A Brain Protein–Centered View of H⁺ Buffering

The traditional view of buffering of hydrogen ions (H⁺) is “proton-centered” because its major premise is that H⁺ are harmful; therefore, anything that minimizes a rise in the plasma H⁺ concentration would be beneficial. Data that may support this view are that a high H⁺ concentration depresses myocardial function, but this interpretation is not consistent with the very high cardiac output observed when acidemia is very severe near the end of the sprint.¹ In addition, this view of the buffering of H⁺ does not consider the prices to pay to achieve this goal.

We explore a different way to analyze the buffering of a H⁺ load and suggest that a “brain protein–centered” view may lead to a better understanding of the pathophysiology, with important implications for therapy. Its major tenet is that buffering not only should diminish the rise in the H⁺ concentration but also should do so while minimizing the binding of H⁺ to proteins in cells of the brain (equation 1). If extra H⁺ bind to proteins, then this will make their “ideal or native” net valence (Protein°) become more cationic or less anionic (H·Protein⁺)² and alter their shape and possibly their function (as enzymes, transporters, contractile elements, and structural compounds).³ (1)

The bicarbonate (HCO₃⁻) buffer system (BBS) is the most important physiologic buffer because it can remove H⁺ without requiring a high H⁺ concentration and thereby avoids a change in protein net charge.⁴ Therefore, we examine the properties to ensure that the BBS and not the proteins will remove the bulk of added H⁺.

The BBS can out-compete the proteins for H⁺ removal mainly because acidemia stimulates ventilation, which lowers the Pco₂ (Figure 1 and equation 2). As a result, H⁺ are forced to react with HCO₃⁻, and the concentration of both reactants will decrease in a 1:1 ratio. Notwithstanding, the percentage decline in the H⁺ concentration is much larger than that of HCO₃⁻ because the former is approximately 10⁶-fold lower than the latter. In addition, the BBS is very effective because the content of HCO₃⁻ in the body is large (approximately 375 mmol in the extracellular fluid (ECF) [25 mM × 15 L] and intracellular fluid (ICF) [12.5 mM × 30 L] compartments in a 70-kg adult). (2)

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Figure 1.

Buffering of H⁺ by the bicarbonate (HCO₃⁻) buffer system (BBS) in vital organs in a patient with a contracted extracellular fluid (ECF) volume. Skeletal muscle cells are shown on the left, and brain cells are shown on the right. Because brain is one 20th the size of muscle, it has far less HCO₃⁻. When the ECF volume is low, the Pco₂ in the venous blood draining muscle is high. This prevents H⁺ from being buffered by HCO₃⁻ in its ECF and intracellular fluid (ICF) compartments. As a result, the H⁺ concentration in plasma rises and more H⁺ will be buffered in brain cells. The latter have their usual BBS because the Pco₂ in venous blood draining the brain will change minimally with all but a very severe degree of contraction of the ECF volume, as the cerebral blood flow rate is autoregulated. Nevertheless, some of this H⁺ load will bind to intracellular proteins. In contrast, when intravenous saline is administered, blood flow to skeletal muscle rises, its venous Pco₂ falls, and more H⁺ are removed by its BBS. As a result, the H⁺ concentration in plasma falls and H⁺ will be released from proteins in brain cells.

The process that lowers the Pco₂ begins with stimulation of the respiratory center in the brain. This is an ideal response because the Pco₂ in the ECF and ICF compartments of the brain is directly proportional to the the rate of production of CO₂, which is constant as is its autoregulated rate of blood flow.⁵ Therefore, by having this ideal Pco₂, there may be only minimal binding of H⁺ to intracellular proteins in the brain during acidemia, which decreases possible detrimental effects on neuronal function. The question, however, is whether a low arterial Pco₂ is sufficient to ensure that the BBS will function optimally in other organs.

Only red blood cells, while in the arterial compartment, have the same Pco₂ as in arterial blood because all other organs consume oxygen and add CO₂ to their capillary blood (Table 1). Because CO₂ diffuses rapidly, distances are short, and time is not a limiting factor, the Pco₂ in capillaries is virtually identical to the Pco₂ in cells; this is also true for the interstitial compartment of the ECF in this region. Therefore, the arterial Pco₂ does not reveal whether the BBS has operated efficiently in the vast majority of the ICF and ECF compartments; notwithstanding, the arterial Pco₂ sets the lower limit for the Pco₂ in capillaries.

The capillary Pco₂ differs in individual organs, but one cannot measure it directly. The venous Pco₂, however, closely reflects the capillary Pco₂ in each venous drainage bed.^6–9 Thus, the venous Pco₂ provides information about the effectiveness of this “good” form of buffering (i.e., the removal of H⁺ without requiring a higher H⁺ concentration⁴). There is, however, an important caveat: If an appreciable quantity of blood shunts from the arterial to the venous circulation and bypasses cells, then this venous Pco₂ will not reflect the Pco₂ in cells in this drainage bed. The question to consider now is which venous Pco₂ should be measured to evaluate effectiveness of the BBS.

The focus should be on skeletal muscle because it has the largest content of HCO₃⁻. If this organ requires a high H⁺ concentration to remove the bulk of the H⁺ load during metabolic acidosis (Figure 1, bottom left), then the resultant increase in acidemia will force more H⁺ to bind to intracellular proteins in the brain (Figure 1, bottom right).⁶

At the usual rates of CO₂ production and with usual blood flow rates at rest, the brachial venous Pco₂ is approximately 46 mmHg when the arterial Pco₂ is 40 mmHg. The Pco₂ in venous blood draining skeletal muscle will be much higher than the arterial Pco₂ in two circumstances: (1) if more oxygen is consumed and the rate of blood flow does not rise by an commensurate amount (e.g., during vigorous exercise) and (2) if the rate of blood flow falls and there is no major decline in the rate of consumption of oxygen.² The main cause of failure of the BBS in skeletal muscle is a marked decline in its blood flow when metabolic acidosis is accompanied by a contracted effective arterial blood volume.^6–9

Turning our attention to therapy with NaHCO₃ for metabolic acidosis, it is not our intention to discuss the controversy about NaHCO₃ therapy for patients with metabolic acidosis who in fact represent a heterogeneous group; rather, we address this topic from a brain protein–centered perspective.

There are circumstances in which NaHCO₃ must be administered at the outset. For example, patients who have metabolic acidosis, a very contracted ECF volume, and large diarrhea losses require therapy with NaHCO₃ because their plasma HCO₃⁻ concentration will fall by dilution, the intestinal loss of NaHCO₃ will be augmented when splanchnic perfusion improves,¹⁰ and the ability to add new HCO₃⁻ by metabolism of organic anions or the excretion of NH₄⁺ cannot occur at a sufficiently rapid rate. In fact, there was a higher mortality rate in these patients when therapy did not include the administration of NaHCO₃.^11,12

The most important goal is to reduce the number of H⁺ bound to proteins in brain cells. To achieve this objective, the Pco₂ in veins draining skeletal muscle must fall. Two events permit this to occur: (1) Lowering the arterial Pco₂ if this value is inappropriately high for the degree of acidemia¹⁰ and (2) improving hemodynamics by infusing saline if the patient has a low ECF volume. One can follow the effectiveness of therapy to achieve this aim by examining serial changes in the venous Pco₂.⁹

One should not assess the effectiveness of NaHCO₃ therapy solely by the rise in the plasma HCO₃⁻ concentration. In more detail, if the administered HCO₃⁻ were titrated by H⁺ bound to proteins in cells, then failure to see a rise in this HCO₃⁻ concentration when NaHCO₃ is administered could be beneficial because proteins now have a less net positive charge. An example of this improvement could be de-inhibition of the key glycolytic enzyme phosphofructokinase when the intracellular pH rises in myocardial cells.¹³ If the rate of anaerobic glycolysis were to increase the administration of NaHCO₃, then this could be viewed as detrimental if one considers only the H⁺ and l-lactate concentrations. However, if part of lactic acid formation occurred in cardiac myocytes and this led to an increased formation of ATP,¹⁴ then the increased energetics may improve the cardiac contractility and thereby improve the cerebral blood flow rate.

Viewed from the brain-centered perspective, calculation of the dosage of NaHCO₃ on the basis of the bicarbonate distribution space has a number of limitations. First, this calculation is based on the concentration of HCO₃⁻, not on its content in the ECF compartment.¹⁵ Importantly, it considers only the HCO₃⁻ that is retained to raise the HCO₃⁻ concentration by a certain amount, whereas a “better” HCO₃⁻ may be one that was consumed by removing a protein-bound H⁺. Moreover, this distribution space will depend on how effective the therapy was to lower the venous Pco₂ in skeletal muscles.

In conclusion, changing from a proton-centered to a brain protein–centered view of buffering highlights the importance of the physiology of the BBS. To do so, one must also measure the Pco₂ in brachial venous blood.¹⁵ These new insights may permit improved design for therapy of individual patients with metabolic acidosis.

• © 2007 American Society of Nephrology