ROCK inhibitor Y-27632 prevents primary graft non-function caused by warm ischemia/reperfusion in rat liver transplantation.
Hepatic stellate cells (HSCs) can easily be activated by ischemia/reperfusion, and this activation results in hepatic microcirculatory disturbance by cell contraction. ROCK is one of the key regulators of the motility of HSCs, and Y-27632 suppresses the activation of HSCs. We examined whether Y-27632 treatment prevents primary graft non-function caused by 45-min warm ischemia in orthotopic liver transplantation (OLT). Donor and recipient rats were administered Y-27632 (3-30 mg/kg). Y-27632 treatment at 30 mg/kg in both donor and recipient prevented congestion of the grafted livers, as demonstrated by analysis of hemoglobin (Hb) content in the grafted livers, using in-vivo near-infrared spectroscopy. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and hyaluronic acid at 4 h after OLT in the 30-mg/kg Y-27632-treated group were significantly lower than those in the control group. Specimens from the untreated control recipients showed sinusoidal congestion and massive fresh hepatocyte necrosis, whereas specimens from the Y-27632-treated recipients demonstrated minimal histological changes. Moreover, Y-27632 pre-treatment dramatically improved the survival of recipients. These results suggest that Y-27632 would be clinically useful for preventing liver failure associated with ischemia/reperfusion in liver transplantation.
Mizunuma
Kazuyuki
K
Second Department of Surgery, Faculty of Medicine, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima 734-8551, Japan.
Ohdan
Hideki
H
Tashiro
Hirotaka
H
Fudaba
Yasuhiro
Y
Ito
Hisao
H
Asahara
Toshimasa
T
D000577:Amides / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000097:blood; D006085:Graft Survival / Q000187:drug effects*; D006454:Hemoglobins / Q000378:metabolism; D007511:Ischemia; D016031:Liver Transplantation / Q000473:pathology / Q000502:physiology*; D008297:Male; D010108:Oxyhemoglobins / Q000378:metabolism; D011183:Postoperative Complications / Q000517:prevention & control*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion; D013997:Time Factors; D014185:Transplantation, Isogeneic
D000577:Amides; D000959:Antihypertensive Agents; D019332:Endothelin-1; D006454:Hemoglobins; D010108:Oxyhemoglobins; D011725:Pyridines; C108830:Y 27632; C100003:deoxyhemoglobin