Respiratory Physiology Lecture 3

• This lecture is the third in a series of three on respiratory physiology.
• After this lecture, students should be able to explain how the basic rhythm of breathing is generated.
• Students should be able to explain how changes in arterial PCO2 and PO2 are sensed and how they influence ventilation
• Students should be able to explain the respiratory and renal mechanisms for the control of extracellular pH

Basic Rhythmicity of Breathing

• Breathing is a rhythmic activity initiated in the medulla and acting on the respiratory muscles; intercostals, diaphragm, and abdominals.
• All respiratory muscles are skeletal and require primary motor control.
• The diaphragm, the main respiratory muscle, is stimulated by the phrenic nerves via the brain stem.
• Intercostal muscles are innervated by segmental spinal nerves via the spinal column.

Medullary Respiratory Centre - DRG

• The Dorsal Respiratory Group (DRG) contains inspiratory neurones.
• These synapse with primary motor neurons that stimulate inspiratory muscles.

Medullary Respiratory Centre - VRG

• The Ventral Respiratory Group (VRG) contains pacemaker neurones.
• Pacemaker neurones generate spontaneous rhythmic bursts of action potentials that set the basal rate of breathing.
• VRG contains expiratory neurones that synapse with primary motor neurones that stimulate expiratory muscles.
• VRG and DRG communicate with each other.

Normal Quiet Breathing

• Pacemaker neurons initiate spontaneous rhythmic bursts of stimulation.
• This leads to the contraction of inspiratory muscles causing inspiration.
• Relaxation occurs, followed by passive recoil, leading to expiration, which does not require expiratory muscles.

Pons

• The Pons offers fine-tuning of the breathing cycle.
• Two regions of the pons feed signals into the medullary respiratory centre.
• The pneumotaxic centre smooths transitions between inspiration and expiration.
• The apneustic centre regulates breath duration.

Control of Breathing

• The limbic system mediates responses to temperature, emotional state, and pain.
• The cerebral cortex can override the respiratory centre.
• Cerebral motor neurons connect directly to respiratory motor nerves, bypassing the pons and medulla.
• This is important in speech, eating, and diving and allows for subconscious/voluntary control of breathing.

Lung Stretch Receptors

• Deep inspiration stretches airways, activating stretch receptors in bronchial smooth muscle.
• This activates the vagus nerve, which sends impulses to the DRG, inhibiting inspiratory neurons.
• Further inspiration is inhibited, preventing over-inflation of lungs and allowing time for expiration before the next breath

Metabolic Demand

• An increased metabolic demand results in an increase in both oxygen consumption and carbon dioxide production.
• For the whole system to remain in equilibrium, arterial oxygen and carbon dioxide must be maintained.
• PO2 is ~ 12.5 kPa while PCO2 is ~ 5.3 kPa.
• PCO2 and PO2 are maintained by adjusting ventilation.

Chemoreceptors

• Central chemoreceptors in the medulla detect changes in [H+] in cerebrospinal fluid in equilibrium with CO2 in arterial blood.
• Peripheral chemoreceptors in carotid bodies detect changes in PO2 and [H+] in arterial blood, triggering a synergistic response if both change.
• PCO2 cannot be detected directly.
• A change in arterial carbon dioxide is reflected by a change in cerebrospinal or arterial [H+].

Resting Ventilation

• Everyday variations in metabolic demand affect ventilation.
• Increased arterial partial pressure of CO2 (PCO2)/[H+] is detected by chemoreceptors, leading to increased ventilation and CO2 expiration.
• Decreased arterial partial pressure of CO2 (PCO2)/[H+] inhibits chemoreceptors, leading to decreased ventilation and CO2 expiration.
• The control of ventilation is a negative feedback.

Arterial Partial Pressure of Carbon Dioxide Effects on Ventilation

• In healthy individuals at rest, arterial partial pressure of CO2 (PCO2) is the primary determinant of ventilation rate.
• High PCO2, known as hypercapnia, is associated with an increased ventilation rate.
• Small changes in arterial PCO2 produce large effects on ventilation, showing a linear relationship.
• The bottom of the curve represents the basal rhythm of the medullary respiratory centre.
• The top of the curve represents the depression of the respiratory centre

Ventilation Increased Above Normal

• Pacemaker neurons lead to spontaneous rhythmic bursts of stimulation.
• This leads to stronger contractions of diaphragm and recruitment of accessory muscles and the contraction of expiratory muscles (abdominals).
• It results mainly in an increased tidal volume during exercise, altitude exposure or disease, which increases ventilation.

Regulation when Arterial Partial Pressure of Oxygen is Low

• At high altitude, inspired PO2 is low, therefore arterial PO2 is low.
• Gaseous exchange is impaired in lung disease, so arterial PO2 is also low.
• Low arterial PO2 and/or arterial PCO2/[H+] are sensed by chemoreceptors, leading to increased ventilation.
• Ventilation is then negatively fed back via O2 absorption & CO2 expiration.

Ventilation at Constant Partial Pressure Constant Partial Pressure of Carbon Dioxide

• The effect of arterial partial pressure of oxygen on ventilation is minor until PO2 drops below ~8 kPa; after which, the response is profound.
• Under normal conditions at rest, PO2 does not contribute significantly to ventilation rate.
• PO2 becomes an important factor at altitude, in respiratory disease, or during intense exercise.

Synergistic Ventilation Effects

• Hypercapnia and hypoxia combined cause the biggest increase in ventilation and the two effects are synergistic.
• Very important in end-stage respiratory disease.

Moderate/Intense Exercise

• Ventilation control maintains arterial partial pressures of oxygen and carbon dioxide during exercise despite big increases in oxygen consumption and big increases of carbon dioxide in muscle.
• Increases in venous carbon dioxide, also drops venous oxygen.
• Ventilation increases due to lactic acid in muscle, sensed by chemoreceptors and muscle and joint mechanoreceptors.
• Exercise is NOT negative feedback.
• Drive from adrenaline and the ‘fight or flight’ response.

Extracellular pH

• pH is the -log M [H+], so more H+ means lower pH and less H+ means higher pH
• Protein function is extremely sensitive to changes in [H+].
• Impairment or dysfunction of protein function will cause illness or death.

Alter pH

• The main physiological buffer = CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3-
• pH = 6.1 + log([HCO3−]/[CO2]).
• Gain of H+ (pH <7.4) = Acidosis.
• Causes include respiratory acidosis as a result of impaired elimination of CO2 in respiratory disease aka hypoventilation. This is typically metabolic acidosis due to increased production of volatile organic acids such as Lactic acid (intense exercise) or Hydroxybutyric acid (diabetes or fasting), or diarrhoea/renal dysfunction.
• Loss of H+ (pH >7.4) = Alkalosis.
• Causes include Respiratory alkalosis as a result of increased elimination of CO2 caused by anxiety aka hyperventilation. This is typically metabolic alkalosis due to increased utilization of H+ in the metabolism of organic molecules in vomit.

Metabolic Acidosis/Alkalosis

• Rapid (within minutes) response to changes in [H+] from sources other than CO2/H2CO3.
• Metabolic acidosis (gain of H+ from organic acids): CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3- (left-ward shift), increased ventilation, H+ loss (as CO2 + H2O).
• Metabolic alkalosis (loss of H+ through metabolism): CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3- (right-ward shift), decreased ventilation, H+ retention (from CO2 + H2O).

Ventilation Combined Effect of PCO2 and pH

• Raised [H+] (low pH) enhances sensitivity to PCO2, while a drop in [H+] does the opposite

Respiratory Compensation

• Respiratory compensation for metabolic acidosis or alkalosis is not sustainable .
• [H+] is corrected at the expense of HCO3-.
• Acidosis causes H+ is converted to CO2, but plasma HCO3- is depleted.
• Alkalosis new H+ is made from CO2, but excess HCO3 accumulates.
• Thus respiratory compensation for metabolic acidosis or alkalosis is therefore only a short-term solution & long-term solution involves the kidney.

Renal Handling

• Renal excretion/reabsorption of H+/HCO3 provides a long-term solution.
• Reabsorbed HCO3 matches filtered HCO3 = in balance.
• Excess H+ excreted as phosphate & HCO3 is reabsorbed (short-term).
• Excess H+ excreted as ammonium & new HCO3 is made (long-term).

Renal Compensation

• In Metabolic acidosis production of organic acids the Body compensates by; Depletion of plasma HCO3 + liver makes more glutamine ,Less HCO3 filtered, More H+ excreted as phosphate ,More H+ excreted as NH4+, More HCO3 and NH4+ made from glutamine More HCO3 reabsorbed ,Plasma [H+] and [HCO3] restored to normal .

Renal Compensation for metabolic alkalosis

• The Body accumulates of HCO3 and depicts H+ and will try to compensate by; decreasing more glutamine ,increased HCO3 filtered and excreted ,reduced H+excreted as phosphate , reduce H+excreted as NH4+ ,reduced HCO3+ and NH4+ ,Plasma [H+] and [HCO3] are restored to normal .