Abstract 10826: GBT1118, a Potent Allosteric Modifier of Hemoglobin Oxygen Affinity Increases Tolerance to Hypoxia in Mice
Introduction: Adaptation to hypoxia involves several mechanisms that influence oxygen (O2) transport and utilization, including a reduction in hemoglobin (Hb) O2 affinity to favor the release of O2 to tissues. Paradoxically, increased Hb O2 affinity has been observed to have beneficial effects during severe hypoxia. Hypothesis: This study was designed to test the hypothesis that pharmacologically increasing Hb O2 affinity with GBT1118 can augment O2 transport during severe hypoxia (10 and 5% O2). Method: Mice were orally dosed with GBT1118 (70 or 140 mg/kg) or only vehicle (Control), and Hb O2 affinity was determined by hemoximetry. During hypoxia, changes in systemic and microvascular hemodynamics, tissue partial pressure of O2 (PO2) and tissue hypoxia were evaluated. At each timepoint, mice with adequate systolic blood pressure (BP) were counted as survived and mice with severe hypotension (BP ≤60 mmHg) were counted as non-survived and were euthanized.
Results: Similar trends were observed at 10 and 5% O2 hypoxia. GBT1118 at 70 and 140 mg/kg decreased the P50 (PO2 at which blood is 50% saturated with O2) by 29 and 35 mmHg, respectively. During 5% O2 hypoxia, GBT1118 at 70 and 140 mg/kg increased SaO2 from 40% (Control) to 57% (70mg/kg) and 80% (140mg/kg), respectively. Moreover, mean BP and heart rate (HR) decreased to 50 mmHg and 375 bpm in control mice, whereas GBT1118-dosed mice sustained higher mean BP and HR in a dose-dependent fashion and improved survival (Figure 1). In addition, GBT1118 preserved microvascular blood flow and tissue oxygenation; consequently, GBT1118 reduced heart and brain hypoxic areas compared with control groups during hypoxia.
Conclusion: Under severe hypoxia, GBT1118-mediated increase in Hb O2 affinity increases SaO2. At the tissue level, local milieu allows for efficient O2 extraction leading to improved oxygenation as measured by decreased lactic acidosis, improved cardiovascular function and ultimately, survival.
Author Disclosures: P. Cabrales: Other Research Support; Significant; Global Blood Therapeutics. K. Dufu: Employment; Significant; Global Blood Therapeutics. A. Hutchaleelala: Employment; Significant; Global Blood Therapeutics. Q. Xu: Employment; Significant; Global Blood Therapeutics. J. Lehrer-Graiwer: Employment; Significant; Global Blood Therapeutics. U. Sinha: Employment; Significant; Global Blood Therapeutics.
- © 2015 by American Heart Association, Inc.