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

• Published in: Journal of applied physiology (1985) 2020-06, Vol.128 (6), p.1467-1476
• Main Authors: Stewart, Glenn M, Chase, Steven, Cross, Troy J, Wheatley-Guy, Courtney M, Joyner, Michael J, Curry, Timothy, Lehrer-Graiwer, Josh, Dufu, Kobina, Vlahakis, Nicholas E, Johnson, Bruce D
• Format: Article
• Language: English
• Subjects: Adult; Affinity; Allosteric properties; Alveoli; Blood pressure; Carbon dioxide; Cardiac output; Desaturation; Dyspnea; Exercise; Female; Gases; Hemodynamics; Hemoglobin; Hemoglobins; Humans; Hyperventilation; Hypoxemia; Hypoxia; Male; Oral administration; Oxygen; Oxygen Consumption; Oxygen content; Oxygen saturation; Partial pressure; Preservation; Pulmonary Gas Exchange; Respiration; Respiratory therapy
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/JAPPLPHYSIOL.00185.2019

Numerous pathophysiological conditions induce hypoxemia-related cardiopulmonary perturbations, decrements in exercise capacity, and debilitating symptoms. Accordingly, this study investigated the efficacy of an allosteric hemoglobin modulator (voxelotor) to enhance arterial oxygen saturation during low-intensity exercise in hypoxia. Eight normal healthy subjects (36 ± 7 yr; 73.8 ± 9.5 kg; 3 women) completed a submaximal cycling test (60 W) under normoxic ([Formula: see text]: 0.21; O partial pressure: 144 mmHg) and hypoxic ([Formula: see text]: 0.125; O partial pressure: 82 mmHg) conditions before ( ) and after ( ) 14 days of oral drug administration. While stationary on a cycle ergometer and during exercise, ratings of perceived exertion (RPE) and dyspnea, oxygen consumption (V̇o ), and cardiac output (Q) were measured noninvasively, while arterial blood pressure (MAP) and blood gases ([Formula: see text], [Formula: see text], and [Formula: see text]) were measured invasively. The 14-day drug administration left shifted the oxygen-hemoglobin dissociation curve (ODC; p50 measured at standard pH and Pco ; : 28.0 ± 2.1 mmHg vs. : 26.1 ± 1.8 mmHg, < 0.05). RPE, dyspnea, V̇o , Q, and MAP were not different between and . [Formula: see text] was similar during normoxia on and while stationary but higher during exercise ( : 95.2 ± 0.4% vs. : 96.6 ± 0.3%, < 0.05). [Formula: see text] was higher during hypoxia on while stationary ( : 82.9 ± 3.4% vs. : 90.9 ± 1.8%, < 0.05) and during exercise ( : 73.6 ± 2.5% vs. : 84.8 ± 2.7%, < 0.01). [Formula: see text] and [Formula: see text]were systematically higher and lower, respectively, after drug ( < 0.01), while the alveolar-arterial oxygen difference was unchanged suggesting hyperventilation contributed to the rise in [Formula: see text]. Oral administration of voxelotor left shifted the ODC and stimulated a mild hyperventilation, leading to improved arterial oxygen saturation without altering V̇o and central hemodynamics during rest and low-intensity exercise. This effect was more pronounced during submaximal hypoxic exercise, when arterial desaturation was more evident. Additional studies are needed to determine the effects of voxelotor during maximal exercise and under chronic forms of hypoxia. In humans, a novel allosteric hemoglobin-oxygen affinity modulator was administered to comprehensively examine the cardiopulmonary consequences of stabilizing a portion of the available hemoglobin in a high-oxygen affinity stat