Currently, there is tremendous commercial interest in the development of blood substitutes as an alternative to real blood for transfusions during scheduled surgery or emergency resuscitation. A 1994 World Health Organization survey found that 90 million units of blood are collected globally each year, yet blood shortages still occur and the cost of banking blood has increased with the need to screen for new blood-borne diseases such as human immunodeficiency virus. Besides increasing supply, blood substitutes could eliminate the need to cross-match blood types during transfusions, because blood type is determined by antigens on the surface of red blood cells.
Various hemoglobin solutions have been tested as blood substitutes since the early 1970s, when scientists made advances in purification and chemical modification of hemoglobin. However, the effectiveness of these substitutes is still not established and, surprisingly, some problems with hemoglobin blood substitutes relate to O2 delivery. When a person loses blood, peripheral blood vessels constrict (e.g., in muscle), and this helps sustain O2 delivery to vital organs. Because blood flow in the microcirculation is also controlled by local Po2 (Chapter 17), hemoglobin blood substitutes may not be effective at reopening microvessels if too much O2 is supplied; high Po2 can increase microvascular resistance. Also, the iron in hemoglobin is an extremely effective scavenger of nitric oxide (NO), which is a powerful vasodilator also known as endothelial derived relaxing factor (EDRF). Finally, when blood flow and O2 delivery are reestablished, hemoglobin solutions can increase the production of oxygen radicals and exacerbate so-called reperfusion injury of tissues.
Recent experiments have discovered new chemical reactions between NO and hemoglobin, and have suggested possible solutions for problems with O2 delivery and the hypertension that occur with hemoglobin blood substitutes. NO can form S-nitrosothiols (RSNOs) with cysteine residues in hemoglobin, and these RSNO compounds retain vasoactive properties like NO. Furthermore, hemoglobin oxygenation modifies this reaction, so O2 exerts allosteric control over NO transport. This promotes a cycle of NO delivery to the microvasculature in tissues (from deoxygenated Hb) and NO loading in the lungs (onto oxygenated hemoglobin). The cysteine residue on the (3-Hb chain responsible for this reaction is highly conserved in all mammals and birds, indicating that it has an important physiologic function that has changed little during evolution. Incorporating this chemistry into hemoglobin used for blood substitutes may increase their clinical usefulness.
fluxes occurring with CO2 transport in blood. CO2 rapidly enters red blood cells from the plasma because it is soluble in cell membranes. Carbonic anhydrase catalyzes the rapid formation of HCO^ and H+ in the cells, and some of this HCO3" is transported out by an electrically neutral bicarbonate-chloride exchanger. The Hamburger (or chloride) shift is an increased intracellular chloride with increased CO2, or vice versa. The H+ produced from CO2 reacts with hemoglobin and affects both the O2 equilibrium curve (Bohr effect) and CO2 equilibrium curve, as described later.
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