Cholinergic and neurogenic mechanisms in obstructive airways disease

Cholinergic and Neurogenic Mechanisms in Obstructive Airways Disease

EUGENE Baltimore,

R. BLEECKER,

M.D.

Maryland

From the Division of Pulmonary Medicine, Department of Medicine, Johns Hopkins School of Meditine, Francis Scott Key Medical Center, Baltimore, Maryland. Requests for reprints should be addressed to Dr. Eugene R. Bleecker, Francis Scott Key Medical Center, 4940 Eastern Avenue, Baltimore, Maryland 21224.

November

Although primary neural control of airway function is through parasympathetic pathways, more recent evidence indicates that there are important adrenergic and non-adrenergic, non-cholinergic neural mechanisms that may also influence respiratory function. The parasympathetic nervous system component includes neural receptors in the airways as well as afferent and efferent pathways that travel in the vagus nerves. Afferent vagal sensory receptors mediate the response to irritant or rapidly adapting receptor activation, Hering-Breuer, and the unmyelinated “C” fibers or “J” receptor pathways. The motor component of the parasympathetic nervous system has several important functions that regulate tone in normal and obstructed airways. These pathways affect the following respiratory structures: (1) bronchial smooth muscle; (2) the mucociliary system; (3) the larynx; and (4) the nose. Finally, the parasympathetic nervous system may play a role in some species in the control of breathing and in the hyperpneic responses associated with airflow obstruction. In addition to cholinergic neural mechanisms, bronchomotor tone may also be influenced by adrenergic mechanisms and non-adrenergic, non-cholinergic neural pathways. Although there is minimal innervation of the airways by the sympathetic nervous system, there is ample evidence that beta-adrenoreceptors are present on bronchial smooth muscle. Beta-receptor stimulation not only relaxes airway smooth muscle, but also inhibits mediator release from mast cells in the airways and may alter vascular permeability. Alpha-adrenoreceptors are found in human airways and stimulation of these receptors causes bronchoconstriction. Although the importance of alpha-adrenoreceptors has been questioned, recent evidence suggests that alpha stimulation may play a role in cold air- and exercise-induced asthma. Finally, non-adrenergic, non-cholinergic nerves have been shown to cause relaxation of human airways in in vivo studies. There is increasing evidence that vasoactive intestinal peptide and peptide histidine methanol are the mediators of these responses. More recently, other neuropeptides (substance P, neurokinin A, and calcitonin gene-related peptide) have been localized in nerves in airways. These cause bronchoconstriction in vitro and may be released from afferent nerve terminals by an axon reflex. Although the precise role of these substances in controlling airway tone and bronchial secretions in humans is not fully understood, they may have important modulatory effects on the neural control of airway function.

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rgure 7. Lower amvay reflex parasympameac pamway. Stimulation of neural receptors in the airway with histamine or other irritants causes afferent activation of neural pathways that are conducted in the vagus nerves and integrated in the central nervous system. The efferent limb of this reflex is also conducted in the vagus nerves and produces effects that include smooth muscle spasm, as welt as possible effects on glandular and vascular function in the lungs.

The purpose of this review is to discuss the importance of autonomic neural pathways in the normal control of airway function and in abnormalities that occur in obstructive pulmonary disease. There is renewed interest in these neural mechanisms since the autonomic nervous system directly affects the regulation of airway smooth muscle tone and mucus secretion, and these neural reflexes may be activated by the development of bronchial inflammation [l-3]. The rapid alterations in airway smooth tone characteristic of airways hyper-reactivity in asthma are at least partially explained by neurogenic mechanisms [4]. Recent links between the presence of bronchial hyper-reactivity and the subsequent development of chronic airflow obstruction emphasize the importance of understanding the autonomic neural regulation of airway function [5-71. Furthermore, this neural component is clinically significant because of the potential role of anticholinergic agents in the treatment of asthma and chronic obstructive pulmonary disease. Muscarinic antagonists were used as bronchodilators well before sympathomimetic agents became available [8]. Writings on the effectiveness of smoking compounds with anticholinergic properties date back thousands of years to ancient Indian medical practice and more recent descriptions from the 19th and 20th centuries discuss various fuming asthma remedies that ranged from powders to cigarettes containing stamonium, lobelia, and belladonna [8,9]. However, use of these agents faded as a

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result of the development of sympathomimetic agonists in the 1930s and the realization that anticholinergics could produce unwanted systemic cardiovascular and neural side effects as well as local drying of respiratory secretions. Concomitantly, the parasympathetic nervous system was thought to have a minor role in the control of bronchomotor tone [lo]. Current interest in these compounds stems from studies reporting the effectiveness of anticholinergic therapy, especially in patients with chronic obstructive pulmonary disease [l l-l 31, and the development of new preparations, virtually without systemic effects, that may be delivered as aerosols directly to the airways [14-181. This discussion first reviews the role of the parasympathetic nervous system in normal and diseased states and then discusses the potential influence of other autonomic neural mechanisms on respiratory function. These include the sympathetic nervous system, nonadrenergic, non-cholinergic nerves, and neuropeptides localized in afferent nerve terminals and autonomic ganglia. PARASYMPATHETIC AIRWAYS

REFLEX

MECHANISMS

IN THE

In evaluating the neurogenic regulation of bronchial tone and airway secretions, the local effects of biologically active substances must be differentiated from reflexes mediated by the autonomic nervous system. Substances such as histamine can directly stimulate smooth muscle to produce bronchospasm and can also activate neural reflex pathways [4,1 g-221. This parasympathetic reflex pathway has an afferent component in which a substance such as histamine activates receptors in the bronchial mucosa whose afferent impulses are carried in the vagus nerves to the central nervous system (Figure 1) [23,24]. Here they are integrated and efferent discharges travel along vagal motor pathways producing bronchoconstriction. Properties of the three major types of afferent parasympathetic receptors in the bronchi are described in Table I. Stimulation of these receptors produces well-characterized lower airway bronchomotor reflexes. Inhalation of irritant substances activates subepithelial or rapidly adapting receptors in the trachea and airways, producing bronchoconstriction and cough [21,22,25,26]. “J” receptors or unmyelinated “C” fiber nerve endings were first demonstrated in the interstitial area surrounding the alveoli and have now been localized in the airways [23]. These are activated by irritant substances or interstitial edema, causing bronchoconstriction and changes in the breathing pattern. Inflation of the lungs in many animal species results in the Hering-Breuer stretch reflex that prolongs the time period after expiration, thereby inhibiting the onset of inspiration [24,27]. This reflex may also produce associated bronchodilation. In humans, the Hering-Breuer reflex has been described in infants and during anesthesia. This reflex pathway may also affect breathing pattern during

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TABLE

I

Primary

Receptor

Parasympathetic

Pulmonary

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Reflexes

Anatomy

Activation

Physiology Airway smooth muscle contraction, cough, hyperventilation Lengthened expiratory pause, inhibition of inspiration, bronchodilation Hyperpnea, bronchial smooth muscle and laryngeal constriction (?)

Rapidly adapting or irritant receptor Slowly adapting or stretch receptor

Subepithelial (medulated nerve) Airway smooth muscle (medulated nerve)

Mechanical stimuli and chemical irritants Increases in lung volume or transpulmonary pressure

Type “J” or “C” fiber receptor

Alveolar interstitial area and intrapulmonary airways (non-medulated nerve)

Chemical agents (histamine, capsaicin) and interstitial edema

sleep. Other cholinergic reflexes modulate mucous gland secretion and submucosal vascular tone, and may contribute to the bronchomotor response to hypercapnia and hypoxia [24]. It is important to realize that the central nervous system integrates these airway reflexes so that stimuli that produce smooth muscle spasm may also alter airway secretions and ventilatory control. These responses do not occur in isolation, and they are associated with secondary effects, perhaps through activation of other reflex pathways that can affect pulmonary and circulatory function [23,24]. These alterations will be further influenced by the level of baseline cholinergic tone, the lability of airway smooth muscle in disorders such as asthma, and the severity of pulmonary function abnormalities in patients with chronic airflow obstruction. The demonstration that a response is caused by a cholinergic reflex pathway requires that the response be abolished by blockade of each of the following: (1) receptor, (2) afferent neural pathway, (3) efferent or motor pathway, or (4) transmission at the neuromuscular junction. In humans, studies of parasympathetic mechanisms have relied on demonstrating that a specific response is altered or blocked by atropine, an anticholinergic agent that blocks the final part of this reflex pathway-post-ganglionic efferent transmission at the neuromuscular junction [28,29]. Since other approaches defining parasympathetic pulmonary reflexes cannot be performed safely in humans [30], these neurophysiologic mechanisms have been largely studied in various animal models. Despite variations in the importance of cholinergic reflex mechanisms in different animal species and the superimposed effects of experimental methods such as the effects of anesthesia [31331, these animal studies have provided useful information about the reflex control of airway smooth muscle tone and secretions [4,34]. In general, the studies have shown that cholinergic tone maintains the airway in a mildly constricted state [35]. Cutting or reversibly blocking the vagus nerves leads to bronchodilation, whereas stimulating the vagus nerves produces bronchoconstriction whose magnitude is regulated by the frequency and magnitude of the electrical stimulation [35-371. Substances such as histamine have been

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shown to directly stimulate vagal sensory receptors, thereby producing their effects not only by direct contraction of airway smooth muscle but also through parasympathetic reflex pathways [19-22,38,39]. DeKock and coworkers [39] demonstrated that histamine caused reflex bronchoconstriction in anesthetized dogs. They showed that the major bronchoconstrictor effects of histamine could be abolished by cutting or cooling the vagus nerves. Histamine also produced contraction of an isolated tracheal pouch that was not directly connected to the rest of the bronchial tree, illustrating the functional importance of neural innervation of this tracheal segment. Studies by Gold et al [40] demonstrated that in anesthetized, paralyzed, allergic dogs, vagal reflex mechanisms were important in mediating the response to inhaled antigen. In this complicated experimental preparation, the right and left lungs were divided with a Carlen catheter and antigen was instilled into the left lung while the bronchomotor responses of both lungs were measured. In addition, the vagus nerves were isolated so that they could be reversibly blocked by cooling. Antigen instilled in the left lung caused an increase in airways resistance in both lungs, whereas bronchoconstriction was prevented by cooling of the left vagus nerve. These experiments demonstrated the importance of the afferent pathway of this parasympathetic reflex in mediating bronchoconstriction in the contralateral lung. In contrast to these findings, other investigators have reported minimal inhibitory effects of postganglionic efferent blockade with inhaled atropine on bronchoconstriction induced by antigen in dogs [41]. Lee et al [42] reported another important function of vagal reflex mechanisms and showed that they mediated induced airways hyper-reactivity. In animals exposed to ozone, increases in non-specific reactivity to histamine develop 24 hours after oxidant exposure. Cooling or cutting of the vagus nerves abolished this induced hyperreactivity, indicating that reflex mechanisms were partially responsible for the increased bronchial reactivity. Finally, there may be interactions of the cholinergic nervous system with various inhaled or endogenous mediators. The degree of bronchoconstriction produced by agents such as histamine may depend on the level of parasympathetic

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of an agonist in the airways (larger airways may have greater parasympathetic innervation) [47,48], and the physiologic methods used to assess airway function. Parasympathetic mechanisms appear to be more important in the control of large airway function as measured by pulmonary function testing or particle deposition techniques [32], whereas in unanesthetized animals [49,50] or when peripheral airway function is measured exclusively [51], a more minor role for cholinergic control of airway tone is found. Even in well-studied animal models, there is still controversy about parasympathetic function. Although there is no question that parasympathetic nerves regulate airway size, the neural control of airway function is complex, with numerous factors modifying cholinergic regulation of bronchial tone.

METHACHOLINE

OTHER PARASYMPATHETIC RESPIRATORY SYSTEM

l 0 i 0

+ l l :

p4011 :

0

i

Normal i Asthma ;gure 2. Reactivity of normal subjects and asthmatic patients to methacholine. The response to methacholine is graphed as the log dose of inhaled methacholine producing a 20 percent decrease in the forced expiratory volume in one second (PDzO FEV,). Asthmatic patients are more reactive to this cholinergic agent than are normal individuals. Closed circles show individuals with one or more positive skin test results to common allergens. Two of the normal subjects with allergies were more reactive and their data overlapped with that of the less methacholine-sensitive asthmatic patients.

tone in the airways [43,44]. Other substances (serotonin) may potentiate vagal effects on airway smooth muscle through sensitizing efferent cholinergic pathways by activating parasympathetic ganglia or nerve terminals [45,46]. Studies have shown that these parasympathetic responses may depend on the type of anesthesia (some anesthetics may increase cholinergic reactivity whereas others may depress it) [31-331, the location of deposition 96

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IN THE

Cholinergic mechanisms play a major role in the regulation of bronchial secretions [34]. The importance of mucociliary function in the pathogenesis of obstructive airways disease, an active area of investigation, is reviewed elsewhere in this supplement. In general, parasympathetic stimulation produces increases in serous and mucous secretions from submucosal glands in the airways, whereas alpha-adrenergic activity stimulates serous glands and beta-sympathetic activity stimulates mucous secretion. Another aspect of parasympathetic function is its role in the modulation of breathing patterns. In animals, blocking vagal transmission produces a slow, deep pattern of breathing, whereas stimulation of afferent vagal pathways causes rapid, shallow ventilation [23,24,52,53]. Cholinergic effects on ventilatory control show wide variability in different animal species and are clearly modified by the type and level of anesthesia. Blocking the vagus nerves prevents ventilatory responses to histamine, antigen, or ozone, illustrating the ability of parasympathetic reflexes to not only affect bronchial tone and mucociliary function, but to alter the control of ventilation in experimental animal models of asthma [49,50,54]. In humans, parasympathetic blockade has been attempted to control dyspnea associated with interstitial lung disease [30]. In addition, parasympathetic effects on breathing pattern may have clinical implications in patients with sleep apnea since drugs with anticholinergic properties improve sleep-disordered breathing [55]. ROLE OF THE PARASYMPATHETIC SYSTEM IN HUMANS

NERVOUS

Although classic cholinergic reflexes are difficult to demonstrate, there are obvious examples of significant parasympathetic activity in humans [56,57]. Responses to inhaled cholinergic agents are well-established tests used routinely to assess non-specific reactivity in patients with obstructive lung disease [4,58-601. Figure 2 illustrates Volume

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the increased responsiveness of asthmatic patients to methacholine when compared with normal subjects without a history of airways disease. There have been numerous studies demonstrating the ability of inhaled or intravenous anticholinergic agents to modify various types of induced bronchoconstriction [4,61-631. Inhaled atropine can shift reactivity to inhaled histamine but does not abolish the bronchoconstriction produced by this substance in asthmatic patients (Figure 3). In these studies, the effects of inhaled histamine were evaluated after treatment with high doses of inhaled atropine (5 mg). Eight of the 10 asthmatic patients displayed a shift in the dose of histamine that caused a 20 percent decline in the one-second forced expiratory volume. Sheppard and co-workers [64] have shown that the response to hyperventilation with cold air was inhibited by atropine in a dose-response fashion, while other investigators have reported that atropine modifies exercise-induced asthma in some asthmatic patients [65-671. Induced hyper-reactivity to histamine in subjects with viral upper respiratory infections appears to be mediated by cholinergic mechanisms [68], and Holtzman et al [69] have reported that induced hyper-reactivity in normal and atopic individuals after ozone exposure was also prevented by atropine pretreatment. Bronchoconstriction produced by the suggestion of a noxious exposure in asthmatic patients is inhibited by pretreatment with atropine [70,71]. Since bronchospasm induced by suggestion must be mediated by neural mechanisms, these findings further support the importance of parasympathetic control of the airways. Other investigators have attempted to determine whether responsiveness to inhaled histamine was dependent on intact parasympathetic reflex pathways [72]. When atopic individuals were treated with a ganglionic blocking agent, hexamethonium, the response to inhaled histamine was blocked. These findings suggest that histamine-induced bronchospasm was dependent on transmission across autonomic ganglia. In contrast, other investigators have been unable to demonstrate that pretreatment with an anticholinergic agent significantly blocks bronchospasm induced by inhaled histamine, antigen, exercise, or hyperventilation with cold dry air [4,73-781. There are differences in cholinergic reactivity in normal individuals and patients with obstructive airways disease [58-601. Indeed, there may be heterogeneity in the responses of individuals to anticholinergic agents that may be caused by variations in baseline cholinergic tone in the airways as well as differences related to the route of delivery and the dose of the inhaled agent [4,38,79]. For example, in animals, intravenous atropine produced greater levels of blockade of the response to acetylcholine than did inhaled atropine [80]. SYMPATHETIC

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2

z

‘f z.I I

1

p
1

-1

A/H Figure 3. The effect of pretreatment with inhaled atropine (!5 mg) on airways reactivity to inhaled histamine. His the baseline histamine reactivity and AIH refers to histamine reactivity after atropine pretreatment. Atropine produced significant shifts in the reactivity to inhaled histamine, expressed as the log dose of histamine that produced a 20 percent decline in the forced expiratory volume in one second (PDzO FEV,).

smooth muscle contraction [81]. In general, it is believed that there is no significant functional sympathetic neural innervation of airway smooth muscle, a conclusion drawn from animal studies in which the relative importance of both sympathetic and cholinergic stimulation has been evaluated [82]. These findings, however, may be species specific, and it is known that sympathetic nerves are found in ganglia, submucosal glands, and the bronchial vessels [3,81]. In addition, adrenergic receptors are present on airway smooth muscle, and beta-adrenergic receptor stimulation relaxes airway smooth muscle [83,84] and inhibits mediator release from mast cells. Patients with obstructive lung disease are routinely treated with betaadrenergic agonists, and circulating catecholamines may affect the response to exercise challenge in asthmatic patients [59,85]. Furthermore, since there are anatomic and physiologic studies demonstrating localization of

Whereas stimulation of the parasympathetic nervous system is excitatory and causes muscle contraction, the sympathetic nervous system is inhibitory, preventing bronchial la,1966

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responses. There are studies reporting that alpha recep tors may be activated or sensitized during cooling or at lower ambient temperatures [93,94]. During exercise or hyperventilation with cold dry air, airway cooling occurs and alpha-sympathetic influences on airway or vascular tone may become more important [92]. NON-ADRENERGICINON-CHOLINERGIC NEURAL PATHWAYS

- . rgure 4. Autonomic neural patnways rn tne lungs. ACtlVation of afferent receptors by inhaled histamine or other irritants can stimulate airway neural receptors, producing a classic parasympathetic reflex (see Figure 1). Neural lmpulses from activation of these receptors may also be conducted in an antidromic fashion (axon reflex), causing release of neuropeptides that can stimulate vascular and airway smooth muscle, bronchial glands, and mast cells in the airway (see text).

sympathetic nerves in parasympathetic ganglia, it is possible that the sympathetic nervous system modulates cholinergic neural transmission [3,81,86]. Therefore, sympathetic neural activity may affect bronchial secretions, vascular permeability and tone, and perhaps, the activity of cholinergic pathways. Bronchial circulatory tone seems to be modulated by alpha-sympathomimetic activity, and stimulation of these receptors produces vasoconstriction [87]. There is also parasympathetic vasodilator activity and pOSBibly pep tinergic vasodilator components [3]. Inhaled alpha-adrenoreceptor agents cause bronchoconstriction in asthmatic patients and may produce vasoconstriction and increases in glandular secretions [88-901. The role of these alphaadrenergic effects in airways disease remains controversial, and treatment of asthmatic patients with alpha-adrenoreceptor blockers in not usually therapeutically effective [91]. Nevertheless, alpha-adrenoreceptor blockade may have a role in modulating specific forms of induced bronchospasm. My laboratory has studied the effects of alphareceptor blockade on a number of different stimuli [92]. Alpha-receptor blockade produced no effects on antigen-, histamine-, or methacholine-induced bronchospasm. However, the responses to exercise and hyperventilation with cold dry air were inhibited, indicating that there may be an alpha-adrenergic component that is active in these 9s

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There are two important new areas of neurogenic control of airways function: the non-adrenergic, non-cholinergic inhibitory system, and the regulatory effects of neuropep tides found in sensory receptors and autonomic ganglia. Richardson and Beland [95] have demonstrated that field stimulation of human airway tissue pretreated with an anticholinergic (atropine) and a beta-sympathetic blocking agent (propranolol) caused bronchial relaxation. The transmitters for this system are believed to be vasoactive intestinal peptide and peptide histidine methanol [3,96]. These vasoactive peptides can be localized in ganglia and nerves in the airways, produce airway smooth muscle relaxation in vitro, and may serve as co-transmitters with acetylcholine in autonomic ganglia [3,81,97]. In humans, Barnes and Dixon [98] studied the effect of inhaled vasoactive peptide on baseline lung function and showed that it has no bronchodilator effect when compared with a potent beta+ympathomimetic agent (salbutamol). However, pretreatment with vasoactive peptides decreased airway responses to inhaled histamine, although not as much as pretreatment with salbutamol. This indicates that although the non-adrenergic, non-cholinergic autonomic component may be weaker than beta-sympathetic stimulation, it may modulate airway responses partially inhibiting induced bronchoconstriction. It is also possible that neural mediators may be released in the airways by mechanisms analogous to the triple response or axon reflex first described by Sir Thomas Lewis [99] (Figure 4). Electron micrographs of airway nerves and ganglia show numerous vesicles that contain a number of different neurotransmitters and neuropeptides [3,81]. Those substances contained in afferent nerve endings include potent neuropeptides (substance P, neurokinin A, and calcitonin gene-related pep tide, among others) that can produce in vitro smooth muscle spasm, vasoconstritiion, alterations in glandular function, and inflammatory mediator release from mast cells [3,100,101]. Stimulation of these afferent nerve endings not only sends impulses centrally, but may spread neural impulses locally by antidromic conduction down afferent fibers, causing the release of neuropeptides (Figure 4). Release of these substances can produce direct local effects on airway smooth muscle, bronchial secretions, and vascular tissue [102-l 051. Substance P is a neuropeptide whose structure and function have been well studied [loo-1051. Exposure of rat peritoneal mast cells to substance P causes histamine Volume 91 (suppl 5A)

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Figure 5. Effect of substance P on vascular and airway function. Substance P was injected directly into the isolated perfused bronchial artery of a sheep. It produced an increase in airway pressure and a decrease in bronchial blood flow and bronchial artery resistance (see text).

release, and injection of substance P produces a wheal and flare reaction in the skin that appears to be caused by the release of histamine, since this response is inhibited to a significant degree by pretreatment with antihistamines [106,107]. Studies performed with Dr. Elizabeth M. Wagner illustrate the physiologic effects of substance P in an animal model designed to evaluate the interaction between the bronchial circulation and airway function [108,109] (Figure 5). Injection of substance P into the bronchial artery produced a drop in bronchial artery pressure at a constant blood flow (decreased bronchial vascular resistance), initially a slight rise in systemic blood pressure, and an increase in airway pressure. Thus, substance P, either directly or through the release of other mediators, produced airway smooth muscle constriction and vasodilation. Studies by Grunstein et al [l lo] have demonstrated that injection of substance P into rabbits causes changes in airway conductance and dynamic compliance. Interestingly, these changes are not affected by vagotomy, although the response to substance P was altered by atropine treatment. Thus, there may be local cholinergic interactions and these neurotransmitters may have a direct role, may act indirectly by modifying cholinergic transmission, or may act as co-transmitters with other neural agents. The precise role of these neuropeptides in human disease is unknown, but these substances can be localized in afferent nerve terminals and are potent bronchoconstrictors in vitro. Further investigation of their actions in humans will occur with the development of effective pharmacologic antagonists of the actions of these neuropeptides. If these substances can be released from afferent

nerve terminals by an axon reflex initiated by irritants or other stimuli, then local physiologic changes may occur that alter bronchial and circulatory smooth muscle function. More importantly, since neuropeptides have been shown to release inflammatory mediators from cellular elements in the airways, there may be important links between neurogenic and inflammatory mechanisms in the development of airways disease [3,106,1071. This leads to a complicated but intriguing model for the autonomic control of airway function (Figure 4). Histamine or other irritants can directly stimulate airway smooth muscle, but they can also activate afferent neural pathways; these pathways can produce a “classic” reflex by activating afferent parasympathetic pathways, producing bronchospasm. They may also have two other effects: (1) The afferent pathways may produce an axon reflex causing the local release of neuropeptides that may alter airway and vascular smooth muscle tone and bronchial secretions. These neuropeptides may cause mast cells in the airways to release inflammatory mediators. (2) Cholinergic neurotransmission within autonomic ganglia may be altered and modulated by sympathetic and non-adrenergic/non-cholinergic mechanisms. Therefore, although the major neural control in the airways is through parasympathetic pathways, there are a number of different ways in which other autonomic neural mechanisms can regulate respiratory function. ACKNOWLEDGMENT

I wish to thank Betty Giacomazza and Lorena Clary for their secretarial assistance, and Jennifer Hubert for the preparation of the illustrations and figures.

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Discussion Dr. Eugene Bleecker: I would like to make a comment regarding the studies I discussed. One of the things we have to watch out for in using animal models is transferring our observations of responses-which may be specific to a species-to man. For example, studies in animal mast cells are not necessarily models for studies in human mast cells-rather, these animal-cell studies are a useful preparation for characterizing the. cellular biochemistry and to see how these cells react with others in the same species. Dr. Edward Bergofsky: Dr. Bleecker, you mentioned some studies in humans, and I was very interested in the study measuring various spirometric responses to atropine and isoproterenol. Are there any studies with ipratropium bromide, particularly combined with other agents? Dr. Stephen Lazarus: Several studies comparing ipratropium bromide and metaproterenol are presented in this issue. These studies describe bronchodilatory effects of the two drugs as a function of the change in a number of spirometric indices.

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Dr. Nicholas Gross: Bauhaus conducted an investigation about 10 years ago of specific components of airway function. His research showed that normal children and adults do experience bronchodilation and a decrease in specific airway resistance when they receive treatment with anticholinergic agents. Bauhaus’ study used atropine sulfate, but it nevertheless is interesting because of the involvement of normal subjects. Of particular note is the fact that in normal people, the same degree of bronchodilation is achieved with anticholinergic drugs as is achieved in patients with chronic obstructive pulmonary disease. That is to say, if response is reported as a percentage of the predicted forced expiratory volume in one second (FEV,), there is about a 6 to 8 percent increase in FEV, from baseline in both normal individuals and patients with chronic obstructive pulmonary disease taking anticholinergic drugs. But then, of course, one has to consider that baseline is quite different between normal individuals and patients with chronic obstructive pulmonary disease.

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