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

摘要

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 mug/ml) or vehicle (0.1% BSA in PBS). Twenty-four hours after injection, we used whole body plethysmog-raphy to record minute ventilation (Ve) tidal volume (V_T), respiratory frequency (f_r), O_2 consumption (V02), and CO2 production (V_(CO_2)) 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_E ( - 25%), due to a decrease of V_T in males and/R in females. Moreover, sEpoR injection decreased the ventilatory response to 12% O_2, assessed as VE/V_(O_2) or Ve/V_(CO_2), in male but not in female mice. In newborn male and female mice sEpoR decreased Ve (-37% in males, -59% in females) and V_T (-38% in males, -47% in females) in normoxia and/R in females. During hypoxia, sEpoR decreased V_E/V_(O_2) and Ve/V_(CO_2) 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.