Role of haemoglobin oxygen affinity for oxygen uptake during exercise

The paper by Dominelli et al. (2020) is a very interesting publication and we follow Jerome Dempsey’s suggestion (Dempsey, 2020) to discuss it. The role of haemoglobin oxygen affinity for oxygen uptake during exercise in normoxia and hypoxia has been investigated and discussed for decades. The importance of the article is to show that a left shift of the oxygen dissociation curve (ODC) of high affinity haemoglobins (HAH) may be beneficial during exercise at moderate altitude (3000 m) not only in animals but also in humans, thus confirming the case report in siblings by Hebbel et al. (1978). Moreover, the surprisingly high arterial oxygen saturation in many Ethiopians (Beall et al. 2002) suggests that high affinity may also be caused by still-unknown effects, because a large number of modified Hb molecules are not known in this population (Cheong et al. 2017). These observations are in contrast to the right shift of the (in vitro! ) standard ODC by upregulation of 2,3-biphosphoglycerate concentration usually observed in moderate hypoxia. However, at extreme altitude (above 5000 m) strong hyperventilation overruns this effect, thus hindering too large a decrease of arterial saturation (Samaja et al. 2003; West et al. 2013). A specially important point is not mentioned in the paper discussed here. Oxygen delivery to the tissues is influenced by not only the position of the ODC, measured as half-saturation pressure P50, but also its shape. According to Berglund (1972) and Boyer et al. (1972) Hill’s n, i.e. the slope of the ODC in a logarithmic presentation, of the high affinity Hb Malmö is much smaller (1.50–1.58) than that of normal Hb (2.86). The stabilizing effect of the marked S-form of the normal dissociation curve on PO2 at low saturation is markedly reduced and therefore the high Hb concentration is especially necessary for a sufficiently high PO2 in the tissue capillaries. What about Hill’s n in Dominelli‘s experiments? Was it normal? This essential aspect is not considered. Interestingly, n is increased in South American highlanders (Schmidt et al. 1990), pointing to an important role of this adaptation. Measurements of the ODC have been mostly performed in vitro; this is also the case in the paper discussed here. The conditions during measurement in the Hemox-Analyzer used by Dominelli et al. are, however, even more artificial: a small volume of red cells is dispersed in a high volume of buffer solution and CO2 is absent. In any case the in vivo curve is steeper because of the lower pH (Bohr effect) and higher temperature in the tissue vessels, especially during exercise. Additionally, the Bohr effect determined in vivo is bigger than in vitro (Braumann et al. 1982), which can be partly explained as follows. The Bohr effect induced by CO2 at low saturation (the condition in tissue capillaries) is larger than for lactic acid (Meier et al. 1974). Lactic acid, however, enters the erythrocytes only slowly. But it liberates CO2 from bicarbonate in the plasma. CO2 diffuses rapidly into the red cells, therefore the in vivo Bohr effect is mainly caused by CO2 (Böning et al. 1991, 2007). Under strenuous exercise conditions, CO2 therefore accumulates in the muscle capillaries and PCO2 may exceed 80 mmHg (Stringer et al. 1994). Due to this quasi-closed system, the Bohr effect strongly modulates the in vivo ODC and must therefore be considered particularly under exercise conditions. Furthermore, various papers published since the 1970s (reviewed in Böning et al. 2014) suggest that unknown factors make the in vivo curve even steeper than expected. Possible causes are concentration changes of chloride, glutathione or glutamate in the erythrocytes. In addition, we have some comments on the conditions in the experiments.