Protective effect of angiotensin 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 (AngI I) is one of the most potent endogenous vasoconstrictors. Angiotensin II ty pe I (AT,) receptor antagonist has been reported to have protective effects on I/R injury of the heart and kidney. However, effect on hepatic I/R inju ry has not been determined. In this study, we investigate our hypothesis th at AT, receptor antagonist, CV-11974, attenuates hepatic I/R injury. Methods. Twelve beagle dogs underwent a 2-hr total hepatic vascular exclusi on with veno-venous bypass. CV-11974 was given to animals at a dose of 0.00 2 mg/kg/min for 5 min followed by 0.001 mg/kg/min for 25 min via portal vei n before ischemia (group II, n=6). Nontreated animals were used as the cont rol (group I, n=6). Animal survival, hemodynamics, hepatic tissue blood flo w (HTBF), liver function, platelet count, renin activity, and AngII concent ration of hepatic vein, energy metabolism, and histopathology were analyzed . Results. Two-week survival was 33% in group I, in contrast, 100% in group I I. Mean arterial blood pressure during early reperfusion was maintained, an d HTBF after reperfusion was significantly higher in group II. Treatment at tenuated liver enzyme release and decrease of platelet count, increased ren in and AngII, suppressed ATP degradation during ischemia and enhanced ATP r esynthesis 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. AT, receptor blockade with C V-11974 attenuated hepatic microcirculatory disturbance and ameliorated I/R injury.