The protective effect of SRI 63-441 on ischemic liver injury using the isolated perfused rat liver: Combined protocol with superoxide dismutase

Prevention or reduction of ischemia/reperfusion injury would be of great benefit in organ transplantation. Here we briefly report preliminary studies evaluating a combined protocol using SRI 63-441 (Sandoz Pharmaceuticals, Raritan, NJ), a potent platelet-activating factor receptor antagonist, and superoxide dismutase (SOD), an oxygen free radical scavenger, in an attempt to reduce ischemic injury to the liver. The preliminary studies with SOD indicated that, as expected, SOD must be present at the time of reperfusion to exert a beneficial effect. The addition of SOD to SRI 63-441 pretreatment did not result in an improvement over SRI 63-441 pretreatment alone. In fact, at this time, the results are equivocal with an improvement in bile production, but none in perfusate transaminases. The complexity and multiplicity of cascades involved in the mediation of ischemia/reperfusion injury make it highly likely that effective pharmacologic modulation of the injury, leading to prolongation of organ preservation, will involve a poly-pharmacy approach. The ultimate 'cocktail' would contain several agents that act at different critical points along the multiple pathways. It is not unexpected, as in the study reported here, that agents anticipated to behave synergistically could upset the fine balance in the cell's homeostatic mechanisms and invoke a detrimental response.