Protective effect of agiotensin II type I receptor antagonist, CV-11974, on ischemia and reperfusion injury of the liver.
BACKGROUND
Microcirculatory disturbance has been shown to play a critical role in hepatic ischemia and reperfusion (I/R) injury. Angiotensin II (AngII) is one of the most potent endogenous vasoconstrictors. Angiotensin II type I (AT1) receptor antagonist has been reported to have protective effects on I/R injury of the heart and kidney. However, effect on hepatic I/R injury has not been determined. In this study, we investigate our hypothesis that AT1 receptor antagonist, CV-11974, attenuates hepatic I/R injury.


METHODS
Twelve beagle dogs underwent a 2-hr total hepatic vascular exclusion with veno-venous bypass. CV-11974 was given to animals at a dose of 0.002 mg/ kg/min for 5 min followed by 0.001 mg/kg/min for 25 min via portal vein before ischemia (group II, n=6). Nontreated animals were used as the control (group I, n=6). Animal survival, hemodynamics, hepatic tissue blood flow (HTBF), liver function, platelet count, renin activity, and AngII concentration of hepatic vein, energy metabolism, and histopathology were analyzed.


RESULTS
Two-week survival was 33% in group I, in contrast, 100% in group II. Mean arterial blood pressure during early reperfusion was maintained, and HTBF after reperfusion was significantly higher in group II. Treatment attenuated liver enzyme release and decrease of platelet count, increased renin and AngII, suppressed ATP degradation during ischemia and enhanced ATP resynthesis after reperfusion. Neutrophil infiltration and histopathological damages were lessened in group II.


CONCLUSIONS
Our data demonstrated that the local renin-angiotensin system might play a role in hepatic microcirculation. AT1 receptor blockade with CV-11974 attenuated hepatic microcirculatory disturbance and ameliorated I/R injury.
Masuko
H
H
First Department of Surgery, Hokkaido University School of Medicine, Sapporo, Japan.
Jin
M B
MB
Horiuchi
H
H
Suzuki
T
T
Taniguchi
M
M
Shimamura
T
T
Fukai
M
M
Magata
S
S
Ogata
K
K
Ishikawa
H
H
Fujita
M
M
Nagashima
K
K
Furukawa
H
H
Todo
S
S
D000804:Angiotensin II / Q000097:blood; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D005260:Female; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D006503:Hepatic Veins; D007511:Ischemia / Q000503:physiopathology*; D008099:Liver / Q000098:blood supply* / Q000502:physiology; D008102:Liver Circulation / Q000187:drug effects / Q000502:physiology*; D008111:Liver Function Tests; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012039:Regional Blood Flow / Q000187:drug effects; D012083:Renin / Q000097:blood; D015427:Reperfusion Injury / Q000517:prevention & control*; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D000804:Angiotensin II; D001219:Aspartate Aminotransferases; D012083:Renin; C081643:candesartan