Effects of an allosteric hemoglobin affinity modulator on arterial blood gases and cardiopulmonary responses during normoxic and hypoxic low-intensity exercise

Stewart, Glenn M.; Chase, Steven C.; Cross, Troy J.; Wheatley‐Guy, Courtney M.; Joyner, Michael J.; Curry, Timothy B.; Lehrer-Graiwer, Josh; Dufu, Kobina; Vlahakis, Nicholas E.; Johnson, Bruce D.

doi:10.1152/japplphysiol.00185.2019

Cited by 11 publications

(11 citation statements)

References 40 publications

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“…This substance binds to 1α valine of the hemoglobin molecule and increases oxygen affinity. A similar effect is caused by Voxelotor ( 66 ). Whether this additional left shift of the ODC is useful, may be questioned.…”

Section: Therapy Of Anemia and Oxygen Affinity Disturbancesmentioning

confidence: 60%

The oxygen dissociation curve of blood in COVID-19

Böning

Kuebler

Bloch

2021

American Journal of Physiology-Lung Cellular and Molecular Phys

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COVID-19 hinders oxygen transport to the consuming tissues by at least 2 mechanisms: In the injured lung saturation of hemoglobin is compromised, in the tissues an associated anemia reduces the volume of delivered oxygen. For the first problem increased hemoglobin oxygen affinity (left shift of the oxygen dissociation curve ODC) is of advantage, for the 2nd, however, the contrary is the case. Indeed a right shift of the ODC has been found in former studies for anemia caused by reduced cell production or hemolysis. This resulted from increased 2,3-biphosphglycerate (2,3-BPG) concentration. In 3 investigations in COVID-19, however, no change of hemoglobin affinity was detected in spite of probably high [2,3-BPG]. The most plausible cause for this finding is formation of methemoglobin, which increases the oxygen affinity and thus apparently compensates for the 2,3-BPG effect. But this "useful effect" is cancelled by the concomitant reduction of functional hemoglobin. In the largest study on COVID-19 even a clear left shift of the ODC was detected when calculated from measurements in fresh blood rather than after equilibration with gases outside the body. This additional „in vivo" left shift possibly results from various factors (e. g. concentration changes of Cl-, 2,3-BPG, ATP, lactate, nitrocompounds, glutathione, glutamate, because of time delay between blood sampling and end of equilibration, or enlarged distribution space including interstitial fluid and is useful for O2 uptake in the lungs. Under discussion for therapy are the affinity-increasing 5-hydroxymethyl-2-furfural (5-HMF), erythropoiesis stimulating substances like erythropoietin, and methylene blue against MetHb formation.

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Section: Therapy Of Anemia and Oxygen Affinity Disturbancesmentioning

confidence: 60%

The oxygen dissociation curve of blood in COVID-19

Böning

Kuebler

Bloch

2021

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In general, allosteric modifiers allow for the manipulation of Hb-O 2 affinity with less perturbations in acid-base balance associated with 2,3-DPG depletion techniques. However, in healthy humans voxelotor induces only a modest decrease in P 50 of ∼2 mmHg (Stewart et al, 2020(Stewart et al, , 2021 compared to the greater range from 3 to 10 mmHg obtained via 2,3-DPG depletion (Gillette et al, 1974;Wranne et al, 1974). The ability to pharmacologically alter Hb-O 2 affinity in humans both acutely and chronically may provide additional insights on the context-dependent circumstances at which high Hb-O 2 affinity is advantageous (i.e., magnitude and duration of hypoxia).…”

Section: Pharmacological Induction Of High Hemoglobin-oxygen Affinitymentioning

confidence: 98%

“…However, methods used to achieve 2,3-DPG depletion often alter acidbase balance and total blood volume, potentially confounding the observed cardiorespiratory adjustments (Birchard and Tenney, 1991). More recent developments of pharmaceuticals that induce high Hb-O 2 affinity allow examination of altered Hb-O 2 affinity with fewer complications (Dufu et al, 2017;Kalfa et al, 2019;Stewart et al, 2020Stewart et al, , 2021. For example, voxelotor binds allosterically to some, but not all hemoglobin and increases Hb-O 2 affinity.…”

Section: Pharmacological Induction Of High Hemoglobin-oxygen Affinitymentioning

confidence: 99%

“…Studies examining the effects of pharmacologically induced high Hb-O 2 affinity on O 2 consumption during normoxia have provided discordant results in both humans and animals (Riggs et al, 1973;Woodson et al, 1973;Wranne et al, 1974;Valeri et al, 1975;Yhap et al, 1975;Bakker et al, 1976;Malmberg et al, 1979;Ross and Hlastala, 1981;Woodson and Auerbach, 1982;Stewart et al, 2020Stewart et al, , 2021. Recently, Stewart et al (2021) showed that pharmaceutical induction of high Hb-O 2 affinity (only ∼2 mmHg decrease in P 50 ) using voxelotor reduced normoxic maximal O 2 consumption ( VO 2max ) in humans.…”

Section: High Hemoglobin-oxygen Affinity and Cardiorespiratory Adjust...mentioning

confidence: 99%

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Influence of High Hemoglobin-Oxygen Affinity on Humans During Hypoxia

et al. 2022

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Humans elicit a robust series of physiological responses to maintain adequate oxygen delivery during hypoxia, including a transient reduction in hemoglobin-oxygen (Hb-O2) affinity. However, high Hb-O2 affinity has been identified as a beneficial adaptation in several species that have been exposed to high altitude for generations. The observed differences in Hb-O2 affinity between humans and species adapted to high altitude pose a central question: is higher or lower Hb-O2 affinity in humans more advantageous when O2 availability is limited? Humans with genetic mutations in hemoglobin structure resulting in high Hb-O2 affinity have shown attenuated cardiorespiratory adjustments during hypoxia both at rest and during exercise, providing unique insight into this central question. Therefore, the purpose of this review is to examine the influence of high Hb-O2 affinity during hypoxia through comparison of cardiovascular and respiratory adjustments elicited by humans with high Hb-O2 affinity compared to those with normal Hb-O2 affinity.

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“…Arterial O 2 saturation increased, perhaps as a result of hyperventilation, but there was little effect on cardiopulmonary responses during normoxic and hypoxic low-intensity exercise. 28 Clinical trial results of voxelotor do not yet confirm the theoretical adverse effects of increasing hemoglobin-O2 affinity (summarized by Howard et al 27 ).…”

Section: Insights From P 0 -Lowering Therapeuticsmentioning

confidence: 99%

Fetal hemoglobin in β hemoglobinopathies: Is enough too much?

Steinberg

2022

American J Hematol

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Cell-based therapies inducing about 40% fetal hemoglobin (HbF), or a HbF-like hemoglobin in most erythrocytes, can-at least in the shortterm-effect a cure or near-cure of β hemoglobinopathies, which are humankind's most common Mendelian diseases. [1][2][3] In sickle cell disease, a point mutation in the normal β-globin gene (HBB) directs the synthesis of sickle hemoglobin (HbS), which polymerizes on deoxygenation, damaging the red cell and triggering a complex pathophysiology. HbF exerts a powerful anti-polymerization effect because the chances of both the HbF tetramer (α 2 γ 2 ) and the hybrid tetramer α 2 γβ S entering the polymer phase are nearly nil. 4 Hundreds of different HBB mutations cause β thalassemia where insufficient β-globin synthesis allows free unpaired α globin to accumulate, leading to ineffective erythropoiesis and severe anemia. γ-Globin pairs with α globin forming HbF and preventing, at its earliest stage, the pathophysiology of the β thalassemia phenotype.

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Effects of an allosteric hemoglobin affinity modulator on arterial blood gases and cardiopulmonary responses during normoxic and hypoxic low-intensity exercise

Cited by 11 publications

References 40 publications

The oxygen dissociation curve of blood in COVID-19

The oxygen dissociation curve of blood in COVID-19

Influence of High Hemoglobin-Oxygen Affinity on Humans During Hypoxia

Fetal hemoglobin in β hemoglobinopathies: Is enough too much?

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