Effect of GBT440 on oxygen-carrying characteristics and its anti-hypoxia effect in hypoxia animal model

Objective To study the effect of hemoglobin allosteric agent Voxelotor(GBT440) on oxygen-carrying characteristics of blood and its anti-hypoxia effect. Methods Whole arterial blood of mice were incubated with different concentrations of GBT440 at 37 ℃ for 1 h, then hemoglobin oxygen dissociation curves(ODCs) were detected by Hemox Analyzer and the P50 was calculated. After the pH value of blood samples changed by adding acid and alkali, the changes of ODCs were detected. SD rats were randomly divided into normoxia control group, normoxia treatment group, hypoxia control group and hypoxia treatment group(n=6). The rats in the control group and the treatment group were given 0 and 100 mg/kg GBT440 respectively by gavage. In 1 h later, the normoxia group and the hypoxia group were respectively placed in closed chambers containing 21% O2 and 10%O2, and their abdominal aortic blood samples were collected for blood-gas test in another 6 h. The male C57 mice were divided into groups and treated as above. The hypoxyprobe was injected intraperitoneally at 1.5 h before the sampling, and the hypoxia level of the liver, kidney and brain tissues of the mice were detected by immunohistochemistry. Results With the increase concentrations of GBT440, ODCs were shifted to the left in a dose-dependent manner and P50 were significantly decreased(P < 0.05). In the present of GBT440, adding acid induced ODCs right-shift, while adding alkali resulted in it left-shift. In the absence of GBT440, p(O2) and SpO2 in the hypoxic group were significantly reduced when compared with the normal group(P < 0.05), and the hypoxic conditions in the liver, kidney and brain tissues were significantly severer. In the presence of GBT440, these indicators were improved in the hypoxia+GBT440 group than the hypoxia group, p(O2) was increased by 21.35% and SpO2 by 8.14%(P < 0.05), and the hypoxic conditions in above organs were obviously ameliorated. Conclusion GBT440 can improve the oxygen carrying capacity of blood and the hypoxic conditions in tissues, and is expected to be an effective anti-hypoxia drug.