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POINT-COUNTERPOINT
1Department of Human Health and Nutritional Sciences
University of Guelph
Guelph, Canada2Department of Medicine
McMaster University
Hamilton, Canada
TO THE EDITOR: The acidification of blood during muscular exercise cannot be understood from an analysis of blood from a single site, nor from examination of only arterial (or arterialized) blood. Acidification of blood during muscular contraction occurs as a result of rapid and marked increases in skeletal muscle mitochondrial CO2 production and decrease of cellular HCO3– (and other CO2 stores; 2) resulting from intra- and extra-cellular acidification. Peak efflux of CO2 occurs during the first 30 s of high (5, 8)- and moderate (7, 9, 13)-intensity exercise. With both high (5, 8)- and moderate-intensity (7, 9) exercise, blood is also acidified due to decreases in plasma strong ion difference, or [SID], and increases in plasma [protein]. The contributions of each of these independent variables of acid-base control to the changes in plasma [H+] and [HCO3–] have been quantified in arterial, femoral, and antecubital venous bloods during leg bicycling exercise and recovery. In femoral venous plasma the increase in PCO2 remains the primary contributor to the plasma acidosis during exercise and the initial recovery period. In mixed venous blood, increased PCO2 is also the primary contributor to the plasma acidosis during exercise (14). The contributions of decreased [SID], due to increased [lactate–] and [pyruvate–], and increased plasma [protein] decreases over time, whereas CO2 efflux from muscle continues. When mixed venous blood perfuses the lungs, the removal of CO2 from erythrocytes profoundly decreases plasma and red cell [H+], however this is accompanied by net efflux of Cl– from red blood cells, which has an acidifying effect on plasma through lowering arterial plasma [SID] (4, 8).
The volume of arterial blood is small compared with the volume of venous blood, and while arterial blood perfuses tissues, arterial blood does not provide an "average" representation of acid-base balance within the body. Arterial [lactate–] is lower than femoral venous [lactate–] because of dilution of femoral venous blood with blood from draining all tissues of the body. Non-contracting tissues also modify the ionic and acid-base composition of plasma and red cells perfusing these tissues (4, 8). Thus blood sampled from noncontracting sites only provide partial and mixed representations of blood draining both noncontracting tissues and contracting muscle. The important point here is that the composition of plasma and erythrocytes are substantially modified as blood perfuses any tissue, whether the lungs, noncontracting tissues, and contracting muscle.
Some sports researchers attempt to equate changes in arterial (arterialized) blood [lactate] with the total change in blood base excess (1). However, the determination of an in vivo base excess assumes greater [hemoglobin] than is actually effective in vivo, where Hb is diluted in the entire extracellular volume (10). Because extracellular fluid is in contact with all cells in the body (not just erythrocytes), the concept of an in vivo base excess is contrived, because changes in base excess, as measured in vivo, represent ion and gas exchanges by all tissues in the body. Base excess cannot be "measured" in vivo, and when attempts are made to apply base excess to intact living systems, arbitrary "correction factors" have to be applied because the entire extracellular fluid compartment is involved with dynamic exchanges of ions and gasses with erythrocytes. This is strikingly evident when in vivo CO2 titrations have been performed (3).
Rather, base excess is a calculated term based on the in vitro strong acid/base (i.e., Cl– or Na+) titration of blood (not plasma) with acid or base return the blood pH to 7.4 at normal PCO2 (11, 12). Titration in one direction with Cl– or lactate– and then the other with an equimolar amount of Na+ will give different results for acid or base added. This is because Cl– and Na+ are not transported and distributed across the erythrocyte membrane in a similar fashion. More germane to exercise is the titration of blood with lactate–; lactate distribution across the erythrocyte membrane differs from that of either Cl– or Na+. Pyruvate–, and hence lactate–, are also produced by erythrocytes, and lactate– transported into erythrocytes can be converted to pyruvate–. The amount of lactate– converted to pyruvate– and transported within erythrocytes is therefore significant.
Furthermore, when assessing the lactate– contribution of plasma and erythrocytes to the acidosis of exercise, it is often incorrectly presumed that the ion distribution, including the distribution of lactate– and Cl–, across the erythrocyte membrane is governed by a Gibbs-Donnan equilibrium. This is not true because ion and gas exchanges between plasma and erythrocytes are active and facilitated transport processes. For a Gibbs-Donnan equilibrium to hold, these ion and gas transport processes would have to be purely passive. For example, consider the substantial net efflux of Cl– (a reaction catalyzed by Band 3 protein) that occurs from erythrocytes as blood perfuses the lungs and releases CO2 transported within erythrocytes as HCO3–, a reaction catalyzed by membrane-bound carbonic anhydrase; this occurs concurrent with decreases in erythrocyte volume and [H+] to maintain osmotic equilibrium between plasma and intra-erythrocytic fluid compartments. While the disequilibrium is relatively small across the erythrocyte membrane, the importance of the facilitated reactions is readily observed when, for example, carbonic anhydrase is inhibited (6). The Gibbs-Donnan equilibrium assumes passive diffusion of small, charged molecules across a semi-permeable membrane, and was later interpreted to provide an explanation for the distribution of ions across semi-permeable membranes in the absence of knowledge that there exists proteins imbedded within plasma membranes that serve to transport ions and CO2.
Some of the key contributions to the acidosis of exercise can be summarized as follows. During exercise, the PCO2 in arterial blood is often low as a result of hyperventilation, therefore when arterial blood is used to determine base excess, the acidifying effects of the increased strong acid [lactate–] are already partially offset by the alkalizing effect of decreased PCO2. Plasma [protein] is also elevated in arterial blood, contributing to acidification. The strong acid/base titration of blood also results in net ion, gas, and water flux across blood cell membranes (primarily erythrocytes) through several transport processes including chloride-transporting Band 3, carbonic anydrase facilitated CO2 diffusion across the membrane, monocarboxylate transporters (lactate– and pyruvate–). Furthermore, proton binding by intracellular compounds (protein histidine groups, 2,3-DPG) is altered in ways that are not representative of blood at rest prior to exercise, plasma and intra-erythrocytic osmolality are increased, as is erythrocyte volume. Therefore the strong base titration of arterial blood sampled during periods of moderate- to high-intensity exercise only provides information on 1) the apparent CO2 deficit; 2) the increase in plasma total weak acid concentration; 3) the net effect of induced ion and gas transfer across erythrocyte plasma membranes; and 4) proton binding within erythrocytes. It would only be coincidental that, at times, with certain types of exercise, that the total amount of fixed base required to tritrate a blood sample to pH 7.4 would equate with the amount of lactate– present.
REFERENCES
This article has been cited by other articles:
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  Rebuttal from Drs. Boning and Maassen J Appl Physiol, July 1, 2008; 105(1): 361 - 361. [Full Text] [PDF]
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E. S. Prakash, R. A. Robergs, B. F. Miller, L. B. Gladden, N. Jones, W. W. Stringer, K. Wasserman, W. Moll, G. Gros, D. S. Rowlands, et al. No single mechanism. J Appl Physiol, July 1, 2008; 105(1): 363 - 364. [Full Text] [PDF]
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D. Boning and N. Maassen Last Word on Point:Counterpoint: Lactic acid is/is not the only physicochemical contributor to the acidosis of exercise J Appl Physiol, July 1, 2008; 105(1): 368 - 368. [Full Text] [PDF]
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M. I. Lindinger and G. J. F. Heigenhauser Last Word on Point:Counterpoint: Lactate is/is not the only physicochemical contributor to the acidosis of exercise J Appl Physiol, July 1, 2008; 105(1): 369 - 369. [Full Text] [PDF]
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Rebuttal from Drs. Lindinger and Heigenhauser J Appl Physiol, July 1, 2008; 105(1): 361 - 362. [Full Text] [PDF]
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