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Structure-Function Relationships in the Airways: Bronchoconstriction Mediated via Vagus Nerves or Bronchial Arteries; Peripheral Lung Constriction Mediated via Pulmonary Arteries

Structure-Function Relationships in the Airways: Bronchoconstriction Mediated via Vagus Nerves or... 7th Conf. R e s . in E m p h y s e m a , A sp en 1 9 6 4 ; M ed. th o r a c . 2 2 : 2 3 1 -2 4 2 (1965) Cardiovascular Research Institute and the Department of Medicine, University of California School of Medicine, San Francisco, California Structure-Function Relationships in the Airways: Bronchoconstriclion Mediated via Vagus Nerves or Rronchial Arteries; Peripheral Lung Constriction Mediated via Pulmonary Arteries1 J . A. NA D E L In the last decade, methods have been developed for measuring the mechanical properties of the lungs (namely, resistance to airflow and pulmonary compliance) and the volume of the conducting air­ ways (namely, anatomic dead space and the volume of an isolated segment of trachea). Combining these techniques with a method for freezing the lungs rapidly, we have attempted to relate the changes in structure and function which occur in the airways during the injec­ tion of smooth muscle constricting substances into the pulmonary or bronchial circulation and during reflex bronchoconstriction mediated via vagal efferent pathways (fig. 1). Methods All methods are described in the original publications [4, 9-13, 18, 19]; and only a brief outline will be given here. We anesthetized cats with pentobarbital (30 mg/kg administered intraperi- toneally), cannulatcd the trachea, and paralyzed and artificially ventilated the animals. We measured total pulmonary resistance ( R l ) and pulmonary compliance (Cl ) using an intrapleural catheter, by measuring flow, volume, and transpulmonary pressure and using a method of electrical subtraction [8]. We measured approximate changes in chest volume with a calibrated pneumograph around the lower thorax and connected to a Statham strain gauge. Anatomic dead space was measured by the 1 This study was supported in part by grants from the California State Depart­ ment of Public Health, Contract No. 385: by Office of Naval Research Contract No. Nonr 222(55); and by Public Health Service Grant HE-06285. 232 N a d e l , S tr u c tu r e - F u n c tio n R e la t io n sh ip s in th e A ir w a y s: P U L M O I\ A R T ■ BRO N CH IAL A R T E R Y F ig .l . Diagram illustrating the anatomic relationships involving the airways: The bronchial arteries and vagal efferent branches are distributed to the large conducting airways, while the pulmonary arteries are distributed to the respiratory bronchioles (R .B .) and alveolar ducts (alv. d.). single-breath technique of Foivler [5], using carbon dioxide as the indicator gas. We anesthetized dogs with pentobarbital (30 mg/kg intravenously) or a mixture of chloralose (50 mg/kg) and urethane (500 mg/kg) intravenously, and we measured R l and Cl with the same techniques described for cats. To measure changes in the volume of the large conducting airways, we isolated a segment of cervical trachea with intact blood and nerve supply [9], and measured changes in volume with a small spirometer. Right sided injections were via a catheter in the right atrium. We stimulated the peripheral ends of the cut cervical vagus nerves with square wave pulses of 5-7 volts, 1.5 msec duration, and at a frequency of 15 per sec. In dogs, we isolated the bronchial arterial blood supply by using a metal tube which could be inserted into the thoracic aorta via the abdominal aorta; the central lumen was wide enough to allow adequate aortic blood flow [4]. Inflating balloons at each end of the tube isolated an aortic segment that included the first 5 aortic inter­ costal arteries. B y tying the intercostal arteries 5 days previously, we effectively isolated the aortic segment to the bronchial arteries, which could be perfused separate­ ly via a catheter incorporated in the wall of the tube. We studied the anatomic changes produced by barium sulfate microemboli and by electrical stimulation of the peripheral ends of the cut cervical vagus nerves in cats with widely opened chest walls and an expiratory pressure of 3.5 cm H20 . After the stimulus was applied, we poured propane cooled in liquid nitrogen over both lungs simultaneously, freezing but not deforming them [15]. B r o n c lio co n stric tio n M e d ia te d v ia V a g u s N e rv e s o r . . . 233 Results Vagal efferent nerves: Reflex Bronclioconstriction. Various stimuli change airway size reflexly in humans and animals. Fig. 2 illustrates diagrammatically the receptors and afferent pathways: Mechanical irritation of the larynx [10] or sulfur dioxide introduced into the upper airway [ 131 constricts the lower airways in cats, probably by stimulating irritant or “ cough” receptors [16]. Inhalation of chemi­ cally inert dust particles [18] or sulfur dioxide [ 13] into the lower air- Avays also constricts the low'er airways, probably by stimulating similar receptors. Since bronclioconstriction during inhalation of sulfur dioxide or inert dust particles in healthy humans can be pre- C. N. S. g l o s s o p h a r y n g e a l VAGUS NERVE-------- MECHANICAL IRRITATION INHALATION OF SOj CAROTID BODY CAROTIO SI NUS COMMON CAROTID ARTERY RECURRENT LARYNGEAL NERVE PULMONARY BRANCH ----------- INHALATION OF DUST ------ INHALATION OF S 0 2 ----- LUNG INFLATION ( D I L A T E S ) Fig. 2. Diagram indicating some stimuli which cause reflex bronclioconstriction. C.N.S. = central nervous system : B.P. blood pressure. Afferent pathways indicat­ ed on left. Stimuli listed on right: dashed line indicates location of responsible re­ ceptor. All stimuli constrict airways except lung inflation which dilates airways by inhibiting vagal efferent activity. Med. thorite., Yol. 22, No. 2 (1965) 234 N a d e l , S tr u c tu r e - F u n c tio n R e la tio n sh ip s in the A ir w a y s: vented by prior intravenous injection of atropine sulfate [18, 13], parasympathetic efferent pathways are probably also involved in humans. Hypoxemia constricts the airways in dogs; the afferent pathway is via the glossopharyngeal nerves (presumably by stimulat­ ing carotid body chemoreceptors [9|). Hypercapnia also results in bronchoconstriction, presumably by stimulating other, possibly central, chemoreceptors [9], Decreasing carotid sinus pressure also constricts the airways slightly, the afferent pathway being via the glossopharyngeal nerves, probably by stimulating baroreceptors [9], Temporary lung inflation dilates the airways (including the extra- thoracic airways), by inhibiting efferent vagal impulses |19J. The a V O L U M E C H E S T lilfflflW lll (ml) I A R Y H G £ A L / R R I T A T I O / J C —> Fig-3. Comparison of changes in transpulmonary pressure ( P t p ) . pulmonary volume ami thoracic volume after injection of histamine into the pulmonary artery (pul- art.) and during laryngeal irritation. Histamine injection increased end-expiratory Ptp and decreased pulmonary and thoracic volumes. Laryngeal irritation increased P t p swing and increased pulmonary and thoracic volumes transiently. B ro n ch o co n strictio n M e d ia te d v ia V a g u s N e rv e s o r . . . responsible receptors are probably the Ilering-Brener inflation re­ ceptors and the afferent pathway is via the vagus nerves. Reflex bronchoconstriction mediated via vagal efferent path­ ways is associated with the following: (1) increased frequency of discharge of vagal efferent fibers to bronchi [17]; (2) bronchoconstric­ tion which can be prevented by vagotomy or atropine; (3) increased Ri., decreased Vo or tracheal volume, but no significant change in Cl. Since the resistance (R) increases without necessarily decreasing compliance (C), the “ time constant” (RC) of emptying becomes pro­ longed [ 71. I f inadequate time for passive expiration occurs, transient retention of air occurs (fig. 3). All of these changes can be explained by constriction of the large conducting airways supplied by vagal efferent fibers, without actual closure of these airways (fig.4 a). Electrical stimulation of the periph- a It Fig. 4 a. Anatomic relation between vagal efferent nerves and airways. Stimulation of vagus nerves contricts large conducting airways. Increased time constant (IIC) may lead to transient air retention (indicated by solid lines showing overexpanded alv'coli). - Fig. 4b. Anatomic relation between tbe pulmonary circulation and pe­ ripheral airways. It.U. = respiratory bronchiole; A.D. = alveolar duct. Note con­ spicuous amounts of smooth muscle in peripheral airways relative to total thickness of their walls. Agents in this circulation capable of causing smooth muscle contraction cause these airways to constrict, decreasing pulmonary compliance and expelling air from the lungs (indicated by solid lines showing constricted alveolar duct and “ pull­ ing-in” o f associated alveoli (from A’add, Colebalch and Olsen [12]). 2 0 * 23f> !\ a lie I oral ends of the cut cervical vagi results in changes in the mechani­ cal properties of the lungs similar to the reflexes [ 14|. Anatomic studies showed constriction of the large airways with no constriction of the peripheral airways (fig. 5). Fig. 5. Effect o f stimulation of peripheral end of a cut cervical vagus nerve on lohar bronchus (BR ). The diameter of the bronchus on the stimulated side (below) is smaller than on the control side (above). The walls of the airway appeared thicker on the stimulated side. Fig. 6. Comparison of control (a) and embolized (b)lung of a cat after rapid freezing. Magnification X75. Alv. = alveolus; A.D. = alveolar duct. Alveolar ducts of em- bolized lung are constricted, and alveoli are pulled in toward alveolar duct, giving a “ rosette” appearance to the terminal lung units (from Nadel, Colebalch and Olsen [ 12]). Fig. 6 238 N a d e l , S t ru c tu re -F u n c tio n R e la tio n sh ip s in the A irw a y s: Pulmonary arteries: Peripheral lung unit Constriction. Injection of 0.2 ml/kg of a 30 per cent suspension of barium sulfate into the pulmonary circulation in cats increased Hi. slightly, but decreased static C l markedly and actually increased Vn [12]. The changes be­ gan an average of 30 sec after the injection and were maximal within 5 min. A single large inflation of the lungs produced temporary or complete reversal. Intravenous isoproterenol (0.5-32 /ig/kg) partially or completely prevented the changes after micro cm holism, suggesting that they were due to smooth muscle contraction. Neither vagotomy nor atropine prevented the changes, indicating that parasympathetic cholinergic fibers were not involved. Prior injection of 48/80 (a histamine relcaser) decreased the changes, suggesting that the cm- V A G U S N E R V I ' S V A G U S N E R V E S N O R M T E M P C O O L E D S E R O T O N I N 1 5 0 > S p 8A (mm Hg) P TP (C m Hz O) « l ï f f f f l ï l \ t m m m 1 0 0 • • . . C l ( m l / c m H2 0 ) 0 • • R l ( c m H¿0/ L/S <Z C) • • H I S T A M I N E 1 5 0 (25/Ag) b p B A ( m m H g ) P T p ( c m H ¿ 0 ) m m CL ( m l / c m H 2 0 ) Q «L 5 ( c m H 2 O / L / S C C ) 10 Sec IN J . A O R T I C S E G M F ig .7. Effect in a dog of serotonin (above) and of histamine (below) injections in the bronchial arteries (aortic segm.) on brachial arterial blood pressure ( B P ba), trans- pulmonary pressure (P t p ). pulmonary compliance (C l ) and total pulmonary re­ sistance (R l ). Arrows indicate times of injections. When the cervical vagus nerves were warm (norm, temp.), both serotonin and histamine increased Pt p swing, in­ creased R l and decreased Cl . When these nerves were cooled to 0°C to block con- puction of nervous impulses through them, serotonin still caused the typical changes, while the effects of histamine were blocked. B ro n ch o co n strictio n M ediated v ia V a g u s N e rv e s o r . . . holism-induced changes depended on histamine release. Injection of 48 80 or histamine into the right side of the heart produced changes similar to those occurring after injection of harium sulfate. Constriction of airways after introduction into or release from the pulmonary circulation of substances capable of constricting airway smooth muscle change the mechanical properties of the lungs as follows: (1) they increase Hi., decrease static Ci. and increase V|>; (2) they increase end-expiratory transpulmonary pressure and de­ crease functional residual capacity (fig.3). Since the compliance (C.) decreases as much or more than the resistance (R) increases, the time constant (RC) usually remains the same or decreases. Thus, the time required for a relaxed expiration remains the same or decreases, and air retention docs not occur. All of these changes can be explained by constriction of terminal respiratory units perfused by the pulmonary circulation without significant narrowing of the large airw;ays, which may actually en­ large (fig.4b). Anatomic studies showed that the principal site of constriction was the alveolar ducts (fig.6). The alveoli in the affected areas were pulled in, giving a “ rosette” appearance to peripheral lung units. Bronchial Arteries: Bronchoconstriction. Injection of small doses of serotonin into the bronchial arteries of dogs increased R|. markedly but only decreased dynamic Ci. slightly (lig.7). These effects were not prevented by vagotomy or atropine. Small doses of histamine injected into the bronchial arteries also increased Hi. (fig.7) |4|. However, this effect was prevented by atropine or bilateral cervical vagotomy. Other experiments showed that the afferent pathway w'as via the pulmonary vagus nerves; the afferent pathway was blocked by cooling the vagus nerves to between 8 12 C. Thus, small doses of serotonin in the bronchial arteries constrict the airways by a local effect on the bronchial smooth muscle perfused by the bronchial arteries while histamine has its effect by stimulating a vagal reflex. Discussion Constriction o f large airways vs peripheral lung unit constriction. Stimulation of vagal efferent nerve fibers or injection of substances capable of constricting airway smooth muscle into the bronchial arteries constricts large conducting airways (thereby increasing re­ sistance to airflow' and decreasing airway volume) without necessarily 240 N a d c l , S tru c t u r e - F u n c t io n R e la t io n sh ip s in the A ir w a y s: decreasing the number of units communicating with the airway (thus, no decrease in static lung compliance). Since the time required for a relaxed expiration is dependent on the time constant, a market! increase in resistance may lead to hyperinflation of the lungs. During spontaneous breathing, the respiration then tends to be slow and deep to minimize the work or force of breathing. Injection of substances capable of causing airway smooth muscle contraction into the pulmonary circulation constricts the peripheral airways (thereby decreasing lung compliance markedly while in­ creasing airflow resistance only slightly). Under these circumstances, the time constant does not increase and may actually decrease. During spontaneous breathing, the respiratory pattern tends to be rapid and shallow. Microemboli also cause peripheral lung unit constriction. Tin- varied manifestations of microembolism, including the shift of ventilation to the unaffected areas, atelectasis of embolized areas, hypoxemia and abnormal breathing pattern may depend on the presence and extent of contraction of peripheral lung units. Reflex Bronchoconstriction due to stimulation o f Cough receptors. All cough stimuli which we have tested appear to cause reflex bron­ choconstriction, mainly in the large conducting airways. Since the purpose of the cough reflex is presumably to prevent deeper penetra­ tion of the irritants and to remove them, it is convenient that the cough receptors are located mainly in the large airways [16|. It is also convenient that the airway constriction associated with couch is also mainly in the large airways (since these are the tubes in which high linear velocities of airflow are possible). In association with cough, reflex narrowing of airways tends to increase linear velocity of airflow in these large airways and assists in the removal of irritants. Reflex Bronchoconstriction due to histamine injection in the Bronchial Arteries. Small doses of histamine injected into the bron­ chial arteries constrict the airways in dogs by eliciting a reflex. Since drugs may act either locally or reflexly or both, the effects of drugs on isolated airways may bear no relation to their effects on airways in the intact animal. Several studies have shown that asthmatic patients have in­ creased bronchial sensitivity to histamine, whether inhaled (1, 3| or injected intravenously [3, 6]. Bouhuys et al. |1| showed that this increased sensitivity in asthmatic patients was decreased by hexa­ méthonium, suggesting that autonomic ganglia were involved in this B ro n eh o co n strio tio n M e d ia te d v ia V a g u s N erves o r . . . action of histamine. This “ sensitivity” could be due to a reflex similar to the one described in llie present experiments. Summitry 1. Reflex bronchoconstriction, mediated via vagal efferent nerve fibers is characterized by increased Hi., decreased V d, with no significant change in static C l . Anatomic studies performed during electrical stimulation of the peripheral ends of the cut cervical vagus nerves showed constriction of large airways with no changes in the peripheral airways. 2. Injection of serotonin in the bronchial arteries resulted in changes in the mechanical properties of the lungs similar to vagal stimulation, presumably by a local action of the drug on the airways perfused by the bronchial arteries. 3. Injection of barium sulfate inicrocmboli into the pulmonary arteries increased R i and V n but decreased C l , presumably by releasing histamine. Right-sided injection of histamine or 48/80 resulted in similar effects. Anatomic studies showed that the principal site of constriction was the alveolar ducts. R E F E R E N C E S 1. Bouhuys,A.; Jonsson, K .; Lichlneckerl, S . ; I.indell. S'. E .; Lundgren,C.; Lundin.G. and Ringquist, T. It.: Effects of histamine on pulmonary ventilation in man. Clin. Sei. 19: 79-94 (1960). 2. Colebatch, H . J . II.; Olsen. C. It. and Nadel, J . A .: Effects of intravenous histamine and 48/80 on lung mechanics. Fed. Proc. 2 1 : 445 (1962). 3. Curry. J . J . : The action of histamine on the respiratory tract in normal and asthmatic subjects. .1. clin. Invest. 2 5 : 785-791 (1946). 4. DeKock, M .; Nadel, Zni. S . ; Olsen, C. and Colebatch, II.: Rellex broncho- constriction and apnea after histamine injection into the bronchial arteries. Fed. Proe. 2 3 : 116 (1964). 5. Fonder, W.S .: Lung function studies. II. The respiratory dead space. Amer. J . Physiol. 154: 405-416 (1948). 6. Mellroy, M. It. and Marshall, It.: The mechanical properties of the lungs in asthma. Clin. Sci. 15: 345 351 (1956). 7. Mellroy, M. l i .; Tierney, D, /•'. and Nadel. J . A . : A new method lor measurement of compliance and resistance of lungs and thorax. J . appl. Physiol. Ill : 424— 427 (1963). 8. Mead, J . and Whittenberger, J . L . : Physical properties of human lungs measured during spontaneous respiration. J . appl. Physiol. 5 : 779-796 (1953). 9. Nadel, J . A . and Widdicombe, J .G .: Effect of changes in blood gas tensions and carotid sinus pressure on tracheal volume and total lung resistance to airflow. J . Physiol.. Loud. 163: 13-33 (1962). 242 N a d c I 10. Nadel, J . A . :uul Widdicombe, J .G .: Ileflcx effects of tipper airway irritation on total lung resistance and blood pressure. J . appl. Physiol. 17: 861-865 (1962). 11. Nadel, J . A . and Widdicombe, J .G .: Reflex control of airway size. Ann. M.Y. Acad. Sci. 109: 712-722 (1963). 12. Nadcl. J . A . ; Colebalch, I I ..1.11. and Olsen, C .R .: Location and mechanism of airway constriction alter barium sulfate microcmbolism. .1. appl. Physiol. 19: 387-391 (1964). 13. Nadcl. J . A . ; Salem. 11.; Tamplin, II. and Tokiua, V .: Mechanism of broncho- constriction during inhalation of sulfer dioxide. J.appl.P h ysio l. 20: 164-167 (1965). 14. Olsen, C .R .; Colebalch. 11..1.11. and Nadcl, J . A . : Bronchoconstrictor responses of each lung to ipsilateral and contralateral efferent vagal stimulation in the dog. Physiologist 5 : 192 (1962). 15. Stanb, N. C. and Storey, IF. Relation between morphological and physiological events in lung studied by rapid freezing. .1. appl. Physiol. 17: 381-390 (1962). 16. Widdicombe, J .G .: Receptors in the trachea and bronchi of the cat. .1. Physiol., Lond. 123: 71-104 (1954). 17. Widdicombe, J .G .: Action potentials in vagal efferent nerve fibres to the lungs of the cat. Nannyn-Schmiedebergs Archiv: vide Arch. exp. Path. Pharmak. 241 : 415-432 (1961). 18. Widdicombe, J .G .; Kent, D.C. and Nadcl, J . A . : Mechanism of bronchoeonstric- lion during inhalation of dust. ,1. appl. Physiol. 17: 613-616 (1962). 19. Widdicombe, J.G . and Nadcl, J . A . : Reflex effects of lung inflation on tracheal vo lum e..). appl. Physiol. I S : 681-686 (1963). A u th o r's a d d r e ss: J . A . N ad cl, M .D ., Curdiovuaculnr Kcseurclt In stitu te , U n iv ersity o f California Medical C enter. S a n F r a n c i s c o . C a l i f o r n i a (U SA ) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Respiration Karger

Structure-Function Relationships in the Airways: Bronchoconstriction Mediated via Vagus Nerves or Bronchial Arteries; Peripheral Lung Constriction Mediated via Pulmonary Arteries

Nadel, J.A.
Respiration , Volume 22 (2): 12 – Jan 1, 2009
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Karger
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© 1965 S. Karger AG, Basel
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0025-7931
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1423-0356
DOI
10.1159/000192407
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Abstract

7th Conf. R e s . in E m p h y s e m a , A sp en 1 9 6 4 ; M ed. th o r a c . 2 2 : 2 3 1 -2 4 2 (1965) Cardiovascular Research Institute and the Department of Medicine, University of California School of Medicine, San Francisco, California Structure-Function Relationships in the Airways: Bronchoconstriclion Mediated via Vagus Nerves or Rronchial Arteries; Peripheral Lung Constriction Mediated via Pulmonary Arteries1 J . A. NA D E L In the last decade, methods have been developed for measuring the mechanical properties of the lungs (namely, resistance to airflow and pulmonary compliance) and the volume of the conducting air­ ways (namely, anatomic dead space and the volume of an isolated segment of trachea). Combining these techniques with a method for freezing the lungs rapidly, we have attempted to relate the changes in structure and function which occur in the airways during the injec­ tion of smooth muscle constricting substances into the pulmonary or bronchial circulation and during reflex bronchoconstriction mediated via vagal efferent pathways (fig. 1). Methods All methods are described in the original publications [4, 9-13, 18, 19]; and only a brief outline will be given here. We anesthetized cats with pentobarbital (30 mg/kg administered intraperi- toneally), cannulatcd the trachea, and paralyzed and artificially ventilated the animals. We measured total pulmonary resistance ( R l ) and pulmonary compliance (Cl ) using an intrapleural catheter, by measuring flow, volume, and transpulmonary pressure and using a method of electrical subtraction [8]. We measured approximate changes in chest volume with a calibrated pneumograph around the lower thorax and connected to a Statham strain gauge. Anatomic dead space was measured by the 1 This study was supported in part by grants from the California State Depart­ ment of Public Health, Contract No. 385: by Office of Naval Research Contract No. Nonr 222(55); and by Public Health Service Grant HE-06285. 232 N a d e l , S tr u c tu r e - F u n c tio n R e la t io n sh ip s in th e A ir w a y s: P U L M O I\ A R T ■ BRO N CH IAL A R T E R Y F ig .l . Diagram illustrating the anatomic relationships involving the airways: The bronchial arteries and vagal efferent branches are distributed to the large conducting airways, while the pulmonary arteries are distributed to the respiratory bronchioles (R .B .) and alveolar ducts (alv. d.). single-breath technique of Foivler [5], using carbon dioxide as the indicator gas. We anesthetized dogs with pentobarbital (30 mg/kg intravenously) or a mixture of chloralose (50 mg/kg) and urethane (500 mg/kg) intravenously, and we measured R l and Cl with the same techniques described for cats. To measure changes in the volume of the large conducting airways, we isolated a segment of cervical trachea with intact blood and nerve supply [9], and measured changes in volume with a small spirometer. Right sided injections were via a catheter in the right atrium. We stimulated the peripheral ends of the cut cervical vagus nerves with square wave pulses of 5-7 volts, 1.5 msec duration, and at a frequency of 15 per sec. In dogs, we isolated the bronchial arterial blood supply by using a metal tube which could be inserted into the thoracic aorta via the abdominal aorta; the central lumen was wide enough to allow adequate aortic blood flow [4]. Inflating balloons at each end of the tube isolated an aortic segment that included the first 5 aortic inter­ costal arteries. B y tying the intercostal arteries 5 days previously, we effectively isolated the aortic segment to the bronchial arteries, which could be perfused separate­ ly via a catheter incorporated in the wall of the tube. We studied the anatomic changes produced by barium sulfate microemboli and by electrical stimulation of the peripheral ends of the cut cervical vagus nerves in cats with widely opened chest walls and an expiratory pressure of 3.5 cm H20 . After the stimulus was applied, we poured propane cooled in liquid nitrogen over both lungs simultaneously, freezing but not deforming them [15]. B r o n c lio co n stric tio n M e d ia te d v ia V a g u s N e rv e s o r . . . 233 Results Vagal efferent nerves: Reflex Bronclioconstriction. Various stimuli change airway size reflexly in humans and animals. Fig. 2 illustrates diagrammatically the receptors and afferent pathways: Mechanical irritation of the larynx [10] or sulfur dioxide introduced into the upper airway [ 131 constricts the lower airways in cats, probably by stimulating irritant or “ cough” receptors [16]. Inhalation of chemi­ cally inert dust particles [18] or sulfur dioxide [ 13] into the lower air- Avays also constricts the low'er airways, probably by stimulating similar receptors. Since bronclioconstriction during inhalation of sulfur dioxide or inert dust particles in healthy humans can be pre- C. N. S. g l o s s o p h a r y n g e a l VAGUS NERVE-------- MECHANICAL IRRITATION INHALATION OF SOj CAROTID BODY CAROTIO SI NUS COMMON CAROTID ARTERY RECURRENT LARYNGEAL NERVE PULMONARY BRANCH ----------- INHALATION OF DUST ------ INHALATION OF S 0 2 ----- LUNG INFLATION ( D I L A T E S ) Fig. 2. Diagram indicating some stimuli which cause reflex bronclioconstriction. C.N.S. = central nervous system : B.P. blood pressure. Afferent pathways indicat­ ed on left. Stimuli listed on right: dashed line indicates location of responsible re­ ceptor. All stimuli constrict airways except lung inflation which dilates airways by inhibiting vagal efferent activity. Med. thorite., Yol. 22, No. 2 (1965) 234 N a d e l , S tr u c tu r e - F u n c tio n R e la tio n sh ip s in the A ir w a y s: vented by prior intravenous injection of atropine sulfate [18, 13], parasympathetic efferent pathways are probably also involved in humans. Hypoxemia constricts the airways in dogs; the afferent pathway is via the glossopharyngeal nerves (presumably by stimulat­ ing carotid body chemoreceptors [9|). Hypercapnia also results in bronchoconstriction, presumably by stimulating other, possibly central, chemoreceptors [9], Decreasing carotid sinus pressure also constricts the airways slightly, the afferent pathway being via the glossopharyngeal nerves, probably by stimulating baroreceptors [9], Temporary lung inflation dilates the airways (including the extra- thoracic airways), by inhibiting efferent vagal impulses |19J. The a V O L U M E C H E S T lilfflflW lll (ml) I A R Y H G £ A L / R R I T A T I O / J C —> Fig-3. Comparison of changes in transpulmonary pressure ( P t p ) . pulmonary volume ami thoracic volume after injection of histamine into the pulmonary artery (pul- art.) and during laryngeal irritation. Histamine injection increased end-expiratory Ptp and decreased pulmonary and thoracic volumes. Laryngeal irritation increased P t p swing and increased pulmonary and thoracic volumes transiently. B ro n ch o co n strictio n M e d ia te d v ia V a g u s N e rv e s o r . . . responsible receptors are probably the Ilering-Brener inflation re­ ceptors and the afferent pathway is via the vagus nerves. Reflex bronchoconstriction mediated via vagal efferent path­ ways is associated with the following: (1) increased frequency of discharge of vagal efferent fibers to bronchi [17]; (2) bronchoconstric­ tion which can be prevented by vagotomy or atropine; (3) increased Ri., decreased Vo or tracheal volume, but no significant change in Cl. Since the resistance (R) increases without necessarily decreasing compliance (C), the “ time constant” (RC) of emptying becomes pro­ longed [ 71. I f inadequate time for passive expiration occurs, transient retention of air occurs (fig. 3). All of these changes can be explained by constriction of the large conducting airways supplied by vagal efferent fibers, without actual closure of these airways (fig.4 a). Electrical stimulation of the periph- a It Fig. 4 a. Anatomic relation between vagal efferent nerves and airways. Stimulation of vagus nerves contricts large conducting airways. Increased time constant (IIC) may lead to transient air retention (indicated by solid lines showing overexpanded alv'coli). - Fig. 4b. Anatomic relation between tbe pulmonary circulation and pe­ ripheral airways. It.U. = respiratory bronchiole; A.D. = alveolar duct. Note con­ spicuous amounts of smooth muscle in peripheral airways relative to total thickness of their walls. Agents in this circulation capable of causing smooth muscle contraction cause these airways to constrict, decreasing pulmonary compliance and expelling air from the lungs (indicated by solid lines showing constricted alveolar duct and “ pull­ ing-in” o f associated alveoli (from A’add, Colebalch and Olsen [12]). 2 0 * 23f> !\ a lie I oral ends of the cut cervical vagi results in changes in the mechani­ cal properties of the lungs similar to the reflexes [ 14|. Anatomic studies showed constriction of the large airways with no constriction of the peripheral airways (fig. 5). Fig. 5. Effect o f stimulation of peripheral end of a cut cervical vagus nerve on lohar bronchus (BR ). The diameter of the bronchus on the stimulated side (below) is smaller than on the control side (above). The walls of the airway appeared thicker on the stimulated side. Fig. 6. Comparison of control (a) and embolized (b)lung of a cat after rapid freezing. Magnification X75. Alv. = alveolus; A.D. = alveolar duct. Alveolar ducts of em- bolized lung are constricted, and alveoli are pulled in toward alveolar duct, giving a “ rosette” appearance to the terminal lung units (from Nadel, Colebalch and Olsen [ 12]). Fig. 6 238 N a d e l , S t ru c tu re -F u n c tio n R e la tio n sh ip s in the A irw a y s: Pulmonary arteries: Peripheral lung unit Constriction. Injection of 0.2 ml/kg of a 30 per cent suspension of barium sulfate into the pulmonary circulation in cats increased Hi. slightly, but decreased static C l markedly and actually increased Vn [12]. The changes be­ gan an average of 30 sec after the injection and were maximal within 5 min. A single large inflation of the lungs produced temporary or complete reversal. Intravenous isoproterenol (0.5-32 /ig/kg) partially or completely prevented the changes after micro cm holism, suggesting that they were due to smooth muscle contraction. Neither vagotomy nor atropine prevented the changes, indicating that parasympathetic cholinergic fibers were not involved. Prior injection of 48/80 (a histamine relcaser) decreased the changes, suggesting that the cm- V A G U S N E R V I ' S V A G U S N E R V E S N O R M T E M P C O O L E D S E R O T O N I N 1 5 0 > S p 8A (mm Hg) P TP (C m Hz O) « l ï f f f f l ï l \ t m m m 1 0 0 • • . . C l ( m l / c m H2 0 ) 0 • • R l ( c m H¿0/ L/S <Z C) • • H I S T A M I N E 1 5 0 (25/Ag) b p B A ( m m H g ) P T p ( c m H ¿ 0 ) m m CL ( m l / c m H 2 0 ) Q «L 5 ( c m H 2 O / L / S C C ) 10 Sec IN J . A O R T I C S E G M F ig .7. Effect in a dog of serotonin (above) and of histamine (below) injections in the bronchial arteries (aortic segm.) on brachial arterial blood pressure ( B P ba), trans- pulmonary pressure (P t p ). pulmonary compliance (C l ) and total pulmonary re­ sistance (R l ). Arrows indicate times of injections. When the cervical vagus nerves were warm (norm, temp.), both serotonin and histamine increased Pt p swing, in­ creased R l and decreased Cl . When these nerves were cooled to 0°C to block con- puction of nervous impulses through them, serotonin still caused the typical changes, while the effects of histamine were blocked. B ro n ch o co n strictio n M ediated v ia V a g u s N e rv e s o r . . . holism-induced changes depended on histamine release. Injection of 48 80 or histamine into the right side of the heart produced changes similar to those occurring after injection of harium sulfate. Constriction of airways after introduction into or release from the pulmonary circulation of substances capable of constricting airway smooth muscle change the mechanical properties of the lungs as follows: (1) they increase Hi., decrease static Ci. and increase V|>; (2) they increase end-expiratory transpulmonary pressure and de­ crease functional residual capacity (fig.3). Since the compliance (C.) decreases as much or more than the resistance (R) increases, the time constant (RC) usually remains the same or decreases. Thus, the time required for a relaxed expiration remains the same or decreases, and air retention docs not occur. All of these changes can be explained by constriction of terminal respiratory units perfused by the pulmonary circulation without significant narrowing of the large airw;ays, which may actually en­ large (fig.4b). Anatomic studies showed that the principal site of constriction was the alveolar ducts (fig.6). The alveoli in the affected areas were pulled in, giving a “ rosette” appearance to peripheral lung units. Bronchial Arteries: Bronchoconstriction. Injection of small doses of serotonin into the bronchial arteries of dogs increased R|. markedly but only decreased dynamic Ci. slightly (lig.7). These effects were not prevented by vagotomy or atropine. Small doses of histamine injected into the bronchial arteries also increased Hi. (fig.7) |4|. However, this effect was prevented by atropine or bilateral cervical vagotomy. Other experiments showed that the afferent pathway w'as via the pulmonary vagus nerves; the afferent pathway was blocked by cooling the vagus nerves to between 8 12 C. Thus, small doses of serotonin in the bronchial arteries constrict the airways by a local effect on the bronchial smooth muscle perfused by the bronchial arteries while histamine has its effect by stimulating a vagal reflex. Discussion Constriction o f large airways vs peripheral lung unit constriction. Stimulation of vagal efferent nerve fibers or injection of substances capable of constricting airway smooth muscle into the bronchial arteries constricts large conducting airways (thereby increasing re­ sistance to airflow' and decreasing airway volume) without necessarily 240 N a d c l , S tru c t u r e - F u n c t io n R e la t io n sh ip s in the A ir w a y s: decreasing the number of units communicating with the airway (thus, no decrease in static lung compliance). Since the time required for a relaxed expiration is dependent on the time constant, a market! increase in resistance may lead to hyperinflation of the lungs. During spontaneous breathing, the respiration then tends to be slow and deep to minimize the work or force of breathing. Injection of substances capable of causing airway smooth muscle contraction into the pulmonary circulation constricts the peripheral airways (thereby decreasing lung compliance markedly while in­ creasing airflow resistance only slightly). Under these circumstances, the time constant does not increase and may actually decrease. During spontaneous breathing, the respiratory pattern tends to be rapid and shallow. Microemboli also cause peripheral lung unit constriction. Tin- varied manifestations of microembolism, including the shift of ventilation to the unaffected areas, atelectasis of embolized areas, hypoxemia and abnormal breathing pattern may depend on the presence and extent of contraction of peripheral lung units. Reflex Bronchoconstriction due to stimulation o f Cough receptors. All cough stimuli which we have tested appear to cause reflex bron­ choconstriction, mainly in the large conducting airways. Since the purpose of the cough reflex is presumably to prevent deeper penetra­ tion of the irritants and to remove them, it is convenient that the cough receptors are located mainly in the large airways [16|. It is also convenient that the airway constriction associated with couch is also mainly in the large airways (since these are the tubes in which high linear velocities of airflow are possible). In association with cough, reflex narrowing of airways tends to increase linear velocity of airflow in these large airways and assists in the removal of irritants. Reflex Bronchoconstriction due to histamine injection in the Bronchial Arteries. Small doses of histamine injected into the bron­ chial arteries constrict the airways in dogs by eliciting a reflex. Since drugs may act either locally or reflexly or both, the effects of drugs on isolated airways may bear no relation to their effects on airways in the intact animal. Several studies have shown that asthmatic patients have in­ creased bronchial sensitivity to histamine, whether inhaled (1, 3| or injected intravenously [3, 6]. Bouhuys et al. |1| showed that this increased sensitivity in asthmatic patients was decreased by hexa­ méthonium, suggesting that autonomic ganglia were involved in this B ro n eh o co n strio tio n M e d ia te d v ia V a g u s N erves o r . . . action of histamine. This “ sensitivity” could be due to a reflex similar to the one described in llie present experiments. Summitry 1. Reflex bronchoconstriction, mediated via vagal efferent nerve fibers is characterized by increased Hi., decreased V d, with no significant change in static C l . Anatomic studies performed during electrical stimulation of the peripheral ends of the cut cervical vagus nerves showed constriction of large airways with no changes in the peripheral airways. 2. Injection of serotonin in the bronchial arteries resulted in changes in the mechanical properties of the lungs similar to vagal stimulation, presumably by a local action of the drug on the airways perfused by the bronchial arteries. 3. Injection of barium sulfate inicrocmboli into the pulmonary arteries increased R i and V n but decreased C l , presumably by releasing histamine. Right-sided injection of histamine or 48/80 resulted in similar effects. Anatomic studies showed that the principal site of constriction was the alveolar ducts. R E F E R E N C E S 1. Bouhuys,A.; Jonsson, K .; Lichlneckerl, S . ; I.indell. S'. E .; Lundgren,C.; Lundin.G. and Ringquist, T. It.: Effects of histamine on pulmonary ventilation in man. Clin. Sei. 19: 79-94 (1960). 2. Colebatch, H . J . II.; Olsen. C. It. and Nadel, J . A .: Effects of intravenous histamine and 48/80 on lung mechanics. Fed. Proc. 2 1 : 445 (1962). 3. Curry. J . J . : The action of histamine on the respiratory tract in normal and asthmatic subjects. .1. clin. Invest. 2 5 : 785-791 (1946). 4. DeKock, M .; Nadel, Zni. S . ; Olsen, C. and Colebatch, II.: Rellex broncho- constriction and apnea after histamine injection into the bronchial arteries. Fed. Proe. 2 3 : 116 (1964). 5. Fonder, W.S .: Lung function studies. II. The respiratory dead space. Amer. J . Physiol. 154: 405-416 (1948). 6. Mellroy, M. It. and Marshall, It.: The mechanical properties of the lungs in asthma. Clin. Sci. 15: 345 351 (1956). 7. Mellroy, M. l i .; Tierney, D, /•'. and Nadel. J . A . : A new method lor measurement of compliance and resistance of lungs and thorax. J . appl. Physiol. Ill : 424— 427 (1963). 8. Mead, J . and Whittenberger, J . L . : Physical properties of human lungs measured during spontaneous respiration. J . appl. Physiol. 5 : 779-796 (1953). 9. Nadel, J . A . and Widdicombe, J .G .: Effect of changes in blood gas tensions and carotid sinus pressure on tracheal volume and total lung resistance to airflow. J . Physiol.. Loud. 163: 13-33 (1962). 242 N a d c I 10. Nadel, J . A . :uul Widdicombe, J .G .: Ileflcx effects of tipper airway irritation on total lung resistance and blood pressure. J . appl. Physiol. 17: 861-865 (1962). 11. Nadel, J . A . and Widdicombe, J .G .: Reflex control of airway size. Ann. M.Y. Acad. Sci. 109: 712-722 (1963). 12. Nadcl. J . A . ; Colebalch, I I ..1.11. and Olsen, C .R .: Location and mechanism of airway constriction alter barium sulfate microcmbolism. .1. appl. Physiol. 19: 387-391 (1964). 13. Nadcl. J . A . ; Salem. 11.; Tamplin, II. and Tokiua, V .: Mechanism of broncho- constriction during inhalation of sulfer dioxide. J.appl.P h ysio l. 20: 164-167 (1965). 14. Olsen, C .R .; Colebalch. 11..1.11. and Nadcl, J . A . : Bronchoconstrictor responses of each lung to ipsilateral and contralateral efferent vagal stimulation in the dog. Physiologist 5 : 192 (1962). 15. Stanb, N. C. and Storey, IF. Relation between morphological and physiological events in lung studied by rapid freezing. .1. appl. Physiol. 17: 381-390 (1962). 16. Widdicombe, J .G .: Receptors in the trachea and bronchi of the cat. .1. Physiol., Lond. 123: 71-104 (1954). 17. Widdicombe, J .G .: Action potentials in vagal efferent nerve fibres to the lungs of the cat. Nannyn-Schmiedebergs Archiv: vide Arch. exp. Path. Pharmak. 241 : 415-432 (1961). 18. Widdicombe, J .G .; Kent, D.C. and Nadcl, J . A . : Mechanism of bronchoeonstric- lion during inhalation of dust. ,1. appl. Physiol. 17: 613-616 (1962). 19. Widdicombe, J.G . and Nadcl, J . A . : Reflex effects of lung inflation on tracheal vo lum e..). appl. Physiol. I S : 681-686 (1963). A u th o r's a d d r e ss: J . A . N ad cl, M .D ., Curdiovuaculnr Kcseurclt In stitu te , U n iv ersity o f California Medical C enter. S a n F r a n c i s c o . C a l i f o r n i a (U SA )

Journal

Respiration – Karger

Published: Jan 1, 2009

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