A reduction in the capacity of blood to carry oxygen leads to increased extraction of oxygen from the blood by peripheral tissues, and consequently to a decrease in the venous partial pressure of oxygen (pO2). At reduced venous pO2 pre-existing venous-arterial shunts gain in influence on arterial pO2 and arterial pO2 also decreases. In addition, physical exercise leads to lactate acidosis earlier and at lower levels of exercise than in healthy subjects. The low arterial pO2 and the low pH of acidosis are sensed by chemoreceptors of the carotid bodies and neural signals are transmitted to centers of the brain stem, where they are integrated and result in the sensation of shortness of breath (dyspnea). The capacity of the blood to carry oxygen is determined not only by the concentration of hemoglobin but also by the binding characteristics of hemoglobin for oxygen, which can be deduced from its molecular structure. In contrast to cases with acute anemia, dyspnea is often absent in patients in whom anemia develops gradually (down to hemoglobin levels of 7 g/dl). This tolerance is not mediated by pulmonary or cardiac compensatory mechanisms also at work in acute anemia, but is due to increases in the concentration of diphosphoglycerate. This allosteric effector molecule induces, by binding to hemoglobin, a decrease in the affinity of hemoglobin for oxygen, thereby leading to improved release of oxygen from hemoglobin in peripheral tissues.(ABSTRACT TRUNCATED AT 250 WORDS)