Carbamylated erythropoietin enhances mice ventilatory responses to changes in O2 but not CO2 levels

• Carbamylated erythropoietin enhanced breathing without stimulating hematopoiesis.
• Chronic treatment increased hyperoxic ventilatory depression.
• Chronic injections enhanced the hypoxic ventilatory response.
• This drug may be advantageous to stimulate breathing without side-effects.

Erythropoietin (EPO) has beneficial tissue-protective effects in several diseases but erythrocytosis may cause deleterious effects in EPO-treated patients. Thus carbamylated-EPO (C-EPO) and other derivatives retaining tissue-protective but lacking bone marrow-stimulating actions have been developed. Although EPO modulates ventilatory responses, the effects of C-EPO on ventilation have not been investigated. Here, basal breathing and respiratory chemoreflexes were measured by plethysmography after acute and chronic treatments with recombinant human C-EPO (rhC-EPO; 15,000 IU/kg during 5 days) or saline (control group). Hematocrit, plasma and brainstem rhC-EPO levels were also quantified. Chronic rhC-EPO significantly elevated tissue rhC-EPO levels but not hematocrit. None of the drug regimen altered basal ventilation (normoxia). Chronic but not acute rhC-EPO enhanced hyperoxic ventilatory depression, and sustained the hypoxic ventilatory response mainly via a reduction of the roll-off phase. By contrast, rhC-EPO did not blunt the ventilatory response to hypercapnia. Thus, chronic C-EPO may be a promising therapy to improve breathing during hypoxia while minimizing adverse effects on cardiovascular function.