As recently shown (Pflügers Arch 499 Suppl 1, S112, 2005), an elevation of the intracranial pressure (ICP) leads to significant increases in plasma Epo concentrations. In order to prove that a brainstem factor is involved in the regulation of the renal Epo production, we investigated the cerebral Epo gene expression of the rat by real time RT PCR (cortex, brainstem, cerebellum, hypothalamus and hypophysis). The experiments were done under hypobaric (increased ICP: 100 mmHg for 10 min) and anaemic hypoxia (lowering of the hematocrit from 40 to 30%). Both local hypoxia, achieved by a raised ICP, and anaemic hypoxia led to a 2- to 5fold induction of Epo-mRNA in all cerebral areas, with the exception of the hypophysis. Here, an increased ICP led to a 100fold induction of the Epo-mRNA, whereas anaemic hypoxia led to a downregulation of the Epo gene expression. Hence the hypophysis seems to take a different part in the regulation of the synthesis of Epo than the rest of the brainstem. These findings support our hypothesis that the hypophysis plays a decisive role in the regulation of the renal Epo production. Under hypoxic conditions the hypophysis possibly releases some yet unknown humoral factors, which trigger Epo synthesis in the kidney. These factors have to be identified by proteomics.