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

Introduction-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. Methods-Eight normal healthy subjects (36+/-7y; 73.8+/-9.5kg; 3 female) completed a submaximal cycling test (60W) under normoxic (FIO2: 0.21) and hypoxic (FIO2: 0.125) conditions before (Day1) and after (Day15) fourteen days of oral drug administration. While stationary on a cycle ergometer and during exercise, ratings of perceived exertion (RPE) and dyspnea, oxygen consumption (VO2) and cardiac output (Q) were measured non-invasively, while arterial blood pressure (MAP) and blood gases (SaO2, PaO2 and PaCO2) were measured invasively. Results-The 14-day drug administration left-shifted the ODC (p50 measured at standard pH and PCO2; Day1: 28.0+/-2.1mmHg vs Day15: 26.1+/-1.8mmHg, p<0.05). RPE, dyspnea, VO2, Q and MAP were not different between Day1 and Day15. SaO2 was similar during normoxia on Day1 and Day15 while stationary, but higher during exercise (Day1: 95.2+/-0.4% vs Day15: 96.6+/-0.3%, p<0.05). SaO2 was higher during hypoxia on Day15 while stationary (Day1: 82.9+/-3.4% vs Day15: 90.9+/-1.8%, p<0.05) and during exercise (Day1: 73.6+/-2.5% vs Day15: 84.8+/-2.7%, p<0.01). PaO2 and PaCO2 were systematically higher and lower, respectively, after drug (p<0.01), while the alveolar-arterial oxygen difference was unchanged suggesting hyperventilation contributed to the rise in SaO2. Conclusion-Oral administration of voxelotor left-shifted the ODC and stimulated a mild hyperventilation, leading to improved arterial oxygen saturation without altering VO2 and central hemodynamics during rest and low-intensity exercise.