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The shape, slope, and P50 of an ODC are influenced by several physiologically important parameters. The most significant of these are pH and Pco2, whose effects are related if not identical (Fig. 3.5). Acidification of blood with protons (hydrogen ion, H+) from any metabolic source reduces HbO2 affinity and increases the measured P50, the so-called acid Bohr effect. Indeed, fluctuations in P50 due to Pco2 are mediated primarily by pH changes caused when dissolved CO2 interacts with H2O to form weakly dissociative carbonic acid, H2CO3. Such Bohr effects are critical physiologically, since high hydrogen ion concentration ([H+]) and CO2 levels in tissues acidify the arriving arterial blood, increasing its P50 and facilitating dissociation of Hb-bound O2. This O2 transfer would occur even if tissue Po2 equaled arterial Po2, when in fact it is much lower. The reverse situation occurs as blood returns to the lungs. There, the high tissue CO2 that caused acidification of venous blood is excreted, causing blood pH to rise. The P50 decreases as a result, signifying higher HbO2 affinity (alkaline Bohr effect) and a greater ability of Hb to bind alveolar O2.
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Interestingly, fluctuations in CO2 levels also affect P50 even if blood pH is held constant, causing what some authors have termed a pure CO2 Bohr effect. In any case, the basis for the Bohr effects of both molecular CO2 and protons is allosteric competition: [H+] and CO2 both can bind reversibly to specific residues on Hb proteins that are remote from heme-coordinated Fe2+ binding sites for O2. Association of [H+] or molecular CO2 at those sites induces conformational changes in Hb that reduce its affinity of Fe2+ sites for O2. As might be expected, the reverse of this allosteric competition is also true: Oxygenation of hemoglobin induces conformational shifts in the protein subunits that decrease their affinity for [H+]. Consequently, Hb becomes a stronger acid as it is oxygenated, a protein that more readily dissociates its bound H+. This Haldane effect is important in the lungs, where Hb oxygenation causes localized release of [H+] that are then available to combine with plasma and erythrocytic HCO–3 to reform H2CO3 and then gaseous CO2.
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Another important regulator of HbO2 affinity in vivo is the erythrocytic intracellular concentration of the glycolytic intermediate, 2,3-diphosphoglycerate ([2,3-DPG]). At a normal concentration within RBCs of about 0.8 mol 2,3-DPG/mol Hb, the [2,3-DPG] reversibly binds with α-amino groups on β-globulin chains, having an allosteric effect analogous to those of CO2 and [H+] by reducing HbO2 affinity and raising the P50 (Fig. 3.6). However, increased levels of intracellular [2,3-DPG] also makes O2 uptake more difficult in the lungs, since [2,3-DPG] levels persist breath-to-breath, unlike CO2 and [H+]. Thus, when [2,3-DPG] increases as sea-level inhabitants ascend rapidly to altitude, it does not facilitate O2 uptake to the extent postulated when first described in 1968. More likely, acute altitude probably evokes the normal response to tissue hypoxia evident at sea level to increase erythrocyte [2,3-DPG] and improve tissue O2 delivery without presuming a decline in inspired Po2 as does occur at altitude. In some mammals lacking a distinct fetal Hb, the P50 of fetal blood is kept below that of maternal blood by maintaining fetal erythrocytes at a low [2,3-DPG]. Thus, O2 moves readily into the fetal circulation with its higher-affinity blood from the lower-affinity maternal circulation.
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Core temperature is a final variable that influences HbO2 affinity. As blood temperature increases, so does its P50, analogous to the effect that thermal energy has on other chemical processes like the dissociation of weak acids. Although temperature gradients exist in the human body at rest and during exercise, it may be erroneous to attach much adaptive significance to this effect. In true poikilothermic (cold-blooded) vertebrates, however, such temperature effects have striking implications on seasonal patterns of ventilation and acid-base regulation.