title: Endogenous brain erythropoietin is a potent sex-specific respiratory stimulant in adult and newborn mice.
abstract: 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 μg/ml) or vehicle (0.1% BSA in PBS). Twenty-four hours after injection, we used whole body plethysmography to record minute ventilation (V̇e) tidal volume (VT), respiratory frequency (fR), O2 consumption (V̇o2), and CO2 production (V̇co2) under normoxia and progressive exposure to hypoxia (12-10-6% O2; 10 min each). In adult male and female mice sEpoR decreased normoxic V̇e (-25%), due to a decrease of VT in males and fR in females. Moreover, sEpoR injection decreased the ventilatory response to 12% O2, assessed as V̇e/V̇o2 or V̇e/V̇co2, in male but not in female mice. In newborn male and female mice sEpoR decreased V̇e (-37% in males, -59% in females) and VT (-38% in males, -47% in females) in normoxia and fR in females. During hypoxia, sEpoR decreased V̇e/V̇o2 and V̇e/V̇co2 in mice of both sexes. Upon extreme hypoxia (6% O2), 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.
authors: Centre de Recherche du CHU de Québec, Pavillon St François d'Assise, Département de Pédiatrie, Faculté de Médecine, Université Laval, Québec, Quebec, Canada.
authors: Orlane
authors: O
authors: Ballot
authors: Centre de Recherche du CHU de Québec, Pavillon St François d'Assise, Département de Pédiatrie, Faculté de Médecine, Université Laval, Québec, Quebec, Canada.
authors: Vincent
authors: V
authors: Joseph
authors: Centre de Recherche du CHU de Québec, Pavillon St François d'Assise, Département de Pédiatrie, Faculté de Médecine, Université Laval, Québec, Quebec, Canada jorge.soliz@crchuq.ulaval.ca.
authors: Jorge
authors: J
authors: Soliz
mesh_terms: D000222:Adaptation, Physiological; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D002245:Carbon Dioxide / Q000378:metabolism; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000378:metabolism*; D005260:Female; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D007276:Injections, Intraventricular; D008297:Male; D008810:Mice, Inbred C57BL; D010101:Oxygen Consumption; D012123:Pulmonary Ventilation; D017467:Receptors, Erythropoietin / Q000008:administration & dosage; D012119:Respiration / Q000187:drug effects; D056152:Respiratory Rate; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects; D013990:Tidal Volume; D013997:Time Factors
chemical_list: D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D002245:Carbon Dioxide
keywords: brain; erythropoietin; hypoxia; newborn and adult mice; respiration; sex dimorphism; soluble erythropoietin receptor