Myocardial hypertrophy, heart failure and cognitive dysfunction as seen in Alzheimer Disease share common risk factors such as hypertension suggesting that similar mechanisms trigger these events. In both tissues, heart and brain, mitochondria are obviously part of the pathomechanism. Cells of the cardiovascular system such as cardiomyocytes and endothelial cells, but also neurons have in common that they highly express uncoupling protein 2 (UCP2) in mitochondria. UCP2 may function as a protonophore but its exact function is unclear. Our recently studies suggest that UCP2 acts as a metabolic sensor that coordinates the use of glucose or fatty acids. The high expression of UCP2 in cardiovascular cells and in neurons let us speculate that genetic deficiency of UCP2 will affect energy metabolism and tissue-specific adaptation to high blood pressure in heart and brain in a similar way. On the other hand, neurons and cardiomyocytes differ in their metabolic flexibility and the expression profile of other UCP isoforms. Therefore, it remains open whether UCP2 may be a potential target for hypertension-related heart failure and Alzheimer Disease. We investigated the effect of UCP2 depletion in rats and furthermore the impact of hypertension (L-NAME model, 4 weeks) to analyze the subsequent consequences in the brain (n=23 rats). In the brain UCP2 and 4 are dominant in the medulla oblongata and bulbus olfactorius but less in neurons of the cortex, whereas UCP3 is mainly expressed in the bulbus olfactorius and UCP5 is the dominant isoform in the cortex. This different expression pattern suggests specific functions for these proteins of the inner mitochondrial membrane in different tissues. Increasing the blood pressure by administration of L-NAME decreased the expression of UCP4 and that of endothelin-1 in the medulla oblongata, bulbus olfactorius and, although to a slightly lesser extent, in the cortex. However, endothelin-1 expression in the aorta was not affected suggesting a specific effect on the brain. The effect on endothelin-1 expression was UCP2-independent. In addition, hypertension induced by L-NAME attenuated phosphorylation of p38 MAP kinase independent of the genotype in the brain. In the brain, inflammatory cytokines (IL6, MCP1) were mainly expressed in the bulbus olfactorius. Hypertension and UCP2 depletion decreased the expression of these inflammatory cytokines in the bulbus olfactroius and also in the spleen, but not in the left or right ventricle or kidney of the same rats. L-NAME and UCP2 depletion had no additive effects. In conclusion these data suggest that hypertension reduced the expression of endothelin-1 in all parts of the brain via an UCP2-independent way. However, the effects of hypertension on inflammatory cytokines in the bulbus olfactorius can be mimicked by genetic deletion of UCP2 suggesting that inhibition of UCP2 uncoupling in mitochondria may trigger this effect. However, in contrast to our initial hypothesis no common targets for UCP2 in heart and brain were found. This suggests that although UCP2 may affect heart and brain adaptation in hypertensives, targeting UCP2 may differentially affect both organs making it unlikely to be a key target for both types of disease.