pH Control Flashcards

Question

Describe voltatile acids

Answer 1

* 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.

Answer 2

* **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

Answer 3

* **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

Answer 4

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).

Answer 5

* 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 PaCO₂**and **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.

Answer 6

* 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.

Answer 7

* **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