TRANSPORT OF GASES.
REGULATION OF BREATHING.
Partial Pressures
Unlike liquids, gases expand to fill the volume available to them, and the volume occupied by a giveumber of gas molecules at a given temperature and pressure is (ideally) the same regardless of the composition of the gas.
Therefore, the pressure exerted by any one gas in a mixture of gases (its partial pressure) is equal to the total pressure times the fraction of the total amount of gas it represents.
The composition of dry air is 20.98% O2, 0.04 CO2, 78.06% N2, and 0.92% other inert constituent such as argon and helium. The barometric pressure (pb) at sea level is
Gas diffuses from areas of high pressure to area of low pressure, the rate of diffusion depending upon the concentration gradient and the nature of the barrier: between the 2 areas. When a mixture of gases is in contact with and permitted to equilibrate with a liquid each gas in the mixture dissolves in the liquid to an extent determined by its partial pressure and its solubility in the fluid. The partial pressure of a gas in a liquid is that pressure which in the gaseous phase in equilibrium with the liquid would produce the concentration of gas molecules found in the liquid.
GAS EXCHANGE IN THE LUNG
Composition of Alveolar Air. Oxygen continuously diffuses out of the gas in the alveoli (alveolar gas) into the bloodstream, and C02 continuously diffuses into the alveoli from the blood. In the steady state, inspired air mixes with the alveolar gas, replacing the O2 that has entered the blood and diluting the CO2 that has entered the alveoli. Part of this mixture is expired. The O2 content of the alveolar gas then falls and its CO2 content rises until the next inspiration. Since the volume of gas in the alveoli is about
Sampling Alveolar Air . Theoretically, all but the first 150 ml expired with each expiration is alveolar air, but there is always some mixing at the interface between the dead space gas and the alveolar air. A later portion of expired air is therefore the portion taken for analysis. Using modern apparatus with a suitable automatic valve, it is possible to collect the last 10 ml expired during quiet breathing. The composition of alveolar gas is compared with that of inspired and expired air.
Diffusion Capacity. Partial Pressures of O2 and CO2 in the body (normal, resting conditions): Alveoli: P.O2 =
Alveolar capillaries
Entering the alveolar capillaries P.O2 =
Partial pressure and diffusion at the respiratory membrane.
While in the alveolar capillaries, the diffusion of gasses occurs: oxygen diffuses from the alveoli into the blood and carbon dioxide from the blood into the alveoli. Leaving the alveolar capillaries: PO2 =
Blood leaving the alveolar capillaries returns to the left atrium and is pumped by the left ventricle into the systemic circulation. This blood travels through arteries & arterioles and into the systemic, or body, capillaries. As blood travels through arteries & arterioles, no gas exchange occurs.
Entering the systemic capillaries: PO2 =
Body cells (resting conditions): PO2 =
Oxygen moves from the alveoli to the red blood cells along the short path. The PO2 of alveolar air is
There is no evidence that any process other than passive diffusion is involved in the movement of O2; into the blood along this pressure gradient. O2 dissolves in the plasma and enters the red blood cells, where it combines with hemoglobin. Diffusion into the blood must be very rapid, since the time for each milliliter of blood is in the capillaries is short. Nevertheless, O2 diffusion is adequate in health to raise the PO2; of the blood to
The diffusion capacity of the lungs for O2 is the amount of O2 that crosses the alveolar membrane per minute per mm Hg difference in PO2 between the alveolar gas and the blood in the pulmonary capillaries. Expressed in terms of STPD, it is normally about 20 ml/min/mm Hg at rest. As a result of capillary dilatation and an increase in the number of active capillaries, it rises to values of 65 or more during exercise. The diffusion capacity for O2 is decreased in diseases such as sarcoidosis and beryllium poisoning (berylliosis) that cause fibrosis of the alveolar walls and produce alveolar-capillary block.
The P.CO2 of venous blood is
The partial pressure gradients for O2 and CO2 have been plotted in graphic form in Fig 44-3 to emphasize that they are the key to gas movement and that O2 “flows downhill” from the air through the alveoli and blood into the tissues whereas CO2 ”flows downhill” from the tissues to the alveoli.
However, the amount of both of these gases transported to and from the tissues would be grossly inadequate if it were not that about 99% O2 which dissolves in the blood combines with the O2 carrying protein hemoglobin and that about 94% of the CO2 which dissolves enters into a series of reversible chemical reactions, which convert it into other compounds. The presence of hemoglobin increases the O2 carrying capacity of the blood 70-fold, and the reactions of CO2 increase the blood CO2 content 17-fold
Oxygen Delivery to the Tissues. The O2 delivery system in the body consists of the lungs and the cardiovascular system. O2 delivery to a particular tissue depends on the amount of O2 entering the lungs, the adequacy of pulmonary gas exchange, the blood flow to the tissue, and the capacity of the blood to carry O2. The blood flow depends on the degree of constriction of the vascular bed in the tissue and the cardiac output. The amount of O2 in the blood is determined by the amount of dissolved O2, the amount of hemoglobin in the blood, and the affinity of the hemoglobin for O2.
OXYGEN TRANSPORT
Reaction of Hemoglobin & Oxygen. The dynamics of the reaction of hemoglobin with O2 make it a particularly suitable O2 carrier. Hemoglobin is a protein made up of 4 subunits, each of which contains a hem moiety attached to a polypeptide chain. Hem is a complex made up of porphyry and 1 atom of ferrous iron. Each of the 4 iron atoms can bind reversibly one O2 molecule. The iron stays in the ferrous state, so that the reaction is an oxygenation, not an oxidation. When hemoglobin takes up a small amount of O2, the R state is favored and additional uptake of O2 is facilitated. This is why the oxygen hemoglobin dissociation curve, the curve relating percentage saturation of the O2-carrying power of hemoglobin to the P.O2, has a characteristic sigmoid shape. Combination of the first hem in the Hb molecule with O2 increases the affinity of the second hem for O2, and oxygenation of the second increases the affinity of the third, etc, so that the affinity of Hb for the fourth O2 molecule is many times that for the first. When hemoglobin takes up O2, the 2/3 chains move closer together; when O2 is given up, they move further apart. This shift is essential for the shift in affinity for O2 to occur. When blood is equilibrated with 100% O2 (P.O2 =
Thus, at rest the tissues remove about 4.6 ml of O2 from each deciliter of blood passing through them (Table 44-4); 0.17 ml of this total represents O2 that was in solution in the blood, and the remainder represents O2 that was liberated from hemoglobin. In this way, 250 ml of O2 per minute is transported from the blood to the tissues at rest.
Figure 44-5. Oxygen hemoglobin dissociation curve pH 7,40. temperature 380.
Factors Affecting the Affinity of Hemoglobin for Oxygen. Three important conditions affect the oxygen hemoglobin dissociation curve: the pH, the temperature, and the concentration of 2,3-diphosphoglycerate (DPG; 2,3-DPG). A rise in temperature or a fall in pH shifts the curve to the right .
When the curve is shifted in this direction, a higher P.O2; is required for hemoglobin to bind a given amount of O2. Conversely, a fall in temperature or a rise in pH shifts the curve to the left, and a lower P O2 is required to bind a given amount of O2. A convenient index of such shifts is the P50, the P O2 at which the hemoglobin is half saturated with O2; the higher the P50, the lower the affinity of hemoglobin for O2.
The decrease in O2 affinity of hemoglobin when the pH of blood falls is called the Bohr effect and is closely related to the fact that deoxyhemoglobin binds H+ more actively than does oxyhemoglobin. The pH of blood falls as its CO2 content increases , so that when the PCO2 rises, the curve shifts to the right and the P50 rises. Most of the unsaturation of hemoglobin that occurs in the tissues is secondary to the decline in the P O2, but an extra 1-2% unsaturation is due to the rise in P.CO2 and consequent shift of the dissociation curve to the right.
2,3-DPG is very plentiful in red cells. It is formed from 3-phosphoglyceraldehyde, which is a product of glycolysis via the Embden-Meyerhof pathway. It is a highly charged anion that binds to the Beta chains of deoxygenated hemoglobin but not to those of oxyhemoglobin. One mole of deoxygenated hemoglobin binds 1 mole of 2,3-DPG. In effect:
HbO2 + 2,3-DPG =Hb–2,3-DPG + O2
In this equilibrium, an increase in the concentration of 2,3-DPG shifts the reaction to the right, causing more O2 to be liberated. ATP binds to deoxygenated hemoglobin to a lesser extent, and some other organic phosphates bind to a minor degree.
Factors affecting the concentration of 2,3-DPG in the red cells include pH. Because acidosis inhibits red cell glycolysis, the 2,3-DPG concentration falls when the pH is low. Thyroid hormones, growth hormone, and androgens increase the concentration of 2,3-DPG and the P50.
Myoglobin. Myoglobin is an iron-containing pigment found in skeletal muscle. It resembles hemoglobin but binds one rather than 4 mol of O2 per mole. Its dissociation curve is a rectangular hyperbola rather than a sigmoid curve. Because its curve is to the left of the hemoglobin curve 5), it takes up O2 from hemoglobin in the blood.
It releases O2 only at low P.O2 values, but the P O2 in exercising muscle is close to zero. The myoglobin content is greatest in muscles specialized for sustained contraction.
The muscle blood supply is compressed during such contractions, and myoglobin may provide O2 when blood flow is cut off. There is also evidence that myoglobin facilitates the diffusion of O2 from the blood to the mitochondria, where the oxidative reactions occur.
NEURAL CONTROL OF BREATHING
Control Systems. Spontaneous respiration is produced by rhythmic discharge of the motor neurons that innervate the respiratory muscles. This discharge is totally dependent oerve impulses from the brain; breathing stops if the spinal cord is transected above the origin of the premix nerves.
Two separate neural mechanisms regulate respiration. One is responsible for voluntary control and the other for automatic control. The voluntary system is located in the cerebral cortex and sends impulses to the respiratory motor neurons via the corticospinal tracts. The automatic system is located in the pons and medulla, and the motor outflow from this system to the respiratory motor neurons is located in the lateral and ventral portions of the spinal cord.
The motor neurons to the expiratory muscles are inhibited when those supplying the inspiratory muscles are active, and vice versa. These reciprocal innervations are not due to spinal reflexes and in this regard differ from the reciprocal innervations of the limb flexors and extensors. Instead, impulses in descending pathways that excite agonists also inhibit antagonists, probably by exciting inhibitory interneurons.
Medullary Centers. Rhythmic discharge of neurons in the medulla oblongata produces automatic respiration. Respiratory neurons are of 2 types: those that discharge during inspiration (I neurons) and those that discharge during expiration (E neurons). Many of these discharge at increasing frequencies during inspiration, in the case of I neurons, or during expiration, in the case of E neurons. Some discharge at decreasing frequencies, and some discharge at the same high rate during inspiration or expiration. I neurons are actively inhibited during expiration, E neurons during inspiration.
The area in the medulla that is concerned with respiration has classically been called the respiratory center, but there are actually 2 groups of respiratory neurons. The dorsal group of neurons near the nucleus of the tracts solitaries is the source of rhythmic drive to the centra lateral premix motor neurons. These neurons also project to and drive the ventral group. This group has 2 divisions. The cranial division is made up of neurons in the nucleus ambiguous that innervate the ipsilateral accessory muscles of respiration, principally via the vagus nerves. The caudal division is made up of neurons in the nucleus retroambigualis that provide the inspiratory and expiratory drive to the motor neurons supplying the intercostal muscles. The paths from these neurons to expiratory motor neurons are crossed, but those to inspiratory motor neurons are both crossed and uncrossed.
Pontine & Vagal Influences. The rhythmic discharge of the neurons in the respiratory center is spontaneous, but it is modified by centers in the pons and by afferents in the vagus nerves from receptors in the lungs. The interactions of these components can be analyzed by evaluating the results of the experiments summarized
Complete transaction of the brain stem below the medulla
1) stops all respiration. When all of the cranial nerves (including the vagi) are cut and the brain stem is transected above the pons, regular breathing continues. However, when an additional transaction is made in the inferior portion of the pons , the inspiratory neurons discharge continuously and there is a sustained contraction of the inspiratory muscles. This arrest of respiration in inspiration is called apneusis. The area in the pons that prevents apneusis is called the pneumotaxic center and is located in the nucleus parabrachialis. The area in the caudal pons responsible for apneusis is called the apneustic center.
When the brain stem is transected in the inferior portion of the pons and the vagus nerves are left intact, regular respiration continues. In an apneustic animal, stimulation of the proximal stump of one of the cut vagi produces, after a moderate latent period, a relatively prolonged inhibition of inspiratory neuron discharge. There are stretch receptors in the lung parenchyma that relay to the medulla via afferents in the vagi, and rapid inflation of the lung inhibits inspiratory discharge (Hering-Breuer reflex). Thus, stretching of the lungs during inspiration reflexly inhibits inspiratory drive, reinforcing the action of the pneumotaxic center in producing intermittency of inspiratory neuron discharge. This is why the depth of inspiration is increased after vagotomy in otherwise intact experimental animals, although breathing continues as long as the pneumotaxic center is intact.
When all pontine tissue is separated from the medulla , respiration continues whether or not the vagi are intact. This respiration is somewhat irregular and gasping, but it is rhythmic. Its occurrence demonstrates that the respiratory center neurons are capable of spontaneous rhythmic discharge.
The precise physiologic role of the pontine respiratory areas is uncertain, but they apparently make the rhythmic discharge of the medullary neurons smooth and regular. It appears that there are topically discharging neurons in the apneustic center which drive inspiratory neurons in the medulla, and these neurons are intermittently inhibited by impulses in afferents from the pneumotaxic center and vagal afferents.
REGULATION OF RESPIRATORY CENTER ACTIVITY
A rise in the P.CO2 or H+ concentration of arterial blood or a drop in its P.O2 increases the level of respiratory neuron activity, and changes in the opposite direction have a slight inhibitory effect. The effects of variations in blood chemistry on ventilation are mediated via respiratory chemoreceptors – receptor cells in the medulla and the carotid and aortic bodies sensitive to changes in the chemistry of the blood which initiate impulses that stimulate the respiratory center. Superimposed on this basic chemical control of respiration, other afferents provide nonchemical controls for the fine adjustments that affect breathing in particular situations held constant, the effects of excess in the blood are combated, and the P.O2; is raised when it falls to a potentially dangerous level. The respiratory minute volume is proportionate to the metabolic rate, but the link between metabolism and ventilation is CO2, not O2. The receptors in the carotid and aortic bodies are stimulated by a rise in the P CO2 or H+ concentration of arterial blood or a decline in its PO2. After denervation of the carotid chemoreceptors, the response to a drop in PO2; is abolished; the predominant effect of hypoxia after denervation of the carotid bodies is a direct depression of the respiratory center.
The response to changes in arterial blood H+ concentration in the pH 7.3-7.5 range is also abolished, although larger changes exert some effect. The response to changes in arterial P.CO2 is affected only slightly; it is reduced no more than 30-35%.
Carotid & Aortic Bodies.There is a carotid body near the carotid bifurcation on each side, and there are usually 2 or more aortic bodies near the arch of the aorta. Each carotid and aortic body (glomus) contains islands of 2 types of cells, type I and type II cells, surrounded by fenestrated sinusoidal capillaries.
NONCHEMICAL INFLUENCES ON RESPIRATION
Afferents from “Higher Centers”.
There are afferents from the neocortex to the motor neurons innervating the respiratory muscles, and even though breathing is not usually a conscious event, both inspiration and expiration are under voluntary control. Pain and emotional stimuli affect respiration, so there must also be afferents from the limbic system and hypothalamus.
Since voluntary and automatic control of respiration is separate, automatic control is sometimes disrupted without loss of voluntary control. The clinical condition that results has been called Ondine’s curse. In German legend, Ondine was a water nymph who had an unfaithful mortal lover. The king of the water nymphs punished the lover by casting a curse upon him that took away all his automatic functions. In this state, he could stay alive only by staying awake and remembering to breathe. He eventually fell asleep from sheer exhaustion and his respiration stopped. Patients with this intriguing condition generally have disease processes that compress the medulla or bulbar poliomyelitis. The condition has also been inadvertently produced in patients who have been subjected to bilateral anterolateral cervical cordotomy for pain. This cuts the pathways that bring about automatic respiration while leaving the voluntary efferent pathways in the corticospinal and rubrospinal tracts intact.
Afferents from Proprioceptors. Carefully controlled experiments have shown that active and passive movements of joints stimulate respiration, presumably because impulses in afferent pathways from proprioceptors in muscles, tendons, and joints stimulate the inspiratory neuron. This effect probably helps increase ventilation during exercise.
Responses to Irritation of the Air Passages. Sneezing and coughing are reflex responses to irritation of receptors in the mucosa of the large respiratory passages. Irritation of the walls of the trachea or large bronchi produces coughing, which begins with a deep inspiration followed by forced expiration against a closed glottis. This increases intrapleural pressure to
Other Pulmonary Receptors. The vagally mediated inhibition of inspiration produced by inflation of the lung has been mentioned above. The response is due to stimulation of stretch receptors located in the smooth muscle of the airways. Pulmonary deflation receptors that trigger inflation have also been described, and the expiratory and inspiratory reflex responses to pulmonary inflation and deflation, respectively, have been known as the Hering-Breuer reflexes. However, the deflation receptors respond better to pulmonary congestion and embolization, producing shallow, rapid breathing, and they have come to be called J receptors instead, because of their juxtacapillary location. There are also lung irritant receptors located between the epithelial cells in the bronchi and bronchioles. When stimulated, they initiate hyperventilation and bronchoconstriction, but their function iormal breathing is not known.
Respiratory Components of Other Visceral Reflexes.
The respiratory adjustments during vomiting, swallowing and gagging; inhibition of respiration and closure of the glottis during these activities not only prevent the aspiration of food or vomitus into the trachea but, in the case of vomiting, fix the chest so that contraction of the abdominal muscles increases the intra-abdominal pressure. Similar glottis closure and inhibition of respiration occur during voluntary and involuntary straining.
Hiccup is a spasmodic contraction of the diaphragm that produces an inspiration during which the glottis suddenly closes. The glottis closure is responsible for the characteristic sensation and sound. Yawning is a peculiar “infectious” respiratory act the physiologic basis and significance of which are uncertain. However, under ventilated alveoli have a tendency to collapse, and it has been suggested that the deep inspiration and stretching open them alveoli and prevent the development of atelectasis. Yawning also increases venous return to the heart.
Respiratory Effects of Baroreceptor Stimulation. Afferent fibers from the baroreceptors in the carotid sinuses, aortic arch, atria, and ventricles relay to the respiratory center as well as the vasomotor and cardioinhibitory centers in the medulla. Impulses in them inhibit respiration, but the inhibitory effect is slight and of little physiologic importance. The hyperventilation in shock is due to chemoreceptor stimulation caused by acidosis and hypoxia secondary to local stagnation of blood flow and is not baroreceptor mediated. The activity of the inspiratory neurons affects the blood pressure and heart rate and activity in the vasomotor center and the cardiac centers in the medulla may have minor effects on respiration.
Effect of irritant receptors in the airways. The epithelium of the trachea, bronchi, and bronchioles is supplied with sensory nerve endings that are stimulated by irritants that enter the respiratory airways. These cause coughing and sneezing. They possibly also cause bronchial constriction in such diseases as asthma and emphysema.
Function of Lung “J” Receptors. A few sensory nerve endings occur in the alveolar walls in Juxtaposition to the pulmonary capillaries, from whence comes the name “J” receptors. They are stimulated when irritant chemicals are injected into the pulmonary blood, and they are also excited when the pulmonary capillaries become engorged with blood or when pulmonary edema occurs in such conditions as congestive heart failure. Though the functional role of the J receptors is not known, their excitation perhaps does give the person a feeling of dyspnea.
Limitation of Inspiration by Lung Inflation Signals – the Hering-Breuer Inflation Reflex
Located in the walls of the bronchi and bronchioles throughout the lungs are stretch receptors that transmit signals through the vagi into the dorsal respiratory group of neurons when the lungs become overstretched. These signals affect inspiration in much the same way as signals from the pneumotaxic center; that is, they limit the duration of
Therefore, when the lungs become overly inflated, the stretch receptors activate an appropriate feedback response that “switches off” the inspiratory ramp and thus limits further inspiration. This is called the Hering-Breuer inflation reflex. This reflex also increases the rate of respiration because of the reduced period of inspiration, the same as is true for signals from the pneumotoxic center.
However, in human beings, the Hering-Breuer reflex probably is not activated until the tidal volume increases to greater than approximately
