Figure 31-1 Control of ventilation.

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 Figure 31-4 The respiratory control center is located in the medulla (the most primitive portion of the brain). The neurons are mainly in two areas called the nucleus
tractus solitarius and the nucleus retroambiguus. C1, first cervical nerve. (From Berne RM, Levy MN, Koeppen BM, Stanton BA: Physiology, ed 5, Philadelphia, 2004,
Elsevier.)

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Figure 31-2 Effect of brainstem transections. A dorsal view of the brain stem and spinal cord, with the cerebellum removed, and records of integrated nerve activity over
one respiratory cycle, following the indicated transection. During inspiration, integrated nerve activity (a moving average of the amplitude and frequency of action
potentials) increases in the nerves to the tongue (e.g., CN XII) and the diaphragm (e.g., phrenic nerve). CN, cranial nerve; DRG, dorsal respiratory group; VRG, ventral
respiratory group.

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 Figure 31-4 The respiratory control center is located in the medulla (the most primitive portion of the brain). The neurons are mainly in two areas called the nucleus
tractus solitarius and the nucleus retroambiguus. C1, first cervical nerve. (From Berne RM, Levy MN, Koeppen BM, Stanton BA: Physiology, ed 5, Philadelphia, 2004,
Elsevier.)

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Figure 31-3 Respiratory patterns in experimental animals.

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Figure 31-6 Different patterns of breathing produced by successive transections of the brainstem in anesthetized animals. These patterns may also occur in humans with
selected brainstem lesions. The four levels of transection correspond to the numbers in Figure 31-5, A. The importance of the sensory division of the vagus nerve,
carrying information about the state of lung inflation, is shown by contrasting the intact to the cut columns. For transection level 1, there is no effect on the basic breathing
pattern, showing that the main controller lies caudal. Furthermore, it eliminates all volitional (conscious) changes in breathing (not shown here). When vagal sensory input
is eliminated, breathing slows, and tidal volume increases. Skipping down to transection level 4, breathing stops completely, showing that the main controller lies rostral.
For transection level 2, as long as sensory input from the vagus nerve continues, ablation of the pontine respiratory group has only a moderate slowing effect on
breathing, with tidal volume increased to maintain alveolar ventilation at approximately normal. After vagotomy, apneustic breathing (deep inspiration held for many
seconds) appears. For transection level 3, irregular, gasping breathing develops, which is not affected by cutting the vagus nerves. Clearly, medullary controllers are
sufficient to sustain life but are not adequate for providing normal modulation of breathing.

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Figure 31-10 The two main types of sleep apnea. A, Central apnea is characterized by no attempt to breathe, as demonstrated by no pleural pressure oscillations. B, In
obstructive sleep apnea, the pleural pressure oscillations increase as CO2 rises. This indicates that airflow resistance is very high owing to upper airway obstruction.
(From Berne RM, Levy MN, Koeppen BM, Stanton BA: Physiology, ed 5, Philadelphia, 2004, Elsevier.)

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Figure 31-3 Respiratory patterns in experimental animals.

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Figure 31-3 Respiratory patterns in experimental animals.

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Figure 31-5 Neural activity during the respiratory cycle. The activity of respiratory-related neurons in the medulla (examples of which are shown in D to I) leads to the
phasic activity of the phrenic nerve (C) and other respiratory nerves, which produces airflow (B), causing lung volume to change (A). ENG, electroneurogram; Exp,
expiration; FRC, functional residual capacity; Insp, inspiration; TV, tidal volume; Vm, membrane potential.

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Figure 31-6 Patterned synaptic input: Reciprocal inhibition. Because of reciprocal inhibition between the early-burst neuron and the lateonset inspiratory neuron, only one
can be maximally active at a time.

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Figure 31-7 Pacemaker activity in respiratory-related neurons. (A, data from Dekin MS, Richerson GB, Getting PA: Thyrotropin-releasing hormone induces rhythmic
bursting in neurons of the nucleus tractus solitarius. Science 229:67, 1985; B, data from Richerson GB, Getting PA: Maintenance of complex neural function during
perfusion of the mammalian brain. Brain Res 409:128, 1987.) DRG, dorsal respiratory group; ENG, electroneurogram; TRH, thyrotropin-releasing hormone.

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Figure 31-7 Pacemaker activity in respiratory-related neurons. (A, data from Dekin MS, Richerson GB, Getting PA: Thyrotropin-releasing hormone induces rhythmic
bursting in neurons of the nucleus tractus solitarius. Science 229:67, 1985; B, data from Richerson GB, Getting PA: Maintenance of complex neural function during
perfusion of the mammalian brain. Brain Res 409:128, 1987.) DRG, dorsal respiratory group; ENG, electroneurogram; TRH, thyrotropin-releasing hormone.

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Figure 31-8 Possible role of pre-Bötzinger complex as the respiratory central-pattern generator. The recordings were made in a brain slice. (Data from Smith JC,
Ellenberger HH, Ballanyi K, et al: Pre-Bötzinger complex: A brainstem region that may generate respiratory rhythm in mammals. Science 254:726, 1991.)

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 Figure 31-9 Chemosensitivity of the carotid body. A, Effect of anoxia on a single, isolated glomus cell. Anoxia elicits a depolarization and small action potentials, as
measured with a patch pipette. B, Effect of respiratory acid-base disturbances on O2 sensitivity. C, Effect of pH changes on CO2 sensitivity. In B and C, the y-axis
represents the frequency of action potentials in single sensory fibers from the carotid body. (A, data from Buckler KJ, Vaughan-Jones RD: Effects of hypoxia on
membrane potential and intracellular calcium in rat neonatal carotid body type I cells. J Physiol 476:423-428, 1994; B, data from Cunningham DJC, Robbins PA, Wolff
CB: Integration of respiratory responses to changes in alveolar partial pressures of CO2 and O2 and in arterial pH. In Cherniack NS, Widdicombe J: Handbook of
Physiology; Section 3, The Respiratory System. Vol II. American Physiological Society, Bethesda, MD 1986. pp. 475-528; C, data from Biscoe TJ, Purves MJ, Sampson
SR: The frequency of nerve impulse in single carotid body chemoreceptor afferent fibers recorded in vivo with intact circulation. J Physiol 208:121-131, 1970.)

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 Figure 31-9 Chemosensitivity of the carotid body. A, Effect of anoxia on a single, isolated glomus cell. Anoxia elicits a depolarization and small action potentials, as
measured with a patch pipette. B, Effect of respiratory acid-base disturbances on O2 sensitivity. C, Effect of pH changes on CO2 sensitivity. In B and C, the y-axis
represents the frequency of action potentials in single sensory fibers from the carotid body. (A, data from Buckler KJ, Vaughan-Jones RD: Effects of hypoxia on
membrane potential and intracellular calcium in rat neonatal carotid body type I cells. J Physiol 476:423-428, 1994; B, data from Cunningham DJC, Robbins PA, Wolff
CB: Integration of respiratory responses to changes in alveolar partial pressures of CO2 and O2 and in arterial pH. In Cherniack NS, Widdicombe J: Handbook of
Physiology; Section 3, The Respiratory System. Vol II. American Physiological Society, Bethesda, MD 1986. pp. 475-528; C, data from Biscoe TJ, Purves MJ, Sampson
SR: The frequency of nerve impulse in single carotid body chemoreceptor afferent fibers recorded in vivo with intact circulation. J Physiol 208:121-131, 1970.)

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 Figure 31-9 Chemosensitivity of the carotid body. A, Effect of anoxia on a single, isolated glomus cell. Anoxia elicits a depolarization and small action potentials, as
measured with a patch pipette. B, Effect of respiratory acid-base disturbances on O2 sensitivity. C, Effect of pH changes on CO2 sensitivity. In B and C, the y-axis
represents the frequency of action potentials in single sensory fibers from the carotid body. (A, data from Buckler KJ, Vaughan-Jones RD: Effects of hypoxia on
membrane potential and intracellular calcium in rat neonatal carotid body type I cells. J Physiol 476:423-428, 1994; B, data from Cunningham DJC, Robbins PA, Wolff
CB: Integration of respiratory responses to changes in alveolar partial pressures of CO2 and O2 and in arterial pH. In Cherniack NS, Widdicombe J: Handbook of
Physiology; Section 3, The Respiratory System. Vol II. American Physiological Society, Bethesda, MD 1986. pp. 475-528; C, data from Biscoe TJ, Purves MJ, Sampson
SR: The frequency of nerve impulse in single carotid body chemoreceptor afferent fibers recorded in vivo with intact circulation. J Physiol 208:121-131, 1970.)

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Figure 31-10 Anatomy of the peripheral chemoreceptors. (B, data from Williams PL, Warwick R (eds): Splanchnology. In: Gray's Anatomy. Philadelphia, WB Saunders,
1980.)

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Figure 31-11 Response of glomus cell to hypoxia, hypercapnia, and acidosis. cAMP, cyclic adenosine monophosphate; CN, cranial nerve; GSH, reduced glutathione;
GSSG, oxidized glutathione.

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Figure 31-12 Effect of arterial hypercapnia on brain pH and ventilation. (A, data from Padget P: The respiratory response to carbon dioxide. Am J Physiol 83:384-389,
1928. B, data from Fencl V: Acid-base balance in cerebral fluids. In Cherniack NS, Widdicombe J: Handbook of Physiology, Section 3, The Respiratory System. Vol II,
Part 1. Bethesda, MD, American Physiological Society, 1986, pp 115-140. C, data from Fencl V, Miller TB, Pappenheimer JR: Studies on the respiratory response to
disturbances of acid-base balance, with deductions concerning the ionic composition of cerebral interstitial fluid. Am J Physiol 210: 459-472, 1966.)

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Figure 31-12 Effect of arterial hypercapnia on brain pH and ventilation. (A, data from Padget P: The respiratory response to carbon dioxide. Am J Physiol 83:384-389,
1928. B, data from Fencl V: Acid-base balance in cerebral fluids. In Cherniack NS, Widdicombe J: Handbook of Physiology, Section 3, The Respiratory System. Vol II,
Part 1. Bethesda, MD, American Physiological Society, 1986, pp 115-140. C, data from Fencl V, Miller TB, Pappenheimer JR: Studies on the respiratory response to
disturbances of acid-base balance, with deductions concerning the ionic composition of cerebral interstitial fluid. Am J Physiol 210: 459-472, 1966.)

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Figure 31-12 Effect of arterial hypercapnia on brain pH and ventilation. (A, data from Padget P: The respiratory response to carbon dioxide. Am J Physiol 83:384-389,
1928. B, data from Fencl V: Acid-base balance in cerebral fluids. In Cherniack NS, Widdicombe J: Handbook of Physiology, Section 3, The Respiratory System. Vol II,
Part 1. Bethesda, MD, American Physiological Society, 1986, pp 115-140. C, data from Fencl V, Miller TB, Pappenheimer JR: Studies on the respiratory response to
disturbances of acid-base balance, with deductions concerning the ionic composition of cerebral interstitial fluid. Am J Physiol 210: 459-472, 1966.)

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Figure 31-13 Chemosensitive neurons in the ventrolateral medulla and raphe. Illustrated in A is a ventral view of a cat medulla showing chemosensitive areas named after
the three physiologists that first described them. The slice to the right shows the location of serotonergic neurons in the ventrolateral medulla and medullary raphe nuclei.
B and C are patch-pipette recordings of neurons cultured from the medullary raphe of rats. Those that are stimulated by acidosis are serotonergic, and those that are
inhibited do not contain serotonin. (A, data from Dermietzel R: Central chemosensitivity, morphological studies. In: Loeschke HL, ed. Acid-base Homeostasis of the Brain
Extracellular Fluid and the Respiratory Control System. Stuttgart: Thieme Edition/Publishing Sciences Group, pp. 52-66, 1976. B and C, data from Wang W, Pizzonia JH,
Richerson GB: Chemosensitivity of rat medullary raphe neurones in primary tissues culture. J of Physiol 511:433-450, 1998.)

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Figure 31-13 Chemosensitive neurons in the ventrolateral medulla and raphe. Illustrated in A is a ventral view of a cat medulla showing chemosensitive areas named after
the three physiologists that first described them. The slice to the right shows the location of serotonergic neurons in the ventrolateral medulla and medullary raphe nuclei.
B and C are patch-pipette recordings of neurons cultured from the medullary raphe of rats. Those that are stimulated by acidosis are serotonergic, and those that are
inhibited do not contain serotonin. (A, data from Dermietzel R: Central chemosensitivity, morphological studies. In: Loeschke HL, ed. Acid-base Homeostasis of the Brain
Extracellular Fluid and the Respiratory Control System. Stuttgart: Thieme Edition/Publishing Sciences Group, pp. 52-66, 1976. B and C, data from Wang W, Pizzonia JH,
Richerson GB: Chemosensitivity of rat medullary raphe neurones in primary tissues culture. J of Physiol 511:433-450, 1998.)

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Figure 31-13 Chemosensitive neurons in the ventrolateral medulla and raphe. Illustrated in A is a ventral view of a cat medulla showing chemosensitive areas named after
the three physiologists that first described them. The slice to the right shows the location of serotonergic neurons in the ventrolateral medulla and medullary raphe nuclei.
B and C are patch-pipette recordings of neurons cultured from the medullary raphe of rats. Those that are stimulated by acidosis are serotonergic, and those that are
inhibited do not contain serotonin. (A, data from Dermietzel R: Central chemosensitivity, morphological studies. In: Loeschke HL, ed. Acid-base Homeostasis of the Brain
Extracellular Fluid and the Respiratory Control System. Stuttgart: Thieme Edition/Publishing Sciences Group, pp. 52-66, 1976. B and C, data from Wang W, Pizzonia JH,
Richerson GB: Chemosensitivity of rat medullary raphe neurones in primary tissues culture. J of Physiol 511:433-450, 1998.)

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 Figure 31-14 Integrated ventilatory response to changes in Pco2 (A) and Po2 (B). (A, data from Nielsen M, Smith H: Studies on the regulation of respiration in acute
hypoxia. Acta Physiol Scand 24:293-313, 1952. B, data from Loeschcke HH, Gertz KH: Einfluss des O2-Druckes in der Einatmungsluft auf die Atemtätigkeit der
Menschen, gepruüft unter Konstanthaltung des alveolaren CO2-Druckes. Pflugers Arch Ges Physiol 267:460-477, 1958.)

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 Figure 31-14 Integrated ventilatory response to changes in Pco2 (A) and Po2 (B). (A, data from Nielsen M, Smith H: Studies on the regulation of respiration in acute
hypoxia. Acta Physiol Scand 24:293-313, 1952. B, data from Loeschcke HH, Gertz KH: Einfluss des O2-Druckes in der Einatmungsluft auf die Atemtätigkeit der
Menschen, gepruüft unter Konstanthaltung des alveolaren CO2-Druckes. Pflugers Arch Ges Physiol 267:460-477, 1958.)

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Figure 31-2 The effects of hypoxia (A) and hypercapnia (B) on ventilation as the other respiratory gas partial pressure is varied. A, At a given Paco2, ventilation increases
as Pao2 decreases. When the Paco2 decreases during hypoxia, ventilation decreases at lower levels of Pao2. The hypoxia response is mediated through the carotid
body chemoreceptors. B, The sensitivity of the ventilatory response to CO2 is enhanced by hypoxia. (From Berne RM, Levy MN, Koeppen BM, Stanton BA: Physiology,
ed 5, Philadelphia, 2004, Elsevier.)
Figure 31-3 Effect of [H+] on ventilatory response to CO2. In chronic metabolic acidosis, the ventilatory sensitivity to CO2 increases, resulting in greater levels of
ventilation than in normal or alkalotic states. (Data from Fencl V et al: J Appl Physiol 27:67, 1969.)

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Figure 31-1 CO2-ventilation response curve. Ventilation is sensitive to Paco2, as shown by the red line (awake). In this example from an adult, the normal operating point
is 5 L/min at 40 mm Hg (large dot). In the awake (alert) state, ventilation becomes insensitive to a decrease in CO2 below 40 mm Hg. When the reticular activating
system is turned off, as during sleep (blue line), the CO2 intercept is increased (shifted to the right), and the slope is decreased (decreased sensitivity).

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Figure 31-15 The Hering-Breuer reflex. In a paralyzed and artificially ventilated animal, preventing lung inflation during inspiratory activity (blue curves) leads to prolonged
phrenic nerve output (i.e., if the animal were not paralyzed, then tidal volume would be large). Inflating the lungs during inspiratory activity (red curves) produces feedback
that shortens the duration of inspiratory activity (i.e., if the animal were not paralyzed, then the tidal volume would be smaller) and also causes the next breath to occur
earlier (respiratory frequency would increase). (Data from von Euler C: Brain stem mechanisms for generation and control of breathing pattern. In Cherniack NS,
Widdicombe J: Handbook of Physiology, Section 3, The Respiratory System. Vol II, Part 1. Bethesda, MD, American Physiological Society, 1986, pp. 1-67.)

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 Figure 27-2 Model of the normal ventilation-perfusion process. The normal matching of ventilation to perfusion is simplified by showing only two parallel lung units, which
are arranged vertically so that the reader will not automatically think of right and left lungs. Each unit receives equal quantities of fresh air ([Vdot]) and blood flow ([Qdot])
for its size. The numbers indicate normal human adult resting values in millimeters of mercury (mm Hg) for the gas partial pressures (P) in inspired air (i), alveolar gas (a),
and mixed venous (v) blood arriving at the capillaries from the right ventricle via the pulmonary artery. pv, pulmonary venous.

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 Figure 31-7 The basic wiring diagram of the brainstem ventilatory controller. The signs of the main outputs (arrows) of the neuron pools indicate whether the outputs are
excitatory (+) or inhibitory (-). Pool A provides tonic inspiratory stimuli to the muscles of breathing. Pool B is stimulated by pool A and provides additional stimulation to the
muscles of breathing, and pool B stimulates pool C. Other brain centers feed pool C (inspiratory cutoff switch), which sends inhibitory impulses to pool A. Afferent
information (feedback) from various sensors acts at different locations: chemoreceptors act on pool A, and intrapulmonary sensory fibers act via the vagus nerves on pool
B. A pneumotaxic center in the anterior pons receives input from the cerebral cortex, and it modulates the pool C group. (From Berne RM, Levy MN, Koeppen BM,
Stanton BA: Physiology, ed 5, Philadelphia, 2004, Elsevier.)

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 Figure 31-8 The locations of the three CO2 ([H+])-sensitive areas on the ventrolateral medulla. The receptor cells are not actually at the surface but are close to it. R, I,
and C refer to the rostral, intermediate, and caudal receptor areas. (From Berne RM, Levy MN, Koeppen BM, Stanton BA: Physiology, ed 5, Philadelphia, 2004, Elsevier.)

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 Figure 31-9 Some important metabolic changes that occur during exercise. The anaerobic threshold (arrow) is marked by a sudden change in the measured variables,
which is due mainly to the developing lactic acidosis as anaerobic glycolysis takes over more and more of the muscle energy supply caused by relative failure of the body
to supply sufficient O2 to the muscles at the rate demanded by the level of exercise. (From Berne RM, Levy MN, Koeppen BM, Stanton BA: Physiology, ed 5,
Philadelphia, 2004, Elsevier.)

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