It is still unknown whether remote ischemic preconditioning is mediated by a humoral or a neurogenic mechanism from the preconditioning to the preconditioned tissue. The purpose of the following study was to identify a possible humoral trigger of ischemic myocardial preconditioning and remote renal preconditioning. Open chest rats were subjected to a coronary artery occlusion period of 45 min followed by 2 h of reperfusion (Control animals; n = 6). The coronary preconditioned group (IPC, n = 6) was subjected to a preceding preconditioning period of 5 min coronary artery occlusion followed by 5 min of reperfusion, repeated three times. The renal preconditioned group (IPR, n = 6) was subjected to a preceding renal artery occlusion period of 10 min followed by 20 min of reperfusion. Area at risk (AAR) and infarcted area (IA) were determined at the end of each protocol. Blood samples were taken at the end of the preconditioning protocols from parallel experiments for proteomic analysis using two-dimensional gel electrophoresis (2-DE), matrix assisted laser desorption and ionization-time of flight-mass spectrometry (MALDI-TOF-MS), and liquid chromatography-electrospray ionization-tandem mass spectrometry (nanoLC-ESI-MS/MS). IA/AAR was 87.8 +/- 10.7% in the control group. IPC and IPR significantly reduced IA/AAR (58.2 +/- 9.3% and 56.9 +/- 9.0%, p < 0.001). Proteomic analyses detected four protein spots which were either up- (n = 3) or down-regulated in the preconditioned groups vs. the control group. The three up-regulated protein spots were identified as albumin fragments, whereas the down-regulated spot was identified as liver regeneration-related protein (LRRG03). Interestingly, albumin modification by brief ischemia has been recently shown and evaluated for the clinical diagnosis of sublethal myocardial ischemia. However, no differentially abundant proteins which possess a known signaling function could be found. Hence, though there is a differential protein expression in blood following IPC and IPR, our data are not in favor of a humoral mediator of remote preconditioning with a molecular weight of more than 8 kDa. Our results rather suggest either a neurogenic pathway or a mediator smaller than 8 kDa.