Effect of alpha-adrenoceptor subtype-selective inverse agonists on non-pregnant and late-pregnant cervical resistance in vitro in the rat.
1. The aim of the present study was to compare and elucidate the effects of alpha(1)-adrenoceptor (alpha(1)-AR) subtype-selective inverse agonists on non-pregnant and late-pregnant rat cervical tone. 2. Cervical resistance was investigated in in vitro stretching tests in the absence or presence of alpha(1)-AR subtype-selective inverse agonists (WB 4101, AH 11110A and BMY 7378; all at 10(-6) mol/L), whereas the mRNA levels and density of the alpha(1)-AR subtypes and the G-protein-activating effects of the inverse agonists were determined by reverse transcription-polymerase chain reaction, western blot and [(35)S]-GTPgammaS binding techniques, respectively. 3. The inverse agonists did not cause any change in resistance in non-pregnant and 18-day-pregnant samples. WB 4101 increased cervical resistance from Day 20, whereas AH 11110A had no effect and BMY 7378 exhibited such an action only on Day 21. Phenylephrine (10(-4) mol/L) had no effect on cervical resistance on Day 22. The mRNA levels and density of all alpha(1)-AR subtypes were increased on Day 18, but no further changes were observed after that. The [(35)S]-GTPgammaS binding studies revealed increased G-protein activation of alpha(1A)-AR and a moderate G-protein activation of alpha(1B)- and alpha(1D)-AR. The effect of WB 4101 to increase [(35)S]-GTPgammaS binding was blocked by pertussis toxin (50 ng/mL). Phenylephrine caused a slight and significant decrease in the amount of activated G-protein on Day 22. 4. The effects of inverse agonists on the alpha(1A)-AR can enhance cervical resistance in the late-pregnant rat in vitro. This action is mediated, at least in part, by a pertussis toxin-sensitive G(i)-protein. This effect of the alpha(1A)-AR inverse agonist WB 4101 may offer a new therapeutic target in the prevention of premature labour.
Kolarovszki-Sipiczki
Zoltán
Z
Department of Pharmacodynamics and Biopharmacy, University of Szeged, Szeged, Hungary.
Gáspár
Róbert
R
Ducza
Eszter
E
Páldy
Eszter
E
Benyhe
Sándor
S
Borsodi
Anna
A
Falkay
George
G
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D002584:Cervix Uteri / Q000187:drug effects* / Q000502:physiology; D004146:Dioxanes / Q000494:pharmacology*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D007097:Imines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics
C434277:AH 11110A; C547715:Adra1a protein, rat; C547718:Adra1b protein, rat; C547721:Adra1d protein, rat; D000316:Adrenergic alpha-Agonists; D004146:Dioxanes; D007097:Imines; D010879:Piperazines; D010880:Piperidines; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D019204:GTP-Binding Proteins; C053428:BMY 7378