Endogenous brain erythropoietin is a potent sex-specific respiratory stimulant in adult and newborn mice

We tested the hypothesis that endogenous brain Epo is a respiratory stimulant. Adult (3 mo) and newborn (10 days) male and female mice received an intracisternal (cisterna magna) injection of soluble Epo receptor (sEpoR; competes with EpoR to bind Epo; 50 mu g/ml) or vehicle (0.1% BSA in PBS). Twenty-four hours after injection, we used whole body plethysmography to record minute ventilation ((V) over dot(E)) tidal volume (V-T), respiratory frequency (f(R)), O-2 consumption ((V) over dot(O2)), and CO2 production ((V) over dot(CO2)) under normoxia and progressive exposure to hypoxia (12-10-6% O-2; 10 min each). In adult male and female mice sEpoR decreased normoxic (V) over dot(E) (-25%), due to a decrease of V-T in males and f(R) in females. Moreover, sEpoR injection decreased the ventilatory response to 12% O-2, assessed as (V) over dot(E)/(V) over dot(O2) or (V) over dot(E)/(V) over dot(CO2), in male but not in female mice. In newborn male and female mice sEpoR decreased (V) over dot(E) (-37% in males, -59% in females) and V-T (-38% in males, -47% in females) in normoxia and f(R) in females. During hypoxia, sEpoR decreased (V) over dot(E)/(V) over dot(O2) and (V) over dot(E)/(V) over dot(CO2) in mice of both sexes. Upon extreme hypoxia (6% O-2), the newborn mice treated with sEpoR showed respiratory depression, signs of asphyxia (gasping) and a high mortality rate in males and females. We concluded that endogenous brain Epo is a potent respiratory stimulant under normoxia and hypoxia in adult and newborn mice. Because sex-specific effects are different in newborn male and female, sex steroids secreted at different ages mice appear to modulate the effects of Epo on respiratory regulation in normoxia and in response to hypoxia.