Role of cyclic nucleotides in ischemia and reperfusion injury of canine livers.
BACKGROUND
In a series of canine liver ischemia experiments, we have shown that amelioration of hepatic injury is achievable by the inhibition of vasoconstriction, cytokine production, platelet aggregation, and neutrophil infiltration. Cyclic adenosine diphosphate (cAMP) was considered to be involved in most of these events. In our study, we tested our hypothesis that augmentation of endogenous cAMP by phosphodiesterase (PDE) 3 inhibitor, amrinone (AM), or adenylate cyclase stimulator, NKH477 (NKH), could attenuate ischemia and reperfusion injury of the liver.


METHODS
Thirty-six beagle dogs were used. They were divided into group CT (untreated control), group AM, group NKH, and group CB (treated by both agents). AM or NKH were administered i.v. 1 hr before ischemia (group preAM and group preNKH) or 15 min before reperfusion (pos-AM and postNKH). Combination group animals were treated only before ischemia. Animal survival, hepatic tissue blood flow, liver enzymes, platelet counts, energy metabolism, hepatic cAMP and cyclic guanosine 3',5'-cyclic monophosphate levels, and histopathology were analyzed.


RESULTS
Two-week animal survival was significantly improved by pre- or posttreatment with either agent. After reperfusion, hepatic tissue blood flow, liver enzyme release, platelet counts, energy metabolism, tissue cAMP levels, and histological architecture were also ameliorated markedly. Combination of both agents induced severe liver damage and lethal hypotension. AM treatment exhibited more protective effects than NKH, particularly when it was given before ischemia. Interestingly, not only cyclic guanosine 3',5'-cyclic monophosphate, were also restored at higher levels after reperfusion by preischemia treatment.


CONCLUSIONS
Administration of amrinone or NKH477 maintained hepatic tissue concentrations of cyclic nucleotides, and attenuated ischemia and reperfusion injury of the liver. Thus, regulation of hepatic tissue cyclic nucleotides is an important alternative for prevention of hepatic damage in liver preservation and surgery.
Ishikawa
Hiroto
H
First Department of Surgery, Hokkaido University School of Medicine, Sapporo, Japan.
Jin
Maeng Bong
MB
Ogata
Toshiro
T
Taniguchi
Masahiko
M
Suzuki
Tomomi
T
Shimamura
Tsuyoshi
T
Magata
Shinichirou
S
Horiuchi
Hiroyuki
H
Ogata
Kenji
K
Masuko
Hiroyuki
H
Fujita
Miri
M
Furukawa
Hiroyuki
H
Todo
Satoru
S
D000255:Adenosine Triphosphate / Q000032:analysis; D000676:Amrinone / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000031:analogs & derivatives / Q000494:pharmacology; D000242:Cyclic AMP / Q000032:analysis / Q000502:physiology*; D006152:Cyclic GMP / Q000032:analysis / Q000502:physiology*; D004285:Dogs; D004734:Energy Metabolism; D005260:Female; D006439:Hemodynamics; D007511:Ischemia / Q000503:physiopathology*; D008099:Liver / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology; D008102:Liver Circulation; D010976:Platelet Count; D011169:Portal Vein / Q000503:physiopathology; D015427:Reperfusion Injury / Q000209:etiology* / Q000517:prevention & control
D005576:Colforsin; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D006152:Cyclic GMP; D000676:Amrinone