15-­‐10-­‐18

Last  class:  “Chemical”  Control  of  

breathing:  Chemorecep:on  
 
Arterial  Blood  Chemical  s:muli  
-­‐ Hypoxia  
-­‐ Carbon  dioxide  
-­‐ Hydrogen  ion  
Caro:d  sinus  nerve  

External  Caro:d  
Chemosensor-­‐effector   artery  
pathways  to  respond  to  
Ryan Chow: don't actually affect respiration
chemical  s:muli  
-­‐  the  periphery   rco
Inte orneu
 
stal ons  
r
t
mo

Control  of  breathing:  chemorecep:on  

• Name  3  s:muli  to  breathe   • Describe  the  central  
chemoreceptor  areas  
• Iden:fy  the  loca:on  of  peripheral  
chemoreceptors,  cell  body   and  their  role  in  the  
loca:on  &  sensory  pathways  to   ven:latory  response  to  
the  CNS   CO2  
• Compare  and  contrast  the   • Outline  the  
chemoreceptor  mechanisms  for   chemoreceptor  
oxygen  and  carbon  dioxide   signaling  mechanisms  in  
•  Describe  the  caro:d  body   hypoxia  
response  to  hypoxia,  CO2  and  H+  
• Discuss  the  shape  of  the  caro:d  
body  response  to  hypoxia  and  its  
evolu:onary  ra:onale  

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Caro:d  body:  cellular  anatomy  

To  what  brain  area?  

• Type  I  cells  or  glomus   Ryan Chow: these are the signalling mechanisms... but it's
a "murky" area
cells  
• Type  II  cells  
sustentacular  cells  that  
surround  Type  I  cells     Type  II    
Cell    
 there are many theories about
how this works
Sensory  endings  synap:c   Ryan Chow: who know what the cells do, but not how they
link  with  Type  I  cells;     work

Type  I  responsible  for  

chemo-­‐sensa:on   Type  II  Cell    
Ryan Chow: surround type I cells
Ryan Chow: similar to glial cells... contribute to signal
transduction?

Caro:d  body:  cellular  anatomy  

• CB  senses  PO2  of   Ryan Chow: you don't need this if you're a snail. (breathes
arterial  blood  or  the   through skin)
dissolved  O2  vs  bound  
to  Hb  
Type  I    
• Carbon  monoxide  has   Cell    
no  effect  on  the  
response   Ryan Chow: b/c it binds to Hg, does not affect partial
pressure of O2

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Caro:d  body:  Hypoxia  Afferent  response  

Ryan Chow: Action potentials in the petrosal ganglia
Nonlinear  response  
(percentage of max response)
• Large  é  discharge  at  
PO2  <  60  mmHg   Ryan Chow: essentially enhances the sensitivity of the
PaCO2=57  mmHg   carotid bodies to oxygen... MULTIPLICATIVE EFFECT
pH=7.22  

 
PaCO2=35  mmHg  
Hypoxia  -­‐  Low  oxygen   pH=7.33  

-­‐ Interac:on  with  CO2  

-­‐ A  Mul:plica:ve  effect  
which  is  more  than  the  
sum  of  the  responses  

Caro:d  body:  CO2  &  H+  Afferent  response  

Impact  of  hydrogen  ion  on  caro:d  body  discharge  
Arterial  [H+]=70  nM  

PaCO2  =  26  mmHg  

Change  CO2  at  diff  [H+]  or  change  [H+]  @  constant  PCO2  

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Caro:d  body:  Organismal  responses  

Inhale  hypoxic  gas  
Oxygen/CO2  Analyzer  
• As  PaO2  drops  add  CO2  
100%  or  21%  or  15%  
to  bag  to  maintain    or  12%  Oxygen   Ryan Chow: essentially simulates drops in partial
“isocapnia”     Condi6on  one:  
pressure (ex. altitude)
PaCO2=35  mmHg  
• e.g.  PaCO2=35  mmHg   pH=7.33      
Condi6on  two:  Hypoxic  
  response  with  increased  
CO2  or  hypercapnia  
PaCO2=57  mmHg  
Hypoxia  +  hypercapnia   pH=7.22  

-­‐ PaO2  response  on  a  

background  of  elevated  
CO2    or  “hypercapnia”    

Oxyhemoglobin  dissocia:on  curve  

• Sigmoid  shape  
• Flat  Plateau  region  
protects  arterial  
content  
• 2  ml  dissolved  
O2/100ml  blood  at  
close  to  100%  O2  
• cardiac  output  5L/min  
• Dissolved  O2  delivery/
min  =  20/L  or  100/min   Ryan Chow: evolution adapted ventilation to match Hb
dissociation, NOT pO2, b/c pO2 is not reliable

Ryan Chow: roughtly 350 mL of oxygen/minute is required

Ryan Chow: ie. you cannot rely solely on dissolved oxygen

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REMEMBER: ventilation curve matches oxyhemoglobin dissociation curve

V40  is  an  index  of  hypoxic  response  

Ven:la:on  (L/min)  

Ven:latory  response  is  sensi:ve    

to  drug-­‐induced  reduc:ons  
Depression  of  the     Ryan Chow: axis is reversed... morphine is a Hypoxic
Controller  or  CPG   Response DEPRESSANT
Reverse  PO2  axis  hi  to  lowà  

The  Human  Response  to  hypoxia  

Why  is  the   Hypercapnic  
isocapnic   PCO2=48  mmHg  
response  
Ven:la:on  (L/min)  

lower?  

Ryan Chow: normocapnic: CO2 is being actively pumped

into inspiratory air

ß  Why  does  
PCO2  ê?   Ryan Chow: this is b/c metabolism is constant

PaCO2 is proportional to (VCO2/VA)

the Carotid Body is the ONLY sensor to detect HYPOXIA.

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Central  chemoreceptors  
The  search  for  central  
chemoreceptors  
-­‐ 1950’s  perfuse  brain  with  
acidic  CSF    
-­‐ 1960’s  Mitchell  &   Ryan Chow: these areas are responsible sensing for H+
Loeschcke  Iden:fied   ions?
regions  on  the  ventral  
surface  of  the  medulla  
that  increased  breathing  
R  =  rostral  area  
C  =  caudal  area  
 

Ryan Chow: co2+h20 --> h+ + HCO3

Central  chemoreceptors  
Central  chemoreceptor  
contribu6on  to  
ven6latory  responses:  
-­‐ approx  2/3  of  the   There's no "buffer" in the CSF
ven:latory  response  
to  CO2  
Ryan Chow: CO2 will cross the blood-brain barrier... and
-­‐ Since  H+  does  not   THEN undergo the hydration reaction
cross  the  blood  brain  
barrier  the  hydra:on  
of  CO2  is  cri:cal    
-­‐ What  does  the  CO2  
response  look  like?  
CO2  +  H2O  à  H2  CO3  à  H+  +  HCO3    
Ryan Chow: respiratory acidosis

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Alveolar  ven:la:on:  sets  the  context  for  the  

ven:latory  response  to  CO2  
hypoventilation: Va is LESS than VCO2, and
PaCO2 goes up (above 40)

Ven:la:on  (L/min)  
hyperventilation: Va is GREATER than VCO2
and PaCO2 goes down (below 40)
Ryan Chow: paper bag example?

..  
Ryan Chow: when CO2 is added to inspired gas, the graph

………
will shift UP
Ryan Chow: O2 will stay contant, but CO2 will increase
Set  Point  
PaCO2 is proportional
to (VCO2/VA)

Measuring  the  Human  response  to  CO2  

Rebreathe  hyperoxic  gas  
+  CO2     Oxygen/CO2  Analyzer  
Rebreathe  95%  oxygen  
• What  happens  to  CO2    &  5%  CO2  
and  O2   Condi6on  one:  
PaCO2=35  mmHg  
• Measure  ven:la:on   pH=7.33       Ryan Chow: eventually CO2 will increase, which
Condi6on  two:  Hypoxic  
response  with  increased  
CO2  or  hypercapnia  
PaCO2=57  mmHg  
pH=7.22  

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The  Human  Response  to  CO2  

Ryan Chow: ventilation is gonna INCREASE greatly

Ven:la:on  (L/min)  

• Ven:latory  responses  are  powerfully  modulated  by  sleep    

and  drugs   Ryan Chow: both CO2 and O2 sensitivity goes down when
sleeping.
CO2  Sensi:vity   O2  Sensi:vity   Ryan Chow: similar to morphine response?

Fully  Saturated   Low  Sat  

CO2  Satura:on  
End  Tidal  PCO2  

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Return  to  Caro4d  Body:  

Sensing  Hypoxia  &  Transduc4on  
Transduc:on  mechanisms  for  acute  hypoxia  should  
be  able  to  account  for  the:  
 
1. par:cularly  high  sensi:vity  of  the  organ  for  changes  
in  PO2    
2. rapidity  of  the  response    -­‐  within  seconds  
3. modula:ng  ac:ons  of  other  natural,  systemic  or  
pharmacological  s:muli  
 

Sensing  Hypoxia—Type  I  neuronal  

response  
 
Type  I  cell  has  a  neurosecretory   func:on  with  
afferent  
  nerve  endings:  
• Evidence  of  an  absolute  requirement  for  Ca2+-­‐
dependent  neurotransmission  
• Elevated  intracellular  Ca2+  derived  from  extracellular  
sources    
• Ca2+  entry  via  voltage  gated  Ca2+  channels  (VGCC)  
subsequent  to  membrane  depolariza:on  
• membrane  depolariza:on  induced  by  inhibi:on  of  K+  
channels  linked  to  a  subcellular  sensor  

 
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Sensing  Hypoxia  
Membrane  hypothesis  –  O2  sensi:ve  K+  channels  
 
• depolariza:on  induced  by  closure  of  selec:ve  K+  
channels  located  in  the  plasma  membrane  of  type  I  
cells  
• a  key  role  in  chemotransduc:on  for  O2-­‐sensi:ve  
plasmalemmal  K+  channels    
• No  single  class  of  K+  channel  across  species  explains  
the  type  I  cell  response  i.e.  lack  intrinsic  O2  sensi:vity  
• Mul:ple  K+  channel  candidates…causal  or  related?  

  Sensing  Hypoxia  
Mitochondrial  hypothesis  –  Confers  appropriate  K+  
channel  
  func:on:  
• O2  sensi:vity  of  K+  channels  of  type  I  cells  is  not  
intrinsic  but  conferred  by  its  coupling  to  an  O2-­‐
dependent  “extrinsic  factor”    
• type  I  cell  mitochondria  differ  in  appearance  to  those  
found  in  both  type  II  cells  and  sinus  nerve  endings…  
•  inhibitors  of  oxida:ve  phosphoryla:on  (i.e.  
mitochondrial  func:on)  have  nonspecific  ac:ons  
upon  K+  channel  ac:vity  

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Sensing  Hypoxia  
ATP  and  AMP-­‐ac:vated  protein  kinase  (AMPK)  
• Caro:d  body  increases  metabolism  during  hypoxia;  
ac:vity  é due  to  excitatory  ac:on  of  hypoxia  on  
afferent  discharge  &thus  altering  ATP  metabolism  
• AMPK  is  a  serine/threonine  kinase    
• ac:vated  by  increases  in  the  cellular  AMP/  ATP  ra:o    
• may  bring  together  K  channel  and  mitochondrial  Ho’s  

Several  other  hypotheses  exist  as  do  several  new  

modulators  of  CB  func:on  

Control  of  breathing:  chemorecep:on  

•  Name  3  s:muli  to  breathe   • Describe  the  central  
chemoreceptor  areas  
• Iden:fy  the  loca:on  of  peripheral  
chemoreceptors,  cell  body   and  their  role  in  the  

the  CNS  
þ
loca:on  &  sensory  pathways  to  

• Compare  and  contrast  the   •

CO2   þ
ven:latory  response  to  

Outline  the  
chemoreceptor  mechanisms  for   chemoreceptor  
oxygen  and  carbon  dioxide   signaling  mechanisms  in  
•  Describe  the  caro:d  body   hypoxia  
response  to  hypoxia,  CO2  and  H+  
• Discuss  the  shape  of  the  caro:d  
body  response  to  hypoxia  and  its  
evolu:onary  ra:onale  

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