Hypercapnic ventilatory response is decreased in a mouse model of excessive erythrocytosis.
The impact of cerebral erythropoietin (Epo) in the regulation of the hypercapnic ventilatory response (HcVR) is controversial. While we reported that cerebral Epo does not affect the central chemosensitivity in C57Bl6 mice receiving an intracisternal injection of sEpoR (the endogenous antagonist of Epo), a recent study in transgenic mice with constitutive high levels of human Epo in brain and circulation (Tg6) and in brain only (Tg21), showed that Epo blunts the HcVR, maybe by interacting with central and peripheral chemoreceptors. High Epo serum levels in Tg6 mice lead to excessive erythrocytosis (hematocrit ~80-90%), the main symptom of chronic mountain sickness (CMS). These latter results support the hypothesis that reduced central chemosensitivity accounts for the hypoventilation observed in CMS patients. To solve this intriguing divergence, we reevaluate HcVR in Tg6 and Tg21 mouse lines, by assessing the metabolic rate [O consumption (V̇) and CO production (V̇)], a key factor modulating ventilation, the effect of which was not considered in the previous study. Our results showed that the decreased HcVR observed in Tg6 mice (~70% reduction; < 0.01) was due to a significant decrease in the metabolism (~40%; < 0.0001) rather than Epo's effect on CO chemosensitivity. Additional analysis in Tg21 mice did not reveal differences of HcVR or metabolism. We concluded that cerebral Epo does not modulate the central chemosensitivity system, and that a metabolic effect upon CO inhalation is responsible for decreased HcVR observed in Tg6 animals. As CMS patients also show decreased HcVR, our findings might help to better understand respiratory disorders at high altitude.
Centre de Recherche du CHU de Québec, Pavillon St François d'Assise, Département de Pédiatrie, Faculté de Médecine, Université Laval, Québec, QC, Canada.
Sofien
S
Laouafa
Centre de Recherche du CHU de Québec, Pavillon St François d'Assise, Département de Pédiatrie, Faculté de Médecine, Université Laval, Québec, QC, Canada.|Molecular biology and Biotechnology Institute, Universidad Mayor de San Andres, La Paz, Bolivia.
Elizabeth
E
Elliot-Portal
Centre de Recherche du CHU de Québec, Pavillon St François d'Assise, Département de Pédiatrie, Faculté de Médecine, Université Laval, Québec, QC, Canada.|Molecular biology and Biotechnology Institute, Universidad Mayor de San Andres, La Paz, Bolivia.
Susana
S
Revollo
Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland; and.
Edith M
EM
Schneider Gasser
Centre de Recherche du CHU de Québec, Pavillon St François d'Assise, Département de Pédiatrie, Faculté de Médecine, Université Laval, Québec, QC, Canada.
Vincent
V
Joseph
Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Laboratoire "Hypoxie et poumons," Bobigny, France.
Nicolas
N
Voituron
Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland; and.|Universidad Peruana Cayetano Heredia (UPCH), Lima, Peru.
Max
M
Gassmann
Centre de Recherche du CHU de Québec, Pavillon St François d'Assise, Département de Pédiatrie, Faculté de Médecine, Université Laval, Québec, QC, Canada; jorge.soliz@crchuq.ulaval.ca.
Jorge
J
Soliz
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002245:Carbon Dioxide / Q000097:blood; D004921:Erythropoietin / Q000378:metabolism*; D006935:Hypercapnia / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011086:Polycythemia / Q000150:complications / Q000503:physiopathology*; D012123:Pulmonary Ventilation
D004921:Erythropoietin; D002245:Carbon Dioxide
CO2 chemosensitivity; brain stem; carotid body; chronic mountain sickness; erythropoietin; hypercapnia; respiration; transgenic mice