Tocolytic activity of formoterol against premature delivery in mice

Abstract

The tocolytic activity of formoterol (eformoterol), a long-acting potent β2-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 μg mL−1/mouse) induced premature delivery, attributable to increased IL-6 secretion, and formoterol suppressed this. Doses of 5–500 μg/mouse thus reduced the number of prematurely delivered newborn, and 50 μg/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 β2-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 (β2-adrenoceptor antagonist), but not atenolol (β1-adrenoceptor antagonist). These findings strongly suggest that formoterol can suppress premature delivery mediated by its actions on IL-6 secretion.