Tocolytic activity of formoterol against premature delivery in mice.
The tocolytic activity of formoterol (eformoterol), a long-acting potent beta(2)-adrenoceptor agonist, was assessed in pregnant mice, with determination of uterine effects on the 15th and 16th days of gestation. For examination in the lipopolysaccharide-induced premature delivery model, osmotic pumps filled with formoterol or saline solution were implanted subcutaneously under the back skin. The mice were sacrificed 18-20 h thereafter, and the numbers of fetuses in the uteri and the newborn were counted. The uteri, amniotic membranes and placenta were also rapidly removed for determination of IL-6 concentrations. Furthermore, the effect of formoterol on IL-6 secretion from mouse amnion cells was determined. Formoterol and ritodrine inhibited contraction responses of isolated mouse uteri and their intravenous administration resulted in lowered uterine motility. Lipopolysaccharide (30 microg mL(-1)/mouse) induced premature delivery, attributable to increased IL-6 secretion, and formoterol suppressed this. Doses of 5-500 microg/mouse thus reduced the number of prematurely delivered newborn, and 50 microg/mouse also depressed IL-6 secretion. On histopathologic analysis, the marked oedema and slight haemorrhage in the mouse cervix induced by lipopolysaccharide were reduced by administration of the beta(2)-adrenoceptor agonist. Neither formoterol (10(-7)-10(-5) M) nor ritodrine (10(-7)-10(-5) M) influenced spontaneous secretion of IL-6 in amnion cells. However, at 10(-7) and 10(-5) M, and 10(-6) and 10(-5) M, respectively, they inhibited lipopolysaccharide-induced IL-6 secretion and this inhibitory effect was competitively reversed by addition of ICI-118,551 (beta(2)-adrenoceptor antagonist), but not atenolol (beta(1)-adrenoceptor antagonist). These findings strongly suggest that formoterol can suppress premature delivery mediated by its actions on IL-6 secretion.
Shinkai
N
N
Research Department, Saitama Daiichi Pharmaceutical Co. Ltd, 8-1, Minamisakae-cho, Kasukabe, Saitama 344-0057, Japan. shinkai@sdsk.co.jp
Takasuna
K
K
Takayama
S
S
D000322:Adrenergic Agonists / Q000494:pharmacology*; D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000650:Amnion / Q000187:drug effects / Q000503:physiopathology; D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D002478:Cells, Cultured; D002584:Cervix Uteri / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D000068759:Formoterol Fumarate; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides; D051379:Mice; D008809:Mice, Inbred C3H; D007752:Obstetric Labor, Premature / Q000517:prevention & control*; D010920:Placenta / Q000187:drug effects / Q000503:physiopathology; D011247:Pregnancy; D011412:Propanolamines / Q000494:pharmacology; D012312:Ritodrine / Q000494:pharmacology; D015149:Tocolytic Agents / Q000494:pharmacology*; D014590:Uterine Contraction / Q000187:drug effects; D014599:Uterus / Q000187:drug effects / Q000503:physiopathology
D000322:Adrenergic Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D004983:Ethanolamines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011412:Propanolamines; D015149:Tocolytic Agents; C026777:ICI 118551; D001262:Atenolol; D012312:Ritodrine; D000068759:Formoterol Fumarate