Terbutaline increases the cervical resistance of the pregnant rat in vitro

R. Gáspár, Zoltán Kolarovszki-Sipiczki, Eszter Ducza, Eszter Páldy, S. Benyhe, A. Borsodi, G. Falkay

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)61-71
Number of pages11
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume371
Issue number1
DOIs
Publication statusPublished - Jan 2005

Fingerprint

Terbutaline
GTP-Binding Proteins
Adrenergic Receptors
Cervix Uteri
Adrenergic Agonists
Premature Obstetric Labor
Propranolol
Pregnancy
Western Blotting
Cervical Ripening
Uterine Contraction
Polymerase Chain Reaction
Messenger RNA
In Vitro Techniques
Myometrium
Nitric Oxide Synthase
Smooth Muscle
Sprague Dawley Rats
Dilatation
Anti-Inflammatory Agents

Keywords

  • β-adrenergic receptors
  • [S]GTPγS binding
  • Cervical resistance
  • Cervical ripening
  • Pregnancy
  • Premature labour
  • Rat
  • Terbutaline

ASJC Scopus subject areas

  • Pharmacology

Cite this

Terbutaline increases the cervical resistance of the pregnant rat in vitro. / Gáspár, R.; Kolarovszki-Sipiczki, Zoltán; Ducza, Eszter; Páldy, Eszter; Benyhe, S.; Borsodi, A.; Falkay, G.

In: Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 371, No. 1, 01.2005, p. 61-71.

Research output: Contribution to journalArticle

@article{52f785701a974d8b87d7c9d1016f1f6f,
title = "Terbutaline increases the cervical resistance of the pregnant rat in vitro",
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.",
keywords = "β-adrenergic receptors, [S]GTPγS binding, Cervical resistance, Cervical ripening, Pregnancy, Premature labour, Rat, Terbutaline",
author = "R. G{\'a}sp{\'a}r and Zolt{\'a}n Kolarovszki-Sipiczki and Eszter Ducza and Eszter P{\'a}ldy and S. Benyhe and A. Borsodi and G. Falkay",
year = "2005",
month = "1",
doi = "10.1007/s00210-004-1010-x",
language = "English",
volume = "371",
pages = "61--71",
journal = "Naunyn-Schmiedeberg's Archives of Pharmacology",
issn = "0028-1298",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - Terbutaline increases the cervical resistance of the pregnant rat in vitro

AU - Gáspár, R.

AU - Kolarovszki-Sipiczki, Zoltán

AU - Ducza, Eszter

AU - Páldy, Eszter

AU - Benyhe, S.

AU - Borsodi, A.

AU - Falkay, G.

PY - 2005/1

Y1 - 2005/1

N2 - 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.

AB - 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.

KW - β-adrenergic receptors

KW - [S]GTPγS binding

KW - Cervical resistance

KW - Cervical ripening

KW - Pregnancy

KW - Premature labour

KW - Rat

KW - Terbutaline

UR - http://www.scopus.com/inward/record.url?scp=15044350443&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=15044350443&partnerID=8YFLogxK

U2 - 10.1007/s00210-004-1010-x

DO - 10.1007/s00210-004-1010-x

M3 - Article

C2 - 15645294

AN - SCOPUS:15044350443

VL - 371

SP - 61

EP - 71

JO - Naunyn-Schmiedeberg's Archives of Pharmacology

JF - Naunyn-Schmiedeberg's Archives of Pharmacology

SN - 0028-1298

IS - 1

ER -