Coumarins with Different Substituents from Leonurus japonicus Have Opposite Effects on Uterine Smooth Muscle

<i>Leonurus japonicus</i> Houtt is an exceptional medicinal herb used to treat obstetrical and gynecological diseases in traditional Chinese medicine, and it has significant effects on the treatment of dysmenorrhea and postpartum hemorrhage. This study investigated the effects of coumarins with diverse substituent groups from <i>L. japonicus</i> on isolated uterine smooth muscle and the preliminary mechanism of the most effective compound. Eight coumarins isolated from <i>L. japonicus</i> were assessed for their effects on the isolated uterine smooth muscle of nonpregnant rats in vitro. Coumarins <b>1</b> and <b>2</b> significantly promoted the contraction of rat uterine smooth muscle strips, whereas coumarins <b>3</b>-<b>5</b> showed remarkable relaxing effects against oxytocin (OT)-induced rat uterine smooth muscle contraction. Further mechanism investigations revealed that bergapten (coumarin <b>1</b>) significantly increased the level of Ca²⁺ in uterine tissues by promoting extracellular Ca²⁺ influx and intracellular Ca²⁺ release, which were related to the activation of L-type Ca²⁺ channels and α-receptors. By contrast, osthole (coumarin <b>5</b>), an α receptor antagonist, inhibited OT-induced uterine smooth muscle contraction by decreasing the level of Ca²⁺ in uterine tissues via inhibition of extracellular Ca²⁺ influx and intracellular Ca²⁺ release. This study demonstrates that the coumarins from <i>L. japonicus</i> are effective substances for regulating uterine smooth muscle contraction, but different coumarins with diverse substituent groups have different, even opposite effects. It can be inferred that coumarins are closely related to the efficacy of <i>L. japonicus</i> in the treatment of dysmenorrhea and postpartum hemorrhage.