Fasudil, a Rho-kinase inhibitor, attenuates lipopolysaccharide-induced vascular hyperpermeability and colonic muscle relaxation in guinea pigs

Abstract

Background: Rho-associated coiled coil-forming protein kinase (Rho-kinase), a downstream target effector of the small GTP-binding protein Rho, plays a key role in cell adhesion, motility, and contraction. The goal of the present study was to determine the role of the Rho/Rho-kinase signal pathway in the pathogenesis of lipopolysaccharide (LPS)-induced vascular hyperpermeability using the Rho-kinase inhibitor fasudil.

Methods: To evaluate plasma leakage, fasudil (3 or 10 mg/kg) or saline was intravenously administered 30 min before LPS injection. LPS (100, 300, and 1,000 μg/0.1 mL/site) and saline (0.1 mL/site) were administered intracutaneously in the dorsum of guinea pigs. Vascular permeability was measured on the dorsal skin by the local accumulation of Evans Blue dye after intracutaneous injection of LPS (100-1000 μg/site) from Escherichia coli. For the measurement of colonic muscle tension, fasudil (3 mg/kg) or saline was intravenously administered 30 min before LPS injection. LPS (1 mg/kg) was administered intravenously.

Results: Dye leakage in the skin increased significantly 2 h after the injection of LPS. This LPS-induced dye leakage was significantly suppressed by fasudil (3 and 10 mg/kg). LPS caused a transient decrease in colonic muscle tension, which peaked 2.5 h after the injection. This decrease in muscle tension was significantly suppressed by pretreatment with fasudil (3 mg/kg).

Conclusions: The Rho/Rho-kinase pathway might play an important role in the pathogenesis of LPS-induced endotoxemia, and fasudil could attenuate LPS-induced microvascular permeability, leading to inhibition of endotoxemia.