Tocolytic effect of magnesium sulfate and/or urinary trypsin inhibitor against lipopolysaccharide-induced preterm delivery in mice.
BACKGROUND
The purpose of this investigation was to evaluate the effect of magnesium sulfate (magnesium) alone or along with urinary trypsin inhibitor (UTI) in a mouse model in the prevention of preterm delivery.


METHODS
On day 17 of pregnancy, female C3H/HeN mice impregnated by male B6D2F1 mice were given two intraperitoneal injections of lipopolysaccharide (LPS; 50 microg/kg) at a 3-hour interval, which treatment induced a 100% incidence of preterm delivery within 25 hours of the second dose. Magnesium (4, 5, 6, 7, or 8 mg/hr, s.c.), UTI (25 x 10(4) units/kg, i.p.), magnesium (5 mg/hr, s.c.) plus UTI (25 x 10(4) units/kg, i.p.), saline solution (0.3 ml/hr, s.c.), or saline solution (0.1 ml/hr, s.c. and 2.5 ml/kg, i.p.) was administered to pregnant animals on day 18 of gestation. UTI was intraperitoneally given 5 times at 2-hour intervals from 8:00 am to 4:00 pm, and magnesium was infused subcutaneously and constantly from 8:00 am to 6:00 pm. In addition, the preventive effect of magnesium on LPS-induced contraction of uterine muscle strips and that of magnesium, UTI, or magnesium plus UTI on LPS-induced calcium influx in uterine smooth muscle cells were examined using muscle tissue isolated from pregnant mice on day 17 of gestation.


RESULTS
The incidence of preterm delivery decreased significantly in a dose-dependent fashion with magnesium treatment, and there was a significant and synergistic decrease after combined treatment with magnesium plus UTI. The in vitro uterine contraction and calcium influx induced by LPS were significantly suppressed by magnesium. The latter was significantly suppressed by UTI and additively reduced by magnesium plus UTI.


CONCLUSIONS
Combination therapy with magnesium plus UTI may possibly be helpful for preventing preterm delivery in humans without the severe side effects induced by hypermagnesemia.
Toxicology Laboratory, Mochida Pharmaceutical Co. Ltd, Fujieda, Shizuoka, Japan.
S
S
Kajikawa
N
N
Kaga
Y
Y
Futamura
Y
Y
Shibutani
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006023:Glycoproteins / Q000627:therapeutic use*; D007751:Labor, Induced; D008070:Lipopolysaccharides; D008278:Magnesium Sulfate / Q000627:therapeutic use*; D051379:Mice; D008809:Mice, Inbred C3H; D007752:Obstetric Labor, Premature / Q000517:prevention & control*; D011247:Pregnancy; D013997:Time Factors; D015149:Tocolytic Agents / Q000627:therapeutic use*
D006023:Glycoproteins; D008070:Lipopolysaccharides; D015149:Tocolytic Agents; D008278:Magnesium Sulfate; C028665:urinastatin