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Terbutaline increases the cervical resistance of the pregnant rat in vitro

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Abstract

Cervical ripening is a crucial process leading to delivery. Early dilation of the pregnant cervix can contribute to premature labour. The maturity of the cervix can be characterized by its resistance to mechanical stretching. Although a number of compounds are considered to increase cervical resistance (e.g., progesterone, nitric oxide synthase inhibitors and nonsteroidal anti-inflammatory drugs), none of them seem to be safe for clinical application. Other compounds, such as β2-adrenergic receptor (β2-AR) agonists, have been used for several decades to stop premature myometrium contractions, but their cervical action has never been investigated. The aim of this study was to detect the effects of the β2-AR agonist terbutaline on nonpregnant and late-pregnant (day 18, 20, 21 or 22) cervices isolated from Sprague–Dawley rats. Cervical resistance was measured by means of a mechanical stretching test in vitro, the β2-AR density was determined by Western blot analysis, the β2-AR mRNA was determined by RT-PCR, while the G-protein activation following cervical β2-AR stimulation with terbutaline was evaluated via a [35S]GTPγS binding assay.

Terbutaline at 10−6 M increased the cervical resistance of the late-pregnant samples in vitro from day18 to day 22, but did not alter the resistance of the nonpregnant samples. This cervical resistance-increasing effect was concentration dependent and antagonized with propranolol on day 21. Terbutaline was ineffective on cervical samples when gradual stretching was omitted. RT-PCR and Western blot studies revealed increased β2-AR mRNA and β2-AR levels respectively on day 18 of pregnancy compared with the nonpregnant cervix, but no further changes were detected up to the end of pregnancy. The [35S]GTPγS binding assay demonstrated a decreased G-protein activation on the days of pregnancy investigated, but no activation was found in the nonpregnant samples. The degree of decrease in G-protein activation by terbutaline was in harmony with its cervical resistance-increasing action. On day 21, the G-protein activation-decreasing effect of terbutaline was antagonized with propranolol.

We presume that the cervical resistance-increasing effect of terbutaline is a consequence of its G-protein activation-decreasing property via β2-ARs, which finally leads to an increased muscle resistance against mechanical stretching. This action of terbutaline seems unique among the smooth muscles, and may open up a new perspective in the prevention of premature labour. Clinical experience indicates that β2-AR agonists will not be sufficient to stop the overall process, but their combination with more potent inhibitors of uterine contractions may be of clinical benefit.

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Acknowledgements

This work was supported by a Hungarian Research Grant OTKA (T 042752) and the Bolyai János Research Fellowship of the Hungarian Academy of Sciences (BO/00074/02). Special thanks are due to Zsuzsanna Magyar and Zsuzsanna Canjavec for technical assistance in the experiments.

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Authors and Affiliations

  1. Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Eötvös u. 6, 6720, Szeged, Hungary

    Róbert Gáspár, Zoltán Kolarovszki-Sipiczki, Eszter Ducza & George Falkay

  2. Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences Szeged, Temesvári krt. 62, 6726, Szeged, Hungary

    Eszter Páldy, Sándor Benyhe & Anna Borsodi

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  1. Róbert Gáspár
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  2. Zoltán Kolarovszki-Sipiczki
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Correspondence to George Falkay.

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Gáspár, R., Kolarovszki-Sipiczki, Z., Ducza, E. et al. Terbutaline increases the cervical resistance of the pregnant rat in vitro. Naunyn-Schmiedeberg's Arch Pharmacol 371, 61–71 (2005). https://doi.org/10.1007/s00210-004-1010-x

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