GBT1118, a potent allosteric modifier of hemoglobin O2 affinity, increases tolerance to severe hypoxia in mice

American Journal of Physiology. Heart and Circulatory Physiology
Kobina DufuPedro Cabrales

Abstract

Adaptation to hypoxia requires compensatory mechanisms that affect O2 transport and utilization. Decreased hemoglobin (Hb) O2 affinity is considered part of the physiological adaptive process to chronic hypoxia. However, this study explores the hypothesis that increased Hb O2 affinity can complement acute physiological responses to hypoxia by increasing O2 uptake and delivery compared with normal Hb O2 affinity during acute severe hypoxia. To test this hypothesis, Hb O2 affinity in mice was increased by oral administration of 2-hydroxy-6-{[(2S)-1-(pyridine-3-carbonyl)piperidin-2yl] methoxy}benzaldehyde (GBT1118; 70 or 140 mg/kg). Systemic and microcirculatory hemodynamics and oxygenation parameters were studied during hypoxia in awake-instrumented mice. GBT1118 increased Hb O2 affinity and decreased the Po2 at which 50% of Hb is saturated with O2 (P50) from 43 ± 1.1 to 18.3 ± 0.9 mmHg (70 mg/kg) and 7.7 ± 0.2 mmHg (140 mg/kg). In a dose-dependent fashion, GBT1118 increased arterial O2 saturation by 16% (70 mg/kg) and 40% (140 mg/kg) relative to the control group during 5% O2 hypoxia. In addition, a GBT1118-induced increase in Hb O2 affinity reduced hypoxia-induced hypotension compared with the control group. Moreover, microvasc...Continue Reading

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Citations

May 29, 2020·Artificial Cells, Nanomedicine, and Biotechnology·Zongtang ChuHong Zhou
Jul 22, 2018·American Journal of Physiology. Heart and Circulatory Physiology·Merry L LindseyDouglas Curran-Everett
Oct 11, 2020·Scientific Reports·Björn BalcerekMichael Fähling
Apr 3, 2021·Therapeutic Advances in Hematology·Alexander K GlarosAhmar U Zaidi
Jul 3, 2021·American Journal of Physiology. Heart and Circulatory Physiology·Kobina DufuPedro Cabrales

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Methods Mentioned

BETA
phosphorescence

Software Mentioned

HEMOX analyzer
GraphPad
Wasabi
Prism
Phoenix WinNonlin

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