Respiratory Control System Notes

Neural and Chemical Control of Breathing

Intended Learning Objectives

• Describe and explain the role of the brainstem in control ventilation including the organization & function of respiratory centers.

• Describe and explain sensors and effectors in neural & chemical control of ventilation.

• Describe and explain the CO2-HCO3 buffer system in context of chemical control breathing and pH homeostasis.

• Describe and explain location, function, enervation, and differences of the peripheral and central chemoreceptors (sensors).

• Interpret graphs showing how alterations in PaO2 and PaCO2 alter ventilation.

Homeostatic Control of Breathing

• Control Center: Medulla, pons.

• Receptors: Peripheral chemoreceptors, central chemoreceptors, pulmonary mechanoreceptors.

• Effector: Respiratory muscles (diaphragm).

• System responds to imbalance and initiates correction.

Nervous System Control of Ventilation - Overview

• Control/adjustments are carried out by several groups of neurons.

• Located in the brainstem - medulla and pons.

• Divided into four major groups of neurons:

  • Dorsal respiratory group (DRG).

  • Ventral respiratory group (VRG).

  • Apneustic center.

  • Pneumotaxic center.

Nervous System Control of Ventilation: Pattern Generator and DRG

• The brain sets the basic, automatic ventilation rate and depth and can rapidly adjust both the number (rate) of breaths and volume (depth) of air in the respiratory cycle.

• The basic rhythm is set by a central pattern generator in the VRG (rostral region) pre-Bötzinger complex, which sends pacemaker signals to the DRG.

• DRG premotor neurons project to groups of spinal motor neurons, including the phrenic nerve (diaphragm) and intercostal nerves (external intercostals).

• Activating these neurons causes inspiration.

• The DRG receives information from various sensors via cranial nerves (CNs) X and IX, including chemoreceptors, lung, and chest wall mechanoreceptors.

• The DRG also receives sensory information from higher brain centers.

Nervous System Control of Ventilation: VRG

• The VRG functions primarily to coordinate accessory muscles for inspiration and expiration.

• It is largely quiescent during quiet breathing but becomes highly active during exercise and any forced ventilatory maneuvers, particularly in people with lung disease.

• VRG premotor neurons control the internal intercostals and other accessory muscles of expiration.

Nervous System Control of Ventilation - Fine Tuning: Pontine Respiratory Centre (Pneumotaxic and Apneustic Centres)

• Limit lung expansion.

• Faster transition from inspiration to expiration - a shorter inspiratory phase leads to an increased breathing rate.

Chemical Control of Ventilation

• Centers in the brainstem activate respiratory muscles rhythmically and subconsciously, setting an automatic rhythm for the contraction of respiratory muscles.

• The system needs to respond to changes in PO2, PCO2, and pH.

• Ventilation needs to accommodate several tasks:

  • Maintain adequate oxygen status.

  • Adjust ventilation for changing metabolic status/needs reflected by altered PO2, PCO2, and pH.

• Peripheral chemoreceptors sense PO2, PCO2, and pH.

• Central chemoreceptors sense PCO_2 (primary stimulus) and pH.

• Both send information to brain respiratory centers, resulting in adjustments both in depth and frequency of ventilation as needed.

Chemical Control Ventilation

• Control Center: Medulla, pons.

• Receptors: Peripheral chemoreceptors, central chemoreceptors, pulmonary mechanoreceptors.

• Effector: Respiratory muscles (diaphragm).

• System responds to imbalance and initiates correction.

Peripheral Chemoreceptors

• Carotid bodies:

  • Located at the bifurcation of the common carotid arteries.

  • Do not confuse with the carotid SINUS (site of baroreceptors).

• Aortic bodies:

  • Located in the aortic arch (thorax).

• Both bodies are primarily sensitive to decreases in arterial PO2, although high PCO2 (hypercapnia) and low pH (acidosis) also stimulate.

• The major function of carotid & aortic bodies is to sense hypoxemia & signal cells in the medulla to increase alveolar ventilation.

How do Glomus cells detect hypoxaemia?

• Hypoxaemia leads to depolarization due to the closure of potassium channels (which when open leak potassium outwards and maintain a negative membrane potential).

• Depolarization triggers the opening of voltage-sensitive calcium channels, triggering the release of acetylcholine and other transmitters.

• These act on receptors on afferent nerve fibers adjacent to the glomus cell and cause action potentials which travel up to brainstem respiratory centers.

Carotid Body Innervation

• The carotid body is also supplied by parasympathetic and sympathetic efferent nerve fibers in the glossopharyngeal and vagus nerves which control sensitivity to hypoxaemia, possibly by constricting or dilating the capillaries in the carotid body and thus regulating the partial pressure of oxygen in tissue.

Carotid Body Afferent Nerves

• Effect of arterial PO_2 on nerve impulse firing rate from the carotid body

• Notice markedly increased firing of nerve once PO_2 has fallen below 60 down to 30 mmHg (8 - 4 kPa) - when hemoglobin saturation with oxygen decreases rapidly.

• 100 mmHg = 13.3 kPa (0.1333 \, x \, mmHg \,convert \,to \, kPa)

Experimental Responses to Inhaled CO_2

• Each curve of total ventilation against alveolar PCO2 is for a different alveolar PO2.

• Note that with the lower levels of oxygen, the curve is steeper, i.e., the sensitivity to CO_2 is increased in hypoxaemia.

• Ventilation Response to alveolar partial pressure of CO_2 is linear.

Experimental Responses to Inhaled O_2

• Responses to hypoxaemia at three different fixed levels of CO_2.

• Note that at a normal level of CO2 (43.7 mmHg), there is very little response of the respiratory system until quite severe hypoxaemia (alveolar PO2 60 mmHg/ 8 kPa).

• However, with hypercapnia, sensitivity to hypoxaemia is much greater.

Bottom Line: What can we deduce from previous graphs?

• The main chemical drive to ventilation in normoxia is hypercapnia (an increase in CO_2).

• Hypoxaemia on its own (without hypercapnia) does not strongly stimulate breathing until the PO_2 is less than 8 kPa.

Peripheral Chemoreceptors and pH

• If peripheral chemoreceptors sense low PO2 and/or high PCO2 they will feed back to medulla respiratory centers to increase minute ventilation – this leads to an increase in PO2 and a decrease in PCO2.

• Peripheral chemoreceptors also increase firing in acidosis, causing increased ventilation - how does increasing minute ventilation compensate for acidosis (low pH – high protons)?

• CO2 strongly influences blood pH – based on the following reaction: CO2 + H20 <-> H2C03 <-> HCO3^- + H^+.

• CO2- HCO3^- is the major buffer system of the body.

pH Homeostasis

• Blood pH is normally maintained between 7.35 and 7.45 via buffers – buffers are required to adjust for changes from metabolism and nutrition.

• It is essential to normal function.

• Acidosis: proteins denature.

• Alkalosis disrupts the function of all excitable cells by decreasing levels of free ionic calcium.

• The body has several extracellular buffer systems though certain body compartments – such as the CNS- only have one - CO2- HCO3^-.

pH Homeostasis

• Major pH extracellular buffer system of body – bicarbonate buffer system: CO2 + H2O <-> H2CO3 <-> H^+ + HCO_3^-.

  • [Dissolved CO_2] = 1.2 mmol/L.

  • [HCO_3^-] = 25 mmol/L.

• Reversible reaction: the rate of the reaction depends on the amounts of reactants and products – “Law of Mass Action”.

pH Homeostasis: Dual Act Kidneys and Respiratory Tract

• Kidney:

  • Increases/decreases HCO_3^- reabsorption and synthesis – takes hours to days.

  • Has other mechanisms to manage acid-base balance discussed in later lectures. SLOW RESPONSE

• Lungs:

  • Increase/decrease CO_2 levels.

  • Rapid response – seconds/minutes.

  • Will be moderated by changing HCO_3^- levels by the kidney, but this takes hours-days. QUICK RESPONSE.

Peripheral Chemoreceptors and pH

• CO2 + H2O <-> H^+ + HCO_3^-.

• Pushes the reaction to the left, more H is consumed, and acidosis improves – a compensatory mechanism by lungs for a metabolic problem causing acidosis (like DKA).

• OR (another way to think about this question):

  • pH \propto \frac{[HCO3^-]}{[CO2]}.

  • If CO2 goes down, as pH is inversely related to CO2, pH increases – improves acidosis.

• How does increasing minute ventilation compensate for acidosis (low pH – high protons)?

Summary Peripheral Chemoreceptors

• Carotid and aortic bodies – bifurcation of the common carotid artery & aortic arch.

• Sensory enervation to the brainstem.

  • Carotid body - branch of CN IX.

  • Aortic body - branch CN X.

• Most sensitive to arterial partial pressure of oxygen - low PO_2.

• But also send increased signals to the brainstem in response to high PCO_2 and low pH.

• Hypoxaemia increases peripheral chemoreceptors’ sensitivity to acidosis and hypercapnia.

• Hypercapnia increases carotid body sensitivity to hypoxaemia.

Central Chemoreceptors

• Specialized neurons located on the BRAIN side of the Blood-Brain Barrier (BBB) - bathed in CSF – in the ventral medulla.

• Sense increases in arterial PCO2 and—much more slowly—decreases in arterial pH, but not arterial PO2.

• When arterial oxygen parameters are normal, central chemoreceptors are the primary source of feedback to the brainstem respiratory centers for needed adjustments.

• If PCO_2 increases suddenly then ventilation increases rapidly - augmenting minute ventilation.

• BBB = endothelial cells of blood vessels in the brain surrounded by pericytes and foot processes (end feet) of astrocytes to create a highly selective permeability barrier.

Central Chemoreceptors - Response to CO_2 and pH

• Central chemoreceptors (CC) actually respond to CSF pH changes caused by changes in CO_2 levels.

• CC do also respond to changes in plasma H^+ - slower response and degree debated.

• Carbon dioxide diffuses freely through the blood-brain barrier into CSF - reacts with water to form carbonic acid.

• The carbonic acid is converted into protons and bicarbonate by the enzyme carbonic anhydrase (CA).

Central Chemoreceptors – how do they sense changes in PCO_2 & pH?

• The BBB has a low permeability to ions such as H^+ and HCO3^-, but high permeability to small molecules like CO2.

• If CO2 levels rise, more CO2 diffuses into the CSF bathing brain cells, including Central Chemoreceptor Neuron Cells.

• The CNS has a very limited HCO_3^- buffering capacity and therefore acidosis develops.

• Even small decreases in pH raise the firing rate of the central chemoreceptor neurons, thus increasing ventilation.

• The opposite happens if CO_2 levels fall.

• BUT if CO_2 levels are chronically high or low, the kidney & CNS compensate.

CNS Compensation for Chronic Respiratory Acidosis

• High CO_2 from problems with the respiratory tract.

• Need to understand the choroid plexus to answer the question.

• Inside brain fluid-filled spaces are cerebral ventricles: the fluid they contain is cerebrospinal fluid (CSF) – bathes neurons.

• The composition is tightly regulated.

Choroid Plexus & CSF

• Specialized tissue within brain ventricles with capillaries allows water and small ions to pass in and out in a regulated manner; this tissue is called the CHOROID PLEXUS.

• Fluid filtered through the choroid plexus forms cerebrospinal fluid (CSF), and this CSF fills ventricles and bathes the brain.

• No plasma proteins are filtered through the choroid plexus - CSF contains almost no protein.

• The lack of protein means it has a much lower pH buffering capacity than blood.

• Only buffer is the CO2-HCO3^- system.

Central Chemoreceptors & Chronic Hypercapnia

• Chronic lung diseases such as emphysematous dominant COPD may lead to chronic hypercapnia.

• If CO2 remains elevated, the pH of CSF slowly recovers (i.e., increases) over 8 - 24 hours – because the choroid plexus increases active transport of HCO3^- into CSF – bicarbonate buffers protons generated by increased CO2, thus CO2-induced acidosis gradually becomes smaller - pH rises in CSF.

• This transport represents CNS metabolic compensation to respiratory acidosis.

• This adjustment also means that a higher level of CO2 is needed to cause acidosis and thereby increase ventilation – thus the CO2 drive for ventilation has been “reset” at a higher level.

• Lastly, there is also metabolic compensation throughout the body for respiratory acidosis - kidneys achieve this by increasing blood bicarbonate through increased reabsorption and synthesis – takes 3-5 days to see the full effect.

• pH \propto \frac{[HCO3^-]}{[CO2]}.

Central Chemoreceptors & Chronic Hypocapnia

• Chronic hypocapnia is rare but occurs at high altitude – triggered by hypoxaemia-induced hyperventilation.

• May also result as compensation for metabolic acidosis.

• Leads to CSF alkalosis.

• If CO2 remains low, the pH of CSF slowly recovers (i.e., decreases) 8 - 24 hours – because the choroid plexus decreases active transport of HCO3^- into CSF – lower HCO3^- leads to increased protons and low CO2 induced alkalosis gradually becomes smaller- CSF pH falls.

• This transport represents CNS metabolic compensation to respiratory alkalosis.

• Lastly, there is also metabolic compensation throughout the body for respiratory alkalosis - kidneys achieve this by decreasing blood HCO_3^- through decreased reabsorption and synthesis – takes 3-5 days to see the full effect.

• pH \propto \frac{[HCO3^-]}{[CO2]}.

Time for Bicarbonate Adjustment

• Adjustment of bicarbonate by the choroid plexus and kidneys takes TIME.

  • CSF – approx. 24 hours.

  • Kidneys 2-5 days maximal effect.

• Thus, if there is adjustment, the acid-base disturbance has been going on for days.

Other Lung Receptors Affecting Ventilation (Mechano & Chemical)

• Pulmonary Stretch Receptors:

  • In bronchioles and small bronchi.

  • 'Cut off switches’ which inhibit inspiration when lungs become fully inflated.

  • Prevent damage to delicate tissues of the lung by overinflation.

  • At the end of inspiration, they send action potentials through afferents in the vagus nerve to brainstem respiratory centers, which inhibits inspiration.

  • This neuronally mediated inhibition of inspiration is known as the Hering–Breuer inflation reflex.

• Irritant receptors:

  • Mechanoreceptors are found in the lining of the trachea and large bronchi.

  • Detect objects in airways too large to be carried away by mucus; they activate cough reflexes.

• J-receptors:

  • Chemoreceptors respond to pulmonary edema, pulmonary emboli, pneumonia, and barotrauma – pathophysiological processes that decrease oxygenation.

  • J receptors stimulate an increase in ventilation.

Summary: Respiratory Responses to Gases

• Response to pCO_2:

  • Arterial PCO_2 is the most important stimulus.

  • Most of the stimulus comes from central chemoreceptors, but peripheral chemoreceptors also contribute, and their response is faster.

  • The response is magnified if the arterial PO_2 is lowered.

• Response to pO_2:

  • Only peripheral chemoreceptors are involved.

  • There is negligible control during normoxic conditions.

  • The response is significantly increased in hypoxaemia.

Inputs Affecting Respiratory Centers

• Higher brain centers (cerebral cortex-voluntary control over breathing).

• Other receptors (e.g., pain) and emotional stimuli acting through the hypothalamus.

• Respiratory centers (medulla and pons).

• Peripheral chemoreceptors (O2, CO2, H^+).

• Central chemoreceptors (CO_2, H^+).

• Stretch receptors in lungs.

• Receptors in muscles and joints.

• Irritant receptors.

Summary: Components of the Respiratory Control System

• Voluntary control (Cerebrum)

• Respiratory control centers (Medulla and Pons)

• Spinal motor neurons

• Phrenic and other nerves

• Muscles of respiration

  • Diaphragm

  • Intercostals and accessory muscles

• Muscle proprioceptors

• Chemoreceptors

  • Central chemoreceptors

  • Peripheral chemoreceptors

    • Carotid

    • Aortic

• Mechanoreceptors

• Lung receptors

  • Stretch

  • J receptors

  • Irritant