- Email: [email protected]
Airway nerves: in vivo electrophysiology
280
Airway nerves: in vivo electrophysiology John J Adcock Information about the activity of airway sensory afferent nerves in vivo can be obtained electrophysiologically by extracellular recording of action potentials. Apart from data capture, the basic techniques used for recording sensory nerve activity have not advanced greatly in 50 years. However, clearly they continue to contribute vastly to our understanding of the role of these nerves in the control and functions of the airways in disease. This is particularly noticeable with the insight gained into exactly which physiological, biochemical and pharmacological events in the control of lung function rely upon the airway sensory afferent nerves and the subsequent airway vagal reflex arcs. Addresses Pneumolabs (UK) Limited, Northwick Park Institute for Medical Research, Y Block, Watford Road, Harrow, Middlesex HA1 3UJ, UK; e-mail: [email protected] Current Opinion in Pharmacology 2002, 2:280–282 1471-4892/02/$ — see front matter © 2002 Elsevier Science Ltd. All rights reserved. Abbreviations RAR rapidly adapting stretch receptor SAR slowly adapting stretch receptor
Introduction Neural control of the airways is more complex than previously recognised. Sensory afferent nerves relay impulses from the airways to the central nervous system so that appropriate changes in bronchomotor tone and breathing patterns
may occur. The activity and functions of the airway sensory afferent nerves in vivo can be measured electrophysiologically by extracellular recording of action potentials travelling from the sensory receptors in afferent fibres in the airways of anaesthetised animals. To focus this short review, the discussion is limited to the methodology used for recording action potentials in single nerve fibres originating from airway sensory receptors in the tracheobronchial tree.
Recording and data-capture methods The methodology for extracellular recording of action potentials travelling in single fibres of the vagus nerves is often described in the literature as ‘conventional’. As such, the fundamentals for examining airways sensory nerves have not changed during the past 50 years except for the processes of data capture. These have progressed from magnetic taping of the nerve activity and Polaroid pictures of oscilloscope traces, to the use of sophisticated computerised data-acquisition software (Figure 1). However, the outcome is the same — recording action potentials in single nerve fibres that result from manipulations of the sensory receptor from which the fibre arises (Figure 2). The current techniques used for in vivo electrophysiological recording of airway sensory nerve fibres are described in detail in Figure 1. The recent introduction of data-acquisition software not only allows the capture of enormous quantities of data but also allows playback and multifaceted analysis of the raw data to produce, for example, pulse-rate histograms (Figure 3).
Figure 1
Vagus nerve Lungs
CNS Single afferent fibre
Recording electrode and headstage Amplifier and filters Oscilloscope
Dataacquisition software
Loudspeaker
Spike processor Current Opinion in Pharmacology
Diagram showing the general arrangement for recording action potentials in single afferent nerve fibres originating from airway sensory receptors. To prepare for recording, the vagus nerve is separated from the sympathetic and aortic nerves, immersed in liquid paraffin and cut at the central end. Single nerve fibres are dissected and placed over a silver recording electrode. The fascia from the vagus nerve is placed over another electrode for reference and the signal from the recording electrode is then subtracted from this reference signal to remove noise. Action potentials from the fibre are picked up at the headstage, pre-amplified, filtered and monitored visually on an oscilloscope and audibly with a loudspeaker. The action potentials (spikes) are processed with a spike processor for output to a chart recorder and acquired and stored on a computer for future analysis using data acquisition software. This type of set-up can be used to record the electrophysiological events that occur in single nerve fibres of the vagus originating from airway sensory receptors when these receptors are exposed to mechanical, physical and chemical manoeuvres, designed to either stimulate or inhibit activity. CNS, central nervous system.
Airway nerves: in vivo electrophysiology Adcock
281
Figure 2 Typical examples of spontaneous impulse activity recorded in single nerve fibres of the left cervical vagus in anaesthetised, paralysed and artificially ventilated cats. Transpulmonary pressure (PTP, in cm H2O) is also shown. Generally, the criteria used to identify the various airway sensory receptors include: pattern of spontaneous discharge, response to hyperinflation and deflation of the lungs, adaptation indices, response to irritant chemicals after systemic and aerosol administration, conduction velocities and confirmation of location of the receptor within the respiratory tract. C-fibre receptors are sub-divided into pulmonary and bronchial depending on the branch of the blood circulation that supplies them. (a) Action potentials (AP) recorded in an A-fibre arising from an SAR in the left lung (conduction velocity = 25.3 m/s, adaptation index = 23%). Stretch as the lung inflates activates the receptors, which adapt slowly and thus generate frequent action potential discharges with respiratory rhythm. (b) Action potentials recorded in an Aδ-fibre arising from an RAR in the left lung (conduction velocity = 15.5 m/s, adaptation index = 100%). These receptors adapt more rapidly, generating only occasional discharges with respiratory rhythm. (c) Action potentials recorded in
(a) SAR
1s AP
PTP (cm H2O)
10 0
(b) RAR
1s AP
PTP (cm H2O)
10 0
(c) C-fibre
1s AP
PTP (cm H2O)
10 0 Current Opinion in Pharmacology
a pulmonary C-fibre arising from the left lung (conduction velocity = 1.3 m/s). C-fibres are not normally activated by
What can’t these techniques reveal?
stretch of the lungs; note the sparse, irregular discharges with no resemblance to respiratory rhythm.
single sensory receptor, then the interpretations are convincing.
Unfortunately, the sensory receptors from which the single nerves originate cannot be accessed directly using the electrophysiological systems available to us today. This is somewhat surprising, considering the vast steps forward taken in other areas of micro-technology. In effect, this approach leaves us with having to make indirect interpretations of the events that actually occur at the sensory nerve ending itself. Nevertheless, because it is possible to record action potentials in single nerve fibres generated by, in all probability, a
What have these techniques revealed? In vivo electrophysiology techniques have contributed enormously to our understanding of the role of sensory nerves in the physiology and pharmacology of the neural control of airways in normal and diseased lungs. In particular, their role in maintaining a normal respiratory pattern, the events leading to reflex bronchoconstriction, mucus secretion and the cough reflex [1•].
Figure 3 Recording to show the effect of histamine on discharges in a single Aδ-fibre originating from an intrathoracic RAR in the respiratory tract of an anaesthetised, paralysed, artificially ventilated rabbit. Data are shown as a pulserate histogram (derived from EGAA data acquisition software) that shows the number of impulses per second (imp/s; absolute values) against time in 0.1 s bins. Histamine was administered as an aerosol (generated with a DeVilbiss ultrasonic nebuliser) in six breaths from a 1 mg/ml solution, marked with an arrow. Histamine activates the receptor, raising the firing frequency of the fibre from the background rate but the activation is short lived.
12 H
10 8 Imp/s
6 4 2 0 0
50
100 Time (s)
150 Current Opinion in Pharmacology
282
Respiratory
Airway sensory fibre types
There are at least three types of sensory receptor in the tracheobronchial tree: slowly adapting stretch receptors (SARs), rapidly adapting stretch receptors (RARs, also known as irritant receptors), and C-fibres [2]; each type identified using several criteria (Figure 2). The afferent discharges from SARs, RARs and C-fibres and, in many cases, the consequent physiological reflexes are relatively clear [2]. However, although the recording of action potentials in the single nerve fibres originating from RARs (Aδ-fibres) and the pulmonary and bronchial C-fibres has been vital in probing the fundamental roles of these sensory receptors in several reflexes of the airways, there is still much controversy surrounding their relative roles in cough [1•,3,4]. Whereas it is widely accepted that activation of RARs evokes the cough reflex, the evidence for a similar direct role for C-fibres is unsubstantiated. Indeed, activation of C-fibres may reflexly inhibit cough [5]. Furthermore, capsaicin — which can evoke a cough reflex when administered by inhalation and which was once assumed to be a selective stimulant of C-fibres — also activates RARs [4]. Pharmacology of airway sensory receptors
Pharmacologically, extracellular recording of action potentials in nerve fibres from sensory receptors allows quantitative analysis of the effects and mechanisms of action of established and potentially useful drugs [6•,7,8]. A number of novel agents have been principally designed to act in the periphery as inhibitors of reflex bronchoconstriction, reflex mucus secretion and reflex cough responses in airway diseases, including asthma and chronic obsructive pulmonary disease (COPD). Indeed, an inhibitory action of dopamine on RARs in dogs, mediated via dopamine D2 receptors, has recently been identified [9•]. This effect is shared by the dual dopamine D2 receptor and β2-adrenoceptor agonist, Viozan (AR-C68397AA; AstraZeneca, Loughborough, UK), which inhibits cough, tachypnoea (rapid shallow breathing) and mucus production [10•]. However, disappointingly, there appears to be no corresponding study of the effect of Viozan on airway C-fibres in relation to the cough response, which may have helped to unravel the controversy surrounding the relative roles of RARs and C-fibres in cough. Sensitisation of airway sensory receptors
Increasing evidence suggests that the excitability of RARs and C-fibres and their reflex actions are enhanced by airway mucosal inflammation [7,11]. One such example is airway hyperresponsiveness, which can be evoked by acute exposure to ozone and involves the hypersensitivity of C-fibres [12]. The mechanisms underlying this may involve the local release of inflammatory mediators such as prostaglandin E2 and histamine, which are known to activate airway sensory receptors and to sensitise C-fibres in the skin, increasing pain sensation in tissue injury and inflammation [13]. Similarly, central sensitisation — a phenomenon known to contribute to pain and hyperalgesia — may also be involved in airway hyperresponsiveness initiated
by peripheral sensitisation and activation of C-fibres in inflamed airways (see also review by SB Mazzone and BJ Canning, in this issue, pp 220–228).
Conclusions Although the basic techniques have not advanced greatly in 50 years, clearly they continue to contribute vastly to our understanding of the physiology and pharmacology of airway sensory nerves, their sensory receptors and the reflexes arising from their activation. It is widely recognised that airway hyperresponsiveness is a characteristic feature of asthma and, in the future, research should focus on the mechanisms of airway sensory receptor sensitisation and the development of approaches to modulate this phenomenon.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest •• of outstanding interest 1. S’ant Ambrogio G, Widdicombe J: Reflexes from airway rapidly • adapting receptors. Respir Physiol 2001, 125:33-45. A detailed description of airway RARs and an up-to-date analysis of the importance of these receptors in laryngeal reflexes and reflexes in the tracheobronchial tree, such as cough, bronchoconstriction and mucus secretion. 2.
Widdicombe J: Airway receptors. Respir Physiol 2001, 125:3-15.
3.
Canning BJ, Reynolds SM, Meeker S, Undem BJ: Electrophysiological identification of tracheal (T) and laryngeal (LX) vagal afferents mediating cough in guinea-pigs (GP). Am J Respir Crit Care Med 2000, 161:A434.
4.
Mohammed SP, Higenbottam TW, Adcock JJ: Effects of aerosol applied capsaicin, histamine and prostaglandin E2 on airway sensory receptors of anaesthetised cats. J Physiol 1993, 469:51-66.
5.
Widdicombe JG: Afferent receptors in the airways and cough. Respir Physiol 1998, 114:5-15.
6. Undem BJ, Carr MJ: Pharmacology of airway afferent nerve activity. • Respir Res 2001, 2:234-244. A long-awaited and excellent review of the pharmacology of airway afferent nerve activity, focusing particularly on agents that interact with various ion channels and receptors within the membrane of the afferent terminals. 7.
Adcock JJ: The relationship between hyperalgesia and hyperresponsiveness in the lung. In Progress in Inflammation Research: Pain and Neurogenic Inflammation. Edited by Brain SD, Moore PK, Parnham MJ. Basel, Boston, Berlin: Birkhauser Verlag; 1999:195-206.
8.
Hills BA, Chen Y: Suppression of neural activity of bronchial irritant receptors by surface-active phospholipid in comparison with topical drugs commonly prescribed for asthma. Clin Exp Allergy 2000, 30:1266-1274.
9. Jackson DM, Simpson WT: The effect of dopamine on the rapidly • adapting receptors in the dog lung. Pulm Pharmacol 2000, 13:39-42. An original observation and description of the effects of dopamine on RARs, mediated via dopamine D2 receptors. 10. Young A, Dougall I, Jackson D, Blackham A, Hallam C, Harper S, , a novel dual D2-receptor • Brown R, Leff P, Eady R, Ince F: Viozan and β-adrenoceptor agonist, inhibits clinically relevant parameters in animal models of airways disease. Am J Respir Crit Care Med 2000, 161:A820.The first description of a dual dopamine D2 receptor and β2-adrenoceptor agonist, which inhibits sensory reflexes in the lung by inhibiting sensory nerve activity. 11. Lee LY, Widdicombe JG: Modulation of airway sensitivity to inhaled irritants: role of inflammatory mediators. Environ Health Perspect 2001, 109:585-589. 12. Ho CY, Lee LY: Ozone enhances excitabilities of pulmonary C-fibres to chemical and mechanical stimuli in anaesthetised rats. J Appl Physiol 1998, 85:1509-1515. 13. Lee LY, Pisarri TE: Afferent properties and reflex functions of bronchopulmonary C-fibres. Respir Physiol 2001, 125:47-65.
Airway nerves: in vivo electrophysiology John J Adcock Information about the activity of airway sensory afferent nerves in vivo can be obtained electrophysiologically by extracellular recording of action potentials. Apart from data capture, the basic techniques used for recording sensory nerve activity have not advanced greatly in 50 years. However, clearly they continue to contribute vastly to our understanding of the role of these nerves in the control and functions of the airways in disease. This is particularly noticeable with the insight gained into exactly which physiological, biochemical and pharmacological events in the control of lung function rely upon the airway sensory afferent nerves and the subsequent airway vagal reflex arcs. Addresses Pneumolabs (UK) Limited, Northwick Park Institute for Medical Research, Y Block, Watford Road, Harrow, Middlesex HA1 3UJ, UK; e-mail: [email protected] Current Opinion in Pharmacology 2002, 2:280–282 1471-4892/02/$ — see front matter © 2002 Elsevier Science Ltd. All rights reserved. Abbreviations RAR rapidly adapting stretch receptor SAR slowly adapting stretch receptor
Introduction Neural control of the airways is more complex than previously recognised. Sensory afferent nerves relay impulses from the airways to the central nervous system so that appropriate changes in bronchomotor tone and breathing patterns
may occur. The activity and functions of the airway sensory afferent nerves in vivo can be measured electrophysiologically by extracellular recording of action potentials travelling from the sensory receptors in afferent fibres in the airways of anaesthetised animals. To focus this short review, the discussion is limited to the methodology used for recording action potentials in single nerve fibres originating from airway sensory receptors in the tracheobronchial tree.
Recording and data-capture methods The methodology for extracellular recording of action potentials travelling in single fibres of the vagus nerves is often described in the literature as ‘conventional’. As such, the fundamentals for examining airways sensory nerves have not changed during the past 50 years except for the processes of data capture. These have progressed from magnetic taping of the nerve activity and Polaroid pictures of oscilloscope traces, to the use of sophisticated computerised data-acquisition software (Figure 1). However, the outcome is the same — recording action potentials in single nerve fibres that result from manipulations of the sensory receptor from which the fibre arises (Figure 2). The current techniques used for in vivo electrophysiological recording of airway sensory nerve fibres are described in detail in Figure 1. The recent introduction of data-acquisition software not only allows the capture of enormous quantities of data but also allows playback and multifaceted analysis of the raw data to produce, for example, pulse-rate histograms (Figure 3).
Figure 1
Vagus nerve Lungs
CNS Single afferent fibre
Recording electrode and headstage Amplifier and filters Oscilloscope
Dataacquisition software
Loudspeaker
Spike processor Current Opinion in Pharmacology
Diagram showing the general arrangement for recording action potentials in single afferent nerve fibres originating from airway sensory receptors. To prepare for recording, the vagus nerve is separated from the sympathetic and aortic nerves, immersed in liquid paraffin and cut at the central end. Single nerve fibres are dissected and placed over a silver recording electrode. The fascia from the vagus nerve is placed over another electrode for reference and the signal from the recording electrode is then subtracted from this reference signal to remove noise. Action potentials from the fibre are picked up at the headstage, pre-amplified, filtered and monitored visually on an oscilloscope and audibly with a loudspeaker. The action potentials (spikes) are processed with a spike processor for output to a chart recorder and acquired and stored on a computer for future analysis using data acquisition software. This type of set-up can be used to record the electrophysiological events that occur in single nerve fibres of the vagus originating from airway sensory receptors when these receptors are exposed to mechanical, physical and chemical manoeuvres, designed to either stimulate or inhibit activity. CNS, central nervous system.
Airway nerves: in vivo electrophysiology Adcock
281
Figure 2 Typical examples of spontaneous impulse activity recorded in single nerve fibres of the left cervical vagus in anaesthetised, paralysed and artificially ventilated cats. Transpulmonary pressure (PTP, in cm H2O) is also shown. Generally, the criteria used to identify the various airway sensory receptors include: pattern of spontaneous discharge, response to hyperinflation and deflation of the lungs, adaptation indices, response to irritant chemicals after systemic and aerosol administration, conduction velocities and confirmation of location of the receptor within the respiratory tract. C-fibre receptors are sub-divided into pulmonary and bronchial depending on the branch of the blood circulation that supplies them. (a) Action potentials (AP) recorded in an A-fibre arising from an SAR in the left lung (conduction velocity = 25.3 m/s, adaptation index = 23%). Stretch as the lung inflates activates the receptors, which adapt slowly and thus generate frequent action potential discharges with respiratory rhythm. (b) Action potentials recorded in an Aδ-fibre arising from an RAR in the left lung (conduction velocity = 15.5 m/s, adaptation index = 100%). These receptors adapt more rapidly, generating only occasional discharges with respiratory rhythm. (c) Action potentials recorded in
(a) SAR
1s AP
PTP (cm H2O)
10 0
(b) RAR
1s AP
PTP (cm H2O)
10 0
(c) C-fibre
1s AP
PTP (cm H2O)
10 0 Current Opinion in Pharmacology
a pulmonary C-fibre arising from the left lung (conduction velocity = 1.3 m/s). C-fibres are not normally activated by
What can’t these techniques reveal?
stretch of the lungs; note the sparse, irregular discharges with no resemblance to respiratory rhythm.
single sensory receptor, then the interpretations are convincing.
Unfortunately, the sensory receptors from which the single nerves originate cannot be accessed directly using the electrophysiological systems available to us today. This is somewhat surprising, considering the vast steps forward taken in other areas of micro-technology. In effect, this approach leaves us with having to make indirect interpretations of the events that actually occur at the sensory nerve ending itself. Nevertheless, because it is possible to record action potentials in single nerve fibres generated by, in all probability, a
What have these techniques revealed? In vivo electrophysiology techniques have contributed enormously to our understanding of the role of sensory nerves in the physiology and pharmacology of the neural control of airways in normal and diseased lungs. In particular, their role in maintaining a normal respiratory pattern, the events leading to reflex bronchoconstriction, mucus secretion and the cough reflex [1•].
Figure 3 Recording to show the effect of histamine on discharges in a single Aδ-fibre originating from an intrathoracic RAR in the respiratory tract of an anaesthetised, paralysed, artificially ventilated rabbit. Data are shown as a pulserate histogram (derived from EGAA data acquisition software) that shows the number of impulses per second (imp/s; absolute values) against time in 0.1 s bins. Histamine was administered as an aerosol (generated with a DeVilbiss ultrasonic nebuliser) in six breaths from a 1 mg/ml solution, marked with an arrow. Histamine activates the receptor, raising the firing frequency of the fibre from the background rate but the activation is short lived.
12 H
10 8 Imp/s
6 4 2 0 0
50
100 Time (s)
150 Current Opinion in Pharmacology
282
Respiratory
Airway sensory fibre types
There are at least three types of sensory receptor in the tracheobronchial tree: slowly adapting stretch receptors (SARs), rapidly adapting stretch receptors (RARs, also known as irritant receptors), and C-fibres [2]; each type identified using several criteria (Figure 2). The afferent discharges from SARs, RARs and C-fibres and, in many cases, the consequent physiological reflexes are relatively clear [2]. However, although the recording of action potentials in the single nerve fibres originating from RARs (Aδ-fibres) and the pulmonary and bronchial C-fibres has been vital in probing the fundamental roles of these sensory receptors in several reflexes of the airways, there is still much controversy surrounding their relative roles in cough [1•,3,4]. Whereas it is widely accepted that activation of RARs evokes the cough reflex, the evidence for a similar direct role for C-fibres is unsubstantiated. Indeed, activation of C-fibres may reflexly inhibit cough [5]. Furthermore, capsaicin — which can evoke a cough reflex when administered by inhalation and which was once assumed to be a selective stimulant of C-fibres — also activates RARs [4]. Pharmacology of airway sensory receptors
Pharmacologically, extracellular recording of action potentials in nerve fibres from sensory receptors allows quantitative analysis of the effects and mechanisms of action of established and potentially useful drugs [6•,7,8]. A number of novel agents have been principally designed to act in the periphery as inhibitors of reflex bronchoconstriction, reflex mucus secretion and reflex cough responses in airway diseases, including asthma and chronic obsructive pulmonary disease (COPD). Indeed, an inhibitory action of dopamine on RARs in dogs, mediated via dopamine D2 receptors, has recently been identified [9•]. This effect is shared by the dual dopamine D2 receptor and β2-adrenoceptor agonist, Viozan (AR-C68397AA; AstraZeneca, Loughborough, UK), which inhibits cough, tachypnoea (rapid shallow breathing) and mucus production [10•]. However, disappointingly, there appears to be no corresponding study of the effect of Viozan on airway C-fibres in relation to the cough response, which may have helped to unravel the controversy surrounding the relative roles of RARs and C-fibres in cough. Sensitisation of airway sensory receptors
Increasing evidence suggests that the excitability of RARs and C-fibres and their reflex actions are enhanced by airway mucosal inflammation [7,11]. One such example is airway hyperresponsiveness, which can be evoked by acute exposure to ozone and involves the hypersensitivity of C-fibres [12]. The mechanisms underlying this may involve the local release of inflammatory mediators such as prostaglandin E2 and histamine, which are known to activate airway sensory receptors and to sensitise C-fibres in the skin, increasing pain sensation in tissue injury and inflammation [13]. Similarly, central sensitisation — a phenomenon known to contribute to pain and hyperalgesia — may also be involved in airway hyperresponsiveness initiated
by peripheral sensitisation and activation of C-fibres in inflamed airways (see also review by SB Mazzone and BJ Canning, in this issue, pp 220–228).
Conclusions Although the basic techniques have not advanced greatly in 50 years, clearly they continue to contribute vastly to our understanding of the physiology and pharmacology of airway sensory nerves, their sensory receptors and the reflexes arising from their activation. It is widely recognised that airway hyperresponsiveness is a characteristic feature of asthma and, in the future, research should focus on the mechanisms of airway sensory receptor sensitisation and the development of approaches to modulate this phenomenon.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest •• of outstanding interest 1. S’ant Ambrogio G, Widdicombe J: Reflexes from airway rapidly • adapting receptors. Respir Physiol 2001, 125:33-45. A detailed description of airway RARs and an up-to-date analysis of the importance of these receptors in laryngeal reflexes and reflexes in the tracheobronchial tree, such as cough, bronchoconstriction and mucus secretion. 2.
Widdicombe J: Airway receptors. Respir Physiol 2001, 125:3-15.
3.
Canning BJ, Reynolds SM, Meeker S, Undem BJ: Electrophysiological identification of tracheal (T) and laryngeal (LX) vagal afferents mediating cough in guinea-pigs (GP). Am J Respir Crit Care Med 2000, 161:A434.
4.
Mohammed SP, Higenbottam TW, Adcock JJ: Effects of aerosol applied capsaicin, histamine and prostaglandin E2 on airway sensory receptors of anaesthetised cats. J Physiol 1993, 469:51-66.
5.
Widdicombe JG: Afferent receptors in the airways and cough. Respir Physiol 1998, 114:5-15.
6. Undem BJ, Carr MJ: Pharmacology of airway afferent nerve activity. • Respir Res 2001, 2:234-244. A long-awaited and excellent review of the pharmacology of airway afferent nerve activity, focusing particularly on agents that interact with various ion channels and receptors within the membrane of the afferent terminals. 7.
Adcock JJ: The relationship between hyperalgesia and hyperresponsiveness in the lung. In Progress in Inflammation Research: Pain and Neurogenic Inflammation. Edited by Brain SD, Moore PK, Parnham MJ. Basel, Boston, Berlin: Birkhauser Verlag; 1999:195-206.
8.
Hills BA, Chen Y: Suppression of neural activity of bronchial irritant receptors by surface-active phospholipid in comparison with topical drugs commonly prescribed for asthma. Clin Exp Allergy 2000, 30:1266-1274.
9. Jackson DM, Simpson WT: The effect of dopamine on the rapidly • adapting receptors in the dog lung. Pulm Pharmacol 2000, 13:39-42. An original observation and description of the effects of dopamine on RARs, mediated via dopamine D2 receptors. 10. Young A, Dougall I, Jackson D, Blackham A, Hallam C, Harper S, , a novel dual D2-receptor • Brown R, Leff P, Eady R, Ince F: Viozan and β-adrenoceptor agonist, inhibits clinically relevant parameters in animal models of airways disease. Am J Respir Crit Care Med 2000, 161:A820.The first description of a dual dopamine D2 receptor and β2-adrenoceptor agonist, which inhibits sensory reflexes in the lung by inhibiting sensory nerve activity. 11. Lee LY, Widdicombe JG: Modulation of airway sensitivity to inhaled irritants: role of inflammatory mediators. Environ Health Perspect 2001, 109:585-589. 12. Ho CY, Lee LY: Ozone enhances excitabilities of pulmonary C-fibres to chemical and mechanical stimuli in anaesthetised rats. J Appl Physiol 1998, 85:1509-1515. 13. Lee LY, Pisarri TE: Afferent properties and reflex functions of bronchopulmonary C-fibres. Respir Physiol 2001, 125:47-65.