Efaproxiral

The oxygen demands of the human body require the constant circulation of blood carrying an enormous concentration of hemoglobin (Hb). Oxygen transport depends not only on the amount of Hb, but also on the control over the affinity of the protein for the gas, which can be optimized for the environmental conditions by changes in the concentration of effectors (hydrogen ions, chloride, CO2, and DPG) inside the red cell. Some pathological conditions affecting Hb may benefit from pharmacological interventions to increase or decrease its affinity for oxygen, or otherwise modify its properties, or alter its biosynthesis. Examples of such conditions include sickle cell anemia, thalassemias and inherited hemoglobinopathies. Effective and safe drugs such as voxelotor, bezafibrate and efaproxiral are available that significantly increase or decrease Hb oxygen affinity. Some medical conditions not directly affecting the blood or its oxygen carrying capacity may also be relieved by the manipulation of Hb. For example, the standard treatment of acute cyanide poisoning requires the oxidation of a fraction of the Hb in the bloodstream so that it efficiently scavenges cyanide. Tumors are often extremely hypoxic and therefore strongly resistant to radiotherapy; the sensitivity of cancerous tissue to X-rays may be increased by improved oxygenation through drugs binding Hb. This review attempts to provide a systematic exploration of the pharmacology of Hb, its molecular basis, and its intended and possible uses.

Physiological systems often have emergent properties but the effects of genetic variation on physiology are often unknown, which presents a major challenge to understanding the mechanisms of phenotypic evolution. We investigated whether genetic variants in haemoglobin (Hb) that contribute to high-altitude adaptation in deer mice (Peromyscus maniculatus) are associated with evolved changes in the control of breathing. We created F2 inter-population hybrids of highland and lowland deer mice to test for phenotypic associations of α- and β-globin variants on a mixed genetic background. Hb genotype had expected effects on Hb–O2 affinity that were associated with differences in arterial O2 saturation in hypoxia. However, high-altitude genotypes were also associated with breathing phenotypes that should contribute to enhancing O2 uptake in hypoxia. Mice with highland α-globin exhibited a more effective breathing pattern, with highland homozygotes breathing deeper but less frequently across a range of inspired O2, and this difference was comparable to the evolved changes in breathing pattern in deer mouse populations native to high altitude. The ventilatory response to hypoxia was augmented in mice that were homozygous for highland β-globin. The association of globin variants with variation in breathing phenotypes could not be recapitulated by acute manipulation of Hb–O2 affinity, because treatment with efaproxiral (a synthetic drug that acutely reduces Hb–O2 affinity) had no effect on breathing in normoxia or hypoxia. Therefore, adaptive variation in Hb may have unexpected effects on physiology in addition to the canonical function of this protein in circulatory O2 transport.