Hypoxia-Stimulated Erythropoietin Secretion in Mice with Different Types of Induced Polycythemia: The Posthypoxic Enigma

Abstract Erythropoietin (EPO) is a hormone that is part of a feedback system that adjust the volume of the red cell mass (RCM) to tissue oxygen demands. Increased plasma EPO concentration (pcEPO) accompanies reduced oxygen supply or increased demands, whereas low levels of pcEPO are observed with increased oxygen supply or reduced demands. Therefore, the increment of RCM induced by transfusion (HT mouse) will enhance oxygen supply to tissues and depress EPO secretion when they are subjected to hypobaric hypoxia (HH, a potent stimulus for EPO secretion). When mice made polycythemic by sustained exposure to HH (PH mouse) are re-exposed to the stimulus after a brief period at sea level condition, they react synthesizing EPO as do normocythemic mice. This study was designed to compare HH-stimulated EPO production in mice in which polycythemia was induced by different maneuvers (exposure to HH [6350 m]) for 2 wks, transfusion of homologous erythrocytes (0.8 ml of packed erythrocytes ip), sustained exposure to air containing 0.06% CO, sustained administration of rHu-EPO (5.5 IU day/2wk) and repeated injections of phenylhydrazyne (60 mg/Kg/3 wk) followed by transfusion. After treatments were completed, all animals were exposed to 337 mmHg for 6 h. Blood collected by cardiac puncture and pcEPO measured by immunoassay (R&D systems). pcEPO was significantly elevated in normocythemic and PH mice in relation to non-exposed controls, whereas pcEPO was not increased in response to HH in the remaining groups. In another experiment, mice were exposed for 2 wk to different simulated altitudes (0, 2500, 3600, 4600, 5500 and 7300 m). They were re-exposed to HH for 6 hr. Linear regression analysis between the variable X (simulated high altitude) and the variable Y (pcEPO) showed a slope of 563.4 ± 116.1 pg/1000m and an r 2 = 0.887. Data indicate that the enhancement of EPO secretion in response to the hypoxic challenge in polycythemic mice only occurs in mice that have been previously exposed to hypoxia. However, the operating mechanism of hypoxia in this state of EPO hypersecretion remains as an open question