Tocolytic effect of a Rho-kinase inhibitor in a mouse model of lipopolysaccharide-induced preterm delivery

Am J Obstet Gynecol. 2005 Mar;192(3):903-8. doi: 10.1016/j.ajog.2004.09.016.

Abstract

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.

Study design: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / pharmacology*
  • Animals
  • Cells, Cultured
  • Dinoprost / pharmacology
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides*
  • Mice
  • Mice, Inbred C3H
  • Obstetric Labor, Premature / chemically induced*
  • Pregnancy
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / physiology
  • Pyridines / pharmacology*
  • Tocolytic Agents / pharmacology*
  • rho-Associated Kinases

Substances

  • Amides
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • Pyridines
  • Tocolytic Agents
  • Y 27632
  • Dinoprost
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases