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Experimental Physiology 91.4 pp 647-654
DOI: 10.1113/expphysiol.2006.033209
© The Physiological Society 2006
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Review Article

The rapidly adapting receptors in mammalian airways and their responses to changes in extravascular fluid volume

C. Tissa Kappagoda1 and Krishnan Ravi2

1 Division of Cardiovascular Medicine, University of California, Davis, CA 95616, USA 2 Vallabh Bhai Patel Chest Institute, University of Delhi, Delhi, India


   Abstract
Top
 Abstract
Introduction
 References
 
In this short review, we shall focus on some recent findings on the physiological stimulus for the rapidly adapting receptors (RAR) of the airways. They are readily activated by a sustained inflation of the lungs and they are usually identified by their rapid adaptation to this stimulus. They are also activated by both tactile stimuli and irritant gases applied to the epithelium of the airways. The investigations reviewed here suggest that these receptors are activated by changes in extravascular fluid volume. The principal factors governing fluid flux from the microcirculation are identified in the Starling equation. These are the hydrostatic pressure, plasma oncotic pressure and capillary permeability. Findings from recent studies suggest that all these factors increase the activity of RAR. In addition, these receptors are also activated by obstruction of lymph drainage from the lung. Evidence is presented to show that manipulation of Starling forces also increases the extravascular fluid volume of the airways in areas where the RAR are located. On the basis of these findings, it is suggested that, along with mechanosensitivity to stimuli such as stretch, inflation and deflation, another physiological stimulus to the RAR is a change in extravascular fluid volume in the regions of the airways where these receptors are located.

(Received 9 January 2006; accepted after revision 21 March 2006; first published online 26 June 2006)
Corresponding author C. Tissa Kappagoda: TB 172 Division of Cardiovascular Medicine, One Shields Avenue, University of California, Davis, CA 95616, USA.  Email: ctkappagoda{at}ucdavis.edu


   Introduction
Top
 Abstract
 Introduction
References
 
It is generally accepted that there are four types of vagal sensory receptors in the airways and lung. They are: (i) slowly adapting receptors (SAR; Adrian, 1933); (ii) rapidly adapting receptors (RAR; Knowlton & Larrabee, 1946); (iii) bronchial C fibre receptors (Coleridge et al. 1965); and (iv) pulmonary C fibre (type J) receptors (Paintal, 1973). In this short review, we will focus on some recent findings on the structure, location and physiological stimulus of the RAR. (These receptors are generally known as ‘irritant’ receptors and ‘cough’ receptors (Coleridge & Coleridge, 1994; Widdicombe, 1995, 1999; Sant'Ambrogio & Widdicombe, 2001) and have their cell bodies mainly in the nodose ganglia. Rapidly adapting receptors in the larynx are also called ‘irritant’ receptors. In addition to the above receptors, vagal A{delta} receptors have been demonstrated in the tracheal epithelium of guinea-pigs. These receptors have cell bodies in the jugular ganglia (Riccio et al. 1996; Undem & Carr, 2001; Undem et al. 2002). Even though these receptors also adapt rapidly to a maintained mechanical stimulus, their sensitivity to some chemicals varies from the conventional RARs (Widdicombe, 2003). Recently, neuroepithelial bodies (NEBs) located in the airways, with afferents in the vagi and spinal nerves, have been reported (Adriaensen et al. 1998). The laryngeal RAR, tracheal A{delta} receptors and airway NEBs will not be discussed in the present review.

The first description of RAR was provided by Keller & Loeser (1930). However, one of the earliest recordings of discrete action potentials in the cervical vagus was reported by Adrian (1933), who observed that while some of the sensory receptors in the lung were stimulated by inflation, a few others were stimulated by forced deflation. The first formal description of RAR was provided by Knowlton & Larrabee (1946), who reported that among the vagal afferents which responded to lung inflation, approximately two-thirds responded with a sustained increase in activity. The remaining one-third showed a sharp increase in activity which adapted within a few seconds of inflation (Fig. 1). The term ‘Rapidly Adapting Receptors’ was applied to the latter group of sensory endings. Based upon their conduction velocities (8–35 m s–1), the nerve fibres originating from these receptors indicated that they were myelinated. Knowlton & Larrabee (1946) defined an adaptation index (AI) also to identify RAR:


Formula

Although this basic definition has been used extensively in the literature, it should be recognized that the inflation applied was in the nature of a ramp as opposed to square-wave stimulus. Widdicombe (1954) extended these observations in a systematic study of vagal afferents in cats. First, he clarified the peak frequency of the AI to mean the frequency at the highest pressure during the inflation. Second, he suggested that an AI of ≥70% was the best indicator for identifying the RAR described by Knowlton & Larrabee (1946) previously. He also attempted to identify the natural stimulus for the RAR using various inflation volumes and techniques to alter the flow of air in the airways. His overall conclusion was that lung collapse and its reversal excited far more RAR than distension and its release. Even though many of them showed irregular resting activity, respiratory modulation was seen in some. However, they did not exhibit a fixed timing with the phases of respiratory cycle; the activity occurred often at peak inspiration and at end-expiration, indicating that a change in the transpulmonary pressure was a contributing factor in their activation (Sant'Ambrogio & Widdicombe, 2001). Finally, he attempted to locate the RAR by inflating a balloon positioned at various points in the airway, and showed that they were predominantly located in the lower portion of the trachea, the carina and the extrapulmonary airways. Even though this procedure activated the receptors, the author remarked that ‘a long lasting regular discharge could not be produced by endo-tracheal stimulation’ (Widdicombe, 1954).


Figure 1
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  		Figure 1.  Adaptation to a sustained inflation of the lung
Recording of action potentials showing the response of a SAR (A) and a RAR (B) to a sustained inflation of the lung. Reproduced with permission from Knowlton & Larrabee (1946).

 
Rapidly adapting receptors and the pulmonary circulation

During the course of investigations designed to identify the vagal sensory receptors activated by pulmonary venous congestion, it was found that the RAR were stimulated in an unusual manner (Fig. 2; Kappagoda et al. 1987). The experiments were undertaken in artificially ventilated, anaesthetized dogs, in which the left atrial pressure was increased by 10 mmHg by partly obstructing the mitral valve. This procedure was carried out by inserting a small balloon into the left atrium through the left atrial appendage and inflating the balloon with 3–5 ml of normal saline. The resulting mitral valve obstruction raised the left atrial pressure. Action potentials from sensory receptors in the lung were recorded from the cervical vagi.


Figure 2
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  		Figure 2.  Comparison of the effects of increasing left atrial pressure by 10 mmHg on pulmonary vagal afferents
The largest effects were seen in the RAR (B). A, SAR; C, bronchial C fibre receptors; and D, pulmonary C fibre receptors. Reproduced with permission from Kappagoda et al. (1987).

 
Unlike the rapid adaptation observed during a maintained inflation of the lung (Fig. 1; Knowlton & Larrabee, 1946), it was observed that the RAR were activated in a sustained manner without any discernible evidence of adaptation. The effects on the SAR and the bronchial C fibre receptors were very small in comparison with the effects on RAR. This stimulus had no effect on pulmonary C fibre receptors (Kappagoda et al. 1987).

This observation suggested that the activity of RAR could be modulated by factors which influence fluid fluxes from the microcirculation of the airways. The anatomical basis for this proposition is the recognition that a significant portion of the venous drainage from the bronchi is directed into the pulmonary veins (Miller, 1947; Harris & Heath, 1986; Wagner et al. 1999). During partial obstruction of the mitral valve, the increase in hydrostatic pressure in the pulmonary veins would raise pressure in the bronchial venules of the proximal airways (Wagner et al. 1998), promoting fluid flux and activation of RAR.

Starling forces and the microcirculation of the lung

The fundamental principle governing the exchange of fluid between microvessels and the extravascular space was proposed by Starling, 1895). He postulated that ‘at any given time, there must be a balance between hydrostatic pressure and the osmotic pressure alteration of the blood ...’ thereby linking the three main factors which determine the extravascular fluid volume (space) in any tissue, i.e. hydrostatic pressure, oncotic pressure exerted by proteins and the flow of lymph.

Three decades later, these ideas were consolidated further by the experiments of Landis (1930), who summarized his findings in the form of the following equation:


Formula

where Jv/A is the rate of fluid filtration or resorption per unit area of vessel wall, Lp is the hydraulic permeability of the vessel wall, Pi and {Pi}i are the hydrostatic and plasma oncotic pressures of the interstitial fluid, respectively, Pc and {Pi}c are the hydrostatic and oncotic pressures of plasma, respectively, and {sigma} is the reflection coefficient of the microvascular wall to plasma protein.

If the RAR are responsive to changes in extravascular fluid volume in the lung, it follows that besides hydrostatic pressure, their activity would be influenced by the other factors in the Starling equation, i.e. plasma oncotic pressure and microvascular (capillary) permeability. In addition, they would also be influenced by perturbations of extravascular fluid volume in the airways caused by lymphatic obstruction.

Effect of altering oncotic pressure on RAR activity

Plasmapheresis is a reliable method of reducing the oncotic pressure in plasma. It can be readily performed by removing 10–12% of the estimated blood volume of an animal and returning the red blood cells suspended in saline. These procedures decrease the concentration of plasma proteins and thereby reduce the oncotic pressure. Such a reduction enhances the transfer of fluid from the vascular compartment to the extravascular one. This increase in fluid flux is reflected in pulmonary lymph flow. The lymph drainage from the lung occurs mainly via the right lymphatic duct (Courtice & Simmonds, 1954). The right lymphatic ducts open into the venous system in the region where the right internal jugular vein joins the right external jugular vein (Fig. 3).


Figure 3
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  		Figure 3.  Right lymphatic duct in the rabbit
The figure shows the location of the main right lymphatic duct on the medial side of the superior vena cava (SVC) prior to entry into the vein. A second lymph duct is shown on the lateral side of the SVC. The lymph ducts were visualized as black vessels after injection of India ink into the interstitial space of the top two lobes of the right lung of the rabbit. A balloon inserted into the left atrium was inflated to increase the left atrial pressure by 10 mmHg in order to facilitate lymph flow. The dissection was performed 2 h after injection of India ink. The caudal end of the SVC is on the right-hand bottom corner, and the cranial end is in the opposite corner. Reproduced with permission from McCormick et al. (2005).

 
The lymph drainage from the lung is approximately 1.0–2.0 ml h–1 in the dog (Uhley et al. 1960) and 0.35 ml h–1 in the rabbit (Hughes et al. 1956). However, as expected from the Starling equation, the flow of lymph is sensitive to both an increase in hydrostatic pressure caused by increments in left atrial pressure and a reduction in oncotic pressure of plasma (Fig. 4). Thus, one could anticipate that raising the left atrial pressure would increase the extravascular fluid volume in the respiratory system and that this increase would be enhanced further after plasmapheresis. Experiments were carried out in anaesthetized dogs to confirm these changes anticipated from the Starling equation (Kappagoda & Ravi, 1989). An example of an experiment in a dog is shown in Fig. 4.


Figure 4
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  		Figure 4.  Combined effect of plasmapheresis and increasing left atrial pressure on lymph drainage from the lung in the dog
The effect of increasing left atrial pressure and plasmapheresis (plasma protein concentration reduced by 11%) on pulmonary lymph flow in an anaesthetized dog. Abscissa, time in minutes; ordinate, lymph flow per 15 min period. Increasing the left atrial pressure (indicated by the bar) causes an increase in lymph flow in the control state (filled). After plasmapheresis (open), the lymph flow is enhanced considerably in the control state and during elevation of left atrial pressure. Reproduced with permission from Kappagoda & Ravi (1989).

 
During the course of this study we also examined the effect of these manoeuvres on the activity of RAR. It was found that the increase in activity observed during the period of increased left atrial pressure was enhanced further by plasmapheresis. These observations were consistent with the claim that the RAR were sensitive to changes in extravascular fluid volume in the lung. The findings are summarized in Fig. 5 (Hargreaves et al. 1991).


Figure 5
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  		Figure 5.  Summary of the combined effects of increasing left atrial pressure (LAP) and plasmapheresis (plasma protein concentration reduced by 18%) on the activity of RAR in the rabbit
Abscissa, left atrial pressure (mmHg); ordinate, RAR activity (action potentials min–1). Reproduced with permission from Hargreaves et al. (1991).

 
Effect of increasing microvascular (capillary) permeability on RAR activity

Histamine.  Histamine increases the permeability of the systemic venules and enhances lymph flow (Haddy et al. 1972). In the bronchial circulation, it promotes broncho-venular permeability and causes bronchial oedema (Pietra et al. 1972; Fishman & Pietra, 1976). It has also been shown that infusion of histamine into the right atrium increases pulmonary lymph flow (Ravi et al. 1989). It was found that even subthreshold doses of histamine enhanced the responses of RAR to pulmonary congestion caused by small elevations of left atrial pressure or by pulmonary lymphatic obstruction (Ravi et al. 1989). Also, against a background of pulmonary lymphatic obstruction, the stimulus–response curve relating histamine and RAR activity was shifted to the left when compared with that elicited in the control state (Ravi et al. 1989; Fig. 6).


Figure 6
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  		Figure 6.  Histamine and RAR
Dose–response curves to histamine. Abscissa, dose of histamine (µg kg–1); ordinate, action potentials (AP) of RAR (Hz). The dose–response curves were obtained in the control state ({blacksquare}) and after obstruction of pulmonary lymph drainage (•).Reproduced with permission from Ravi et al. (1989).

 
Histamine is known to constrict the airway smooth muscle. In the study described above, it was observed that the threshold dose of histamine required for activation of RAR in dogs was 0.82 µg kg–1 and that for increasing airway pressure was 1.0 µg kg–1. Of the seven RAR investigated, a dose of 0.5 µg kg–1 was sufficient to stimulate three. Additionally, it was observed that histamine infusion (dose, 0.4 µg kg–1 min–1 for 10 min) produced a sustained stimulation of RAR without producing any detectable change in airway pressure (Ravi et al. 1989). These results indicate that some of the effects of histamine on RAR are likely to be mediated by changes in the permeability of the bronchial vasculature.

Angiotensin converting enzyme (ACE) inhibitors and bradykinin.  Angiotensin converting enzyme inhibitors are prescribed frequently for the treatment of hypertension and heart failure. Even though ACE inhibitors are tolerated well by the patients, one side-effect that has been reported frequently is a troublesome cough (Semple & Herd, 1986). It has been suggested that the cough is caused by the stimulation of sensory receptors of the airways which are activated by chemicals that accumulate after ACE inhibition. One chemical that has been implicated in the cough response is bradykinin (Williams, 1988). We tested this hypothesis in rabbits using the ACE inhibitor enalapril. It was observed that enalapril given I.V. increased the resting activity of RAR. Additionally, in presence of enalapril, the dose–response curve relating receptor activity to bradykinin was found to be shifted towards the left, suggesting that the sensitivity of RAR to bradykinin was enhanced by enalapril (Hargreaves et al. 1992).

Bradykinin, which is a powerful vasodilator, increases permeability of bronchial venules when administered into the bronchial circulation (Fishman & Pietra, 1976; Corfield et al. 1991). This effect is mediated by B2 receptors (Mashito et al. 1999). Of the eight RAR investigated in the above study (Hargreaves et al. 1992), the threshold dose of bradykinin required for the stimulation was 0.53 ± 0.11 µg kg–1 and that for increasing airway pressure was 1.0 µg kg–1. Additionally, at these doses, bradykinin did not stimulate the SAR. The results suggest that besides a direct effect, bradykinin may stimulate RAR indirectly by increasing the permeability of bronchial vasculature.

The findings of a study involving substance P in rabbits also suggest that RAR are sensitive to changes in permeability of capillaries (Bonham et al. 1996). In these experiments, the response of RAR to pulmonary venous congestion was enhanced by substance P.

Effect of lymphatic obstruction on the activity of RAR

The final aspect of the responsiveness of RAR to changes in extravascular fluid volume is the effect of lymphatic obstruction. The lymph drainage from the lung could be obstructed in a reversible manner by creating a pouch from the superior vena cava. A vascularly isolated pouch (length, approximately 3 cm) was created in this region as previously described (Ravi et al. 1988; Hargreaves et al. 1991; Fig. 7). A saline reservoir was connected to the pouch by means of a polyethylene catheter inserted through the axillary vein. The lymph flow was obstructed in a reversible manner by alternately raising the fluid level of the reservoir to a height of 35 cm.


Figure 7
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  		Figure 7.  Experimental preparation for causing obstruction of lymph drainage from the lung
Left, dog; right, rabbit. In each instance a pouch is created in the right external jugular vein into which the lymph ducts drain. The pouch is pressurized by raising the reservoir. Ax, axillary vein; B, balloon; C, catheter; PA, pulmonary artery; Pv, pulmonary vein; RAp and LAp, right and left atrial appendages; Inn, innominate artery; RA, right atrium; LV and RV, left and right ventricle; SVC, superior vena cava. Reproduced with permission from Ravi et al. (1988) (left figure) and Hargreaves et al. (1991) (right figure).

 
Rapidly adapting receptors were stimulated by obstruction of lymph drainage in both dogs (Ravi et al. 1988) and rabbits (Hargreaves et al. 1991; Ravi et al. 1994). Again the activity was sustained for the duration of obstruction with no evidence of adaptation. When pulmonary lymphatic drainage was obstructed against a background of pulmonary congestion (increased left atrial pressure), the two effects appeared to be additive.

Location of RAR

Since there was presumptive evidence that the RAR were sensitive to extravascular fluid fluxes, it was likely that the receptors themselves would be located in the vicinity of the bronchial venules. It is now recognized that a significant proportion of the venous drainage from the bronchial circulation is directed into the pulmonary veins (Kappagoda et al. 1990). For this reason, we examined the bronchi to determine whether there were putative nerve endings in the vicinity of the bronchial venules. This study, which was undertaken in the rat, clearly demonstrated nerve endings located adjacent to the bronchial venules. The sensory nature of these endings was established by demonstrating Wallerian degeneration after cervical vagotomy. These presumptive receptors were ideally located to detect fluid fluxes from the airways. An example of a nerve ending is shown in Fig. 8.


Figure 8
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  		Figure 8.  Nerve ending adjacent to a bronchial vein
Example of a putative RAR adjacent to a bronchial venule in the rat. Left panel shows a silver-stained nerve ending (light microscopy). Right panel shows an ultrathin section of the same nerve ending viewed by transmission electron microscopy (see Kappagoda et al. 1990 for details). The terminal was associated with a myelinated nerve, and the sensory nature of these endings was established by demonstrating Wallerian degeneration after cervical vagotomy.

 
The link between the activity of RAR and extravascular fluid volume

The seminal work of Staub and associates established that in heart failure, extravascular fluid accumulates in the lungs and airways according to a well-defined pattern (Staub, 1974; Staub et al. 1967). In the earliest phase of left ventricular dysfunction, fluid accumulates in the airways in the area of the carina and bronchi. When the capacity of the pulmonary lymphatics to drain this fluid is exceeded, it extends into the alveoli, resulting in overt pulmonary oedema. In order to link the activity of RAR to these changes in fluid flux, it was necessary to establish, by direct measurements, the changes in extravascular fluid in the airways under the precise conditions in which the RAR were activated. Using a gravimetric technique, it was possible to show that increases in left atrial pressures of 5–10 mmHg not only increased the activity of RAR but also increased the extravascular fluid in areas where the RAR were located, i.e. in the carina and proximal bronchi. Simultaneously, it was possible to show that there was no increase in extravascular fluid in the alveoli until the left atrial pressure was in excess of 25 mmHg (Gunawardena et al. 1998, 1999, 2002). These findings are summarized in Table 1. The overall scheme for activation of RAR is shown in Fig. 9.


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  		Table 1. Changes in extravascular fluid (% wet weight) in the airways and lung in control rabbits and those with an increased left atrial pressure (LAP)
 

Figure 9
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  		Figure 9.  Schematic of the physiological stimulus to RAR

 
Thus it was concluded that the activity of RAR mirrored the changes in extravascular fluid in the airways. In addition, the recent investigations have shown that the pulmonary C fibre receptors (from the lungs) are not responsive in the early phases of left ventricular dysfunction. The bronchial C fibre receptors are stimulated slightly when the left atrial pressure is increased by 10 mmHg (Kappagoda et al. 1987). They are stimulated also by combining Starling forces (e.g. lymphatic obstruction and a reduction in plasma oncotic pressure) even though individually these stimuli do not activate them. However, when overt pulmonary oedema occurs, RAR together with C fibre afferents from the airways and the periphery of the lung are activated. Thus there appears to be a hierarchy in the activation of sensory receptors in the lung, the RAR being sensitive to the earliest changes in fluid flux and, as the condition proceeds, other receptor types being recruited.

Potential relevance to left ventricular dysfunction

In left ventricular dysfunction, pressures in the left atrium and pulmonary veins increase, resulting in pulmonary venous congestion. As the condition progresses and the left atrial pressure exceeds 25 mmHg (Guyton & Lindsay, 1959), alveolar flooding (pulmonary oedema) supervenes. During the early phases of left ventricular dysfunction, i.e. during pulmonary venous congestion, patients complain of dyspnoea on exertion and exhibit a cough or a respiratory ‘wheeze’ associated with increases in respiratory rate and bronchomotor tone. It is known that procedures which activate RAR also increase respiratory rate, airway tone and airway secretions and cause a cough. It is suggested that the RAR could play a role in generating the symptomatology of left ventricular dysfunction (Ravi & Kappagoda, 1990).


   References
Top
 Abstract
 Introduction
 References
 
Adriaensen D, Timmermans JP, Brouns I, Berthoud HR, Neuhuber WL & Scheuermann DW (1998). Pulmonary intraepithelial vagal nodose afferent nerve terminals are confined to neuroepithelial bodies: an anterograde tracing and confocal microscopy study in adult rats. Cell Tissue Res 293, 395–405.[CrossRef][Medline]

Adrian ED (1933). The afferent impulses in the vagus and their effects on respiration. J Physiol 79, 332–358.[Free Full Text]

Bonham AC, Kott KS, Ravi K, Kappagoda CT & Joad JP (1996). Substance P contributes to rapidly adapting receptor responses to pulmonary venous congestion in rabbits. J Physiol 493, 229–238.[Medline]

Coleridge HM & Coleridge JC (1994). Pulmonary reflexes: neural mechanisms of pulmonary defense. Annu Rev Physiol 56, 69–91.[CrossRef][Medline]

Coleridge HM, Coleridge JC & Luck JC (1965). Pulmonary afferent fibres of small diameter stimulated by capsaicin and by hyperinflation of the lungs. J Physiol 179, 248–262.[Free Full Text]

Corfield DR, Webber SE, Hanafi Z & Widdicombe JG (1991). The action of bradykinin and lys-bradykinin on tracheal blood flow and smooth muscle in anesthetized sheep. Pulm Pharmacol 4, 85–90.[CrossRef][Medline]

Courtice FC & Simmonds WJ (1954). Physiological significance of lymph drainage of the serous cavities and lungs. Physiol Rev 34, 419–448.[Free Full Text]

Fishman AP & Pietra GG (1976). Permeability of pulmonary vascular endothelium. Ciba Found Symp 38, 29–48.[Medline]

Gunawardena S, Bravo E & Kappagoda CT (1998). Effect of chronic mitral valve damage on activity of pulmonary rapidly adapting receptors in the rabbit. J Physiol 511, 79–88.[Abstract/Free Full Text]

Gunawardena S, Bravo E & Kappagoda CT (1999). Rapidly adapting receptors in a rabbit model of mitral regurgitation. J Physiol 521, 739–748.[Abstract/Free Full Text]

Gunawardena S, Ravi K, Longhurst JC, Kaufman MP, Ma A, Bravo M & Kappagoda CT (2002). Responses of C fiber afferents of the rabbit airways and lungs to changes in extra-vascular fluid volume. Respir Physiol Neurobiol 132, 239–251.[CrossRef][Medline]

Guyton AC & Lindsay AW (1959). Effect of elevated left atrial pressure and decreased plasma protein concentration on the development of pulmonary edema. Circ Res 7, 649–657.[Abstract/Free Full Text]

Haddy FJ, Scott JB & Grega GJ (1972). Effects of histamine on lymph protein concentration and flow in the dog forelimb. Am J Physiol 223, 1172–1177.[Free Full Text]

Hargreaves M, Ravi K & Kappagoda CT (1991). Responses of slowly and rapidly adapting receptors in the airways of rabbits to changes in the Starling forces. J Physiol 432, 81–97.[Abstract/Free Full Text]

Hargreaves M, Ravi K, Senaratne MP & Kappagoda CT (1992). Responses of airway rapidly adapting receptors to bradykinin before and after administration of enalapril in rabbits. Clin Sci (Lond) 83, 399–407.[Medline]

Harris P & Heath D (1986). The Human Pulmonary Circulation, 3rd edn. Churchill Livingstone, New York.

Hughes R, May AJ & Widdicombe JG (1956). The output of lymphocytes from the lymphatic system of the rabbit. J Physiol 132, 384–390.[Free Full Text]

Kappagoda CT, Man GC & Teo KK (1987). Behaviour of canine pulmonary vagal afferent receptors during sustained acute pulmonary venous pressure elevation. J Physiol 394, 249–265.[Abstract/Free Full Text]

Kappagoda CT & Ravi K (1989). Plasmapheresis affects responses of slowly and rapidly adapting airway receptors to pulmonary venous congestion in dogs. J Physiol 416, 79–91.[Medline]

Kappagoda CT, Skepper JN, McNaughton L, Siew EE & Navaratnam V (1990). Morphology of presumptive rapidly adapting receptors in the rat bronchus. J Anat 168, 265–276.[Medline]

Keller VCJ & Loeser A (1930). Ueber die Bedeutung Muskelsinnesorgame fur die Lokomotion und reflektorische Hemmung. Zeitchrift Fur Biologie 89, 373.

Knowlton GC & Larrabee MG (1946). A unitary analysis of pulmonary volume receptors. Am J Physiol 147, 100–114.[Free Full Text]

Landis EM (1930). Microinjection studies of capillary blood pressure in human skin. Heart 15, 209–228.

McCormick KM, Bravo EM & Kappagoda CT (2005). Role of adrenergic receptors in the reflex diuresis in rabbits during pulmonary lymphatic obstruction. Exp Physiol 90, 341–347.[Abstract/Free Full Text]

Mashito Y, Ichinose M & Shirato K (1999). Bradykinin B2 antagonist HOE 140 inhibits late allergic microvascular leakage in guinea pig airways. Immunopharmacology 43, 249–253.[Medline]

Miller WS (1947). The Lung. Charles C. Thomas, Springfield, IL, USA.

Paintal AS (1973). Vagal sensory receptors and their reflex effects. Physiol Rev 53, 159–227.[Free Full Text]

Pietra GG, Szidon JP & Fishman AP (1972). Leaky pulmonary vessels. Trans Assoc Am Physicians 85, 369–376.[Medline]

Ravi K, Bonham AC & Kappagoda CT (1994). Effect of pulmonary lymphatic obstruction on respiratory rate and airway rapidly adapting receptor activity in rabbits. J Physiol 480, 163–170.[Medline]

Ravi K & Kappagoda CT (1990). Reflex effects of pulmonary venous congestion: role of vagal afferents. News Physiol Sci 5, 95–99.[Abstract/Free Full Text]

Ravi K, Teo KK & Kappagoda CT (1988). Stimulation of rapidly adapting pulmonary stretch receptors by pulmonary lymphatic obstruction in dogs. Can J Physiol Pharmacol 66, 630–636.[Medline]

Ravi K, Teo KK & Kappagoda CT (1989). Action of histamine on the rapidly adapting airway receptors in the dog. Can J Physiol Pharmacol 67, 1499–1505.[Medline]

Riccio MM, Myers AC & Undem BJ (1996). Immunomodulation of afferent neurons in guinea-pig isolated airway. J Physiol 491, 499–509.[Medline]

Sant'Ambrogio G & Widdicombe J (2001). Reflexes from airway rapidly adapting receptors. Respir Physiol 125, 33–45.[CrossRef][Medline]

Semple SR & Herd GW (1986). Cough and wheeze caused by inhibition of angiotensin converting enzyme. N Engl J Med 314, 61.[Medline]

Starling EH (1895). The production and absorption of lymph. In Textbook of Physiology, ed. Schaefer EA, chap. 1, pp. 285–311 Pentland, London.

Staub NC (1974). Pulmonary edema. Physiol Rev 54, 678–811.[Free Full Text]

Staub NC, Nagano H & Pearce ML (1967). Pulmonary edema in dogs, especially the sequence of fluid accumulation in lungs. J Appl Physiol 22, 227–240.[Free Full Text]

Uhley HN, Leeds SE, Sampson JJ & Friedman M (1960). Right duct lymph flow in dogs measured by a new method. Dis Chest 37, 532–534.[Medline]

Undem BJ & Carr MJ (2001). Pharmacology of airway afferent nerve activity. Respir Res 2, 234–244.[CrossRef][Medline]

Undem BJ, Carr MJ & Kollarik M (2002). Physiology and plasticity of putative cough fibres in the Guinea pig. Pulm Pharmacol Ther 15, 193–198.[CrossRef][Medline]

Wagner EM, Blosser S & Mitzner W (1998). Bronchial vascular contribution to lung lymph flow. J Appl Physiol 85, 2190–2195.[Abstract/Free Full Text]

Wagner EM, Mitzner W & Brown RH (1999). Site of functional bronchopulmonary anastomoses in sheep. Anat Record 254, 360–366.[CrossRef][Medline]

Widdicombe J (1954). Receptors in the trachea and bronchi of the cat. J Physiol 123, 71–104.[Free Full Text]

Widdicombe JG (1995). Neurophysiology of the cough reflex. Eur Resp J 8, 1193–1202.[Abstract]

Widdicombe JG (1999). Advances in understanding and treatment of cough. Monaldi Arch Chest Dis 54, 275–279.[Medline]

Widdicombe J (2003). Functional morphology and physiology of pulmonary rapidly adapting receptors (RARs). Anat Record 270, 2–10.[Medline]

Williams GW (1988). Converting enzyme inhibitors in the treatment of hypertension. N Engl J Med 319, 1517–1525.[Medline]





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expphysiol.2006.033209v1
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