Obtaining enough O₂ is a special challenge in some circumstances. How does a mammalian fetus in its mother’s uterus take up O₂ from its mother’s blood? How do animals that live at high altitude obtain O₂ under conditions of low pO₂? In each case, the species adapts by evolving forms of hemoglobin with higher binding affinity.

In mammals, the mother’s respiratory and cardiovascular systems must provide the fetus with O₂ and remove CO₂, as well as supply nutrients and remove waste. Maternal and fetal blood do not mix. Rather, they exchange gases across the placenta. Yet the O₂ concentration gradient at this exchange point does not strongly favor the movement of O₂ from the mother’s blood to the fetal blood. Fetal mammals solve the problem of extracting O₂ from their mother’s hemoglobin by producing a form of hemoglobin before birth that has a higher affinity for O₂ than their mother’s hemoglobin. The O₂ dissociation curve for fetal hemoglobin is shifted to the left of the curve for maternal hemoglobin (Fig. 39.15a), allowing the fetal hemoglobin to extract O₂ from its mother’s circulation. At birth, when the newborn begins to breathe, its red blood cells rapidly shift to producing the adult form of hemoglobin, maintaining this form throughout life.

Many animals live at high altitude. For example, birds have been observed flying over the highest peaks (taller than 9000 m) despite the fact that air at this altitude has less than one-third the O₂ content of air at sea level. Similarly, llamas inhabit the Andes at altitudes up to 5000 m, where at a pO₂ of approximately 80 mmHg the air has about one-half the O₂ content of air at sea level. Consequently, the lung pO₂ of a llama is only about 50 mmHg. How do high-flying birds and llamas obtain enough O₂? Their hemoglobin has a higher affinity for O₂ and binds O₂ more readily than the hemoglobin of mammals living at sea level. Consequently, their O₂ dissociation curve is shifted to the left, favoring the binding of more O₂ at a given pO₂.

Tissue and blood pH also have an important physiological effect on the O₂ affinity of hemoglobin. When pH falls during exercise (that is, when H+ concentration increases), the affinity of hemoglobin for O₂ decreases, resulting in a rightward shift in the O₂ dissociation curve (Fig. 39.15b). This phenomenon is called the Bohr effect after Christian Bohr, the Danish physiologist who first described it in 1904. Decreases in pH occur when CO₂ is released from metabolizing cells, or when an inadequate supply of O₂ leads to the production of lactic acid (Chapter 7). Because hemoglobin’s affinity for O₂ is reduced, more O₂ is released and supplied to the cells for aerobic ATP synthesis.

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Carbon dioxide also reacts with the amine (NH₂) groups of hemoglobin, reducing hemoglobin’s affinity for O₂. Thus, when released from respiring tissues, CO₂ promotes increased O₂ delivery both through its direct effect on hemoglobin and its contribution to a decrease in blood pH by the Bohr effect. While the production of CO₂ promotes O₂ release at the tissues, its elimination at the lung increases hemoglobin’s affinity for O₂, enhancing O₂ uptake.

Quick Check 4 Sickle-cell anemia is a genetic disorder of individuals homozygous for a mutation of hemoglobin that causes their red blood cells to be sickle shaped and stiff under conditions of low pO₂. Why is this disease life threatening?