of in vitro and in vivo inhibitory effects of peptide and nonpeptide oxytocin antagonists on radioligand binding and uterine contractility of rats during pregnancy.

OBJECTIVE

Our purpose was to compare the effects of peptidyl and nonpeptidyl oxytocin antagonists on the pregnant rat uterus in relation to the progress of gestation.

STUDY DESIGN

Pregnant rats with gestational ages of 17 and 21 days were used. A saturation binding of tritiated oxytocin to myometrial membrane preparation and its displacement by unlabeled oxytocin and the oxytocin antagonists were examined. The inhibitory effects of peptidyl and nonpeptidyl oxytocin on spontaneous, oxytocin-induced, and prostaglandin F2 alpha-induced uterine contractions were also evaluated in vitro in vivo.

RESULTS

The number of tritiated oxytocin binding sites in myometrial membranes of pregnant rats increased markedly at day 21 of gestation compared with day 17 of gestation, whereas the dissociation constants for tritiated oxytocin did not differ significantly. As for the binding affinities to oxytocin receptors of myometrial membranes, the inhibition constant values of nonpeptidyl oxytocin were 79 and 351 times larger than those of peptidyl oxytocin at pregnancy days 17 and 21, respectively. Both drugs remarkably inhibited oxytocin-induced uterine contractions in a dose-dependent manner. However, peptidyl oxytocin did not effect spontaneous and prostaglandin F2 alpha-induced contractions except for spontaneous ones of rats of pregnancy day 21 in vivo. On the other hand, nonpeptidyl oxytocin suppressed spontaneous and prostaglandin F2 alpha-induced contractions of the uterus both in vivo (pregnancy day 17) and in vitro (pregnancy day 21).

CONCLUSION

These results suggest that peptidyl oxytocin may inhibit uterine contractions by selectively antagonizing the oxytocin action at the receptor site, whereas nonpeptidyl oxytocin at high concentrations may have the additional effect of directly suppressing the contractions. This effect of nonpeptidyl oxytocin may become therapeutically advantageous in clinical application for preterm labor.