Proopiomelanocortin (POMC) is expressed in pituitary, CNS and in a few peripheral tissues. This study addresses the hypothesis that metabolic stressors such as acidosis may induce the release of POMC derivatives into the cardiovascular system not only from the pituitary, but also from other sites of POMC expression. In our study we investigated the liberation of POMC derivatives from peripheral tissues under a state of acidosis achieved by tourniquet-induced ischemia, alteration of lactate concentration and base-excess. In eight patients undergoing knee arthroplasty under spinal anesthesia, catheters were inserted into the femoral vein proximally to thigh tourniquet location. Blood was drawn from these catheters 5 minutes before, 40 seconds, 5 and 10 minutes after tourniquet deflation to measure plasma concentrations of N-acetyl--endorphin immunoreactive material (IRM), -endorphin IRM, authentic -endorphin (-endorphin(1-31)), ACTH, lactate as well as pH and base-excess. In five out of eight patients we found a significant increase of -endorphin IRM levels 40 seconds after tourniquet deflation in comparison to predeflation levels; 5 and 10 minutes after tourniquet deflation the -endorphin IRM levels were below the detection limit. Thus, -endorphin IRM was released from ischemic limb tissues into the cardiovascular system. Only a small part of the determined -endorphin IRM corresponded to -endorphin(1-31). 40 Seconds after tourniquet deflation the -endorphin IRM concentration correlated with base-excess (r<0.71 (p<0.05)); no significant correlations were found with pH or lactate levels. Thus, it was shown here for the first time that ischemic stress may induce the release of -endorphin IRM from non-pituitary tissues.