Increased hemoglobin affinity for oxygen with gbt1118 improves hypoxia tolerance in sickle cell mice

In this study, GBT1118, an analog of voxelotor, was used to assess the impact of increasing Hb affinity for O2 on brain tissue oxygenation, blood pressure, heart rate, O2 delivery, and tolerance to hypoxia in Townes transgenic SCD mice. Brain oxygenation and O2 delivery were studied during normoxia and severe hypoxic challenges. GBT1118's pharmacokinetics in SCD mice allowed it to achieve the degree of Hb modification that voxelotor targets clinically. Chronic treatment with GBT1118 increased Hb affinity for O2, reducing the PO2 for 50% Hb O2 saturation (P50) in SCD mice from 31 mmHg to 18 mmHg. Chronic treatment with GBT1118 significantly improved hematological, hemodynamic, and oxygenation parameters during hypoxia, preserved cortical oxygenation during normoxia and improved cortical oxygenation during hypoxia, and increased tolerance to severe hypoxia. Independent of hematological changes induced by chronic treatment, a single dose of GBT1118 significantly improved tolerance to hypoxia, highlighting the benefits of increasing Hb affinity for O2 in preventing the complete deoxygenation of blood and consequent RBC sickling during hypoxia in SCD.PMID:34213392 | DOI:10.1152/ajpheart.00048.2021
Source: American Journal of Physiology. Heart and Circulatory Physiology - Category: Physiology Authors: Source Type: research