Recent advances have led to increased use of ultraprofound hypothermia for cardiopulmonary bypass, organ preservation and trauma patients and have introduced the possibility of targeted pharmacologic intervention during the hypothermic period. In this study, rabbit renal cortex slices were used to examine the effect of administering quinacrine (100 microM) during hypothermia induced after a warm ischemic injury (60 min at 37 degrees C) on recovery of biochemical function during 3.5 hr of simulated warm reperfusion. In ischemic tissue slices, ATP content was reduced to near zero and only recovered about 50% by the end of reperfusion. Hypothermic storage of ischemic slices for 18 hr restored slice ATP content to about 80% of control levels but was followed by a decline during reperfusion to levels similar to ischemic slices. Administering quinacrine (100 microM) during 18 hr of hypothermic storage of ischemic slices resulted in a significant and sustained increase in slice ATP content during warm reperfusion. Slices stored at hypothermia only 3 hr with quinacrine had reduced swelling during reperfusion even though total ATP content was unaffected. Administering quinacrine (100 microM) only during reperfusion after ischemia or hypothermia did not affect tissue ATP content. This study showed that drug administration during hypothermic storage has potential therapeutic benefits for resuscitating tissues after warm ischemia and is more effective than the same drug given only during reperfusion. Tissue pretreatment was not required to obtain improved function in this study which suggests that future adaptations of these principles may have practical applications for specific clinical conditions where ischemic and reperfusion injury are significant factors.