pH Control

Question 1

Explain step 1 and step 2

Answer 1

• Metabolic acidosis followed by respiratory compensation

Question 2

Explain step 1 and 2

Answer 2

• Respiratory alkalosis followed by renal compensation

Question 3

Explain step 1 and 2

Answer 3

• Metabolic alkalosis followed by respiratory acidosis

Question 4

Explain step 1 & 2

Answer 4

• Respiratory acidosis followed by renal compensation

Question 5

What drug or condition could cause step 1? Explain your answer

Answer 5

• Metabolic acidosis
• Acetalozamide
  
  • Inhibits carbonic acid anhydrase
  • Reduces H⁺ and HCO₃^- generation within the renal tubular cells resulting in metabolic acidosis

Question 6

What drug or condition could cause step 1?

Answer 6

• Respiratory alkalosis
• Anxiety (hyperventillation)
  
  • Excessive respiratory removal of CO₂

Question 7

What drug or condition could cause step 1?

Answer 7

• Metabolic alkalosis
• Loop diuretics & thiazides
  
  • Furosemide inhibits Na⁺-K⁺-Cl^- co-transporter on apical side
  • Bendoflumethiazide inhibits Na⁺Cl^- symporter on apical side
• Increased distal tubular sodium concentration results in reuptake of Na⁺ by apical epithelial Na⁺ channels which increases Na⁺ influx via the Na⁺-H⁺ exchanger resulting in greater HCO₃^- reabsorption and more H⁺ secretion into the tubular lumen.

Question 8

What drug or condition could cause step 1?

Answer 8

• Respiratory acidosis
• Opioids

Question 9

What is pH?

Answer 9

A measure of [H⁺] defined by the equation pH = -log₁₀[H⁺]

Question 10

What is an acid?

Answer 10

H⁺ donor

Question 11

What is a base?

Answer 11

H⁺ acceptor

Question 12

What is an alkali?

Answer 12

• Soluble base

Question 13

What is an acid-base disturbance?

Answer 13

A primary abnormality of acid-base balance that has the potential to shift plasma pH outside of the normal range (7.35 – 7.45) if there were no compensation

Question 14

What is compensation?

Answer 14

• A secondary response of the pH regulatory system to a primary acid-base balance disutrbance that maintains plasma pH within the normal range

Question 15

What is acidosis?

Answer 15

An abnormal condition/process in which plasma pH could be lowered if there were no compensation (can lead to acidaemia)

Question 16

What is alkalosis?

Answer 16

An abnormal condition/process in which plasma pH could be raised if there were no compensation. (can lead to alkalaemia)

Question 17

What is acidaemia?

Answer 17

Plasma pH < 7.35

Question 18

What is alkalaemia?

Answer 18

Plasma pH > 7.45

Question 19

Why is pH maintained?

Answer 19

• pH homeostasis is important because changes in [H⁺] alter the valence of proteins, promoting alterations in bonding patterns that lead to conformational changes, disrupting normal function such as enzyme activity
• Phosphofructokinase activity falls by 90% with a 0.1 unit change in pH
• Cell mitogenic activity can fall by 85% when the pH falls by only 0.4

Question 20

Describe the systems which control pH?

Answer 20

• The physiological systems that control of influence pH are:
  
  • They act to reduce pH disturbances by physiological activity
• Buffer system
  
  • Sequesters or releases free H⁺
• Respiratory & renal system
  
  • Eliminates acids or bases from the body fluids

Question 21

Name physiological activities that can change pH

Answer 21

• Exercise
• Ketogenesis
  
  • Diet

Question 22

Explain the traditional model

Answer 22

• The traditional model of acid-base balance emphasises the matching of H⁺ input to and output from the body fluids.
• It relies on the HCO₃^- buffer system and the Henderson-Hasselbalch equation (HHE).

HCO₃^- buffer system

• The HCO₃^- buffer equilibrium is depicted in the equation below:

Carbonic anhydrase

CO₂ + H₂O

H⁺ + HCO₃^-

Henderson-Hasselbalch equation

• The HHE can be derived by the modification of the equilibrium constant equation of this reaction.

pH = 7.4

pK = -logK = 6.1

[HCO₃^-] = 24 mM (normal)

a: Solubility coefficient of CO₂ = 0.03 mM/kPa

PCO₂ : Partial pressure of CO₂ in blood = 5.3 kPa (normal)

• The HHE states that pH is dictated by the [HCO₃^-]/PCO₂ ratio.
• An increase in the ratio results in an increase in pH, while a decrease lowers pH.

Increase in ratio

Increase in pH – alkalosis

Decrease in ratio

Decrease in pH - acidosis

• The two independent variables that control pH are:
  (1) PCO₂
  (2) [HCO₃^-]

HCO₃^-

Regulated by the kidneys

PCO₂

Regulated by the lungs

Question 23

Evaluate the traditional model

Answer 23

• Advantages
  
  • The advantage of the traditional model is that it is simple to understand
• Disadvantages
  
  • Does not take other factors into account
  • Does not include buffers other than HCO₃^-
  • [HCO₃^-] is not a true independent variable

Question 24

• Under normal conditions with a Western diet, how much is the net addition to the body fluids?

Answer 24

• 70mEq/day

Question 25

Describe voltatile acids

Answer 25

• In aerobic conditions, carbohydrates and fatty acids are metabolised to CO₂, which diffuses into the ECF and promotes a decrease in pH (via HCO₃^- equilibrium)
• CO₂ is described as volatile acid because it generates H⁺ after reaction with H₂O.
• PCO₂ is regulated by the lungs because CO₂ can be exchanged with the alveolar air.

Question 26

Describe non-volatile acids

Answer 26

• Non-volatile acids (NVAs) are those not derived from CO₂ hydration.
• These include H₂SO₄, HCl, and certain organic acids, which are produced by the metabolism of:
  
  • (1) sulfur-containing amino acids
    
    • e.g. cysteine and methionine
  • (2) cationic amino acids
    
    • e.g. lysine
• Plasma [NVA] is controlled by the kidney.
• Some is offset by HCO₃^- production from amino acid metabolism

Question 27

Explain the buffer system

Answer 27

• Buffers are substances that reversibly bind free H⁺ in equilibrium reactions.
• Buffers mediate short term regulation of pH on the timescale of seconds.
  
  • Rise in [H⁺] promotes rapid H⁺ sequestration
  • Fall in [H⁺] promotes H⁺ release

Buffers in compartments

• Plasma buffers
  
  • The most quantitatively important plasma buffers are HCO₃^- and haemoglobin (Hb) in red blood cells.
  • Other plasma buffers include phosphate species (HPO₄^2-, H₂PO₄^-) and plasma proteins.
  • Proteins and Hb
    
    • Proteins have negatively charged groups that can accept H⁺ such as carboxyl, phosphate, and imidazole groups.
    • Deoxygenated Hb has a greater buffering capacity than other plasma proteins because (1) of its large quantity and (2) each molecule has a large number of imidazole groups.
    • RBC also mediate Cl- shift (exchange HCO3- in the cell for Cl-)
• Bone
  
  • Bone matrix can also act as a buffer.
  • Short term buffering is mediated by the displacement of Ca²⁺ from CaCO₃ by H⁺.
    
    • In long term acidosis, osteoclasts degrade bone matrix and release HCO₃^- which is why chronic acidosis can lead to osteoporosis
• Cells
  
  • Cells can also buffer H+ by transcellular shifts with K+
  • In acidosis, H+ can be exchanged for K+, leading to hyperkalemia
    
    • In alkalosis, the reverse reaction occurs (k+ into cells) leading to hypokalemia
• Intracellular buffers
  
  • Within cells, phosphate and proteins bind to H+ and HCO3- that is exchanged over the cell membrane from the ECF

Question 28

What are the limitations of the buffer system?

Answer 28

Closed system

• Buffers do not contribute to long term pH regulation because they do not exchange H⁺ with the external environment, constituting a closed system.

Finite

• Although the buffering capacity is large, eventual depletion of buffers would lead to an extreme shift in pH.
• Open systems of pH regulation are therefore required (respiratory and renal).

Question 29

Explain respiratory control

Answer 29

• Respiratory control of plasma pH is driven by changes in pulmonary ventilation (PV), which alter the rate of CO₂ removal from the plasma and thus affect PCO₂.
• CO₂ expiration removes the CO₂ (volatile acid) generated by aerobic cellular metabolism.
• Importance of an open system
  
  • The lungs have infinite ability to excrete CO₂, thus pull the equilibrium of the HH equation towards CO₂ production
  • This is important as the normal pKa of the blood does not favour CO₂ production (instead HCO₃^- production), but as it is an open system, the concentration gradient maintains the activity.
• Ventilation provides rapid adjustment of pH, acting on the timescale of minutes.

Chemoreceptors

• Changes in plasma PCO₂ and pH independently control ventilation by stimulating chemoreceptors, which deliver signals to respiratory muscles via the medullary respiratory centre.
• Low pH
  
  • In low pH conditions, the central chemoreceptors detect a rise in brain extracellular [H⁺] due to a rise in P_aCO₂
    
    • Central chemoreceptors = medullary neurones
  • Peripheral chemoreceptors in the carotid bodies are stimulated by high PaCO₂and low pH
  • Increase in pulmonary ventilation
    
    • thus increasing CO₂ removal from the blood, lowering PaCO₂, increasing [HCO₃^-]/PCO₂ and raising pH
  • Altitude
    
    • Peripheral chemoreceptors are important at altitude to stimulate an increase in PV in phase 1 and 2 of acclimatisation
    • This is because unlike central chemoreceptors, they are sensitive to low PO₂ (in phase 1)
    • Hyperventilation results in respiratory alkalosis that inhibits the central chemoreceptors during phase 2 of acclimatisation
• High pH
  
  • Has opposite effect
  • Promotes decreased pulmonary ventilation and increasing PaCO₂, lowering [HCO₃^-]/PCO₂, and lowering pH.

Question 30

Explain kidney control

Answer 30

• The kidney is the most powerful pH regulatory system but is slow, acting on a timescale of days.

Acid Load

• The kidney mediates the neutralisation of non-volatile acids (NVAs) that cannot be expired by the lungs such as H₂SO₄, HCl, and certain organic acids.
• NVAs are produced by the metabolism of:
  
  1. Sulfur-containing amino acids
• E.g. cysteine and methionine
  
  1. Cationic amino acids
• E.g. lysine

Acid-base models

Traditional

• The function of the kidney in the traditional model is the replenishment of plasma HCO₃^- by:
  
  1. HCO₃^- reabsorption
  2. HCO₃^- regeneration
• The HCO₃^- then buffers acid in the extracellular fluids.

Stewart model

• In the Stewart model, the kidney regulates pH by modulation of the strong ion difference (SID) – this involves adjustments to the absorption and secretion of strong ions such as Na⁺, K⁺ and Cl^-

The renal control of pH can be seen in clinical and experimental evidence.

Question 31

Explain HCO_3^- reabsorption

Answer 31

• HCO₃^- reabsorption is important because a large amount of HCO₃^- is filtered by the kidneys each day, which would lead to a large decrease in the buffering capacity of the plasma if excreted in urine.
  
  • 5 mMol HCO₃^- filtered daily

Diagram

• Of the filtered HCO₃^-, the proximal tubule (PT) reabsorbs 80% and the thick ascending limb of the loop of Henle (TALH) reabsorbs 15% by the mechanism depicted in the diagram below:

Steps

1. Firstly, carbonic anhydrase in the proximal tubule cell catalyses the reaction: CO₂ + H₂O à H⁺ + HCO₃
2. The HCO₃^- is moved across the basolateral membrane into the interstitial fluid and plasma by the Na⁺/3HCO₃^- cotransporter and the HCO₃^-/Cl^- cotransporter (the anion exchanger)
3. The H⁺ is moved across the apical membrane into the tubule fluid by the Na⁺/H⁺ exchanger isoform 3 (most important) and H⁺ ATPase
4. In the lumen, H⁺ reacts with filtered HCO₃^- in the following reaction: H⁺ + HCO₃^- à H₂O + CO₂, which is catalysed by carbonic anhydrase in the apical membrane.
5. The CO₂ produced diffuses into the PT cell and participates in the reaction of step (1).

• The overall effect is a net movement of one HCO₃^- from the tubule fluid to the plasma.
• In the distal nephron, HCO3- is regenerated
• In acidosis, the upregulation of the NH₃ to increase the reabsorption of bicarbonate
  
  • This is unusual as the PCT is not usually regulated and is the site of bulk reabsorption
• However, the increased reabsorption is important for regeneration

Mechanism

NH3 is upregulated (absolute transport capacity) in acidosis

This is thought to be due to phosphorylation by PKC

1. In acidosis the PCT cell is acidified
2. Leads to intracellular calcium displacement
3. PKC activation

NHE3 phosphorylation

Importance

Reabsorption of all the filtered HCO₃^- decreases the extent to which HCO₃^- needs to be regenerated in the distal nephron and allows HCO₃^- to be regenerated earlier

The upregulation of NH₃ is important HCO₃^- reabsorption is limited by H+ availability