I. Chemistry of gases
A. partial pressure of a gas, written as PGAS (e.g., PO2, PCO2):
1. in gas phase, is almost exactly proportional to the molar percentage of each gas in a mixture of gases; thus, if air is 20.9%O2 and 78% N2, and total pressure is 760 mmHg, then PO2 = 159 mmHg (0.2 x 760) and PN2 = 593 mmHg (0.78 x 760)
2. in liquid, can be considered to be the tendency of the gas to come out of solution
3. Net transport of a gas goes down a partial pressure gradient. If partial pressure of a gas in a solution is higher than its partial pressure in the gaseous phase above the liquid, net movement of the gas will be out of the liquid, no matter what its concentration is in the liquid.
4. Solubility of a gas is important in determining partial pressure in solution. Some gases reach much higher concentrations in water than others do before the tendency to come out of solution balances the tendency to go into solution (equilibrium).
a. CO2 is ~22 times more soluble in water than O2.
b. CO2 (O=C=O) is a doubly polar molecule, partially positive at C, partially negative at both O's; interacts well with water, but also reacts with water to form H2CO3 (carbonic acid), which can dissociate into HCO3- (bicarbonate) and H+, increasing acidity of solution.
c. O2 is non-polar and doesn't interact well with water, but its effective solubility can be increased by addition to the solution of something that chemically binds O2.
C. Hemoglobin -- O2-binding protein in red blood cells (review Fig. 9.8, p. 241)
1. tetrameric protein with one O2-binding site in each of the 4 subunits; cooperativity among subunits produces sigmoidal binding curve of % O2 saturation vs PO2, with high binding affinity when all four subunits bind O2, lower affinity when only one or two bind O2 -- helps to load blood with O2 in lungs, where PO2 is high and release O2 in tissues, where PO2 is low.
2. When saturated with O2, blood has about 60 times more O2 than could be carried in the same volume of plasma (blood without the cells).
3. Binding affinity for O2 is decreased at lower pH and at higher temperature -- increases the release of O2 in very active tissues with high levels of CO2 and other acidic metabolic byproducts (e.g., lactic acid). Blood pH is 7.4 in arterial blood, can be < 7.3 in active tissues.
II. Transport of O2 (for simplification, we will concentrate on partial pressures after equilibration in lungs and after equilibration in tissues
A. Fresh air taken into lung (PO2 = 150 mmHg, after saturation with H2O at 37° C) mixes with air that remained in alveoli, then equilibrates with deoxygenated blood entering alveolar capillaries so both air and blood reach PO2 of 100 mmHg.
1. Equilibrates in ~ 1/3 sec; blood cell takes ~1 sec to go through pulmonary capillary.
2. ~ 2/3 of pulmonary capillaries are collapsed during quiet breathing; expansion of lung during deeper breathing opens remaining capillaries.
3. Lungs can accommodate ~10-fold increase in blood flow with only ~3-fold increase in blood velocity through capillary, so there is still just enough time for equilibration.
B. Blood with PO2 of 100 mmHg reaches tissues, where reversible reaction of O2 with hemoglobin goes the other way in low PO2 (equilibrating at ~40 mmHg), releasing some O2 to tissues.
1. In some inactive tissues, PO2 around capillaries may be > 40 mmHg and only ~20% of O2 is released from blood (see Fig. 11.6).
2. In very active tissues, PO2 may be < 20 mmHg; together with "acid shift" of O2 binding curve, this may cause > 85% of blood's O2 to be released to these tissues.
3. These chemical mechanisms add to the circulatory controls regulating blood flow to different tissues to insure effective O2 delivery where it is needed most.
C. After diffusion into tissue fluid around capillary, O2 continues down partial pressure gradient into active cells, where it is used by mitochondria to produce ATP.
1. At mitochondria, PO2 may be < 5 mmHg.
2. In aerobic muscles, there is a high concentration of an O2-binding protein called myoglobin, with a very high affinity for O2. It releases O2 mostly below PO2 of 10 mmHg and acts as a cellular O2 reservoir to ward off complete O2 starvation of very active muscle cells.
D. At altitude of 10,000 ft, outside air with PO2 of ~100 mmHg equilibrates with alveolar capillaries at PO2 of ~60 mmHg, still high enough on O2-hemoglobin binding curve to load ~90% of the O2 that could be bound at sea level. (Fig. 11.6, "C")
III. Transport of CO2 -- end product of metabolism (mitochondrial)
A. Capillary blood equilibrates with PCO2 of ~46 mmHg in tissue spaces
1. ~5% of CO2 is carried as dissolved CO2 in plasma.
2. ~7% is carried in reversible chemical bonds to hemoglobin molecules.
3. ~88% is carried as bicarbonate (HCO3- ) after reaction with water.
a. Carbonic anhydrase enzymes, carried in red blood cells, greatly accelerate (~13,000 times) reaction of CO2 + H2O <----> H2CO3 (either direction).
b. H2CO3 quickly dissociates into H+ and HCO3-.
c. HCO3- leaves red cells via Cl-/HCO3- exchangers to be carried in plasma.
d. Most H+ formed is bound by hemoglobin (keeps pH from changing too much).
B. In lungs, above reactions are driven the opposite direction by lower PCO2 in alveoli; air and blood equilibrate at PCO2 of ~40 mmHg.
IV. Control of ventilation/perfusion
A. Intrinsic controls (within lungs)
1. With a partly or completely blocked bronchiole leaving a group of alveoli with low PO2, the lung constricts the arteriole supplying blood to those alveoli to limit the amount of poorly oxygenated blood that would otherwise mix with other pulmonary blood returning to the left heart -- hypoxic pulmonary vasoconstriction. (Note that this is opposite to the effect of low PO2 in other tissues, which tends to cause increased blood flow.)
2. When there is restricted blood flow ("perfusion") to a group of alveoli, the lung responds by constricting the bronchiole that brings air to those alveoli and by slightly dilating the arteriole for better balancing of ventilation and perfusion.
B. Extrinsic controls
1. Basic involuntary rhythms of inspiration and expiration, carried out through respiratory motor neurons and muscles of respiration, are maintained by the medulla in the brain stem, with additional influences from higher brain centers. (Fig. 11.14)
2. Ventilation may be increased or decreased depending on neural inputs from several chemical sensors:
a. O2 chemoreceptors in the carotid arteries and the aorta monitor PO2 of arterial blood, gradually increase ventilation in response to low PO2 (most effective at very low PO2).
b. H+ chemoreceptors in carotid arteries and in medulla
i. more important than O2 receptors for modulating ventilation under most conditions; i. e., we feel an urgent need to take another breath more because of rising PCO2 than because of falling PO2
ii. Medulla is most sensitive to changes in PCO2, because blood-brain barrier prevents entry of most ions from blood, but allows membrane-permeant CO2 to enter, where it dissociates into HCO3- and H+; cerebro-spinal fluid is not as well buffered as blood, so small changes in PCO2 cause greater pH change in CSF than in blood; and the pH changes in CSF are more closely tied to PCO2 than to other acids or bases in the blood.
iii. A major function of the respiratory system is maintenance of blood pH, balancing the ratio of bicarbonate to CO2, in concert with the kidneys (described in next lectures). We don't exhale all the CO2 that reaches the lungs from the tissues; PCO2 only drops from 46 to 40 mmHg. Ventilation is automatically modulated to maintain that 40 mmHg level, to keep arterial blood at pH 7.4.
3. voluntary control, from cerebral cortex -- for holding one's breath, speaking, singing, blowing out the birthday candles, etc.
4. Hyperventilation (breathing faster and more deeply than necessary), involuntary (e.g., due to anxiety) or voluntary, brings almost no additional O2 to blood, but can greatly lower PCO2. The urge to take another breath (signals from H+ sensors) may be so greatly delayed that one loses consciousness from falling PO2 of blood.
5. Certain drugs or hormones can stimulate or depress brain stem's breathing centers.
a. Epinephrine stimulates -- increases breathing rate and depth of inspiration.
b. Alcohol and heroin depress breathing -- overdose deaths are typically due to inadequate O2 delivery to the brain.
Appendix
I. Carbon monoxide poisoning
A. Carbon monoxide (CO) is a byproduct of incomplete combustion of carboniferous fuels. Common sources are burning charcoal, automobile engines, and poorly adjusted (or poorly vented) furnaces.
B. Hemoglobin's O2-binding site binds CO ~200 times more tightly than it binds O2.
1. O2 is substantially displaced by CO on hemoglobin even when PCO is quite low.
2. Binding is so tight that the site is essentially permanently unavailable for O2 carrying.
3. Death results when too little O2 is delivered to the brain, even though pulmonary ventilation and blood circulation are normal.
II. Diseases related to tobacco smoking:
A. lung cancer
1. most common cause of cancer death in U.S.
2. Cigarette smoking is leading cause of lung cancer.
3. Lung cancer recently surpassed breast cancer as the leading cause of cancer death among women in the U.S.
B. emphysema
1. breakdown of tissue that separates individual alveoli
2. Air spaces become larger, with much less surface area for gas exchange; O2 delivery is greatly impaired.
3. Remaining tissue becomes thickened and stiffened; ventilation becomes more difficult.
4. Advanced emphysema is very debilitating and usually fatal, if another disease doesn't kill the patient first.
C. Chronic obstructive pulmonary disease (COPD)
1. combines emphysema with chronic bronchitis
2. Excessive mucus production slows cleansing action of respiratory epithelium, allows increased infections.
3. Inflammation and thickening of bronchial walls obstruct the flow of air.
4. Edema (excessive fluid in lung tissue and air spaces) increases distances for diffusion of gases.