The Effect of Fractionated Administration of Erythropoietin in Splenectomized or Shamoperated Erythraemic Mice

Splenectomy does not influence the ESF‐response in erythraemic mice after a single i.v. administration of less than 2.0 IRP‐units of ESF. A significantly smaller response, however, is observed in splenectomized mice than in sham operated animals when ESF‐doses larger than 2.0 IRP‐units are administered. Comparison of the ESF‐dose‐response in ESF‐prestimulated, splenectomized or sham operated mice with that of non‐prestimulated controls indicates that ESF leads to an increase in the number of primitive erythropoietin‐responding cells, and that this increase mainly, if not exclusively, takes place in the spleen. Although the number of primitive erythropoietin‐responding cells does not increase in splenectomized mice following stimulation with ESF, divided administration of large ESF‐doses to such animals causes a moderate but significant increase in the dose‐response as compared to that of un‐divided administration. As ESF is eliminated exponentially, divided administration of a large ESF‐dose will increase the ‘stimulation time’, i.e. the time during which the dose is effective. A mathematical expression for the ‘stimulation time’ as a function of the dose and the number of fractions used for administration of the dose is advanced. It is suggested that an extension of the ‘stimulation time’ explains the enhanced response observed after fractionated administration of ESF to splenectomized animals. It is concluded that the substantial increase in ESF‐response obtained by fractionated administration of ESF to erythraemic mice with intact spleen is caused partly by an extension of the ESF‐stimulation‐time and partly by an increase in the number of erythropoietin‐responding cells induced by the first fraction of the dose.