While the structure and function of erythropoietin (Epo) are well documented, the mechanisms of the regulation of the renal synthesis of Epo are still poorly understood. Especially, the description of the localization and function of the O₂-sensitive sensor regulating the renal synthesis of Epo is insufficient. A body of evidence suggests that extrarenal O₂-sensitive sensors, localized particularly in the brain-stem, play an important role in this connexion. To support this concept, a high cerebral pressure with a consecutive hypoxia of the brain-stem was generated by insufflation of synthetic cerebrospinal fluid into the catheterized cisterna magna of rats. When the cerebral pressure of the rats was above the level of their mean arterial blood pressure or the high cerebral pressure persisted for a longer period ( 10 min), the Epo plasma concentration increased significantly. Bilateral nephrectomy or hypophysectomy prior to the initiation of the high intracranial pressure abolished this effect. Systemic parameters (heart rate, blood pressure, p_aO₂, p_aCO₂, p_aH, renal blood flow, glucose concentration in blood) were not affected. Other stressors like the restriction of the mobility of the rats had no effect on Epo production. Hence, the effect of the high cerebral pressure on the renal synthesis of Epo seems to be specific. Increasing the cerebral hydrostatic pressure leads to an increased renal synthesis of Epo. Obviously, during hypoxia cerebral O₂-sensitive sensors release humoral factors triggering the renal synthesis of Epo. The structure and function of these 'Epo-releasing-factors' have to be characterized in future experiments.