A novel inhibitor of Rho-associated protein kinase, Y-27632, ameliorates hepatic ischemia and reperfusion injury in rats.
BACKGROUND
A Rho-ROCK signal system induces vascular contraction and neutrophil migration, both of which are characteristic features found with ischemia and reperfusion injury of the liver. We tested our hypothesis that a novel ROCK I inhibitor, Y-27632, attenuates hepatic ischemia and reperfusion injury.


METHODS
Rats underwent 70% partial hepatic ischemia for 120 minutes and subsequent reperfusion. Y-27632 of 10mg/kg was given orally 1 hour before ischemia, while distilled water was given to the control animals. One week animal survival, systemic hemodynamics, hepatic tissue blood flow, liver function tests, plasma endothelin-1, serum hyaluronic acid levels, myeloperoxidase activity and malondialdehyde level in liver tissue, membrane attack complex-1 and intracellular adhesion molecule-1 staining, and histological architecture were analyzed.


RESULTS
Y-27632 prolonged 1-week animal survival from 25% of untreated animals to 75% accompanied with significant amelioration of hepatic tissue blood flow, liver function tests and histological architecture without any adverse effects on systemic hemodynamics. In addition, plasma endothelin-1 and serum hyaluronic acid levels decreased markedly compared to the control, concomitant with remarkable suppression of membrane attack complex-1 stain positive neutrophils infiltration, myeloperoxidase activity and malondialdehyde level.


CONCLUSIONS
Present study suggests that activation of a Rho-ROCK signal system is associated with ischemia and reperfusion injury of the liver, and that Y-27632 may be an attractive agent for application in major liver resection using temporary inflow occlusion and hepatic preservation.
Takeda
Keisa
K
First Department of Surgery, Department of Organ Transplantation and Regenerative Medicine, Hokkaido University School of Medicine, N15-W7, Kita-ku, Sapporo 060-8638, Japan.
Jin
Maeng Bong
MB
Fujita
Miri
M
Fukai
Moto
M
Sakurai
Tsunenori
T
Nakayama
Masato
M
Taniguchi
Masahiko
M
Suzuki
Tomomi
T
Shimamura
Tsuyoshi
T
Furukawa
Hiroyuki
H
Todo
Satoru
S
D000410:Alanine Transaminase / Q000097:blood; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D019332:Endothelin-1 / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006339:Heart Rate; D006820:Hyaluronic Acid / Q000097:blood; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D008102:Liver Circulation; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D054460:rho-Associated Kinases
D000577:Amides; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C108830:Y 27632; D008315:Malondialdehyde; D006820:Hyaluronic Acid; D009195:Peroxidase; D000410:Alanine Transaminase; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases