Polycythemia and high levels of erythropoietin in blood and brain blunt the hypercapnic ventilatory response in adult mice

Abstract

Changes in arterial Po2, Pco2, and pH are the strongest stimuli sensed by peripheral and central chemoreceptors to adjust ventilation to the metabolic demand. Erythropoietin (Epo), the main regulator of red blood cell production, increases the hypoxic ventilatory response, an effect attributed to the presence of Epo receptors in both carotid bodies and key brainstem structures involved in integration of peripheral inputs and control of breathing. However, it is not known whether Epo also has an effect on the hypercapnic chemoreflex. In a first attempt to answer this question, we tested the hypothesis that Epo alters the ventilatory response to increased CO2 levels. Basal ventilation and hypercapnic ventilatory response (HCVR) were recorded from control mice and from two transgenic mouse lines constitutively expressing high levels of human Epo in brain only (Tg21) or in brain and plasma (Tg6), the latter leading to polycythemia. To tease apart the potential effects of polycythemia and levels of plasma Epo in the HCVR, control animals were injected with an Epo analog (Aranesp), and Tg6 mice were treated with the hemolytic agent phenylhydrazine after splenectomy. Ventilatory parameters measured by plethysmography in conscious mice were consistent with data from electrophysiological recordings in anesthetized animals and revealed a blunted HCVR in Tg6 mice. Polycythemia alone and increased levels of plasma Epo blunt the HCVR. In addition, Tg21 mice with an augmented level of cerebral Epo also had a decreased HCVR. We discuss the potential implications of these findings in several physiopathological conditions.

Hypercapnic ventilatory response is decreased in a mouse model of excessive erythrocytosis

“…Tg21 mice compared with corresponding control animals showed similar HcVR, metabolism, and ventilatory equivalent ratio to O 2 and CO 2 (V E/V O 2 and V E/V CO 2 ). Contrary to these results, the previous study in which HcVR was evaluated in transgenic mice reported a decreased HcVR in Tg21 mice (29). However, the published data show large variability and a P value in the limit to allow the data to be considered as significantly different (P ϭ 0.043).…”

“…By performing an intracisternal injection (cisterna magna) of the endogenous antagonist of Epo (the sEpoR), we showed that cerebral Epo does not affect the central CO 2 chemosensitivity of C57BL6 mice (2). However, a recent study in which Tg6 and Tg21 mice were used suggests that Epo decreases the HcVR, maybe by interacting with the central and peripheral chemoreceptors (29). To solve this divergence, here we reevaluate the HcVR in Tg6 and Tg21 animal strains by additionally measuring the metabolism (V O 2 and V CO 2 ).…”

“…On the other hand, by blocking the Epo's activity in the brain stem of adult C57Bl6 mice by intracisternal injections of the soluble Epo receptor (sEpoR), we reported that Epo reduced the basal minute ventilation by~25%, but did not affect the central chemosensitivity (2). In contrast, a recent study using transgenic mice (Tg6: Epo overexpression in brain and circulation; Tg21: Epo overexpression in brain) suggested that Epo, presumably by interacting with central and peripheral respiratory chemocenters, blunts the HcVR (29). As such, the relevant question whether Epo decreases (or not) the CO 2 chemosensitivity is debated.…”

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

“…Ventilation of conscious animals was recorded using noninvasive whole-body barometric plethysmography (EMKA Technologies, Paris, France), as previously described (Menuet et al, 2016). Two days before recordings, the mice were habituated to the plethysmograph chamber to reduce stress.…”

“…Therefore, chronic rhEPO therapy was suggested as a reliable approach for treating respiratory disorders (Caravagna et al, 2015;Soliz, 2013). However, we have recently shown that polycythemia alone or increased rhEPO levels in plasma and brain blunts the hypercapnic ventilatory response (Menuet et al, 2016). This potentially deleterious effect on breathing may represent another limitation for prescription of chronic rhEPO treatment in patients.…”