Unexpected hypoxia-dependent erythropoietin secretion during experimental conditions not affecting tissue oxygen supply/demand ratio

Unexpected hypoxia-dependent erythropoietin secretion during experimental conditions not affecting tissue oxygen supply/demand ratio. Although a great deal of evidence supports the hypothesis that plasma erythropoietin (EPO) levels of mammals are related to the oxygen supply to the tissues relative to their oxygen needs, several observations millitate against its inherent simplicity. This study presents our results obtained from in vivo experiments that suggest that hypoxia-dependent EPO production can be altered by conditions which apparently do not modify the tissue oxygen supply/demand ratio. Hypoxia-dependent EPO production rate (EPO-PR), derived from plasma EPO titers and plasma EPO half-lives, were estimated in both transfused-polycythemic and normocy-themic mouse models subjected to different treatments. From calculations of the o2 carrying capacity of blood and body o2 consumption, it was assumed that the tissue supply/demand ratios were similar in both experimental and control mice of the same model at the time of induction of EPO production. The following observations were worth noting: (1) EPO-PRs in transfused polycythemic mice whose erythropoietic rates were stimulated by intermittent exposure to hypobaria (0·5 atm, 18 hr/day × 3 weeks), phenylhydrazine administration (40 mg/kg at weekly intervals × 3 weeks) or repeated rh-EPO injections (1500 U/kg 3 times a week × 3 weeks) before transfusion were more than five times higher than in comparabily polycythemic mice whose erythropoietic rates were not stimulated previously; and (2) EPO-PR in response to hypobaric hypoxia was 2·08 times normal in normocythemic mice with cyclophosphamide (100 mg/kg) induced depression of erythropoiesis, and 0·33 times normal in normocythemic mice with rh-EPO (400 U/kg × 2) induced enhancement of erythropoiesis. Although the results obtained in polycythemic mice are difficult to explain, those from normocythemic mice suggest the existence of a feedback mechanism between EPO-responsive cells and EPO-producing cells. Both demonstrate the existence of experimental conditions in which modulation of the hypoxia-dependent expression of the EPO gene appears to occur. This modulation would be dependent on factors other than oxygen

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

Increased intrinsic stiffness and mineralization in femurs of adult rats after high intensity treadmill running training

Physical activity plays a tremendous role in determining bone mechanical behavior, which is superimposed to gravidity. OBJECTIVE: Compare the geometric and material responses of the rat femur to a high intensity treadmill running training of a relatively short duration, as assessed by 3-point mechanical test. METHODS: Mature male rats (180.0±30 g) were assigned (7 rats/group) to no exercise (NE) or treadmill exercise (EX). After preconditioning period, the running speed was set at 45 cm.seg−1 during 2 wks, frequency 5 d/wk, 2-hour sessions/day. Body weight and weight of the crural quadriceps were registered at euthanasia. The right femur was mechanically tested through 3-point bending. The left femur was ashed to estimate bone mineral content. Geometric and material bone properties were estimated directly or calculated by appropriate equations. RESULTS: Final body weight was 14% reduced in EX rats, while the crural quadriceps was 47% increased. Yield and fracture loads, and structural stiffness were significantly higher in the EX rats, as were the apparent elastic modulus, the bone mineral content and the degree of mineralization. Geometric properties were not affected. CONCLUSIONS: High intensity treadmill running training increases bone strength and stiffness by increasing material stiffness and mineralization, without affecting geometric bone parameters

Increased intrinsic stiffness and mineralization in femurs of adult rats after high intensity treadmill running training

Physical activity plays a tremendous role in determining bone mechanical behavior, which is superimposed to gravidity. OBJECTIVE: Compare the geometric and material responses of the rat femur to a high intensity treadmill running training of a relatively short duration, as assessed by 3-point mechanical test. METHODS: Mature male rats (180.0±30 g) were assigned (7 rats/group) to no exercise (NE) or treadmill exercise (EX). After preconditioning period, the running speed was set at 45 cm.seg−1 during 2 wks, frequency 5 d/wk, 2-hour sessions/day. Body weight and weight of the crural quadriceps were registered at euthanasia. The right femur was mechanically tested through 3-point bending. The left femur was ashed to estimate bone mineral content. Geometric and material bone properties were estimated directly or calculated by appropriate equations. RESULTS: Final body weight was 14% reduced in EX rats, while the crural quadriceps was 47% increased. Yield and fracture loads, and structural stiffness were significantly higher in the EX rats, as were the apparent elastic modulus, the bone mineral content and the degree of mineralization. Geometric properties were not affected. CONCLUSIONS: High intensity treadmill running training increases bone strength and stiffness by increasing material stiffness and mineralization, without affecting geometric bone parameters