bio2a03-respiration lecture notes
TRANSCRIPT
2. respira*on Cellular respira+on. Metabolic processes within cells. e.g. C6H12O6 +6 H2O+ 6O2 à 12H2O + 6CO2 + 38 ATP
1. respira*on Gas exchange. Movement of O2 from environment to cell (mitochondria) and movement of CO2 in opposite direc*on
Two meanings of the term “respira*on” (both are correct)
Metabolism: Ch 3 pages 72-‐90
External respira*on
Internal respira*on
RESPIRATION
Chapters 16 and 17
Oxygen Transport Pathway (also called the O2 cascade) The sequen*al series of ‘steps’ involved in moving oxygen from the environment to mitochondria in cells CO2 moves along the same pathway, but in the opposite direc*on The following series of lectures will focus on the importance of ven*la*on, pulmonary diffusion, and blood gas transport for gas exchange and acid-‐base homeostasis
EXTERNAL RESPIRATION
Ven*la*on
Pulmonary Diffusion
Circula*on
Tissue Diffusion
Cellular U*liza*on
or Produc*on
RESPIRATION LEARNING OBJECTIVES • Differences between external and internal respiration • Major structures of the respiratory tract, and their function • Structure and gas-exchange function of the alveoli and
respiratory membrane • Role of pulmonary surfactant • The breathing cycle, different lung volumes and capacities, total
and alveolar ventilation, breathing frequency • Neural mechanisms that establish the respiratory rhythm and
those that modify it (chemoreceptors) • Transport pathways for oxygen and carbon dioxide, and the
partial pressures of each throughout the pathway • Mechanisms of oxygen and carbon dioxide transport in the blood,
including the function of haemoglobin • Relationship between CO2 and pH in the blood • Respiratory and other compensatory mechanisms that help
maintain acid-base homeostasis
_________ zone -‐ No gas exchange between air & blood here
__________ zone – Site of gas exchange
Anatomy of the respiratory tract
Fig. 16-‐2
Conduc*ng Zone. Reinforced with _______ and smooth muscle
Respiratory Zone. Lidle car*lage or smooth muscle -‐ allows for ___ ________ with blood
Fig. 16-‐3
Anatomical features
30 Million alveoli – 100m2 Surface Area
|<-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐ sm
ooth m
uscle -‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐>|
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Important Conduc*ng Zone Func*ons
The ‘epiglohs’ at the opening of larynx prevents food from entering trachea. Larynx also contains the __________.
Car*lage and smooth muscle provide strength, which prevents airway collapse during inspira*on
Warms air to 37oC and humidifies it to 100% rela*ve humidity
Cleanses air – epithelium creates mucus and sweeps it upwards (the “mucus escalator”); ___________ ingest par*cles
Smooth muscle in bronchioles constrict/relax to vary resistance to air flow SNS ===> NE ===> β2-‐adrenergic receptors -‐ bronchodila*on PSNS ===>ACH ===>muscarinic receptors -‐ bronchoconstric*on
The Respiratory Zone – site of O2 & CO2 exchange with blood
Alveoli are arranged in clusters connected by pores to allow equaliza*on of ________ in the lungs
Type I cells = epithelial layer
Type II cells = produce surfactant Macrophages = engulf foreign par*cles and pathogens
Fig. 16-‐5
The Respiratory Membrane
The Respiratory Zone – site of O2 & CO2 exchange with blood
Fig. 16-‐4
• Separates the air in the alveoli from blood in the capillaries
• Extremely thin
• Alveoli accomplish 90% of gas exchange
• Respiratory bronchioles • Alveolar ducts Only 10% of exchange
Reduced by __________ (e.g., emphysema)
The alveolar surface is moist à High _____________ at air-‐water interface
Alveoli are small (radius ~ 0.1 mm)
Surface tension creates an innate tendency for alveoli to collapse
LePlace’s Law: Pressure necessary to prevent collapse = 2T / r
T= surface tension, r = alveolus’s radius
The Respiratory Zone – site of O2 & CO2 exchange with blood
Alveolar “Type II Cells” secrete surfactant (a protein + phospholipid = ________-‐like substance) which reduces surface tension by up to 90%
Nega*ve pressure outside the alveoli (-‐4 mm Hg below atmospheric pressure) in the intrapleural space also helps to hold the alveoli open The other func*on of the intrapleural space is to serve as flexible, lubricated connec*on between the lungs and the thoracic wall
Factors preven*ng alveolar collapse 1. Without surfactant a smaller alveolus will collapse
2. Surfactant is more highly concentrated in smaller alveoli, reducing T = no collapse
Note: “Respiratory Distress Syndrome” (RDS) in pre-‐mature babies is due to inadequate surfactant.
1. 2.
Pulmonary surfactant toolbox, p. 467/463
Pressure in Intrapleural space -‐ 756mmHg (-‐4mmHg rela*ve to outside air)
Chest Wall and Pleural Sac
Parietal pleura Adached to thorax
Intrapleural space Fluid (mucus)
Visceral pleura Adached to lung wall
Pressure in Alveoli -‐ 760mmHg (same as outside air)
Consider a res2ng lung (no airflow, a?er exhala+on)…
Fig. 16-‐7
Fig. 16-‐8
Chest Wall and Pleural Sac
Fig 16-‐9
Pneumothorax -‐ a rupture which connects the __________ space to the outside atmosphere.
The flexible, lubricated connec*on created by the _______ pressure in the intrapleural space ensures that when the thorax changes size during breathing, the lungs will follow
This eliminates the nega*ve pressure and breathing becomes ineffec*ve and the lung may collapse.
Each lung has its own pleural sac, so the opposite lung will not collapse
Breathing Cycle – alveolar pressure and volume
Expansion of chest wall during inspira*on reduces alveolar pressure (Palv) à Numbers shown are the
differences from Patm (atmospheric pressure)
Rebound of chest wall during expira*on increases alveoli pressure
Air flow = Patm – Palv R
Boyle’s Law Pressure α 1 / Volume
Fig 16-‐10
Inhala*on – Always an _____ process (rest and exercise)
Breathing Cycle
External intercostal muscles pull ribs upwards and outwards
Diaphragm shortens and moves _____
sternum
With Inhala*on: 1. Thoracic volume increases 2. Lung volume increases 3. Nega*ve pressure is created 4. Air flows in from atmosphere
Fig 16-‐11
• Internal intercostal muscles contract to pull ribs in and down
• Abdominal muscles contract, pushing “guts” in and displacing diaphragm upwards
Exhala*on – ______ during quiet breathing (i.e., at rest)
Exhala*on – ______ during intense breathing (e.g., exercise)
• Due to elas*c recoil of thoracic & lung components
Breathing Cycle
With Exhala*on: 1. Thoracic & lung volumes decrease 2. Posi*ve pressure is created 3. Air flows out to atmosphere
Spirometry – lung volumes and capaci*es
Pulmonary func*on can be assessed by measuring lung volumes and capaci*es by spirometry
Fig 16-‐15
Tidal Volume (VT) = Amount of air breathed in and out on a single breath ~ 0.5 L Inspiratory Reserve Volume (IRV) = Maximum inhaled above a normal inhala*on ~ 3 L Expiratory Reserve Vol. (ERV) = Maximum exhaled beyond a normal exhala*on ~ 1 L Residual Volume (RV) = Volume of air in lungs that cannot be exhaled ~ 1.2 L Inspiratory Capacity (IC) = Maximum inhaled above a normal exhala*on ~ 3.5 L Func*onal Residual Capacity (FRC) = Volume in lungs axer a normal exhala*on ~ 2.2 L Vital Capacity (VC) = Maximum inhaled axer a maximal exhala*on ~ 4.5 L Total Lung Capacity (TLC) = VC + RV, ~ 5.7 L
Spirometer record
Fig 16-‐16
Total Ven*la*on (VTot) = Total air flow into (and out of) the _________ ______ per minute (‘minute ven*la*on’)
= Tidal Volume (VT) x Breathing Frequency (fR)
e.g., 6750 ml/min = 450 ml x 15 / min
Anatomical Dead Space – the volume of air lex in the conduc*ng zone axer each breath – leads to the difference between VTot and VA
e.g., 4500 ml/min = [ 450 ml -‐ 150 ml ] x 15/min
Alveolar venHlaHon dictates gas exchange
Alveolar Ven*la*on (VA) = Total air flow into (and out of) the ______ per minute
= [VT -‐ Dead Space Volume (VD)] x fR
Ven*la*on
Anatomical Dead Space
Fig 16-‐19
300 ml of “new” air is mixing with the 2500 ml func*onal residual capacity, which contains “old” air
DiluHon = 300 ml new = ~ 10% 300 ml new + 2500 ml old
à Only ~ _____ replacement of alveolar air per breath at rest
Consequence: Alveolar O2 is lower and alveolar CO2 is higher than in outside air
Increases in *dal volume (e.g., during exercise) bring alveolar O2 and alveolar CO2 values closer to those in outside air
The func*onal residual capacity includes the volume remaining in both the conduc*ng zone (i.e., anatomical dead space) & alveoli
Alveolar ven*la*on (VA) = fR x (VT – VD) = 12 breaths/min x (500 ml -‐ 150 ml) = 4200 ml/min
Doubling fR: VA = 8,400 ml/min Doubling VT: VA = 10,200 ml/min
It is beVer for gas exchange to increase VT than to increase fR
Which leads to a greater improvement in gas exchange, increases in 2dal volume or increases in breathing frequency?
Diffusion of gases What dictates the diffusion of gases across the respiratory membrane ?
Ven*la*on
Pulmonary Diffusion
Circula*on
Tissue Diffusion
Cellular U*liza*on
or Produc*on
Diffusion of gases
T: Membrane thickness A: Surface area K: Permeability gas constant
Diffusion rate = K Î A Î ΔP T
ΔP: ParHal pressure gradient
What dictates the diffusion of gases across the respiratory membrane ?
Fig 17-‐2
Par*al Pressure – A measure of the _____________ ______ of gas molecules
Dalton’s Law: Total pressure = sum of par*al pressures
Total (barometric) air pressure ≈ 760 mm Hg = 760 Torr = PN2 + PO2 + PCO2 + PH2O
= 563 + 150 + 0.2 + 47 (depends on RH) “Torr” = in honour of Torricelli,
inventor of barometer
ParHal pressure of gases
diffuse Gases dissolve according to their par*al pressures, not
react necessarily according to their concentra*ons
In the air phase, we can calculate par*al pressure as
Par*al Pressure = Total Pressure Î Volume (Mole) Frac*on
Remember: • Equal moles of gases occupy equal volumes • 1 mole of any gas occupies 22.4 L at S.T.P.
Dry Room Air: PO2 = 760 Torr x 21% (210 ml O2 / 1000 ml air) = 160 Torr
PCO2 = 760 Torr x 0.03% (0.3 ml CO2 / 1000 ml air) = 0.23 Torr
ParHal pressure of gases
In a fluid phase, the situa*on is more complicated
The par*al pressure of a gas that is dissolved in a liquid is equal to the par*al pressure of that gas in the air phase with which the fluid is in _________
Henry’s Concentra*on of = Par*al Î Solubility Law: a dissolved gas Pressure Coefficient
PO2 = 150 Torr PO2 = 150 Torr
PO2 = 0 Torr PO2 = 150 Torr
ParHal pressure of gases
Fig 17-‐3
[Oxygen] in water = 150 Torr x = 0.034 ml O2 5.1 ml O2 1000 ml water . Torr 1000 ml water
[Oxygen] in air = 21% of every litre of air = 210 ml O2 1000 ml air
The capacity of water to hold O2 is much lower than that of air
Carbon dioxide is about ___ more soluble than O2 in water
The capacity of water to hold CO2 is comparable to that of air
For both O2 and CO2 (and all gases) they diffuse according to their par*al pressures, not according to their concentra*ons
[CO2] in water = 0.3 Torr x = 0.67 ml CO2 0.2 ml CO2 1000 ml water . Torr 1000 ml water
[CO2] in air = 0.03% of every litre of air =
ParHal pressure of gases
0.3 ml CO2 1000 ml air
Diffusion of gases
Diffusion rate = K Î A Î ΔP T
Diffusion occurs down the gas’ parHal pressure (ΔP) gradient: ΔPO2 = Alveolar PO2 – Blood PO2 ΔPCO2 = Blood PCO2 – Alveolar PCO2
Differences in par+al pressure between alveoli and blood drive diffusion
Fig 17-‐2
The par*al pressure of O2 drops with each step in the O2 transport pathway
PO2 at the ___________ must remain high enough to support ATP synthesis
Oxygen cascade
Ven*la*on
Pulmonary Diffusion
Circula*on
Tissue Diffusion
Cellular U*liza*on
O2 Par*al Pressure (kPa)
There is a minimum PO2 at which mitochondria can func*on
1. Alveolar par*al pressures are very different from outside air
PO2 160 PCO2
0.3 100
40 2. Par*al pressures are very similar in alveolar air and the blood leaving the lungs (slightly less in blood)
100 40
3. Par*al pressures are the same in blood leaving the lungs and entering the ______________beds
100 40
2. Pul. veins
3. Systemic art.
4. Par*al pressures in cells very different from blood
1. Alveolar air
4. cells
≥46 ≤40
All in mmHg (Torr)
46 40
5. Systemic veins
5. Par*al pressures are the same in “venous” blood leaving the systemic capillaries & entering the pulmonary capillary beds
46 40
5. Pul. Art.
1. Atmospheric air
Fig 17-‐4 See Table 17-‐1
O2 and CO2 par*al pressures
Fig 17-‐5
O2 and CO2 par*al pressures Diffusion is rapid at lungs and blood equilibrates in ~0.25 seconds with alveolar air.
Leaves a large “safety margin” to accommodate increases in the rate of blood flow
____% -‐ physically dissolved in plasma and RBC cytoplasm
____% -‐ chemically combined with haemoglobin (Hb)
280 x 106 Hb molecules per RBC 4 O2 molecules bound per Hb molecule
~ 109 O2 molecules per RBC ~ 5 x 109 RBC’s per ml of blood
~ 5 x 1018 O2 molecules per ml of blood (at 100% satura*on)
Hb drama*cally increases the blood’s ability to carry O2 (rela*ve to plasma/water), so it is comparable to air (0.21 ml O2 per ml of air)
Transport of oxygen in the blood
~ 6 x 1023 O2 molecules per mole, ~ 22.4 litres per mole
~ 0.2 ml O2 per ml of blood
Hb exhibits the property of allosteric modula*on = “binding at one site on a molecule affects binding at a second site, usually by changing the shape of the molecule.”
Hb is a _______ (M.W. ~ 68,000), composed of 4 similar units
Each unit consists of a “heme” ring structure that binds 1 O2 and a polypep*de chain (“globin”) that binds CO2, H+, phosphates, etc.
Fig 15-‐3
Haemoglobin (recall lectures 6 & 7)
1 Hb protein = 4 globins (2α chains and 2β chains) + 4 hemes
Transport of oxygen via haemoglobin
As blood passes through the lungs the high PO2 promotes the forma*on of “_____________”
Fig 17-‐6
Hb leaving the lungs is ~98% saturated with O2. Almost all of the binding sites are occupied
Fig 17-‐7
Transport of oxygen via haemoglobin
As blood passes through the *ssues, the low PO2 promotes the forma*on of “________________”
Fig 17-‐6
Hb becomes desaturated at the *ssues. At rest, only 75% of the binding sites of Hb are occupied by O2 axer leaving the *ssues
Fig 17-‐7
1. O2 bound to Hb does not contribute directly to blood PO2, only dissolved O2 does
2. O2 bound to Hb does contribute to the total concentra*on of O2 that is available to diffuse
As discussed earlier, diffusion is a func*on of the par*al pressure gradient, which is dictated by the dissolved oxygen frac*on.
Transport of oxygen in the blood
[O2]=[O2] [O2]<[O2]
-‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐
Fe2+
Fe2+
Fe2+
Fe2+
-‐ NH2
-‐ NH2
-‐ NH2 -‐ NH2
-‐ -‐ -‐ -‐
-‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐
-‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐
-‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ X X X X X
X X X X X
X X X X X
X X X X X
O2
O2
O2
O2
Hemes Globins
CO2
CO2
CO2
CO2 H+ H+ H+ H+ H+
H+ H+ H+ H+ H+ P P P P P
P P P P P
H+, CO2, & phosphate are nega*ve allosteric modulators of O2 binding
O2 is a nega*ve allosteric modulator of H+, CO2, & phosphate binding
Therefore O2 is a _______ allosteric modulator for further O2 binding
________ co-‐opera*vity: the 1st O2 helps the 2nd, & the 2nd helps the 3rd; the 4th is not helped
A “func*onal” model of Hb
Increase in temperature weakens the ionic bond between Fe2+ and O2
Allosteric co-‐opera*vity is the reason for the ________ (S-‐shaped) “O2 equilibrium curve” (also called the “O2 dissocia*on curve”) of the blood.
1
2
3
4
Fig 17-‐8
The Hb-‐oxygen equilibrium curve
0
50
100
150
200
ml O
2 per 100
0 ml blood
Veno
us re
serve
Loading point
Unloading point
PaO2 PvO2
At rest, only 25% of the O2 bound by Hb is offloaded at the *ssues. 50 ml of O2 leaves each L of blood
75% of the O2 remains as a “venous reserve”
At rest
The Hb-‐oxygen equilibrium curve
Fig 17-‐8
The affinity of Hb for O2 affects the shape of the curve
O2 affinity is quan*fied by calcula*ng the “P50” – the PO2 at which Hb is _____ % saturated
P50 ~ 25 Torr ~ 32 Torr
~ 42 Torr
Hb with a higher affinity has a lower P50
1. Flat region at top provides an important ___________for O2 loading if arterial PO2 (PaO2) falls (e.g., high al*tude, respiratory disease, etc.)
1 2. Knee and steep part is ideally located to enhance O2 unloading during exercise, with only a rela*vely small decrease in venous PO2 (PvO2) and therefore *ssue PO2 2
PvO2 rest PvO2 exercise
3. @ rest 40 Torr à ~75 % Hb-‐O2
@ exercise 20 Torr à ~35 % Hb-‐O2
Exercise
The Hb-‐oxygen equilibrium curve
3
Fig 17-‐8
The Bohr shi` improves O2 unloading during exercise:
1. An increase in PvCO2 shixs the curve to the right à Caused by increased
*ssue ____________
2. A decrease in venous pH also shixs the curve to the right
à [H+] increases from lac*c acid and CO2 produc*on in the *ssues: CO2 + H2O à H+ + HCO3
-‐
(we will come back to this)
The Hb-‐oxygen equilibrium curve
Fig 17-‐10
Increases in blood temperature shix the curve to the right, and thus enhance unloading of O2
Ac*ve muscle warms up, increasing the temperature of blood in the capillaries
Increases in temperature improve O2 unloading during exercise:
The Hb-‐oxygen equilibrium curve
Fig 17-‐10
The combined effects of temperature and the Bohr shix during exercise can increase O2 unloading to 90% (i.e., venous reserve reduced to 10%)
Organic phosphate molecules are also important _______ allosteric modifiers of O2 binding, but play lidle role during exercise
Mammals -‐ 2,3-‐diphosphoglycerate (2,3-‐DPG) Birds -‐ IP5 (inositol pentaphosphate) Fish & amphibians -‐ ATP & GTP
Increases in RBC [phosphate] generally shix the curve to ____.
The Hb-‐oxygen equilibrium curve
Fetal mammals use a different Hb than adult mammals, in which 2 gamma chains are used instead of 2 beta chains
Fetal Hb is insensi*ve to 2,3-‐DPG and therefore has a higher affinity for O2 than maternal Hb à facilitates O2 transfer across the placenta
1 fetal Hb = 2α chains + 2γ chains + 4 heme groups
There is a lot more CO2 than O2 in the blood
1. 10 % is physically dissolved in plasma and RBC cytoplasm
1
2
2. 30% binds Hb to form carbamino-‐CO2
3
3. 60% is transported as HCO3-‐
ion, mainly dissolved in plasma
Carbonic anhydrase (CA), which catalyzes the above reac*on, is the second most abundant protein in erythrocytes axer Hb
3B
3A. Buffered by Hb
3B. Moves into plasma in exchange for Cl-‐
Transport of carbon dioxide in the blood
CO2 + H2O H2CO3 HCO3-‐ + H+ CA
fast
3A
Fig 17-‐11
Both of these reac*ons shix the O2 equilibrium curve to the right, thereby helping to unload O2.
“Band 3” protein for Cl-‐/HCO3-‐
exchange = ___________
Fig 17-‐11
Most bicarbonate transported in plasma
Driving pressure for diffusion: Cells (>46 Torr) à capillary (40 Torr)
HCO3-‐
Transport of carbon dioxide in the blood
Both of these reac*ons shix the O2 equilibrium curve to the lex, thereby helping to load O2.
Fig 17-‐11
Driving pressure for CO2 Blood (46 Torr) à alveoli (40 Torr)
Lungs
Cl-‐/HCO3-‐ exchange reversed
Bicarbonate moves from plasma to rbc and converted to CO2
Transport of carbon dioxide in the blood
The Haldane Effect
The addi*on of O2 to the Hb helps to ______ CO2 and H+ at the pulmonary capillaries
The removal of O2 from the Hb helps to load CO2 and H+ at the systemic capillaries
Although these effects are small at rest, they become more pronounced during exercise
‘Mirror image’ of the ____ Effect (both are nega*ve allosteric effects)
Fig 17-‐12
Transport of carbon dioxide in the blood
Transport of gases in the blood
As blood passes through pulmonary capillaries: Increasing PO2; Decreasing PCO2 and [H+] The O2 equilibrium curve shixs lex, which accentuates O2 loading and CO2 unloading
As blood passes through systemic capillaries: Decreasing PO2; Increasing PCO2 and [H+] The O2 equilibrium curve shixs right, which accentuates O2 unloading and CO2 loading
The Bohr and Haldane Effects (as well as temperature effects) facilitate gas exchange at rest, and are exaggerated during exercise
48
Transport of gases in the blood
Pulmonary Capillaries Systemic Capillaries
Fig 17-‐13
Genera*on of breathing rhythm
A typical person taking 15 breaths per minute will inspire hundreds of millions of *mes in their life*me
What generates these breaths?
Genera*on of breathing rhythm Side view
Fig 17-‐15
Front view
Genera*on of breathing rhythm
Pre-‐Bötzinger Complex (PBC)
The “central rhythm generator” is composed of a rhythmically ac*ve group of neurons in the Pre-‐Bötzinger Complex (PBC) in the ventro-‐lateral medulla
Hypothesis 1: Individual neurons spontaneously depolarize to generate ac*on poten*als, thus ac*ng like pacemakers
Hypothesis 2: Complex interac*ons between neurons in a network generate the a rhythm
Genera*on of breathing rhythm
The rhythmicity center in the medulla includes the PBC along with inspiratory and expiratory neurons
Inspiratory (I) neurons in the DRG and VRG (shown in blue) fire during inspira*on (in response to the PBC)
Rhythm
icity
Ce
nter I neurons
E neurons
Expiratory (E) neurons in the VRG (shown in yellow) fire during ac+ve exhala*on (e.g. exercise)
The PRG in the pons contains I, E, and mixed neurons that “fine-‐tune” the ac*vity of the rhythmicity center, facilitate the transi*on between insp. and exp., and control breathing depth to Respiratory Muscles
I, E, & mixed neurons
Genera*on of breathing rhythm
The inspiratory muscles (diaphragm and external intercostals) are innervated by the phrenic and external intercostal nerves, respec*vely
Expiratory muscles (internal intercostals) are innervated by the internal intercostal nerve, but are only ac*vated to contract during heavy breathing
Fig 17-‐14
Neural control of breathing
to Respiratory Groups in medulla and pons
Various sensory receptors provide input to the respiratory centers in the brainstem to regulate breathing
Central and peripheral chemoreceptors sense chemical signals (PCO2, PO2, pH, glucose, etc.)
Pulmonary stretch receptors sense the degree of lung infla*on
Etc.
Central chemoreceptors
More sensi*ve and accurate than peripheral chemoreceptors
Monitors cerebral spinal fluid (CSF) pH and PCO2 (through the lader’s affect on pH via carbonic anhydrase)
CO2 can cross the blood-‐brain barrier but H+ cannot, so arterial PCO2 (but not arterial pH) is also sensed
Increases in CSF PCO2 also occur when neural metabolism increases, which would necessitate higher rates of breathing and gas exchange
Monitor PCO2/pH (not PO2) in medulla near the rhythmicity center
Central chemoreceptors are the most important sensor controlling ven*la*on, causing it to increase in response to increases in CO2
Fig 17-‐20
Pons Medulla
Caro*d chemoreceptors
Aor*c chemoreceptors
Peripheral (“arterial”) chemoreceptors (PCO2, pH, and PO2)
Glosso-‐pharyngeal (IX) (afferent branches)
Vagus (X) (afferent branches)
S*mulate an increase in ven*la*on in response to a rise in arterial PCO2, suppor*ng the central chemoreceptors
Increase ven*la*on in response to a decrease in arterial pH (i.e., increased [H+])
Mainly a fine-‐tuning, back-‐up and safety system which becomes more important during special circumstances
Increase ven*la*on in response to a decrease in arterial PO2
Monitor arterial PO2 at a setpoint ~ 100 Torr à S*mulate ven*la*on in response to large decreases in PO2 (small changes do not cause a large effect)
Chemoreceptors
Mediated en*rely by peripheral chemoreceptors
Hb % satura*on starts dropping
Peripheral receptors are very important at high al*tudes, where the PO2 of ambient air is much lower
Fig 17-‐19
Figure 13.35
Mediated almost en*rely by peripheral chemoreceptors (H+ does not easily cross blood-‐brain barrier)
pH change not due to PCO2 (e.g. lactate during exercise)
Mediated largely by the central chemoreceptors
Ven*la*on Effects of PCO2
Chemoreceptors
Fig 17-‐19
Figure 17.21
Chemoreceptor Reflexes
1. Most important: HCO3
-‐ + H+ H2CO3 2. Protein buffer: Prot-‐ + H+ H.Prot
Acid-‐base regula*on -‐ the control of ECF and ICF pH 7.00 ß ß 7.20 ß 7.40 à 7.60 à à 7.80
Normal pH range ECF (pHa)~7.4, ICF~7.0
Depression of nervous system & coma
Over-‐excitability of nervous system & tetany of muscles
Inputs of acid Blood buffers Outputs (compensa*on) Dietary and metabolic sources. CO2 acts as an acid
1. Respiratory system rapidly changes breathing to alter expira*on of CO2
2. Renal system slowly (hours to days) excretes or reabsorbs H+ or HCO3
-‐ à Reduces but does not eliminate pH changes
Fig 19-‐24
1. General (equilibrium) equa+on: HCO3-‐ + H+ H2CO3
pH = pK + log [anion of an acid] = pK + log [HCO3-‐]
[acid] [H2CO3]
The major principles of acid-‐base regulaHon can be understood by following the CO2/HCO3
-‐ system
Bicarbonate Buffer System of the Blood The rela*onship between CO2 and pH (the CO2/HCO3
-‐ buffer system) can be described by the Henderson-‐Hasselbalch Equa*on
2. Carbonic Anhydrase Reac+on: H2CO3 H2O + CO2
Dissolved [CO2] = PCO2 Î Solubility Coefficient (αCO2)
Henderson-‐Hasselbalch pH = pK’ + log [HCO3-‐] = 6.1 + log [HCO3
-‐] Equa+on for Blood: [CO2] PCO2 Î αCO2
~Constant
Regulated by breathing (fast)
CA
****
pH = 7.4 = 6.1 + log [HCO3-‐]
40 Î 0.03
Arterial pH is regulated at 7.4 by keeping [HCO3
-‐]:[CO2] at ~20:1
Bicarbonate Buffer System of the Blood
pH = 6.1 + log [HCO3-‐]
PCO2 Î αCO2
αCO2 = 0.03 mM/Torr Arterial PCO2 = 40 Torr Arterial pH = 7.4
What is the concentra+on of bicarbonate in arterial blood?
7.4 -‐ 6.1 = log [HCO3-‐]
40 Î 0.03
10(7.4 -‐ 6.1) = [HCO3-‐]
40 Î 0.03 [HCO3
-‐] = 40 Î 0.03 Î 10(7.4 -‐ 6.1) = 24 mM
[CO2] = PCO2 Î αCO2 = 40 Î 0.03 = 1.2 mM
The CO2/bicarbonate buffer system dictates pH in the blood (and wherever there is carbonic anhydrase). Other buffer systems (e.g., proteins, phosphate, NH3) remain in equilibrium (Isohydric Principle)
Acid-‐Base disturbances and compensa*ons
CO2 + H2O H2CO3 H+ + HCO3-‐
_________________ -‐ If CO2 excre*on by the respiratory system is less than produc*on (‘_____________’) à net H+ and HCO3
-‐ buildup
Kidney slowly compensates by accumula*ng HCO3-‐ (increased reabsorp*on)
and excre*ng H+ to bring [HCO3-‐]:[CO2] back to ~20:1 and thus restore pH
Respiratory Alkalosis -‐ If CO2 excre*on by the respiratory system exceeds produc*on (‘hyperven*la*on’) à net H+ and HCO3
-‐ loss
Kidney slowly compensates by excre*ng HCO3-‐ and
accumula*ng H+ to help restore pH
CO2 + H2O H2CO3 H+ + HCO3-‐
[HCO3-‐] < 20
[CO2]
[HCO3-‐] > 20
[CO2]
CA
CA
Acid-‐Base disturbances and compensa*ons
________________ -‐ If an acid (H+) other than CO2 is added to the blood (e.g. lac*c acid) , reac*on is driven to lex à CO2 buildup
Ven*la*on increases quickly to compensate, which lowers arterial PCO2 (and thus [CO2]) and helps reduce [H+]
Metabolic Alkalosis -‐ If a base (OH-‐, HCO3-‐ ) is added to the blood, it
forms or adds HCO3-‐, driving the reac*on lex à net H+ loss
Ven*la*on decreases quickly to compensate, which increases arterial PCO2 and helps maintain pH
CO2 + H2O H2CO3 H+ + HCO3-‐
CA [HCO3
-‐] < 20 [CO2]
CO2 + H2O H2CO3 H+ + HCO3-‐ CA
[HCO3-‐] > 20
[CO2]
Fig 19-‐28
Acid-‐Base disturbances and compensa*ons
Acid-‐Base disturbances and compensa*ons
What is the challenge to acid-‐base balance at high al2tudes, and how is it overcome?