Peripheral chemoreceptors

Question 1

Castro et al 1938?

Answer 1

• Castro 1928 – that there was enormous vascularity of the carotid body 20 mls min^-1 gm^-1. Therefore, concluded that the function of the carotid body is to taste the chemical composition of blood.
  
  • It is now known that the peripheral chemoreceptors are stimulated by blood oxygen, carbon dioxide and pH. (hypoxic hypoxia – lowered PO₂) (stagnant hypoxia – PO₂ normal, low blood flow) (histotoxic hypoxia – chemicals) (hypercapnia increased PaCO₂)

Question 2

Heymans and Bouckeart 1930?

Answer 2

• This idea was supported by Heymans and Bouckaert 1930 – during dual dog blood flow, experiment, whereby, hypoxic circulation increases respiratory reflexes.

Question 3

Phillipson et al 1981?

Answer 3

• Phillipson et al 1981 – in six awake sheep, used venous-venous extracorporeal perfusion included two carbon dioxide membrane lungs (CDML) designed to facilitate the removal of CO2 from blood in order to demonstrate that CO₂ levels in the blood is the major drive to breathe via proportional reductions in minute volume of ventilation (VE)

Question 4

What did Pan et al 1983 do?

Answer 4

• Pan et al 1983 then showed that the primary role of carotid chemoreceptors during room breathing has been thought to ‘fine-tune’ alveolar ventilation in order to minimize fluctuations in arterial blood gases and pH.

Question 5

What did Smith et al 1995 do?

Answer 5

• Smith et al 1995 showed that in awake dogs, perfusion of the surgically isolated carotid chemoreceptors with hyperoxic/hypocapnic blood reduced eupneic breathing by 30%.

Question 6

What did Forster et al 2008 do?

Answer 6

• It was shown many years later Forster et al. 2008 presented evidence to suggests that the carotid chemoreceptors contribute about 1/3 of the overall response to CO2 challenge and play an even more significant role in controlling arterial PCO2 during eupneic (normal) breathing.

Question 7

What did Pan et al 1998 do?

Answer 7

• Pan et al., 1998 studied the ventilatory changes during several days after bilateral CBD in adult awake goats. Found a marked hypoventilation at rest and during exercise along with a 60% reduced CO2 sensitivity, which were greatest about 4–7 days after CBD.
  
  • About 7–10 days after CBD, all ventilatory responses began to return towards normal control, nearly reaching pre-CBD status in an additional week.

Question 8

What did Dahan et al 2007 do?

Answer 8

• Dahan et al 2007 CBD in humans with carotid body tumours. Post surgery there was a 9mmHg increase in PaCO₂ (demonstrating lack of PCR)
  
  • There was recovery/plasticity shown across animals and humans. Therefore, the data indicates that the arterial chemoreflex to CO₂ sensitivity after CBD can be compensated for via central chemoreceptors.

Question 9

Hodges et al 2005?

Answer 9

• Further evidence for this compensatory role has been shown by Hodges et al 2005 whereby although the glutamatergic “drive” are reduced following CBD, a compensatory upregulation of ventilatory responses to raphé injections of the glutamate neurotoxin - ibotenic acid was greatly enhanced following CBD.

Question 10

What is the generic oxygen sensitivty mechanism?

Answer 10

• Glomus cell (peripheral chemoreceptor) of carotid body detects:
  
  • Drop in PO₂
  • The drop is sensed by the glomus cell “Oxygen sensor”
  • Leading to inhibition/closure of potassium channels.
  • This causes membrane depolarization.
  • Resulting in opening of voltage gated calcium channel (calcium entry)
  • Neurosecretion by the glomus cell à activating the afferent fibres of the carotid sinus nerve.

Question 11

What did Trapp et al 2008 do?

Answer 11

• Trapp et al 2008 - TASK-1 channels play a key role in the control of ventilation by peripheral chemoreceptors in response:
• TASK-1 knockout mice
  
  • (10% FiO₂) caused a 49% reduction in chemoafferent discharge in carotid sinus nerve.
  • Normoxic hypercapnia (3-6% CO₂ inspired air) caused 68% reduction in chemoafferent in carotid sinus nerve.
• TASK-3 deficient mice showed no change in response

Question 12

Poss et al 1995?

Answer 12

• Another hypothesis, is the enzyme haemoxygenase-2 (HO-2) which uses oxygen as a substrate, and may close associated K+ channels through the action of its products CO and haem.
  
  • Poss et al 1995 proposed that HO-2 could act as an O2 sensor through the production of CO, which is by itself a maxi-K+ channel activator

Question 13

What did Mill et al 1978 do?

Answer 13

• 3) Or it could be specialised mitochondria of the carotid bodies, senses the drop in PO₂ (which is different to other mitochondria) and then reduces ATP, and thus inhibition of K+ channels.
  
  • Mills et al 1978 inhibitors of the electron transport chain (ETC) or mitochondrial uncouplers increase the afferent activity of the CB sinus nerve

Question 14

What did Chang et al 2015 do?

Answer 14

• ) Chang et al 2015 demonstrated that oxygen sensitivity of glomus cell is mediated by smell receptor - OLFR78 GENE expressed in carotid body (olfactory receptor gene).
  
  • is expressed in oxygen-sensitive glomus cells of the carotid body.
  • Olfr78 (knockout mice) mutants fail to increase ventilation in hypoxia 10% oxygen but respond normally to hypercapnia. Hypoxia-induced carotid body activity is diminished.
  • Lactate, a metabolite that rapidly accumulates in hypoxia and induces hyperventilation activates Olfr78 in heterologous expression experiments - induces calcium transients in glomus cells, and stimulates carotid sinus nerve activity through Olfr78.

Question 15

Conclusion?

Answer 15

• Guyenet 2008 showed that he RTN/pFRG receives a powerful excitatory input from the NTS on peripheral chemoreceptor stimulation and provides an excitatory input to the rhythm generating circuitry in the PreBotC.
• Basting et al 2016 - RTN plasticity is responsible for recovery of PCO₂ set point after CBD in rats.
• In normoxia or hypoxia, RTN optogenetic inhibition produced a more sustained hypopnea post-CBD than before; in hyperoxia, the responses were identical.
• RTN optogenetic inhibition produces a more sustained hypopnea after CBD than before but this change may simply result from the loss of the fast feedback action of the CBs.
• There is increasing research into the interdependence of peripheral and central chemoreceptors on CO2 detection.