G. M. Rodgers

Elevated cyclic GMP concentrations in rabbit bone marrow culture and mouse spleen following erythropoietic stimulation

Abstract The effects of erythropoietin and hypoxia on cyclic nucleotide concentrations in erythroid tissue were evaluated. A rabbit bone marrow culture system and a mouse spleen model provided evidence that erythropoietin and an hypoxic stimulus which increases erythropoietin production may enhance erythropoiesis by initiating reciprocal changes in erythroid cell cyclic nucleotide levels. Cyclic GMP appears to be the active signal in mediating the response to erythropoietin, whereas cyclic AMP may be a passive signal allowing full expression of the cyclic GMP response. Whether the type of response mediated by cyclic nucleotides is proliferative, differentiative or both is not clear, but our data and that of other investigators suggest that cyclic GMP mediates the proliferative actions of erythropoietin.

Increase in Hematocrit, Hemoglobin and Red Cell Mass in Normal Mice after Treatment with Cyclic AMP

Summary Chronic treatment of normal mice with either dibutyryl cyclic AMP or erythropoietin produced elevations in the hematocrit, hemoglobin concentration and red cell mass when compared to these same hematological parameters in untreated mice. Dibutyryl cyclic AMP increased red cell mass by 46% while ESF treatment resulted in a 56% increase in red cell mass. These studies confirm earlier reports of the effects of cyclic AMP in increasing radioactive iron incorporation into red cells and further indicate that this change is associated with an absolute increase in red cell mass. Agents which increase renal cyclic AMP concentrations probably stimulate erythropoiesis as a consequence of increased kidney production of erythropoietin.

Elevation of renal cyclic GMP concentrations and plasma lysosomal enzyme activity following cobalt treatment in rats

Summary Following an erythropoietic dose of cobalt in rats, elevations in renal guanosine 3′,5′-monophosphate (cyclic GMP) concentrations occurred within 10 minutes reaching peak levels within 40 minutes of injection. Subsequent to the cyclic CMP changes, activities of lysosomal enzymes in plasma (β-glucuronidase, acid phosphatase) increased markedly, with maximal elevations of both enzyme activities occurring 2 hours after cobalt treatment. Bilateral nephrectomy abolishes the elevations in plasma lysosomal enzyme activity following cobalt treatment, suggesting that the kidney is the source of these enzymes. It is proposed that a cyclic GMP-mediated release of lysosomal enzymes from the kidney may be an early effect of cobalt leading to the generation of renal erythropoietin.

Renal cyclic GMP and cholinergic mechanisms in erythropoietin production

Abstract Cobalt treatment in rats produced sequential elevations in both renal cyclic GMP concentration and lysosomal enzyme activity in plasma. These effects of cobalt were significantly inhibited by atropine pretreatment, as was cobalt-mediated erythropoietin (ESF) production. Physostigmine, an inhibitor of acetylcholinesterase, potentiated the erythropoietic effect of cobalt. These data are consistent with the hypothesis that the erythropoietic effect of cobalt is associated with a cholinergic mechanism involving cyclic GMP-mediated lysosomal enzyme release. These cholinergic events may precede a previously described cyclic AMP activation of a renal erythropoietic factor.

Activation of the renal erythropoietic factor by a cyclic AMP-dependent protein kinase.

Summary A protein kinase, which is one of the key components of a renal cyclic AMP mechanism, has been isolated, characterized, and studied with respect to its ability to generate erythropoietin (ESF) in an in vitro system. This enzyme was found to activate the renal erythropoietic factor (erythrogenin) in the presence of cyclic AMP which led to an increase in the generation of ESF from plasma. These data suggest that this renal cyclic AMP-dependent protein kinase which is present in the normal kidney plays an important role in kidney ESF production after erythropoietic stimulation.