Premed · Premed · Anatomy Physiology 2
Lecture 12: Transport of Gases and Respiratory Regulation
Anatomy and Physiology II
Learning Objectives
By the end of this lecture, students will be able to:
- Describe how oxygen is transported in the blood
- Interpret the oxygen-hemoglobin dissociation curve and factors that shift it
- Describe how carbon dioxide is transported in the blood
- Explain the neural control of breathing (medullary and pontine centers)
- Describe the chemical factors that regulate breathing rate and depth
- Identify other factors that influence respiration
Lecture Content
I. Oxygen Transport
Oxygen travels in the blood in two forms. A small fraction, approximately 1.5%, dissolves directly in the plasma according to Henry's law, and the dissolved oxygen determines the PO2 of the blood. The vast majority, approximately 98.5%, is bound to hemoglobin as oxyhemoglobin (HbO2).
Oxygen-Hemoglobin Association
Each hemoglobin molecule has four heme groups, each capable of binding one molecule of oxygen. Oxygen saturation (SaO2) describes the percentage of hemoglobin binding sites occupied by oxygen. At a PO2 of 100 mmHg (arterial blood), hemoglobin is approximately 97 to 99% saturated. At a PO2 of 40 mmHg (venous blood), saturation falls to approximately 75%. Oxygen binding to hemoglobin is both reversible and cooperative: once one oxygen molecule binds, hemoglobin undergoes a conformational change from the T (tense) state to the R (relaxed) state, increasing its affinity for subsequent oxygen molecules. This cooperative binding produces the characteristic sigmoidal shape of the dissociation curve.
Oxygen-Hemoglobin Dissociation Curve
This curve plots oxygen saturation of hemoglobin against PO2 and has two functionally important regions. The plateau region (PO2 60 to 100 mmHg) shows that hemoglobin remains well saturated even with moderate drops in PO2, ensuring adequate oxygen loading even at moderate altitudes. The steep region (PO2 20 to 40 mmHg) shows that small decreases in PO2 cause large amounts of oxygen to be unloaded, ensuring efficient delivery to metabolically active tissues.
Factors That Shift the Curve
A right shift (decreased affinity, enhanced oxygen unloading to tissues) is produced by increased temperature, increased PCO2 (the Bohr effect), increased hydrogen ion concentration (decreased pH, acidosis), and increased 2,3-bisphosphoglycerate (2,3-BPG/DPG), a metabolite produced by red blood cells during anaerobic glycolysis. These are precisely the conditions found in exercising tissues, ensuring that oxygen is released where it is needed most.
A left shift (increased affinity, reduced oxygen unloading) results from decreased temperature, decreased PCO2, decreased hydrogen ions (increased pH, alkalosis), decreased 2,3-BPG, carbon monoxide binding (CO binds hemoglobin with 200 times greater affinity than oxygen), and fetal hemoglobin (HbF), which has a higher oxygen affinity than adult HbA, facilitating oxygen transfer from mother to fetus.
<image>An oxygen-hemoglobin dissociation curve. Panel A: The standard sigmoidal curve with percent O2 saturation of hemoglobin on the y-axis (0–100%) and PO2 on the x-axis (0–120 mmHg). Key points labeled: arterial point at PO2 = 100 mmHg showing ~97% saturation, venous point at PO2 = 40 mmHg showing ~75% saturation, and the P50 value (~26 mmHg) marked. The plateau and steep portions are annotated. Panel B: Right-shifted and left-shifted curves overlaid on the normal curve, with the factors causing each shift listed in boxes beside the respective curves (right shift: increased temperature, CO2, H+, 2,3-BPG; left shift: decreased temperature, CO2, H+, 2,3-BPG, CO binding, fetal Hb). Arrows clearly show the direction of shift and the functional consequence (enhanced unloading vs. enhanced loading).</image>
II. Carbon Dioxide Transport
Carbon dioxide is transported in three forms. Approximately 7 to 10% is dissolved directly in the plasma, and this dissolved CO2 determines the PCO2 of the blood. About 20 to 23% binds to hemoglobin as carbaminohemoglobin, attaching to the globin protein's amino groups rather than to the heme group. This binding is enhanced when hemoglobin is deoxygenated, a relationship known as the Haldane effect. The largest fraction, approximately 70%, travels as bicarbonate ions (HCO3-), the most important transport form. Inside red blood cells, the enzyme carbonic anhydrase catalyzes the reaction CO2 + H2O to form carbonic acid (H2CO3), which rapidly dissociates into H+ and HCO3-. The bicarbonate is transported out of the red blood cell into the plasma via the chloride shift, an exchange mechanism in which chloride ions move into the cell to maintain electrical neutrality. The hydrogen ions released during this process are buffered by deoxyhemoglobin, which binds H+ more readily than oxyhemoglobin.
The Haldane Effect
The Haldane effect describes how deoxygenated hemoglobin carries more CO2 than oxygenated hemoglobin, both by binding more carbaminohemoglobin and by buffering more H+ to drive bicarbonate formation. At the tissues, oxygen unloading promotes CO2 loading. At the lungs, oxygen loading promotes CO2 unloading. The Haldane effect and Bohr effect work together as complementary mechanisms to optimize gas exchange.
CO2 Unloading at the Lungs
At the lungs, all the reactions reverse. Bicarbonate re-enters the red blood cells as chloride exits (reverse chloride shift). Carbonic anhydrase catalyzes the recombination of bicarbonate and hydrogen ions to form carbonic acid, which breaks down to CO2 and water. The CO2 then diffuses from the blood into the alveoli to be exhaled.
<image>A diagram of CO2 transport and the chloride shift. Panel A (At the tissues): A systemic capillary adjacent to tissue cells. CO2 diffuses from tissue into the capillary. Inside the red blood cell: carbonic anhydrase converts CO2 + H2O to H2CO3, which dissociates into H+ (buffered by deoxyhemoglobin) and HCO3- (transported out of the RBC into plasma via the HCO3-/Cl- antiporter, with Cl- moving in — the chloride shift). CO2 also binds directly to hemoglobin as carbaminohemoglobin. The three transport forms are shown with their approximate percentages. Panel B (At the lungs): The reverse process in a pulmonary capillary — HCO3- re-enters the RBC, combines with H+, carbonic anhydrase converts H2CO3 back to CO2 + H2O, and CO2 diffuses into the alveolus. O2 binding to hemoglobin is shown displacing CO2 and H+ (Haldane effect).</image>
III. Neural Control of Respiration
Medullary Respiratory Centers
The ventral respiratory group (VRG), located in the ventral medulla, contains both inspiratory and expiratory neurons and houses the primary rhythm generator. The pre-Botzinger complex within the VRG generates the basic respiratory rhythm. Inspiratory neurons stimulate the diaphragm and external intercostals via the phrenic and intercostal nerves during inspiration. Expiratory neurons are mostly inactive during quiet breathing but become active during forced expiration.
The dorsal respiratory group (DRG), in the dorsal medulla associated with the nucleus tractus solitarius, consists primarily of inspiratory neurons. It receives sensory input from peripheral chemoreceptors and lung stretch receptors via the vagus and glossopharyngeal nerves, and it modifies the breathing rhythm based on this input.
Pontine Respiratory Centers
The pneumotaxic center (pontine respiratory group), in the upper pons, sends inhibitory signals to the inspiratory center, limiting the duration of inspiration and thereby controlling respiratory rate. Strong pneumotaxic signals produce shorter inspirations and faster breathing, while weak signals allow longer inspirations and slower breathing. The apneustic center, in the lower pons, sends excitatory signals to the inspiratory center, promoting prolonged, deep inspirations (apneusis). Under normal circumstances, the pneumotaxic center and vagal input override the apneustic center.
Hering-Breuer Reflex (Inflation Reflex)
Stretch receptors in the visceral pleura and bronchial walls are activated by excessive lung inflation. They send inhibitory signals via the vagus nerve to the medullary inspiratory center, terminating inspiration and triggering expiration. This protective mechanism prevents overinflation of the lungs and is primarily active during forced breathing rather than quiet breathing in adults.
IV. Chemical Regulation of Breathing
The most important stimuli adjusting breathing rate and depth are chemical: PCO2, PO2, and H+ concentration (pH).
Central Chemoreceptors
Central chemoreceptors, located on the ventral surface of the medulla, respond primarily to changes in H+ concentration in the cerebrospinal fluid (CSF). Because CO2 crosses the blood-brain barrier freely, an increase in arterial PCO2 leads to increased CO2 in the CSF, where it combines with water to form carbonic acid, releasing H+. This elevated H+ stimulates the central chemoreceptors, which increase ventilation. The system is remarkably sensitive: a rise of just 5 mmHg in arterial PCO2 doubles alveolar ventilation. Central chemoreceptors are the most important regulators of ventilation under normal conditions.
Peripheral Chemoreceptors
Peripheral chemoreceptors reside in the carotid bodies (at the bifurcation of the common carotid arteries) and aortic bodies (in the aortic arch). They respond primarily to decreased PO2, becoming significantly active when arterial PO2 drops below approximately 60 mmHg. They also respond to increased PCO2 and decreased pH. Their signals travel via the glossopharyngeal nerve (CN IX, from carotid bodies) and vagus nerve (CN X, from aortic bodies) to the medullary respiratory centers.
Hypercapnia (Elevated PCO2)
Hypercapnia is the most potent chemical stimulus for breathing under normal conditions. It is detected primarily by central chemoreceptors via H+ changes in the CSF. The response is increased rate and depth of breathing, which blows off CO2 and returns PCO2 to normal. Hypocapnia (low PCO2) has the opposite effect, decreasing ventilation. Extreme voluntary hyperventilation can lower PCO2 enough to cause apnea because the drive to breathe is temporarily suppressed.
Hypoxia (Low PO2)
Hypoxia is detected by peripheral chemoreceptors but only becomes a significant stimulus when arterial PO2 falls below approximately 60 mmHg, because above this threshold hemoglobin remains well saturated. Under normal conditions, oxygen plays a relatively minor role in driving ventilation. However, in patients with chronic CO2 retention (such as severe COPD), central chemoreceptors adapt to chronically elevated PCO2 and lose their sensitivity. In these patients, the hypoxic drive becomes the primary stimulus for breathing, which is why administering high-concentration oxygen must be done with caution, as it may suppress the drive to breathe.
V. Other Influences on Respiration
Higher brain centers exert significant influence on breathing. The cerebral cortex allows voluntary control, such as holding the breath or deliberately hyperventilating, though this voluntary override is limited because chemical drives eventually prevail. The limbic system and hypothalamus modulate breathing in response to emotional states such as fear, pain, and excitement. Proprioceptors in muscles and joints stimulate increased ventilation at the very onset of exercise, even before any chemical changes have occurred. Irritant receptors in the airways trigger protective reflexes such as coughing, sneezing, and bronchoconstriction. Juxtacapillary (J) receptors in the alveolar walls near capillaries are stimulated by pulmonary congestion and trigger rapid, shallow breathing. Body temperature affects ventilation, with fever increasing it and hypothermia decreasing it. Drugs such as opioids and barbiturates depress the respiratory centers, while caffeine and amphetamines stimulate them.
VI. Clinical Correlations
Hyperventilation produces excessive ventilation that decreases PCO2, causing respiratory alkalosis, cerebral vasoconstriction, dizziness, and tingling. Hypoventilation produces inadequate ventilation that increases PCO2, resulting in respiratory acidosis. Chronic obstructive pulmonary disease (COPD) encompasses emphysema, in which destruction of alveolar walls decreases surface area and causes air trapping and loss of elastic recoil, and chronic bronchitis, characterized by chronic inflammation and excessive mucus production that obstruct the airways. Asthma involves reversible bronchoconstriction, inflammation, and mucus production causing episodic airway obstruction. Sleep apnea involves repeated cessation of breathing during sleep and may be obstructive (upper airway collapse) or central (malfunction of the medullary respiratory center). Carbon monoxide (CO) poisoning occurs because CO binds hemoglobin with 200 times greater affinity than oxygen, displacing oxygen and causing tissue hypoxia despite a normal arterial PO2.
<image>A diagram of the neural and chemical control of breathing. Panel A: A midsagittal view of the brainstem showing the locations of the pneumotaxic center and apneustic center in the pons, and the dorsal respiratory group (DRG) and ventral respiratory group (VRG) in the medulla, with arrows showing their interconnections and outputs to the phrenic nerve (to diaphragm) and intercostal nerves (to intercostal muscles). Panel B: A flowchart of chemical regulation — central chemoreceptors in the medulla detecting H+ changes in CSF driven by CO2 diffusion across the blood-brain barrier, and peripheral chemoreceptors in carotid and aortic bodies detecting low PO2, high PCO2, and low pH, both feeding into the medullary respiratory centers. The negative feedback loop is shown: increased PCO2 → increased ventilation → decreased PCO2 back to normal. Panel C: A graph showing the ventilatory response curves — ventilation (L/min) on the y-axis vs. arterial PCO2 on the x-axis showing a steep linear relationship, and a second curve showing ventilation vs. arterial PO2 showing minimal response until PO2 drops below 60 mmHg then a steep increase.</image>
