Regulation of blood pH

Introduction

The body regulates blood pH to stay within a narrow range of 7.35 to 7.45. Fluctuations outside of this range can be detrimental to cellular processes. Enzymatic function can be hindered at suboptimal pH ranges, leading to cellular death.

To keep blood pH within the optimal range, multiple homeostatic mechanisms regulate processes and molecules which contribute to pH:

1. Chemical acid-base buffer systems
2. Respiration, and its control by the respiratory centre
3. The kidneys

Chemical acid-base buffer systems can react to changes in pH within seconds to minutes, and the respiratory centre can also react within minutes. The kidneys, while being the most powerful of the regulatory processes, take hours to days to respond.

This article will cover the different homeostatic mechanisms which regulate blood pH. 

pH

pH is a scale that describes how acidic or basic a fluid is.

The pH scale is logarithmic and is inversely proportional to the concentration of hydrogen ions (H⁺) in the fluid. This means that a difference of one pH unit is equivalent to a tenfold difference in hydrogen ion concentration.

When the acidity of a solution is increased by adding H⁺, the pH value decreases. The pH scale runs from 0 to 14, with a pH of 7 indicating neutrality, where the concentration of hydrogen ions equals the concentration of hydroxide ions (OH^–).

Blood pH buffer systems

Buffer systems work by neutralising added acid or base to resist changes to pH. For example, when H⁺ is added, the buffer system acts to ‘mop up’ excess H⁺. When H⁺ is low, or excess base is added, the buffer can ‘donate’ its own H⁺ to the solution to try and minimise the pH change.

Bicarbonate buffer system

The bicarbonate buffer system is quantitatively the largest buffer system of the blood. Carbonic anhydrase is a metalloenzyme found in the blood that catalyses the reaction of carbon dioxide (CO₂) and water (H₂O) to form carbonic acid (H₂CO₃), as well as the inverse reaction.

Carbonic acid is a weak acid and can donate a hydrogen ion to form bicarbonate (HCO₃^–), which functions as a weak base. These reversible reactions function as a buffer system. Bicarbonate ions bind with the H⁺ from introduced acids, while introduced bases receive a donated H⁺ from carbonic acid, effectively neutralising them.

The buffer system works to keep the pH within the optimum range unless the amount of acidic or basic additions overcomes the reserve amount of buffer molecules in the extracellular fluid.

Other buffer systems

Two other intravascular buffers aid in pH homeostasis. The first is proteins, of which haemoglobin is the most numerous and quantitatively the strongest. Histidine residues on the haemoglobin function as proton (H⁺) acceptors at physiological pH levels, noting that the buffering capacity of haemoglobin increases in its deoxygenated state.

The other buffer is the phosphate buffer system. Inorganic phosphate (HPO4₂^–) can reversibly bind free hydrogen ions. Compared to bicarbonate its concentration in the blood is low, and therefore its impact on blood pH is low. However, it is critical for buffering the pH of urine.

Respiratory regulation of acid-base balance

CO₂ is generated from cellular metabolism. It enters the bloodstream and is incorporated into the bicarbonate buffer system or dissolved in the plasma.

Respiration affects blood pH by dictating the rate of removal of CO₂ from the blood.

Hypoventilation causes CO₂ retention, and the bicarbonate buffer system compensates by forming carbonic acid, lowering blood pH. Hyperventilation, on the other hand, increases CO₂ removal and thus pushes the bicarbonate buffer system towards forming CO₂ and H₂O while decreasing H⁺, thereby increasing blood pH.

Ventilation can also be used by the body to alter the pH in response to changes caused by other means. An increase in blood H⁺ concentration signals the respiratory centre via chemoreceptors to stimulate alveolar ventilation, increasing the rate and/or depth of respiration. By removing CO₂ via respiration, the body can increase blood pH.

Renal regulation of acid-base balance  

The kidneys control acid-base balance by removing excess acid or base in the urine, and reabsorption and generation of HCO₃^–.

Substantial amounts of HCO₃^– are continuously filtered into the tubules. However, most is reabsorbed to conserve the buffer system of the extracellular fluid. H⁺ is also secreted into the tubular lumen, which includes the non-volatile acids generated by metabolism.

HCO₃^– must react with H⁺ to form H₂CO₃ within the lumen before it can be reabsorbed. Thus, the reabsorption of HCO₃^– is linked to the secretion of H⁺ into the tubular lumen.

Only a small amount of H⁺ can be excreted in the urine in its ionic form. Two main buffers in tubular fluid aid H⁺ excretion: the phosphate buffer and the ammonia buffer.

Phosphate buffer

The phosphate buffer can aid tubular cells to replenish extracellular HCO₃^– when stores are low.

Monohydrogen phosphate (HPO₄^2-) is concentrated in tubular fluid due to a low reabsorption rate. Most H⁺ excreted into tubular fluid combines with HCO₃^–. However, once all HCO₃^– has been reabsorbed, the H⁺ can be combined with HPO₄^2- and excreted as a salt (NaH₂PO₄). The removal of H+ allows the bicarbonate buffer system to create more HCO₃^– as per Le Chatelier’s principle, which can then be reabsorbed.

Ammonia buffer

The ammonia buffer works in two areas to ‘trap’ H⁺ in the urine and increase the HCO₃^– of the body. In the collecting tubules, H⁺ is generated from CO₂ and H₂O in the tubular cells. The H⁺ is actively secreted into the lumen, where it combines with ammonia (NH₃) to form an ammonium ion (NH₄⁺). The collecting ducts are almost impermeable to NH₄⁺ compared to NH₃, so H⁺ is ‘trapped’ in the lumen and excreted. For every H⁺ generated, one HCO₃^– molecule is reabsorbed into the bloodstream.

In the epithelial cells of the proximal and distal tubules, as well as the thick ascending loop of Henle, metabolism of glutamine molecules generates two HCO₃^– molecules and two NH₄⁺ molecules. While the NH₄⁺ is excreted into the lumen, the HCO₃^– is transported across the basolateral membrane and taken up by peritubular capillaries.²

When there is alkalosis of the extracellular fluid, the kidneys secrete less H⁺ into the urine, and fail to reabsorb all the filtered HCO₃^–. Due to the buffering nature of HCO₃^– in the bicarbonate buffer system, this loss of HCO₃^– raises the extracellular H⁺ concentration and thus acts to correct the alkalosis.

When there is acidosis of the extracellular fluid, the kidneys secrete additional H⁺ which also leads to reabsorption of higher amounts of filtered HCO₃^–. New HCO₃^– is also produced by the buffers in the tubules. The new and reabsorbed HCO₃^– act via the bicarbonate buffer system to correct the acidosis.

Key points

• Blood pH is regulated by multiple homeostatic mechanisms, including chemical buffers, respiration, and the kidneys.
• The bicarbonate buffer system can act within seconds to minutes to counteract changes in pH, while the lungs take minutes, and the kidneys take hours to days.
• Respiration alters acid-base balance by changing the carbon dioxide concentration of the blood, while the kidneys work by changing bicarbonate generation and reabsorption, as well as modifying hydrogen ion excretion.
• The phosphate buffer and the ammonic buffer in the kidneys work to ‘trap’ hydrogen ions in the urine, while also generating bicarbonate ions.

Editor

Dr Chris Jefferies

References

1. Stephen Lower. Le Chatelier’s Principle. Published in 2022. Available from: [LINK]
2. Hall JE, Hall ME. Guyton, and Hall Textbook of Medical Physiology. 14^th edition. Published in 2021.

Image references

• Figure 1. OpenStax College. 2325 Carbon dioxide transport. Licence [CC BY 3.0]