Ishizaki, N

Jin, MB

Lee, RG

Starzl, TE

Subbotin, VM

Tanaka, H

Todo, S

Zhang, S

Zhu, Y

English

PubMed

D-Scholarship@Pitt

~A ~~ ELSEVIER Attenuation of Ischemic Liver Injury by a Non-Selective Endothelin Receptor Antagonist M.B. Jin, Y. Zhu, S. Zhang, N. Ishizaki, H. Tanaka, V.M. Subbotin, R.G. Lee, T.E. Starzl, and S. Todo THE ability of the liver to recovcr from ischcmia/rcperfu-sian (I/R) injury depends on the integrity of thc micro-circulation. 1 It has been recently reported that endothelin (ET) plays a major role in the regulation of hepatic microcir-culation.2 The aim of this study is to determine whether inhibition of the binding of endothelin to its receptors by a non-selective (ET 1\' ET B) receptor antagonist. TAK-044" can lessen livcr injury after 2 hours of warm ischemia. MATERIALS AND METHODS Two-hour complete hepatic ischemia was induced in adults female beagle dogs by clamping the vena cava (above and below the liver) and the portal triad. Splanchnic and inferior systemic venous beds were decompressed using veno-venous bypass. TAK-044 (donated by Takeda Chemical Industries. Ltd, Osaka, Japan), dissolved in normal saline and given to animals at a dose of 5,0 mglkg, was given as a continuous intravenous infusion (via a peripheral vein) over 30 minutes, just before hepatic ischemia (Group 2, n = 5), Control animals (Group I, n = 10) received a 30-minute infusion of normal saline, Serial arterial aspartate aminotransferase (AST), alanine amino-transferase (ALT). and bile acid (BA) levels and hepatic venous immunoreactive endothelin-I (irET-I) levels were determined. Intraoperative hepatic tissue blood flow (HTBF) was measured serially using a laser-doppler flow meter (ALF21; Advance, Co, Ltd, Tokyo, Japan). Post-ischemic liver tissues (wedge biopsies) were stained with hematoxylin and eosin for histological analysis. Results are presented as the mean ::':: the standard error of the mean. Statistical analysis of the results was performed using the Log Rank test (for survival), and the Mann-Whitney U test (all others). A P value less than .05 was considered significant. RESULTS Two-week animal survival in Group 2 (100%) was signifi-cantly better than Group 1 (30%). Peak AST and ALT levels in Group 1 were significantly higher than AST and AL T levels in Group 2. The AST and AL T of Group 1 livers 12 hours after reperfusion were 1152 ± 1014 UIL and 13563 ± 1379 UIL, respectively, while AST and ALT of Group 2 livers at 12 hours were 3407 ± 420 UIL and 4228 ± 1167 UIL, respectively. Bile acid levels in Group 1 increased after reperfusion, and peaked at 175 ± 39 mmollL 24 hours after reperfusion. On the other hand, bile acid levels in Group 2 peaked 58 ± 21 mmollL 1 hour after reperfusion, and returned to normal levels 12 hours after reperfusion. Neither the infusion of T AK-044 (Group 2), nor the normal © 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 29, 1335 (1997) saline (Group 1). caused any change in hemodynamics. Reper-fusion caused a significant hemodynamic change in animals of both groups; howevcr, the changc was significantly less pro-nounced in Group 2 (60% of pre-ischemia MAP) than Group I (40% of pre-ischemia MAP). Conversely. peak portal vein pressure after reperfusion was significantly higher in Group 1 (12.7 ± 1.9 mm Hg) than in Group 2 (4.2 :!: 0.9 mm Hg). Most importantly, however. hepatic tissue blood flow aftcr repcrfusion was significantly better in Group 2 (51.4 ::t:: 1.6% of normal) than in Group 1 (26.8 ± 1.7%). Two hours of complete normothermic hepatic ischemia caused a 20-fold increase in irET-llevels in the hepatic venous blood of Group I (pre-ischemia: 0.8 ::t:: 0.2 pg/mL vs post-ischemia: 17.6 ± 6.3 pg/mL). The increase of irET-1 was further enhanced by T AK-044 treatment (47.8 ± 10.4 pglmL). Histological analysis of post-ischemic liver tissue revealed that microthombi formation and heterotopic blood in sinu-soid were significantly worse in Group 1 than in Group 2. DISCUSSION The infusion of T AK-044, a nonselective ET NB receptor antagonist, before prolonged complete hepatic ischemia improved post-reperfusion hemodynamics, hepatic tissue blood flow, liver function, and tissue histology. As described in other studies,2 our results suggest that endogenous endothelin influences hepatic microcirculation, and can induce microcirculatory disturbances after ischemia and reperfusion. Our results also suggest that the inhibition of endothelin binding to its receptors by the non-selective ET NB receptor antagonist. T AK-044, provides effective pro-tection against ischemia and reperfusion injury to the liver. REFERENCES 1. Vollmar B, Glasz J, Post S. et al: J Sur Res 60:49, 1996 2. Housset CN. Rockey DC, Friedman SL, ct al: J Hepatology 22:55, 1995 3. Kikuchi T, Ohtaki T, Kawata A, et al: Biochem Biophys Res Commun 200:1708, 1994 From the Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Supported by Research Grants from the Veterans Administra-tion and Project Grant No DK-29961 from the National Institutes of Health, Bethesda, Maryland. Address reprint requests to M.B. Jin, 4C Falk Clinic, 3601 Fifth Ave, Pittsburgh, PA 15213. 0041-1345/97/$17.00 Pll S0041-1345(96)00582-9 1335 • 

Attenuation of ischemic liver injury by a non-selective endothelin receptor antagonist

Name not available

M.B. Jin

Y. Zhu

S. Zhang

N. Ishizaki

H. Tanaka

V.M. Subbotin

R.G. Lee

T.E. Starzl

S. Todo

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http://d-scholarship.pitt.edu/5290/1/31735062133693.pdf

Attenuation of ischemic liver injury by a non-selective endothelin receptor antagonist

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