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Mitogen-Activated Protein Kinase Cascade Is Involved in Endothelin-1-Induced Rat Puerperal Uterine Contraction

Department of Obstetrics and Gynecology (A.K., M.O., T.T., H.K., H.I., K.M., J.H., T.K., A.M., Y.M.), Osaka University Medical School, Suita, Osaka 565, Japan; Department of Obstetrics and Gynecology (K.K., M.I.), Kanazawa University Medical School, Kanazawa, Ishikawa 920, Japan; and Kissei Pharmaceutical Company Ltd (M.K., M.A.), Minamiazumi, Nagano 399–83, Japan

Address all correspondence and requests for reprints to: Dr. Masahide Ohmichi, Osaka University Medical School, 2–2 Yamadaoka, Suita, Osaka 565, Japan. E-mail: masa{at}gyne.med.osaka-u.ac.jp

The regulation of mitogen-activated protein (MAP) kinase by endothelin-1 (ET-1) in cultured rat puerperal uterine myometrial cells was investigated. ET-1 caused the rapid stimulation of MAP kinase activity. ET-1-induced MAP kinase activation is neither extracellular Ca²⁺- nor intracellular Ca²⁺-dependent. ET-1 stimulation also led to an increase in phosphorylation of son-of-sevenless (SOS), and transfection of dominant negative SOS attenuated the ET-1-induced MAP kinase activity. Phorbol-12-myristate 13-acetate (PMA) also induced the MAP kinase activity, but pretreatment of the cultured cells with PMA, to down-regulate protein kinase C (PKC), did not abolish the activation of MAP kinase by ET-1. In addition, down-regulation of PKC had no effect on ET-1-induced SOS phosphorylation. Pertussis toxin, which inactivates Gi/Go proteins, blocked the ET-1-induced MAP kinase activation but not the PMA-induced MAP kinase activation. The results suggested that MAP kinase is acutely activated by ET-1 through a pertussis toxin-sensitive G protein and SOS, not through the PMA-sensitive PKC. In addition, although reverse-transcriptase PCR assays detected messenger RNA for both ET-1 receptor subtypes in cultured rat puerperal uterine myometrial cells, ET-1-induced MAP kinase activity and uterine contraction were blocked by treatment with BQ485, an antagonist selective for an ET type A receptor (but not by BQ788, an ET type B receptor antagonist). Ritodrine, which is known to relax uterine muscle contraction, attenuated ET-1-induced MAP kinase activity. We further examined the role of MAP kinase pathway in uterine contraction using an inhibitor of MEK activity, PD098059. This inhibitor completely inhibited the ET-1-induced MAP kinase activation and partially, but significantly, inhibited the ET-1-induced uterine contraction. These results indicate that ET-1-induced MAP kinase signaling cascade may play an important role in the ET-1-induced uterine contraction.

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