THE AUSTRALIAN NATIONAL UNIVERSITY

1. THE AUSTRALIAN NATIONAL UNIVERSITY Oxygen Delivery To TissuesChristian StrickerAssociate Professor for Systems PhysiologyANUMS/JCSMR - ANUChristian.Stricker@anu.edu.auhttp://stricker.jcsmr.anu.edu.au/Oxygen_Delivery.pptx

3. Aims The students should • understand the shape of the Hb saturation curve and know which factors modify it; • appreciate resting and max. O2 consumption rates; • be aware of where O2 and CO2 are metabolised; • understand the O2partial pressure in mitochondria; • grasp how diffusion rates change along capillary; • be aware of how CO2 is removed from periphery; • recognise the central role of EC in CO2 removal; and • be able to state the differences between O2 and CO2 saturation curves.

4. Contents • Metabolism and energy production. • Characteristics of O2 saturation curve. • O2 binding and unbinding incl. right shifts. • Compartments for O2 consumption/CO2 production. • from nose to mitochondrion. • Diffusion profiles along capillary. • CO2 from tissue and forms that CO2 can take. • Central role of CAH, Cl/HCO3- exchanger and Hb. • How CO2 modulates O2 unbinding from Hb. • CO2 saturation curve.

5. Requirements for Energy Production • Energy is generated by katabolising • sugars: glucose + 6 O2→ 6 H2O and 6 CO2with -2881 kJ/mol in energy; equimolar gas consumption & production. • fats: produce more energy than glucose (see biochemistry); more O2 consumed than CO2 is produced. • amino acids: more O2 consumed than CO2 is produced; in addition, urea is generated (see biochemistry). • How does O2 get from lungs to periphery? • Mostly as O2-Hb; very small amount dissolved in plasma. • How does CO2 get from periphery to lungs? • Mostly as bicarbonate; ~30% in other forms.

6. O2-Saturation of Haemoglobin • Diffusion dissolves O2 in plasma; linear increase with increasing . • Dissolved O2 reacts with Hb. • O2 capacity ≈ 1.35 mL O2/g Hb. • Maximal O2 bound in blood: • i.e. ~200 mL O2 can be maximally bound to Hb in 1 L blood plus a small amount dissolved (a few %). • i.e. ~50 mL / L is metabolised. • Hb-saturation: Modified from Boron & Boulpaep, 2003

7. O2 Delivery to Tissue • Resting is not very meaningful, but is a good predictor of athletic potential (normalised per kg weight). • Normal = 3.5 L/min (75 kg); normalised 45 mL/min∙kg. • On a short time scale, O2 delivery can increase by ~14 times. • Endurance sports people have high . • Cyclists (Indurain 88), cross-country skiers (Daehlie100 mL/min∙kg) • Perspective: horses (180) and dogs (240 mL/min∙kg)

8. O2 Binding and Unbinding • Unbinding in periphery in steepest area of curve: largest O2 release for small change in . • Under resting conditions, there is good reserve for O2 unbinding (end of steep part). • Helps keep periphery oxygenated. • If curve is “right-shifted”, even more O2 is released. • Metabolic “stressors”: T↑, pH↓, ↑, 2,3-DPG↑, etc. • For a “left-shifted” curve, much less O2 is available. Modified from Boron & Boulpaep, 2003

9. O2 Unbinding in Active Tissue • Active tissue “burns” substrates while consuming O2 and producing CO2. • Local consequence • ↓ • ↑ • pH↓ • Temperature ↑ • Causing locally • right-shift of O2-dissociation curve and • additional O2 unbinding from Hb. • Local metabolic activity favours O2 unbinding. Modified from Boron & Boulpaep, 2003

10. Metabolism of O2 and CO2 • O2 consumption in mitochondria • via diffusion in solute through cytosol to mito. cytochrome oxidase (diss). • Gradient from capillary → mito. • Driven by and solubility in cyto-plasm (poorer than that for CO2). • < • The further away the mitochondria from capillary, the lower . • CO2 production in mitochondria • At location of dehydrogenases … • Gradient from mito. → capillary. • Dissolved immediately and conver-ted mostly into HCO3- (see later). • Diffuses much easier than O2.

11. O2 Profile Along Capillary Despopoulos & Silbernagl 2003 • Inflow = 12 kPa; outflow = 3.5 kPa: active tissue. • Steep concentration gradient at inflow of capillary, much shallower at outflow in normoxia; core better oxygenated than surround. • Lateral diffusion rate dependent concentration gradient. • In hypoxia, shallower gradients at inflow = 4.6 kPa.

12. from Nose to Mitochondria • is smaller than that in capillary and certainly in artery. • is dependent on cellular activity. • Muscle resting: = 5.0 kPa. • Muscle under strenuous exercise: = 0.5 kPa.

13. How CO2 Production Assists O2 Unbinding from Hb Central Role of Intracellular Bicarbonate Handling How CO2 Ultimately Helps to Unbind O2

14. CO2 Takes Several Different Forms • CO2 can be transported in three different forms: • CO2 dissolved in plasma as well as within EC: 5% in arterial blood. • Can bind to amino termini of proteins: carbamino-compounds (importantly Hb): 5% in arterial blood. • In water, CO2 can form (see acid-base metabolism): • Carbonic acid (H2CO3): negligible at normal blood pH ~7.4. • Bicarbonate ( ): quantitatively most important: 90% in arterial blood (RR: 24 – 28 mM). • Carbonate ( ): negligible at normal pH ~7.4. • CO2is transported largely as bicarbonate: as an ion in solute (more in intra- than extracellular compartment). • Bicarbonate is osmotically active (see earlier). • ECs in veins are larger than those in arteries (haematocrit !).

15. Total CO2 in Blood: Arterial - Venous • Total CO2 in blood is much higher than that of O2 (> 2 x)! • Arterio-venous CO2 difference:40 mL/L of blood. • Of total CO2 in blood, • 11% in plasma (extracellular) • 6% dissolved • 5% as bicarbonate • 89% in erythrocyte (intracellular) • 4% dissolved • 21% as carbamino-Hb • 64% as bicarbonate • Most CO2 moves intracellularly. • What are mechanisms favoring intracellular CO2 transport? • Carbonic anhydrase: RBC enzyme • Haemoglobin: H+-buffer • exchanger: Cl-shift. Modified from Boron & Boulpaep, 2003

16. How CO2 Displaces O2 from Hb Modified from Borom & Boulpaep, 2003

17. How O2 Unbinds from Hb in Periphery • 3 effects contribute to O2 unbinding: • ↓ in local perfused tissue: Hb dumps O2; “movement along the saturation curve to the left”. • pH↓ in local tissue as a consequence of • anaerobic metabolic activity (plasma pH; glycolysis); • 2,3-DPG formation in EC when ↓ (over many days); and • carbonic anhydrase, particularly within EC: right-shift of saturation curve; i.e. H+ displacing O2. • ↑in local tissue as a consequence of • aerobic metabolic activity: right-shift of saturation curve. • Carbamino-Hb formation.

18. CO2 Dissociation Curves • Depend on Hb saturation. • With ↓, total CO2 content rises: uptake of CO2 in periphery and vice versa in lung. • Very steep relationship between total CO2 and : 40 mL/L within 0.8 kPa. • Compare with 8.0 kPa for 50 mL/L O2. • Quasi-linear relationship between total CO2 andwithin physiological range. Modified from Borom & Boulpaep, 2003

19. Take-Home Messages • O2 consumption rate is ~ 50 mL/min. • O2 extraction is ~ 7 kPa under resting conditions. • Saturation curve predicts largest O2 unbinding in capillaries. • Central to peripheral O2 unbinding are ↓, pH↓ and ↑. • O2 consumed in mitochondria, CO2 produced in cytoplasm. • is smaller than and depends on O2 solubility and local metabolic activity. • Steepness of O2 gradients determine lateral diffusion rates. • CO2 is transported in many different forms, mostly in RBCs. • CAH, Cl--HCO3--exchange and Hb are vital to CO2 transport. • CO2 uptake rises as ↓. • CO2 saturation curves are much steeper than those for O2.

20. MCQ Which of the following combinations of factors results in the largest amount of total CO2 carried in the blood?

21. That’s it folks…

22. MCQ Which of the following combinations of factors results in the largest amount of total CO2 carried in the blood?