Tocolytic effect of a Rho-kinase inhibitor in a mouse model of lipopolysaccharide-induced preterm delivery.
OBJECTIVE
The small guanosine triphosphatase RhoA/Rho-kinase cascade has been implicated in uterine contraction. Our purpose was to evaluate the tocolytic effect of a Rho-kinase inhibitor, Y-27632, in lipopolysaccharide-induced preterm delivery in mice.


METHODS
We used an animal model of lipopolysaccharide-induced preterm delivery in C3H/HeN x B6D2F1 pregnant mice. Y-27632 was delivered continuously through an osmotic pump that was implanted into the peritoneal cavity 6 hours before lipopolysaccharide treatment. The primary outcome was the preterm delivery rate. To further study the possible involvement of this cascade in lipopolysaccharide-induced preterm delivery, we determined the effect of lipopolysaccharide and prostaglandin F2alpha on RhoA activation in mouse myometrial cells and uterine smooth muscle tissues.


RESULTS
The rate of preterm delivery for lipopolysaccharide-treated animals was 94.4%. The administration of Y-27632 (1 or 10 mg/kg/d) significantly reduced the preterm delivery rate to 61.1% or 15.8%, respectively. The level of guanosine triphosphate-bound RhoA was increased after the addition of lipopolysaccharide or prostaglandin F2alpha.


CONCLUSIONS
The RhoA/Rho-kinase cascade is involved in lipopolysaccharide-induced preterm delivery, which suggests that Rho-kinase could be used as a new therapeutic target for the prevention of preterm labor.
Tahara
Masahiro
M
Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan. taharam@gyne.med.osaka-u.ac.jp
Kawagishi
Rikako
R
Sawada
Kenjiro
K
Morishige
Kenichiro
K
Sakata
Masahiro
M
Tasaka
Keiichi
K
Murata
Yuji
Y
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D015237:Dinoprost / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D051379:Mice; D008809:Mice, Inbred C3H; D007752:Obstetric Labor, Premature / Q000139:chemically induced*; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D015149:Tocolytic Agents / Q000494:pharmacology*; D054460:rho-Associated Kinases
D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D011725:Pyridines; D015149:Tocolytic Agents; C108830:Y 27632; D015237:Dinoprost; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases