Terbutaline increases the cervical resistance of the pregnant rat in vitro.
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 beta(2)-adrenergic receptor (beta(2)-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 beta(2)-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 beta(2)-AR density was determined by Western blot analysis, the beta(2)-AR mRNA was determined by RT-PCR, while the G-protein activation following cervical beta(2)-AR stimulation with terbutaline was evaluated via a [(35)S]GTPgammaS binding assay. Terbutaline at 10(-6) M increased the cervical resistance of the late-pregnant samples in vitro from day 18 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 beta(2)-AR mRNA and beta(2)-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 [(35)S]GTPgammaS 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 beta(2)-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 beta(2)-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.
Gáspár
Róbert
R
Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Eötvös u. 6, 6720 Szeged, Hungary.
Kolarovszki-Sipiczki
Zoltán
Z
Ducza
Eszter
E
Páldy
Eszter
E
Benyhe
Sándor
S
Borsodi
Anna
A
Falkay
George
G
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001696:Biomechanical Phenomena; D015153:Blotting, Western; D020070:Cervical Ripening / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007743:Labor, Obstetric / Q000502:physiology; D008297:Male; D009129:Muscle Tonus / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011247:Pregnancy; D011433:Propranolol / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018343:Receptors, Adrenergic, beta-2 / Q000096:biosynthesis / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013726:Terbutaline / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D011433:Propranolol; D019204:GTP-Binding Proteins; D013726:Terbutaline