UNEXPECTED HYPOXIA-DEPENDENT ERYTHROPOIETIN SECRETION DURING EXPERIMENTAL CONDITIONS NOT AFFECTING TISSUE OXYGEN SUPPLY DEMAND RATIO/

Unexpected hypoxia-dependent erythropoietin secretion during experimen tal conditions not affecting tissue oxygen supply/demand ratio, Althou gh a great deal of evidence supports the hypothesis that plasma erythr opoietin (EPO) levels of mammals are related to the oxygen supply to t he tissues relative to their oxygen needs, several observations milita te against its inherent simplicity. This study presents our results ob tained from in vivo experiments that suggest that hypoxia-dependent EP O production can be altered by conditions which apparently do not modi fy the tissue oxygen supply/demand ratio. Hypoxia-dependent EPO produc tion rare (EPO-PR), derived from plasma EPO titers and plasma EPO half -lives, were estimated in both transfused-polycythemic and normocythem ic mouse models subjected to different treatments. From calculations o f the O-2 carrying capacity of blood and body O-2 consumption, it was assumed that the tissue supply/demand ratios were similar in both expe rimental and control mice of the same model at the time of induction o f EPO production. The following observations were worth noting: (1) EP O-PRs in transfused polycythemic mice whose erythropoietic rates were stimulated by intermittent exposure to hypobaria (0.5 atm, 18 hr/day x 3 weeks), phenylhydrazine administration (40 mg/kg at weekly interval s x 3 weeks) or repeated rh-EPO injections (1500 U/kg 3 times a week x 3 weeks) before transfusion were more than five times higher than in comparability polycythemic mice whose erythropoietic rates were not st imulated previously; and (2) EPO-PR in response to hypobaric hypoxia w as 2.05 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 x 2) induced enhancement of e rythropoiesis. Although the results obtained in polycythemic mice are difficult to explain, those from normocythemic mice suggest the existe nce of a feedback mechanism between EPO-responsive cells and EPO-produ cing cells. Both demonstrate the existence of experimental conditions in which modulation of the hypoxia-dependent expression of the EPO gen e appears to occur. This modulation would be dependent on factors othe r than oxygen.