Physiology BENG 140A, 25th Lecture

Instructor: Pedro Cabrales Respiratory System Gas transport and regulation Chapter 13 (Cont)

Ventilation

Elastic recoil

Elastic recoil is defined as the tendency of an elastic structure to oppose stretching or distortion.

Respiration rate, volumes and O2

Respiration rate, volumes and O2

Dead Space

Airflow in the lungs is called ventilation.

[AIR]
EXCHANGE

Gases exchange by diffusion.

[BLOOD]

Blood flow through the pulmonary capillaries is driven by the contraction of the right ventricle.

In the lungs, the concentration gradients favor the inward (toward the blood) diffusion of oxygen and the outward (toward the alveolar air) diffusion of carbon dioxide; owing to the metabolic activities of cells, these gradients are reversed at the interface of the blood and the active cells.

Changes in the concentration of dissolved gases are indicated as the blood circulates in the body. Oxygen is converted to water in cells; cells release carbon dioxide as a byproduct of fuel catabolism.

Oxygen Tranport

Hemoglobin (Hb) and O2 Transport

Hb has 4 globin polypeptide chains

4 heme groups that bind O2

Each heme has a ferrous ion that can bind one molecule of oxygen

each Hb can carry 4 O2

280 million hemoglobin molecules per RBC

Each can carry over a billion oxygen molecules

Hemoglobin (Hb) and O2 Transport

Normal heme contains Fe2+ - can share electrons and bond with oxygen (oxyhemoglobin)

loads with O2 to form oxyhemoglobin in pulmonary capillaries

Deoxyhemoglobin (reduced hemoglobin) oxyhemoglobin dissociates to release oxygen

Unloading in tissues

Affinity of Hb for O2 changes with a number of physiological variables

Hemoglobin as an O2 Carrier
Hb Hb Hb

Dissolved O2 = 3 1 5 N=5 1 3

Dissolved O2 = 0 1 5 3 N=7 9 5

Now Finally, A Hemoglobin 5 Equilibrium O molecule add one another of is O now reached hemoglobin will are binds hemoglobin move dissolved when 4 to Ois molecules, there added in molecule. solution right is to no and the leaving difference on The bind solution both remaining to only sides hemoglobin. in on one the the of3 in the right, O2 2 molecules 2 2 the Another but solution. semi-permeable concentration molecules has not O There are will yet of quickly move is bound membrane dissolved now to bound, a O the 5:1 (still O (no right dissolved leaving in no net the and net movement). two no movement). equilibrium O dissolved compartments ratio (O is O now again on moves (no the net 2 2 2 2 2 2 achieved. from movement). right. left to right).

Oxyhemoglobin Dissociation Curve

Gives % of Hb sites that have bound O2 at different PO2

Reflects loading and unloading of O2 Steep part of curve, small changes in PO2 cause big changes in % saturation

Differences in % saturation in lungs and tissues

Why is Hb-O2 association S-shaped?

O2 (OxyHb - DeoxyHb) Configuration states (R - T) Structural changes

Conformational change induced by the movement of the iron atom on oxygenation are transmitted to parts of the molecule that are far away

Why is Hb-O2 association S-shaped?

100 hyperbolic curve with highest K

% saturation hyperbolic curve with lowest K 0

25 50 75 100

tissue PO2

PO2, mm Hg

lung PO2

O2 (OxyHb - DeoxyHb) Configuration states (R - T) Structural changes

Conformational change induced by the movement of the iron atom on oxygenation are transmitted to parts of the molecule that are far away

Why is Hb-O2 association S-shaped?

O2 (OxyHb - DeoxyHb) Configuration states (Relax - Tense) Structural changes

tissue PO2

lung PO2

Spectral characteristics of Hemoglobin:

color changes with reaction of iron heme

Oxygenation:
Hb (deep red to bluish) (deoxyhemoglobin) + O2 <--> HbO2
(oxyhemoglobin; red)

readily reversible
iron must remain in reduced state, Fe2+

in fact, since Hb is a tetramer the reaction is really

Hb + 4O2 <--> Hb(O2)4

Oxidation:

Hb(Fe2+) -------> Hb(Fe3+)

difficult to reduce

(methemoglobin; brownish)

CO reaction:
Hb + CO -------------------> HbCO
(carboxyhemoglobin; bright red, pink)

very high affinity (230X greater than for O2)

Hb oxygen dissociation curve

Oxygen transport

A normal oxyhemoglobin dissociation curve and curves for the case of a 50 percent anemia and the case of a 50 percent carboxyhemoglobinemia.

Advantages & Mechanistic Basis of the Bohr effect

(change in pH or PCO2)

100 pH 7.4 % saturation

Effect of pH
PCO2 effect is the same as the pH effect

pH 7.2

CO2 + H2O H2CO 3 H+ + HCO3-

Protonic association alters O2 affinity

PO2 100 mm Hg
R - CH2 - C NH HC N Fe O2 O2 CH H+ R - CH2 - C NH HC CH NH+ Fe H+

Effect of pH Effect of PCO2

PCO2 effect is the same as the pH effect CO2 + H2O H2CO 3 H+ + HCO3(Bohr Effect: covered later)

Effect of temperature

2,3-Diphosphoglyceric acid has important physiological consequences

2,3 DPG alters O2 affinity
100 Hb "stripped" of 2,3 BPG

% saturation Hb + add back 2,3 BPG

25 50 tissue PO2

75

100 lung PO2

PO2 , mm Hg

2,3-Bisphosphoglycerate (BPG) [2,3-Diphosphoglyceric acid (DPG)]

RBC metabolism

Glucose
Glucose Glucose-6-phosphate 2 ADP Hexose monophosphate NADP+ 2 GSH Glutathione peroxidase GS-SG 2 H2O H2O2

Glycolytic pathway

Glucose 6-phosphate Glutathione dehydrogenase reductase Glyceraldehyde 3-phosphate 6-Phosphate gluconate 2,3 DPG NADPH

2 ATP Pyruvate 2 Lactate

Biochemical & functional differences of Fetal Hemoglobin

Expression of Hb differs during development

advantage

Fetal red blood cells have a higher oxygen affinity than do maternal red cells, because the hemoglobin has a lower affinity for BPG than does adult hemoglobin, making fetal red cells behave like adult red cells stripped of BPG.

Carriage of blood gases

How are gases carried by the blood?
all values are in ml of gas/100 ml solution H2O or plasma (pH = 7.4) dissolved 0.3 2.6 combined 0 43.8 Whole blood (Hct = 0.45) dissolved 0.3 2.6 combined 19.5 46.4

O2 (at a PO2 = 100 mm Hg) CO2 (at a PCO2 = 40 mm Hg)

note the difference in units

SCO2 = 0.03 mmol/L / mm Hg SO2 = 1.37 mol/L / mm Hg

PCO2 effect is the same as the pH effect CO2 + H2O H2CO 3 H+ + HCO3-

CO2 Transport

SCO2 = 0.03 mmol/L / mm Hg SO2 = 1.37 mol/L / mm Hg

CO2 transported in blood in three forms:

as dissolved CO2 (10%) in the plasma (CO2 ~21 times more soluble than O2 in water) as carbaminohemoglobin (20%) attached to an amino acid in hemoglobin Effect - of as bicarbonate ion, HCO 3 2(70%) that accounts for most PCO of the CO2 carried by blood

In RBCs carbonic anhydrase catalyzes formation of H2CO3 from CO2 + H2O

Favored by the high PCO2 found in capillaries of systemic circulation

Gas Transport

Effect of pH

Chloride movement inside RBC

High CO2 levels in tissues causes the reaction:

CO2 + H2O H2CO3 H+ + HCO3to shift right in RBCs (decrease affinity)

Results in high H+ and HCO3- levels in RBCs

H+ is buffered by proteins HCO3- diffuses down concentration and charge gradient into blood causing RBC to become more positive Cl moves into RBC (chloride shift)

Carbon Dioxide Transport and the Chloride Shift

CO2 transported as

Dissolved CO2 gas Carbaminohemoglobin H2CO3 and HCO3-

When bicarbonate diffuses out of the RBCs

Cl- diffuses in to retain electrical neutrality This exchange is the chloride shift

Reverse Chloride Shift

Blood reaches pulmonary capillaries deoxyhemoglobin converted to oxyhemoglobin

Oxyhemoglobin has weaker affinity for H+ than deoxyhemoglobin so H+ released within RBCs Attracts bicarbonate (HCO3-) from plasma combines with H+ to form carbonic acid (H2CO3) H+ + HCO3- H2CO3

Lower PCO2 as in pulmonary capillaries carbonic anhydrase catalyzes conversion of H2CO3 to CO2 + H2O

Reverse Chloride Shift

In lungs: CO2 + H2O H2CO3 H+ + HCO3-, moves to left as CO2 is breathed out Binding of O2 to Hb decreases its affinity for H+

H+ combines with HCO3- and more CO2 is formed

Cl- diffuses down concentration and charge gradient out of RBC (reverse chloride shift)

Acid-Base Balance of the Blood

Blood pH is maintained within narrow pH range by lungs and kidneys (normal = 7.4) Bicarbonate most important buffer in blood

H2O + CO2 H2CO3 H+ + HCO3Excess H+ is buffered by HCO3-

Kidney role to excrete H+ into urine

Acid-Base Balance of the Blood

CO2 produced by tissue cells through aerobic cell respiration

Transported by blood to the lungs where it can be exhaled Volatile acid: carbonic acid can be converted to a gas e.g. CO in bicarbonate buffer system can be 2 breathed out + H2O + CO2 H2CO3 H + HCO3 All other acids are nonvolatile and cannot leave the blood e.g. lactic acid, fatty acids, ketone bodies

2 major classes of acids in the body:

Acid-Base Balance of the Blood

Acidosis when pH < 7.35 and Alkalosis when pH > 7.45 Respiratory acidosis caused by hypoventilation

Causes rise in blood CO2 and thus carbonic acid Results in too little CO2 e.g. excess ketone bodies in diabetes or loss of HCO3- (for buffering) in diarrhea

Respiratory alkalosis caused by hyperventilation

Metabolic acidosis results from excess of nonvolatile acids

Metabolic alkalosis caused by too much HCO3- or too little nonvolatile acids

e.g. from vomiting out stomach acid

Acid-Base Balance of the Blood

Normal pH is obtained when ratio of HCO3- to CO2 is 20:1 Henderson-Hasselbalch equation uses CO2 and HCO3- levels to calculate pH: pH = 6.1 + log [HCO3-] [0.03PCO2]

Ventilation and Acid-Base Balance

Ventilation usually adjusted to metabolic rate to maintain normal CO2 levels With hypoventilation not enough CO2 is breathed out in lungs

Acidity builds, causing respiratory acidosis

With hyperventilation too much CO2 is breathed out in lungs

Acidity drops, causing respiratory alkalosis

Summary of CO2 movement

Capillary Dynamics
alveolar space

Two routes for possible fluid loss from pulmonary capillary: i) interstitium ii) alveolar space
Normal lymph flow allows adequate drainage and no fluid accumulation.

hydrostatic

oncotic

arterial end

Pc = 10

pulmonary cap.

c = 25

venous end

Pi = 0

interstitial space

= 15

Starling forces
net fluid movement = K
Fluid movement out of cap.

[(Pc-Pi) - (c- i)]

lymphatic flow

= K x P

= K [(10-0) - (25-15)] = K[~0 mm Hg]

Lungs

Carriage of CO2 is almost entirely a simple chemical and physical set of reactions.

Tissues

Control of Breathing

Normal breathing = rhythmic; involuntary Nervous Control = Respiratory Center 1.located in pons & medulla of brain stem 2.Medullary Rhythmicity area a.composed of dorsal respiratory group which controls the basic rhythm of breathing; b.ventral respiratory group which controls forceful breathing. 3.Pneumotaxic area = pons: a. controls rate of breathing.

Brain Stem Respiratory Centers

Rhythmicity center in medulla oblongata generates automatic

Consists of inspiratory neurons that drive inspiration and expiratory neurons that inhibit inspiratory neurons

Their activity varies in a reciprocal way and may be due to pacemaker neurons

Basic rhythmic breathing and Inspiratory Neuronal Activity

The basis of rhythmic breathing. During inspiration the activity of inspiratory neurons increases steadily. DRG, dorsal respiratory group.

Recorded from DRG neurons

Control of Breathing

Factors affecting breathing: A number of factors affect breathing rate and depth including: Partial pressure of oxygen (Po2) Partial pressure of carbon dioxide (Pco2) acidosis pH Degree of stretch of lung tissue Emotional state Level of physical activity Receptors involved include mechanoreceptors and central and peripheral chemoreceptors

The Oxygen Sensors

The Oxygen Sensors

(How do they work?)

(e.g., recorded from glossopharyngeal nerve)

Central (medullary) Chemoreceptors (mechanisms) the H+ (CO2) sensors

blood here

cerebrospinal fluid between

H+

brain here

Control of Breathing
Factors affecting breathing: pH, O2 and CO2 -> chemoreceptors Motor impulses can travel from the + respiratory center to the diaphragm and external intercostal muscles Contraction-> expand stimulating -> mechanoreceptors _ Inhibitory impulses -> mechanoreceptors back to the respiratory center prevent overinflation of the lungs

Control of Breathing

CNS Control of Breathing

A Summary of Chemoreceptor Reflexes

Hypoxia -

O2 deficiency at the tissue level.

1. Hypoxic-hypoxia. PO2 of arterial blood is reduced. Delayed effects of altitude Acclimatization 2. Anemic-hypoxia. Essentially low Hb content. CO poisoning. 3. Stagnant-hypoxia. Low blood flow. Shock, congestive heart failure. 4. Histotoxic-hypoxia. Inhibition of tissue oxidative processes.

Altitude, Barometric Pressure and PO2

ambient air

PO2, mm Hg San Francisco Lake Tahoe Mt. Whitney

(sea level)

150 110 80

(6,500) (14,500)

Mt. Everest

(29,500)

30

Adaptation to High Altitude

Involves increased ventilation, increased 2,3 DPG, and increased Hb levels Hypoxic ventilatory response initiates hyperventilation which decreases PCO2 which slows ventilation

Chronic hypoxia increases nitric oxide (NO) production in lungs which dilates capillaries there

NO binds to Hb and is unloaded in tissues where may also increase dilation and blood flow NO may also stimulate CNS respiratory centers

Altitude increases DPG, causing Hb-O2 curve to shift to right Hypoxia causes kidneys to secrete EPO which increases RBCs

Acclimatization to High Altitude

Disorders Caused by High Partial Pressures of Gases

Total atmospheric pressure increases by an atmosphere for every 12m below sea level At depth, increased O2 and N2 can be dangerous to body Breathing 100% O2 at < 2 atmospheres can be tolerated for few hrs

O2 toxicity can develop rapidly at > 2 atmospheres Oxidative damage

Disorders Caused by High Partial Pressures of Gases

At sea level, nitrogen is physiologically inert

It dissolves slowly in blood Under hyperbaric conditions takes more than hour for dangerous amounts to accumulate Nitrogen narcosis resembles alcohol intoxication

Amount of nitrogen dissolved in blood as diver ascends decreases due to decrease in PN2

If ascent is too rapid, decompression sickness occurs as bubbles of nitrogen gas form in tissues and enter blood, blocking small blood vessels and producing bends

Ventilation During Exercise

During exercise, breathing becomes deeper and more rapid

delivering much more air to lungs (hyperpnea)

2 mechanisms underlie this increase:

neurogenic mechanism, sensory activity from exercising muscles stimulates ventilation; and/or motor activity from cerebral cortex stimulates CNS respiratory centers humoral mechanism, either PCO2 and pH may be different at chemoreceptors than in arteries

Ventilation during exercise

Ventilation During Exercise

Arterial blood gases and pH do not significantly change during moderate exercise

Because ventilation increases to keep pace with increased metabolism arterial PO2, PCO2, and pH remain fairly constant

Lactate Threshold and Endurance Training

The maximum rate of oxygen consumption before blood lactic acid levels rise as a result of anaerobic respiration

Occurs when 50-70% maximum O2 uptake has been reached

Endurance-trained athletes have higher lactate threshold, because of higher cardiac output

Have higher rate of oxygen delivery to muscles and greater numbers of mitochondria and aerobic enzymes

Carriage of blood gases

How are gases carried by the blood?
all values are in ml of gas/100 ml solution H2O or plasma (pH = 7.4) dissolved 0.3 2.6 combined 0 43.8 Whole blood (Hct = 0.45) dissolved 0.3 2.6 combined 19.5 46.4

O2 (at a PO2 = 100 mm Hg) CO2 (at a PCO2 = 40 mm Hg)

note the difference in units

SCO2 = 0.03 mmol/L / mm Hg SO2 = 1.37 mol/L / mm Hg

PCO2 effect is the same as the pH effect CO2 + H2O H2CO 3 H+ + HCO3-

Control of Breathing

Normal breathing = rhythmic; involuntary Nervous Control = Respiratory Center 1.located in pons & medulla of brain stem 2.Medullary Rhythmicity area a.composed of dorsal respiratory group which controls the basic rhythm of breathing; b.ventral respiratory group which controls forceful breathing. 3.Pneumotaxic area = pons: a. controls rate of breathing.

Lung Cancer

Healthy lung

Smoker lung