Plasma-volume contraction and exercise-induced hypoxaemia modulate erythropoietin production in healthy humans

Abstract

This study examined exercise-induced hypoxaemia (EIH) and plasma volume contraction as modulators of serum erythropoietin (Epo) production. Five athletes cycled for 3 min at supra-maximal power outputs, at each of two different elevations (1,000 m and 2,100 m). Five subjects were exposed to normobaric hypoxia (F(I)O(2)=0.159), seven subjects underwent plasmapheresis to reduce plasma volume and eight subjects were time controls for Epo levels. Oxyhaemoglobin saturation was significantly reduced during exercise and during normobaric hypoxia. The time period of haemoglobin oxygen saturation <91% was 24+/-29 s (mean+/-S.D., n=5) for exercise at 1000 m, 136+/-77 s (mean+/-S.D., n=5) for exercise at 2100 m and 178+/-255 s (mean+/-S.D., n=5) with resting hypoxic exposure. However, significantly increased serum Epo levels were observed only following exercise (24+/-3%; mean+/-S.D., n=5 at 1,000 m and 36+/-5%; mean+/-S.D., n=5 at 2,100 m). Volume contraction also resulted in increased serum Epo (35+/-6%; mean+/-S.D., n=7) in spite of a significant rise in haematocrit of 2.2%. Despite similar degrees of arterial desaturation, only the hypoxaemia induced by exercise was associated with an increase in serum Epo. This finding indicates that other factors, in addition to hypoxaemia, are important in modulating the production of Epo in response to exercise. Volume depletion in the absence of exercise resulted in increases in Epo levels that were comparable with those observed in response to exercise. The paradoxical responses of the increased haematocrit and the increase in Epo in subjects undergoing plasmapheresis suggests that plasma volume may also modulate the production of Epo.

AMP‐activated protein kinase mediates erythropoietin‐induced activation of endothelial nitric oxide synthase

“…Our results showed that the serum level of EPO in mice was still high after 4 weeks of exercise training. However, this result is inconsistent with the previous findings by Roberts et al (2000) that the elevation of plasma EPO by exercise-induced hypoxemia declined to the basal level within 72 h in human. Similarly, high altitude hypoxia-increased plasma EPO was returned to basal level within one week even under hypoxia-persisting situation.…”

Long‐term intermittent hyperoxic exposures do not enhance erythropoiesis

“…Contrary to the NBO 2 group, [EPO] increased significantly in the AIR group during the mid-and post-periods. This increment was unexpected, because the AIR group breathed normoxic air during all the sessions; none of the participants performed any strenuous activity a day before the blood tests nor did they change their normal daily routines throughout the 2-week period [23], as evident from their individual activity diaries, which they maintained during this period. Present results do not allow us to discern which mechanisms might underlie this enhancement of [EPO].…”

Age‐dependent impairment of the erythropoietin response to reduced central venous pressure in HFpEF patients

“…In contrast, HUT did not alter circulating EPO in HFpEF patients and EC, differing from the rise in EPO observed in YC. Whilst speculative, the age-related impairment of the hemodynamic regulation of EPO could contribute to the prevalent RBCV deficit in the HFpEF population , given that the prominent stimulus for EPO synthesis, that is, the hypoxic drive, effectively operates at very low hematocrit levels (Kurtz and Eckardt 1990;Le Hir et al 1991;Roberts et al 2000;Wenger and Kurtz 2011). In fact, provided that pulmonary gas exchange is not impaired, EPO production cannot be spurred by hypoxia-dependent mechanisms unless RBCV and hemoglobin mass are markedly reduced, particularly when arterial oxygen content is preserved due to a concomitant reduction of PV as observed in heart failure patients long-term treated with loop diuretics (Anand et al 1989;Feigenbaum et al 2000;Bonfils et al 2010), a common prescription in our study population .…”

“…These hormones control the two major constituents of BV, that is, plasma volume (PV) and red blood cell volume (RBCV) (Montero et al 2016a). A reduction in CVP induced by either moderate blood loss or head-up tilt (HUT) activates the renin-angiotensin-aldosterone system (RAAS) and enhances the production of vasopressin and erythropoietin (EPO) (Ehmke et al 1995;Roberts et al 2000;Montero et al 2016a), the principal hormones regulating fluid homeostasis and erythropoiesis, respectively. On the other hand, infusion of BV expanders or sustained head-down tilt leading to increased CVP prompts the release of natriuretic peptides by atrial cells in parallel to decreasing circulating EPO levels (Gunga et al 1996;Breymann et al 2000) eventually resulting in substantial reductions in PV and RBCV (Fortney et al 1994).…”