7.4 Transport of Oxygen/CO2 and Neural/Chemical Control of Breathing

7.4 Transport of Oxygen/CO2 and Neural/Chemical Control of Breathing

Efficient tissue oxygenation and metabolic carbon dioxide elimination rely on blood gas transport mechanisms and homeostatic feedback control. Neural networks within the brainstem dynamically adjust ventilation based on arterial blood gas parameters and cerebrospinal fluid pH.

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Oxygen Transport & Hemoglobin Dynamics

Oxygen is carried in blood in two forms:

1. Dissolved Oxygen: Unbound $O_2$ dissolved in plasma ($0.003\text{ mL } O_2 / 100\text{ mL blood / mmHg } PaO_2$). At a normal $PaO_2$ of $100\text{ mmHg}$, dissolved $O_2$ is only $0.3\text{ mL } O_2 / 100\text{ mL blood}$, insufficient to support tissue metabolism.
2. Hemoglobin-Bound Oxygen: Represents ~98.5% of total blood oxygen. Each adult Hemoglobin A ($HbA = \alpha_2\beta_2$) molecule is a tetramer containing four globin subunits, each bound to an iron-containing heme moiety with iron in the ferrous state ($\text{Fe}^{2+}$). One $Hb$ molecule can reversibly bind up to four $O_2$ molecules.

The Oxygen-Hemoglobin Dissociation Curve

The relationship between $PO_2$ and percent hemoglobin saturation ($SaO_2$) forms a characteristic sigmoidal (S-shaped) curve due to positive cooperativity:

• Cooperativity: Binding of the first $O_2$ molecule to a heme subunit converts hemoglobin from the low-affinity Tense (T) state to the high-affinity Relaxed (R) state, progressively facilitating binding of subsequent $O_2$ molecules.
• $P_{50}$ Parameter: The partial pressure of oxygen at which hemoglobin is 50% saturated. Normal human $P_{50}$ is approximately $26\text{ mmHg}$. An elevated $P_{50}$ signifies reduced affinity (right shift), whereas a decreased $P_{50}$ indicates heightened affinity (left shift).

Curve Shift Dynamics:
  [Left Shift]  <───  Normal Curve (P50 ≈ 26 mmHg)  ───>  [Right Shift]
  • High O2 Affinity                                     • Low O2 Affinity
  • Decreased O2 Unloading                               • Increased O2 Unloading to Tissues
  • Triggers: ↓ Temp, ↓ CO2, ↑ pH,                        • Triggers: ↑ Temp, ↑ CO2, ↓ pH (Acid),
    HbF, CO, MetHb                                          ↑ 2,3-BPG ("CADET face Right")

Factors Shifting the Oxygen-Hemoglobin Curve

• Carbon Monoxide (CO) Poisoning: CO binds heme with ~200-fold greater affinity than $O_2$, forming carboxyhemoglobin. It occupies $O_2$ binding sites and locks remaining sites in the high-affinity R state, causing a severe leftward shift of the curve and starving tissues of $O_2$.
• Methemoglobinemia: Iron in heme is oxidized from ferrous ($\text{Fe}^{2+}$) to ferric ($\text{Fe}^{3+}$) state (induced by nitrites/sulfonamides). $\text{Fe}^{3+}$ cannot bind $O_2$ and shifts remaining subunits leftward, causing tissue hypoxia and cyanosis.

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Carbon Dioxide Transport Mechanisms

Metabolically produced $\text{CO}_2$ is transported from tissues to lungs via three primary mechanisms:

1. Dissolved in Plasma (~7%): Free $\text{CO}_2$ dissolved in plasma.
2. Carbaminohemoglobin (~20%): $\text{CO}_2$ bound directly to terminal amino groups of hemoglobin (not to heme iron). The Haldane Effect dictates that oxygenation of $Hb$ in pulmonary capillaries promotes $\text{CO}_2$ dissociation from $Hb$, enhancing $\text{CO}_2$ clearance in the lungs.
3. Bicarbonate Ion ($\text{HCO}_3^-$) in Plasma (~73%): Principal transport pathway.

The Erythrocyte Bicarbonate & Chloride Shift Cascade

Tissue Cell (CO2 production)
  ↓ (CO2 diffuses into RBC)
CO2 + H2O ──[Carbonic Anhydrase]──> H2CO3 ──> H+ + HCO3-
                                                   │
                                    [AE1 / Band 3 Exchanger]
                                                   ↓
HCO3- exits RBC into plasma  <===>  Cl- enters RBC (Chloride Shift)

1. Tissue $\text{CO}_2$ diffuses into red blood cells (RBCs).
2. Inside RBCs, Carbonic Anhydrase rapidly hydrates $\text{CO}_2$ into carbonic acid: $\text{CO}_2 + \text{H}_2\text{O} \rightleftharpoons \text{H}_2\text{CO}_3$.
3. $\text{H}_2\text{CO}_3$ spontaneously dissociates into $\text{H}^+$ and $\text{HCO}_3^-$.
4. $\text{H}^+$ is buffered by deoxygenated hemoglobin.
5. $\text{HCO}_3^-$ exits the RBC into plasma via Anion Exchanger 1 (AE1 / Band 3 protein) in exchange for a chloride ion ($\text{Cl}^-$) entering the RBC—known as the Chloride Shift (Hamburger Phenomenon). In pulmonary capillaries, the process reverses completely.

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Chemical Control of Breathing: Central vs. Peripheral Chemoreceptors

Ventilatory output is continuously adjusted by central and peripheral chemoreceptors sensing blood gas and arterial pH alterations.

Chemoreceptor Functional Comparison

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Brainstem Respiratory Centers

Automatic, rhythmic breathing originates in neural networks located within the medulla oblongata and pons:

Medullary Control Centers

• Dorsal Respiratory Group (DRG): Located in the nucleus tractus solitarius. Serves as the primary driver for quiet inspiration. Sends phrenic nerve signals to the diaphragm.
• Ventral Respiratory Group (VRG): Contains inspiratory and expiratory neurons. Inactive during quiet breathing; activated during forced exhalation (stimulating internal intercostals and abdominal wall muscles) and strenuous exercise.

Pontine Control Centers

• Pneumotaxic Center (Upper Pons): Smooths respiration by limiting the duration of inspiration ("turns off" the DRG), increasing respiratory frequency and controlling tidal volume.
• Apneustic Center (Lower Pons): Promotes deep, prolonged inspiration by exciting the DRG; inhibited by pneumotaxic signals.