2005 Fiscal Year Final Research Report Summary
Tolerance induction against hepatic ischemia/reperfusion injury by an artificial regulation of the intracellular signal
| Project/Area Number |
16591288
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Akita University |
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Principal Investigator |
KUME Makoto Akita University, School of Medicine, Assistant, 医学部, 助手 (00372326)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Yuzo Akita University, School of Medicine, Professor, 医学部, 教授 (70281730)
SATO Tsutomu Akita University, School of Medicine, Associate Professor, 医学部, 助教授 (90235367)
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| Project Period (FY) |
2004 – 2005
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| Keywords | hepatic ischemia / reperfusion injury / cyclic AMP / protein kinase A / phosphodiesterase-3 inhibitor / liver transplantation |
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| Research Abstract |
Aim. The purpose of this study was to determine the influence of PKA on the hepatoprotective effect of milrinone on warm ischemia-reperfusion (I/R) injury of rat livers.
Methods. Male Lewis rats were randomly allocated into three groups. Group A : Milrinone was administrated continuously i.v. at 5 μg/kg/min for 10 min, then 0.5 μg/kg/min for 10 min. Group B : PKA inhibitor Rp-8-Br-cAMPS was injected prior to milrinone administration. Group C : control without pre-treatment. Then, all animals were exposed to a 45-min hepatic warm ischemia by Pringle's maneuver. Concentration of cAMP in the liver tissue before ischemia was measured by enzyme immunoassay. PKA activity was measured by kinaseassay, andtheactivity was quantified as active PKA / total PKA ratio. I/R induced liver damage was quantified by serum ALT at 6 hours of reperfusion. Survival rate were compared on the 7^<th> postoperative day.
Results. Tissue cAMP concentration was significantly elevated in group A and B than that of group C
(A: 2.8 ± 0.2, B: 3.0 ± 0.2, C: 2.2 ± 0.2 (pmol/mg protein)). PKA inhibitor effectively suppressed PKA activity ratio after a milrinone treatment (A: 28.7 ± 5.0, B: 19.8 ± 1.9, C: 20.2 ± 2.5 (%)). In
group A, ALT level was well suppressed and the survival rate was significantly better than
in group C. Despite the elevated level of cAMP, elevated ALT level after reperfusion was significantly higher and survival rate was significantly lower in group B than in group A. ALT ; A; 1302 ± 387, B; 2590 ± 378 and C; 2889 ± 1306 (U/L), survival ; A: 15/16, B: 9/16, C: 9/16, (p <0.05).
Conclusion. PKA dependent signal pathway is a key structure element in the acquisition of ischemic tolerance of the liver by milrinone.
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