A prolonged occlusion of hepatic inflow may result in significant hepatic dysfunction from acute hepatic ischemia and following reperfusion.
Pharmacological modulation of hepatocyte functions during warm ischemia and early reperfusion have shown some beneficial effects.
The author conducted an experiment to evaluate the effect of verapamil and urokinase on the restoration of hepatic functions in dogs after 90 minutes of acute hepatic ischemia.
Eighteen mongrel dogs were divided into the following three groups of six dogs each: control, urokinase, and verapamil.
Before the experiments were begun, autogenous venous meso-caval shunts were made in all animals to alleviate intestinal congestion and there by minimize systemic hemodynamic instability during the occlusion of hepatic inflow.
Acute hepatic ischemia was induced through the application of portal triad cross clamping (PTCC) for 90 minutes. The shunt was kept open while PTCC was applied(clamp), but was immediately closed upon the removal of PTCC(declamp). After declamp in
each
experimental group, 0.3mg/kg of verapamil and 4,000 unit/kg of urokinase were infused via the common hepatic artery.
The following information was ascertained before clamp, 90 minutes after clamp, 60 minutes after declamp, and 120 minutes after declamp: mean arterial pressure(MAP), cardiac output (CO), liver enzyme levels(ALT, AST, ALP and LDH), oxygen
consumption,
serum lactate, and ketone body ratio(KBR).
A serial liver biopsy was performed whenever blood samples were taken.
@ES The results were as follows:
@EN 1) MAP feel slightly in the control and urokinase groups after declamp, but fell markedly in the verapamil group.
2) CO decreased rapidly after clamp in all groups, but recovered more slowly in the verapamil group than in the other two groups.
3) Liver enzyme levels(AST, ALT, LDH and ALP) increased steadily after declamp in the control and verapamil groups, but increase rapidly 60 minutes after declamp and then keep a plateau curve in the urokinase group.
4) Oxygen consumption was rapidly decreased in all groups during clamping, and rapid recovery was noted in control and urokinase groups, but in verapmail group it was slow.
5) The serum lactate level increased gradually in the control group, but to a lesser extent in the urokinase and verapamil groups.
6) The arterial KBR decreased markedly during the clamping period for all groups. Although KBR returned to normal levels 120 minutes after reperfusion in the verapamil and urokinase groups, it failed to do so in the control group.
7) There was no significant change in the total serum calcium and ionized calicum levels.
8) Light microscopic(L-M) examination of liver biopsy revealed centrilobular necrosis during PTCC in all groups. Much improvement was noted in the urokinase and verapamil groups 120 minutes after declamp, but not in the control group.
In conclusion, both verapamil and urokinase revealed significant hepatocyte functional protection effects when used before the start of reperfusion. However, verapmil caused serous systemic hemodynamic alteration, which may reduce the hepatocyte
protection effect. Moreover, urokinase exhibited excellent hepatic functional restoration without changing the systemic hemodynamics or the coagulation mechanism.
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