Because of vastly improved control of organ rejection since the introduction of Cyclosporin-A, liver transplantation has become an accepted form of therapy for certain liver diseases. However, the realtive intolerance of the liver to ischemia remains a limiting factor. Attempts at overcoming this program include the use of hypothermia, intracellular-type solutions and various perfusion techniques. There has not, however, been a systematic investigation into the use of pharmacological agents to address the specific needs of the liver during ischemia. Ischemia in the liver results in depletion of energy stores, loss of cellular electrolyte balance, production of toxic substances and ultimately hepatocellular and microcirculatory failure. The proposed studies will determine the specific needs of the liver during hypothermic ischemia and constitute a systematic approach to the development of a liver preservation solution that utilizes various pharmacologic interventions to specifically attack the various needs of the liver during ischemia. Such an approach offers the advantages of great potential effectiveness plus simplicity of application. Thus, unlike elaborate perfusion technique, pharmacologic stabilization of hepatic function could be easily and rapidly applied to clinical practice and would further enhance the efficacy of perfusion techniques for longer term preservation. Currently, blood is washed out of the donor liver Ringer's lactate followed by infusion of the cold preservative, usually a Collins solution. Prior to implanting in the recipient, the liver is again flushed with Ringer's lactate. Our hypothesis is that the addition of various agents to these solutions to specifically address the needs of the liver during ischemia will prolong the allowable ischemic time. The interventions to be tested include gluconeogenesis inhibitors, ATP-MgC12, Ca2+ antagonists, free radical scavengers, hypertonic mannitol and thromboxane inhibitors. These agents will be added to the washout and preservation solutions for the cold preservation of rat livers. Their efficacy will then be determined by evaluating a broad spectrum of cellular and organ functions primarily using the isolated perfused liver model following cold preservation. This will allow evaluation of a large number of permutations in a sensitive and cost-effective manner. This approach should produce improved liver preservation techniques that can quickly be applied clinically.
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