DEPRESSION OF STIMULATED ERYTHROPOIETIN PRODUCTION IN MICE WITH ENHANCED ERYTHROPOIESIS

Background. The reports of lower plasma erythropoietin (EPO) in anemic patients with active erythropoiesis (hyperplastic) than in comparably anemic subjects with erythroid hypoplasia have generally been interpr eted as the result of EPO utilization by the target cells of the hormo ne. An alternative explanation could be that there is a feedback mecha nism through which EPO formation by EPO-producing cells is modulated b y the erythroid activity of the erythropoietic organs. The present stu dy was thus designed to investigate EPO production during acute hypoxe mia in a mouse model in which the oxygen-carrying capacity of blood, t he plasma EPO level, the blood viscosity and the plasma EPO half-life are within normal values in spite of an intense stimulation of erythro poiesis. Materials and Methods. Adult female mice of the CF1 strain wi th either normal or increased rates of erythropoiesis were used in thi s study. Erythropoiesis was stimulated by two injections of 10 units o f rhEPO given 24 h apart. All experimental determinations were perform ed 24 h after the second EPO injection. Erythropoiesis was measured by the percent of a tracer dose of Fe-59 incorporated into the spleen. H ypobaric hypoxemia was induced by exposing mice to atmospheric air mai ntained at 50% atmospheric pressure for 6 h. Plasma EPO concentration was determined by RIA. Plasma disappearance of radiolabeled rhEPO was determined by i.v. injection of the hormone and sampling by cardiac pu ncture every hour for 6 h. Results. Administration of rhEPO to mice in creased splenic Fe-59 uptake significantly without affecting the hemat ocrit, the plasma EPO level or the plasma disappearance of radiolabele d EPO. Plasma EPO titer after 6 h of exposure to hypobaric air was abo ut 70% lower in mice with EPO-induced stimulation of erythropoiesis th an in mice with normal erythropoiesis. Conclusions. The results of thi s study suggest that there is an inverse relationship between the rate of stimulated EPO production and erythropoietic marrow activity. They also suggest that the variations in plasma EPO levels during periods of rapidly increasing erythropoiesis are the reflection of a decrease in the rate of production rather than an increase in the rate of utili zation by a proliferating pool of erythroid cells.