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The Proceedings of the American Thoracic Society 2:305-310 (2005)
© 2005 The American Thoracic Society

ß2-Agonist and Anticholinergic Drugs in the Treatment of Lung Disease

Becky J. Proskocil and Allison D. Fryer

Oregon Health and Science University, Portland, Oregon

Correspondence and requests for reprints should be addressed to Allison D. Fryer, Ph.D., Professor, Physiology and Pharmacology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, MC L334, Portland, OR 97239. E-mail: fryera{at}ohsu.edu


   ABSTRACT
TOP
 ABSTRACT
NEURONAL INNERVATION OF THE...
 MUSCARINIC RECEPTORS SIGNALING
 ADRENERGIC RECEPTOR SIGNALING
 RECEPTOR CROSSTALK
 RECEPTOR DISTRIBUTION
 DYSFUNCTION OF NEURONAL M2...
 CONCLUSIONS
 REFERENCES
 
The lungs are innervated by both the sympathetic and parasympathetic nervous systems, which entails the activation of adrenergic and muscarinic receptors, respectively. Both the adrenergic and muscarinic receptors are G-protein–coupled receptors, and they share many similar signal transduction molecules. These receptors are widely expressed in the lung and the specific receptor expression can vary among the species. The location and the subtype of receptor expressed are important in the regulation of normal airway function. Acetylcholine released from the parasympathetic fibers activates the M3 muscarinic receptors located on the airway smooth muscle, causing bronchoconstriction. To counter this activity, M2 muscarinic receptors located on the parasympathetic nerves inhibit release of acetylcholine. ß2-Adrenergic receptors are expressed on the airway smooth muscle where activation causes bronchodilation. Adrenergic receptors are also on the autonomic nerves where they can modulate neurotransmitter release. The crosstalk between these G-protein–coupled receptors and downstream pathways ensures normal airway function. The prejunctional and postjunctional muscarinic and adrenergic receptors control autonomic tone and any imbalance or selective blockade of the receptors can compromise the system and cause the airways to become hyperreactive. The location, function, and crosstalk of the adrenergic and muscarinic receptors must be considered in the design, development, and use of drugs to combat airway diseases.

Key Words: acetylcholine • adrenergic receptors • asthma • muscarinic receptors


   NEURONAL INNERVATION OF THE LUNGS
TOP
 ABSTRACT
 NEURONAL INNERVATION OF THE...
MUSCARINIC RECEPTORS SIGNALING
 ADRENERGIC RECEPTOR SIGNALING
 RECEPTOR CROSSTALK
 RECEPTOR DISTRIBUTION
 DYSFUNCTION OF NEURONAL M2...
 CONCLUSIONS
 REFERENCES
 
The lungs are innervated by both parasympathetic and sympathetic nerve fibers, although the parasympathetic system provides the dominant role in airway bronchoconstriction (1). The vagus nerve (cranial nerve X) provides the parasympathetic innervation to the lungs and several other organs including the heart and intestines. The vagus originates in the brainstem and synapses on ganglia that are located within the airway walls. On stimulation, the vagus releases acetylcholine onto the ganglia, which initiates a depolarization and release of acetylcholine from the ganglion cell onto an effector target. The effector targets in the lung include the airway smooth muscle, submucosal mucus glands, and blood vessels (2). Acetylcholine release and stimulation of bronchoconstriction is mediated by muscarinic receptors located on preganglionic and postganglionic nerves and on the effector targets.

Sympathetic nerve fibers emerge from the spinal cord and release acetylcholine onto the sympathetic trunk located on either side of the spinal column. The postganglionic nerve fibers extend to the lung to release norepinephrine on similar effector targets as the parasympathetic nerves. The extent of sympathetic innervation to the lung is species dependent (3). Cats and guinea pigs have extensive sympathetic innervation in the lung including the innervation of the airway smooth muscle (2). In humans, sympathetic fibers innervate the submucosal mucus gland, blood vessels, and the parasympathetic ganglia, but do not directly innervate airway smooth muscle (4, 5). Despite the lack of direct sympathetic innervation of airway smooth muscle, adrenergic receptors are present throughout the lung (6, 7). Furthermore, sympathetic nerves are in close proximity to the cholinergic parasympathetic nerve fibers, allowing for communication between the two systems (8).


   MUSCARINIC RECEPTORS SIGNALING
TOP
 ABSTRACT
 NEURONAL INNERVATION OF THE...
 MUSCARINIC RECEPTORS SIGNALING
ADRENERGIC RECEPTOR SIGNALING
 RECEPTOR CROSSTALK
 RECEPTOR DISTRIBUTION
 DYSFUNCTION OF NEURONAL M2...
 CONCLUSIONS
 REFERENCES
 
Five muscarinic receptors have been identified (M1–M5) by pharmacology and molecular cloning. Muscarinic receptors are G-protein–coupled receptors that are activated by the endogenous ligand acetylcholine. M1, M3, and M5 muscarinic receptors are coupled to the stimulatory G protein (Gq), and the M2 and M4 are coupled to the inhibitory G protein (Gi/o). Activation of the odd numbered muscarinic receptors stimulates phospholipase C, which generates the formation of diacylglycerol and inositol triphosphate. These respectively stimulate protein kinase C and stimulate the release of Ca2+ from internal stores. The increase in intracellular concentrations of Ca2+ can then activate Ca2+-dependent ion channels and activate adenylate cyclase through the interaction with calmodulin. Activation of Gi/o-coupled muscarinic receptors (M2, M4) inhibits adenylate cyclase, limiting any increase in Ca2+ concentration (for review see Ref. 9).


   ADRENERGIC RECEPTOR SIGNALING
TOP
 ABSTRACT
 NEURONAL INNERVATION OF THE...
 MUSCARINIC RECEPTORS SIGNALING
 ADRENERGIC RECEPTOR SIGNALING
RECEPTOR CROSSTALK
 RECEPTOR DISTRIBUTION
 DYSFUNCTION OF NEURONAL M2...
 CONCLUSIONS
 REFERENCES
 
The adrenergic receptors are also G-protein–coupled receptors and can be grouped into two families. The {alpha}-adrenergic receptors, {alpha}1 and {alpha}2, are coupled to Gq and Gi/o, respectively. These are the same G proteins coupled to the muscarinic receptors and the signaling cascades have been described previously. ß-Adrenergic receptors are coupled to Gs, where stimulation by a ß-agonist activates adenylate cyclase and increases (3',5'adenosine monophosphate) cAMP level. cAMP increases protein kinase A activity, which phosphorylates downstream protein modulators (10). The overall activation of this signal transduction pathway can lead to the inhibition of phosphoinositol hydrolysis, a fall in intracellular Ca2+ levels, and the activation of large conductance potassium channels in which the latter is important for the bronchodilation response (11).


   RECEPTOR CROSSTALK
TOP
 ABSTRACT
 NEURONAL INNERVATION OF THE...
 MUSCARINIC RECEPTORS SIGNALING
 ADRENERGIC RECEPTOR SIGNALING
 RECEPTOR CROSSTALK
RECEPTOR DISTRIBUTION
 DYSFUNCTION OF NEURONAL M2...
 CONCLUSIONS
 REFERENCES
 
Both the muscarinic and adrenergic receptors are G-protein–coupled receptors that can activate or modulate similar signal transduction pathways. Because these receptors are expressed in the same cell, they have the capacity to modulate the activity of each other (12, 13). M2 muscarinic receptors are linked to the inhibitory G protein (Gi/o) and the ß-adrenergic receptors are linked to the stimulatory G protein (Gs). Expression and activation of these receptors in a single cell is likely to have countering effects on cellular function. Additionally, the expression of one receptor may be modulated by the activity of the other. For example, in human embryonic lung 299 cells, the activation of the ß2-adrenergic receptors with a selective ß-agonist decreased the cell surface M2 muscarinic receptor expression (desensitization), and loss of M2 muscarinic receptor expression was contingent on the activation of a cAMP-dependent kinase (14).

Ca2+ is important for the release of neurotransmitters. The differential activation of muscarinic and adrenergic receptors regulates the concentration of intracellular Ca2+ and regulates neurotransmitter release. Including Ca2+, the activation of several G-protein–activated signal transduction molecules can affect the opening or closing of membrane ion channels, determining the depolarization status of a neuron. On a longer time scale, the consistent activation or inhibition of these pathways may affect the synthesis of new proteins. The induction of cAMP can affect gene transcription through the cAMP response element promotor on several genes. The cAMP response element binding protein is a transcription factor (15) that is phosphorylated by the cAMP-induced activation of protein kinase A. Moreover, the suppression of the cAMP signaling pathway may restrain the synthesis of certain proteins.


   RECEPTOR DISTRIBUTION
TOP
 ABSTRACT
 NEURONAL INNERVATION OF THE...
 MUSCARINIC RECEPTORS SIGNALING
 ADRENERGIC RECEPTOR SIGNALING
 RECEPTOR CROSSTALK
 RECEPTOR DISTRIBUTION
DYSFUNCTION OF NEURONAL M2...
 CONCLUSIONS
 REFERENCES
 
The control by the muscarinic and adrenergic receptors in regulating airway function relies on the location of these receptors and subtypes expressed. The balance of these two systems throughout the lungs seems to be imperative in preserving healthy lungs.

Ganglia Cells
Acetylcholine is released from the preganglionic nerve fiber onto the super cervical ganglia in the sympathetic trunk, and activation of the super cervical ganglia is modulated by M1 and M2 muscarinic receptors (16, 17) by excitatory or inhibitory postsynaptic potentials, respectively (16). Human parasympathetic ganglia in the lung express M1 (17) and M2 (18) muscarinic receptors. M1 muscarinic receptors enhance ganglia depolarization by excitatory postsynaptic potentials (19, 20), whereas activation of preganglionic M2 muscarinic receptors inhibits acetylcholine release on the ganglia (18).

Smooth Muscle
Parasympathetic nerves maintain airway tone by releasing acetylcholine onto M3 receptors (21, 22), because blockade of these receptors induces relaxation of airway smooth muscle and bronchodilation. Airway smooth muscle expresses both M2 and M3 muscarinic receptors (23), with M2 the most abundant of the muscarinic receptors on airway smooth muscle (24, 25). These M2 receptors may contribute to muscle contraction by limiting adrenergic relaxation. In some species, both ß1- and ß2-adrenergic receptors are expressed on airway smooth muscle (26); however, in humans only the ß2-adrenergic receptors are expressed (6). In humans, sympathetic nerves do not directly supply these receptors, but when these receptors are stimulated with a ß-agonist, levels of adenylate cyclase increase, causing muscle relaxation and bronchodilation (27). Postjunctional M2 muscarinic receptors inhibit ß2-adrenergic receptor–mediated increase in adenylate cyclase and limit bronchodilation (28–30). Nonselective antagonists that block M2 muscarinic receptors, in addition to blockade of the M3, on airway smooth muscle may provide additional bronchodilation by removing the inhibitory effect they have on ß2-agonist–induced relaxation (31–33). Combination therapies directed at both adrenergic and muscarinic receptors should provide greater, and potentially additive, bronchodilation compared with a ß2-agonist or a muscarinic antagonist alone.

Parasympathetic Innervation
Neuronal M2 muscarinic receptors in the postganglionic parasympathetic nerves have been described in every species studied (34), including humans (35). These receptors limit release of acetylcholine from the parasympathetic nerves supplying airway smooth muscle (35, 36) and from the nerves supplying the glands (37). Blockade of the neuronal M2 muscarinic receptors with antagonists increases acetylcholine release fivefold (38). In vivo blockade of the neuronal M2 muscarinic receptors with selective antagonists, such as gallamine (36, 39), and with nonselective antagonists, such as atropine and ipratropium bromide (40), significantly potentiates vagally induced bronchoconstriction by removing the inhibitory action of the M2 muscarinic receptors (Figure 1).



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  		Figure 1. Ipratropium potentiates vagally induced bronchoconstriction (VS, solid line) by inhibiting neuronal M2 muscarinic receptors at doses that have little effect on the postjunctional M3 receptors as shown by the lack of effect on IV acetylcholine-induced bronchoconstriction (dashed line). In the absence of ipratropium, bronchoconstriction induced by stimulation of the vagus nerves and IV acetylcholine were matched (bar graph to the left). Reprinted by permission from reference 40.

 
Contrary to the role of the M2 muscarinic receptors, neuronal ß2-adrenergic receptors enhance acetylcholine release. In several species, including the guinea pig (Figure 2), ß2-agonists facilitate release of acetylcholine from parasympathetic nerves (41–45). These neuronal ß2-adrenergic receptors may be constitutively active (46). These receptors present a potential complication for therapy with ß-agonists, because agonists could enhance release of acetylcholine, offsetting bronchodilation. Conversely, in in vitro preparations of human trachea and bronchi, ß-agonists have been shown to inhibit acetylcholine release by ß2-adrenergic receptors on the parasympathetic nerves (47, 48). Disparity in these studies may be due to species differences. A species variation in the number of ß2-adrenergic receptors compared with M2 muscarinic receptors on the parasympathetic nerve endings may also affect the overall significance of ß2-agonist–induced acetylcholine release. No study has examined whether ß2-adrenergic function is physiologically significant or is altered by disease in humans or animals.



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  		Figure 2. Fenoterol (10-7–10-4 M) enhances acetylcholine release from guinea pig trachea. Acetylcholine release induced by electrical field stimulation is shown in the absence (C) and after 1 to 15 minutes preincubation with increasing concentrations of fenoterol. Reprinted by permission from reference 43.

 
Sympathetic Innervation
Muscarinic and adrenergic receptors are expressed on sympathetic nerves where they modulate norepinephrine release. Located on the prejunctional sympathetic nerves, M1 muscarinic receptors (49) and ß2-adrenergic receptors (43) enhance the release of norepinephrine. Additionally, M2 muscarinic receptors (50) and {alpha}2-adrenergic receptors (51, 52) inhibit release of norepinephrine. The physiologic significance of receptors in the sympathetic nerves supplying the airways is not clear, because in humans, airway smooth muscle is not innervated by sympathetic nerve fibers. These fibers innervate the parasympathetic ganglia, the submucosal mucus gland, and the blood vessels (4, 5), which are also effected in the development of airway diseases.

Mucus Secreting Cells
Mucus secretion is also controlled by muscarinic and ß2-adrenergic receptors (37). Acetylcholine release from the parasympathetic nerves stimulates mucus secretion from human bronchi (53). Muscarinic receptors mediate secretion from nasal and submucosal glands (37, 54–57) and most likely from goblet cells (58, 59). ß-Adrenergic receptors are localized to the submucosal glands in the human airways (6). ß2-agonists may have little effect on mucus secretion in humans (37), but they initiate an increase in mucus clearance and ciliary beat frequency (60, 61).

Inflammatory Cells
Nonneuronal acetylcholine has been described in many cells, including airway epithelium and inflammatory cells (62). Macrophages express M3 muscarinic receptors that mediate macrophage chemotaxis and expression of additional chemotactic factors for neutrophils and eosinophils (63, 64), which may themselves be activated by acetylcholine (65). Other inflammatory cells, such as eosinophils, may also express muscarinic receptors (A. D. Fryer, unpublished data). The subtype and function of these receptors, however, is not yet known. Blockade of muscarinic receptors may also alter, depending on which inflammatory cells express them, inflammation of the lung. ß2-Agonists are also antiinflammatory. They inhibit neutrophil inflammation in chronic obstructive pulmonary disease (66, 67), and inhibit interleukin-8 and myeloperoxidase production in asthma (68).

Conclusions
Lung function and airway tone relies on muscarinic and adrenergic receptors classically described on effector targets including the airway smooth muscle. In addition it relies on the communication between parasympathetic and sympathetic nerves supplying the lungs and supplying each other. This crosstalk between the autonomic nerves is mediated by muscarinic and ß-adrenergic receptors (Figure 3). Acetylcholine release from the parasympathetic nerves stimulates the M3 muscarinic receptors on airway smooth muscle to cause bronchoconstriction, and this event is controlled by other muscarinic and adrenergic receptors. Released acetylcholine activates M2 muscarinic receptors on the prejunctional parasympathetic nerves to inhibit further release of acetylcholine. Activation of the ß2-adrenergic receptors on the airway smooth muscle causes bronchodilation, countering the activation of the M3 muscarinic receptors. An additional control is the activation of the M2 muscarinic receptors also located on the airway smooth muscle, which inhibits the activity of the ß2-adrenergic receptor-induced bronchodilation. Activation of ß2-adrenergic receptors by norepinephrine is likely from circulating levels of catecholamines and not from a direct nerve supply in humans. The balance of the muscarinic and adrenergic receptor regulation of airway nerve and smooth muscle activity is important normal lung function. Drugs that target either a whole receptor family or a single receptor subtype may cause imbalance in this system. ß-Agonists may cause bronchodilation, increase inflammation, and enhance acetylcholine release. M3 antagonists may cause less bronchodilation than nonselective antagonists because they spare the postjunctional M2 receptors. Alternatively, selective M3 antagonists may prove more effective because they spare the neuronal M2 receptors, allowing these receptors to continue to inhibit neurotransmitter release. The pattern changes, however, with airway disease, which can also change the balance of muscarinic and adrenergic control of airway tone.



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  		Figure 3. Muscarinic and adrenergic receptors are expressed in airway smooth muscle and in the nerves supplying smooth muscle. Receptors that cause enhance neurotransmitter release are marked with a +, receptors that inhibit release have a –. Sympathetic nerves do not supply airway smooth muscle in humans (dashed line), but probably supply parasympathetic nerves. PKC = protein kinase C.

 

   DYSFUNCTION OF NEURONAL M2 RECEPTORS
TOP
 ABSTRACT
 NEURONAL INNERVATION OF THE...
 MUSCARINIC RECEPTORS SIGNALING
 ADRENERGIC RECEPTOR SIGNALING
 RECEPTOR CROSSTALK
 RECEPTOR DISTRIBUTION
 DYSFUNCTION OF NEURONAL M2...
CONCLUSIONS
 REFERENCES
 
Airway diseases are often manifested by airway hyperreactivity. A significant amount of research has shown that neuronal M2 muscarinic receptors are not functional in airway hyperreactivity, whereas M3 muscarinic receptors on the smooth muscle are spared (69–71). Prejunctional M2 muscarinic receptors on postganglionic nerves are not responsive to agonists in animal models of airway hyperreactivity. In guinea pigs that have been sensitized and challenged with antigen (72), infected with parainfluenza virus (73), exposed to ozone (74), or exposed to organophosphate pesticides (75, 76), neuronal M2 muscarinic receptor function is compromised, leading to increased acetylcholine release and vagally mediated hyperreactivity. In none of these studies is the function of postjunctional M3 receptors altered. The mechanisms of M2 muscarinic receptor dysfunction include blockade by the endogenous antagonist, eosinophil major basic protein (77–79); loss mediated by macrophage activation (80); or down-regulation by interferon (81), resulting from viral replication (82). Neuronal M2 muscarinic receptors also do not function properly in humans with asthma (83, 84), although the M2 muscarinic receptors seem to be functionally stable in patients with chronic obstructive pulmonary disease (85).

Dysfunction of ß-Adrenergic Receptors
Whether there is a dysfunction of the ß-adrenergic receptor in asthma and other airway diseases is not clear (86–88). Studies in guinea pigs show a reduction in ß-adrenergic receptor density, without a change in airway function (89) suggesting a large number of spare receptors. In humans, many studies use tissue collected from fatal asthma attacks, and many of these reports show no change in ß-adrenergic receptor density in the airway smooth muscle of individuals with asthma compared with healthy patients (90, 91). In human airway diseases, expression of ß-adrenergic receptor number is not changed.

Use of Anticholinergic and Adrenergic Drugs
The presence of M2 in addition to M3 muscarinic and ß2-adrenergic receptors on airway smooth muscle potentially complicates the use of ß-agonists and muscarinic antagonists to treat airway diseases. When considering the receptors on airway smooth muscle, maximum bronchodilation should be achieved by stimulation of the ß2-adrenergic receptors coupled with complete blockade of both M3 and M2 muscarinic receptors on airway smooth muscle. Additionally, any increase in acetylcholine release mediated by either the ß2-adrenergic agonists or M2 muscarinic receptor antagonists could be blocked by a fully effective inhibition of the postjunctional M3 receptors.

The presence of neuronal receptors complicates the use of both muscarinic antagonists and ß2-agonists. ß-agonists could stimulate the release of acetylcholine by the presence of ß2-adrenergic receptors on the parasympathetic nerve terminals. Stimulation of neuronal ß2-adrenergic receptors or blockade of neuronal M2 muscarinic receptors increases acetylcholine release and offsets any bronchodilation induced by the use of these drugs. With the presence of muscarinic receptors (37) and likely ß-adrenergic receptors (92) on nerves supplying the glands, drugs designed to induce bronchodilation and inhibit mucus secretion may be less effective than predicted. This would be especially true for muscarinic antagonists, because vagus nerves provide the dominant autonomic control for the muscle and glands (21, 37). If the neuronal M2 receptors were fully dysfunctional in asthma as seems from human studies (83, 84), there would be no reason to spare them by using a selective M3 antagonist. If they were fully dysfunctional, a nonselective antagonist would block the postjunctional M3 and M2 receptors, not only inhibiting acetylcholine-induced bronchoconstriction, but also protecting ß-agonist–induced bronchodilation. In chronic obstructive pulmonary disease, where the M2 receptors are still functional (85), an M3 selective antagonist, which spares the M2 on the nerves, may be more effective.


   CONCLUSIONS
TOP
 ABSTRACT
 NEURONAL INNERVATION OF THE...
 MUSCARINIC RECEPTORS SIGNALING
 ADRENERGIC RECEPTOR SIGNALING
 RECEPTOR CROSSTALK
 RECEPTOR DISTRIBUTION
 DYSFUNCTION OF NEURONAL M2...
 CONCLUSIONS
REFERENCES
 
The location and the function of the muscarinic and ß2-adrenergic receptors in the lungs of healthy individuals or in patients afflicted with airway diseases, such as asthma or chronic obstructive pulmonary disease, is important to consider for drug development. ß2-adrenergic receptors and muscarinic receptors are present in glands, inflammatory cells, and airway smooth muscle. The physiology of these receptors would predict that combination therapy would be most effective in the treatment of airway disease compared with single drug treatments. Other factors that should be considered, and are yet unexplored, however, include the contribution of changed receptor function to disease. Furthermore, the effects of altering the inflammatory response or mucus clearance by manipulation of neuronal and postjunctional muscarinic and adrenergic receptors are also unknown. The presence of neuronal receptors that inhibit (M2 muscarinic receptor) and enhance (ß2-adrenergic receptor) acetylcholine release create a conundrum. These neuronal receptors have important functions in animals and probably also in humans, but whether treatment should be designed to spare the neuronal receptors with selective antagonists or completely shut down the neural pathways with potent cholinergic antagonists remains to be determined.


   FOOTNOTES
 
Conflict of Interest Statement: B.J.P.'s spouse is an employee at GlaxoSmithKline and he holds shares with GlaxoSmithKline. A.D.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form April 14, 2005; accepted in final form July 5, 2005)


   REFERENCES
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 ABSTRACT
 NEURONAL INNERVATION OF THE...
 MUSCARINIC RECEPTORS SIGNALING
 ADRENERGIC RECEPTOR SIGNALING
 RECEPTOR CROSSTALK
 RECEPTOR DISTRIBUTION
 DYSFUNCTION OF NEURONAL M2...
 CONCLUSIONS
 REFERENCES
 

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