Inflammatory processes enhance cAMP-mediated uterus relaxation in the pregnant rat: the role of TNF-alpha.
The objective of this study was to assess the in vitro uterus relaxing potency of beta(2)-adrenergic receptor (beta(2)-AR) agonists in pregnant rats after in utero administration of the bacterial lipopolysaccharide, Escherichia coli endotoxin (LPS). The LPS (100 microg/kg) was injected into the uterine lumen on day 16 of pregnancy. The effects of beta(2)-AR agonist terbutaline was tested in vitro, in isolated uterine rings precontracted by electric field stimulation. Uterine beta(2)-AR densities were detected by radioligand binding assay, the activated G-protein levels were investigated by a radiolabelled GTP binding assay. Uterine cAMP accumulation and the serum tumor necrosis factor-alpha (TNF-alpha) levels were measured by enzyme immunoassay. The endotoxin-evoked preterm delivery occurred on day 21. Higher pD(2) values of terbutaline (p < 0.001) were detected in endotoxin-treated rats: 9.14 +/- 0.36 vs. 7.71 +/- 0.12 compared with sham-operated rats. The densities or the equilibrium dissociation constants of beta(2)-ARs were not different (p > 0.05) in LPS-treated vs. control animals. Serum TNF-alpha level rose threefold after LPS treatment, but this rise was abolished by thalidomide. In LPS + thalidomide-treated rats, the effect of terbutaline became similar to that in sham-operated controls. By the measurement of myometrial cAMP levels, we documented that the concentration-response curve of terbutaline on cAMP accumulation was shifted to the left in the LPS-treated rats, with a significant rise in the pD(2). We concluded that in the case of uterine inflammation, the in vitro uterus-relaxing potency of beta(2)-agonists enhances, which is possibly mediated by TNF-alpha and uterine cAMP levels and that may serve as a rationale for the use of beta(2)-AR agonists in the attenuation of preterm uterine contractions on an inflammatory basis.
Klukovits
Anna
A
Department of Pharmacodynamics and Biopharmacy, University of Szeged, H-6720 Szeged, Eötvös u. 6., Szeged, Hungary. klukovits.anna@pharm.u-szeged.hu
Márki
Arpád
A
Páldy
Eszter
E
Benyhe
Sándor
S
Gálik
Márta
M
Falkay
George
G
Gáspár
Róbert
R
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy / Q000378:metabolism* / Q000382:microbiology; D066298:In Vitro Techniques; D008070:Lipopolysaccharides; D011247:Pregnancy; D047928:Premature Birth / Q000378:metabolism / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D013726:Terbutaline / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D014590:Uterine Contraction / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D013726:Terbutaline