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. 2021 Sep;22(3):249-262.
doi: 10.1089/ham.2020.0159. Epub 2021 Jun 21.

Impact of Pharmacologically Left Shifting the Oxygen-Hemoglobin Dissociation Curve on Arterial Blood Gases and Pulmonary Gas Exchange During Maximal Exercise in Hypoxia

Glenn M Stewart  1 , Troy J Cross  1   2 , Michael J Joyner  3 , Steven C Chase  1 , Timothy Curry  3 , Josh Lehrer-Graiwer  4 , Kobina Dufu  4 , Nicholas E Vlahakis  4 , Bruce D Johnson  1
Affiliations

Impact of Pharmacologically Left Shifting the Oxygen-Hemoglobin Dissociation Curve on Arterial Blood Gases and Pulmonary Gas Exchange During Maximal Exercise in Hypoxia

Glenn M Stewart et al. High Alt Med Biol. 2021 Sep.

Abstract

Stewart, Glenn M., Troy J. Cross, Michael J. Joyner, Steven C. Chase, Timothy Curry, Josh Lehrer-Graiwer, Kobina Dufu, Nicholas E. Vlahakis, and Bruce D. Johnson. Impact of pharmacologically left shifting the oxygen-hemoglobin dissociation curve on arterial blood gases and pulmonary gas exchange during maximal exercise in hypoxia. High Alt Med Biol. 22:249-262, 2021. Introduction: Physiological and pathological conditions, which reduce the loading of oxygen onto hemoglobin (Hb), can impair exercise capacity and cause debilitating symptoms. Accordingly, this study examined the impact of pharmacologically left shifting the oxygen-hemoglobin dissociation curve (ODC) on arterial oxygen saturation (SaO2) and exercise capacity. Methods: Eight healthy subjects completed a maximal incremental exercise test in hypoxia (FIO2: 0.125) and normoxia (FIO2: 0.21) before (Day 1) and after (Day 15) daily ingestion of 900 mg of voxelotor (an oxygen/Hb affinity modulator). Pulmonary gas exchange and arterial blood gases were assessed throughout exercise and at peak. Data for a 1,500 mg daily drug dose are reported in a limited cohort (n = 3). Results: Fourteen days of drug administration left shifted the ODC (p50 measured under standard conditions, Day 1: 28.0 ± 2.1 mmHg vs. Day 15: 26.1 ± 1.8 mmHg, p < 0.05). Throughout incremental exercise in hypoxia, SaO2 was systematically higher after drug (peak exercise SaO2 on Day 1: 71 ± 2 vs. Day 15: 81% ± 2%, p < 0.001), whereas oxygen extraction (Ca-vO2 diff) and consumption (VO2) were similar (peak exercise Ca-vO2 diff on Day 1: 11.5 ± 1.7 vs. Day 15: 11.0 ± 1.8 ml/100 ml blood, p = 0.417; peak VO2 on Day 1: 2.59 ± 0.39 vs. Day 15: 2.47 ± 0.43 l/min, p = 0.127). Throughout incremental exercise in normoxia, SaO2 was systematically higher after drug, whereas peak VO2 was reduced (peak exercise SaO2 on Day 1: 93.9 ± 1.8 vs. Day 15: 95.8% ± 1.0%, p = 0.008; peak VO2 on Day 1: 3.62 ± 0.55 vs. Day 15: 3.26 ± 52 l/min, p = 0.001). Conclusion: Pharmacologically increasing the affinity of Hb for oxygen improved SaO2 during hypoxia without impacting exercise capacity; however, left shifting the ODC in healthy individuals appears detrimental to exercise capacity in normoxia. Left shifting the ODC to different magnitudes and under more chronic forms of hypoxia warrants further study.

Keywords: GBT440; hematology; hypoxia; maximal oxygen uptake; oxygen affinity of hemoglobin; voxelotor.

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Conflict of interest statement

The study was funded by Global Blood Therapeutics, and authors J.L.-G., K.D., and N.E.V. are employees of Global Blood Therapeutics.

Figures

FIG. 1.
FIG. 1.
Schematic of the study design and experimental procedures.
FIG. 2.
FIG. 2.
Oxygen uptake (A), carbon dioxide production (B), peripheral oxygen saturation (SpO2, C), and regional tissue saturation at the site of the vastus lateralis (r-SO2, D) measured during the normoxic (FIO2 = 0.21, circles) and hypoxic (FIO2 = 0.125, triangles) maximal exercise tests before (Day 1, black symbols) and after (Day 15, gray symbols) 14 days of 900 mg daily oral voxelotor administration. *Significantly different to Day 1.
FIG. 3.
FIG. 3.
Measures of arterial oxygen saturation (SaO2, A) and content (CaO2, B), arterial partial pressure of oxygen (PaO2, C) and carbon dioxide (PaCO2, D), and calculated venous oxygen content (CvO2, E) and arterial/venous oxygen difference (a-vO2 diff, F) during maximal hypoxic (FIO2 = 0.125) exercise before (Day 1, black triangles) and after (Day 15, gray triangles) 14 days of 900 mg daily oral voxelotor administration. *Significantly different to Day 1.
FIG. 4.
FIG. 4.
Measures of arterial oxygen saturation (SaO2, A) and content (CaO2, B), arterial partial pressure of oxygen (PaO2, C) and carbon dioxide (PaCO2, D), and calculated venous oxygen content (CvO2, E), and arterial/venous oxygen difference (a-vO2 diff, F) during maximal normoxic (FIO2 = 0.21) exercise before (Day 1, black circles) and after (Day 15, gray circles) 14 days of 900 mg daily oral voxelotor administration. *Significantly different to Day 1.
FIG. 5.
FIG. 5.
Data comparing the change in arterial blood gas and oxygen transport variables at a similar submaximal exercise workload (97 ± 2 W) and at peak exercise from before (Day 1) to after (Day 15) 14 days of daily oral voxelotor administration at either 900 mg (low dose, n = 8) or 1,500 mg (high dose, n = 3).
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