Rapidly Adapting Pulmonary Stretch Receptors Research Articles

Modeling rapidly adapting pulmonary stretch receptor activity to step-wise and constant pressure inflation of the lungs

Rapidly-adapting pulmonary stretch receptors (RAPSRs) provide the central nervous system with information regarding the rate of lung inflation, lung compliance and the sensation of dyspnea. Other than satisfying parameters of an adaptation index to constant pressure lung inflation for identification, no mathematical model has been ascribed to the stimulus-response relationship of lung volume-pressure to RAPSR activity. Herein, linear, power, polynomial and non-linear (four parameters logistic) models are tested for the best “goodness of fit” line of RAPSR activity to step-wise lung inflation to four times tidal volume and constant pressure inflation to 10, 20, 30 and 40 cm H2O of the lungs of guinea pigs and dogs. Goodness of fit was determined by evaluating coefficient of determination (R2) and visual inspection. The best “goodness of fit” is one of a non-linear symmetrical, stimulus-response function.

Effects of prolonged lung inflation or deflation on pulmonary stretch receptor discharge in the alligator (Alligator mississippiensis)

The American alligator (Alligator mississippiensis) is a semi-aquatic diving reptile that has a periodic breathing pattern. Previous work identified pulmonary stretch receptors, that are rapidly and slowly adapting, as well as intrapulmonary chemoreceptors (IPC), sensitive to CO2, that modulate breathing patterns in alligators. The purpose of the present study was to quantify the effects of prolonged lung inflation and deflation (simulated dives) on pulmonary stretch receptors (PSR) and/or IPC discharge characteristics. The effects of airway pressure (0–20cm H2O), hypercapnia (7% CO2), and hypoxia (5% O2) on dynamic and static responses of PSR were studied in juvenile alligators (mean mass=246g) at 24°C. Alligators were initially anesthetized with isoflurane, cranially pithed, tracheotomized and artificially ventilated. Vagal afferent tonic and phasic activity was recorded with platinum hook electrodes. Receptor activity was a mixture of slowly adapting PSR (SAR) and rapidly adapting PSR (RAR) with varying thresholds and degrees of adaptation, without CO2 sensitivity. Receptor activity before, during and after 1min periods of lung inflation and deflation was quantified to examine the effect of simulated breath-hold dives. Some PSR showed a change in dynamic response, exhibiting inhibition for several breaths after prolonged lung inflation. Following 1min deflation, RAR, but not SAR, exhibited a significant potentiation of burst frequency relative to control. For SAR, the post-inflation receptor inhibition was blocked by CO2 and hypoxia; for RAR, the post-inflation inhibition was potentiated by CO2 and blocked by hypoxia. These results suggest that changes in PSR firing following prolonged inflation and deflation may promote post-dive ventilation in alligators. We hypothesize that PSR in alligators may be involved in recovery of breathing patterns and lung volume during pre- and post-diving behavior and apneic periods in diving reptiles.

Henry Head and his paradoxical reflex.

Henry Head and his paradoxical reflex.

Effects of potassium channel blockers on hyperinflation-induced rapidly adapting pulmonary stretch receptor stimulation in the rabbit

The effects of K + channel blockers, such as 4-aminoprydine (4-AP) and tetraethylammonium (TEA), on the excitatory responses of rapidly adapting pulmonary stretch receptor (RAR) activity to hyperinflation (inflation volume=3 tidal volumes) were investigated in anesthetized, artificially ventilated rabbits after vagus nerve section. The changes in the RAR adaptation index (AI) produced by constant-pressure (approximately 30 cmH 2O, 29.7±0.2 cmH 2O) inflation of the lungs were also examined before and after pretreatment with 4-AP and TEA. The administration of 4-AP (0.7 and 2.0 mg/kg) potentiated hyperinflation-induced RAR stimulation in a dose-dependent manner. During hyperinflation after 2.0 mg/kg 4-AP administration the discharge of RARs showed a relatively regular firing pattern in both inflation and deflation phases. The RAR AI values during constant-pressure inflation of the lungs were significantly reduced by 4-AP treatment (2.0 mg/kg). TEA treatment (2.0 and 7.0 mg/kg) did not significantly alter either the excitatory response of RAR activity to hyperinflation or the RAR AI values seen during constant-pressure inflation of the lungs. These results suggest that during hyperinflation in in vivo experiments on rabbits, RARs may be maintained at a lower activity by opening the 4-AP-sensitive K + channels on the receptor endings, which can determine accommodation of the receptor discharge.

Morphology of pulmonary rapidly adapting receptor relay neurons in the rat.

The term rapidly adapting pulmonary stretch receptor (RAR) refers to one of the major pulmonary sensory receptors that responds to inflation and deflation of the lungs as well as to irritant stimuli with rapidly adapting irregular discharges. The functional role and central pathways are largely unknown. The aim of this study was to elucidate morphological characteristics of second-order neurons (RAR cells) activated by vagal afferent fibers originating from RARs. A mixture of horseradish peroxidase (HRP) and Neurobiotin was injected intracellularly into physiologically identified RAR cells in Nembutal-anesthetized, immobilized, and artificially ventilated Wister rats. Direct visualization of individual RAR cells (n = 12), including their somata, dendritic arborizations, and fine axonal branches with terminal boutons, was possible for the first time. Their somata were located in the commissural or medial subdivision of the nucleus of the solitary tract, caudal to the level of the area postrema. The RAR cells had, in addition to dendrites extending into the NTS area, one or two long dendrites extending laterally and/or ventrolaterally into the medullary reticular formation. The stem axons issuing from the RAR cells first coursed ventrolaterally toward the reticular formation in the vicinity of the ambiguus nucleus and then bifurcated into ascending and descending axons: three RAR cells possessed only ascending axons. Some of the ascending axons could be traced as far as the level of the facial nucleus and some of the descending axons beyond the spinomedullary junction. These ascending and/or descending axons gave off extensive axon collaterals distributing boutons within and in the vicinity of the ambiguus nucleus. These results, showing an anatomical substrate for the network implicated in RAR-evoked reflexes, provide useful clues for study of the RAR system.

Identification of deflation-sensitive inspiratory neurons in the dorsal respiratory group of the rat

It has been well established that inspiratory neurons of the dorsal respiratory group (DRG) are classified into two types based on whether they receive inputs from slowly-adapting pulmonary stretch receptors (SARs) or not. Inspiratory neurons with SAR inputs are called Iβ and the others are called Iα neurons. In this study, we identified a novel group of inspiratory neurons in Nembutal-anesthetized, paralyzed, and artificially-ventilated rats. (1) These DRG inspiratory neurons were activated characteristically by lung deflation. (2) They were orthodromically activated by electrical stimulation of the vagus nerve at a low intensity just above the threshold for afferents from SARs or rapidly-adapting pulmonary stretch receptors (RARs). (3) The orthodromic latencies (ranged from 1.9 to 2.5 ms) indicated that they receive direct inputs from low-threshold vagal afferents. (4) Unlike Iβ neurons, they hardly responded to lung inflation and never exhibited tonic firing in response to maintained lung inflation. (5) The majority (92%) of them were antidromically activated by electrical stimulation of the cervical spinal cord. These deflation-sensitive inspiratory neurons clearly form a distinct group, and their firing pattern is consistent with the hypothesis that they receive inputs from RAR afferents as well as the central inspiratory drive. The results indicating that DRG inspiratory neurons are classified into at least three groups provide new insights into the organization and role of the DRG.

The cough reflex and its relation to gastroesophageal reflux

Each cough involves a complex reflex arc beginning with the stimulation of sensory nerves that function as cough receptors. There is evidence, primarily clinical, that the sensory limb of the reflex exists in and outside of the lower respiratory tract. Although myelinated, rapidly adapting pulmonary stretch receptors (RARs), also known as irritant receptors, are the most likely type of sensory nerve that stimulates the cough center in the brain, afferent C-fibers and slowly adapting pulmonary stretch receptors (SARs) also may modulate cough. RARS, C-fibers, and SARs have been identified in the distal esophageal mucosa; however, studies have not been performed to determine whether they can participate in the cough reflex. Although gastroesophageal reflux disease can potentially stimulate the afferent limb of the cough reflex by irritating the upper respiratory tract without aspiration and by irritating the lower respiratory tract by micro- or macroaspiration, there is evidence that strongly suggests that reflux commonly provokes cough by stimulating an esophageal–bronchial reflex. Theoretically, the pathways of this reflex may be modeled in a variety of ways, and these are speculated upon in this article. The predominant role of acid in triggering cough by means of this reflex is unclear because of conflicting results from provocative challenge studies. It is interesting to speculate that a distal esophageal–bronchial reflex evolved as an early warning defense so that coughing could be started, just in case the refluxate were to reach the inlet of the lower respiratory tract. That is, thinking teleologically, it is possible that an esophageal–bronchial reflex evolved as one of several mechanisms designed to protect the lungs from aspiration of gastric contents.

Interaction of vagal lung afferents with inhalation of histamine aerosol in anesthetized dogs.

In seven alpha-chloralose anesthetized dogs we examined the contribution of lung afferents to the rapid, shallow breathing induced by inhalation of 10 breaths of histamine aerosol. In four spontaneously breathing dogs, the inhalation of histamine caused an increased respiratory frequency, decreased tidal volume, and decreased dynamic lung compliance. Selective blockade of pulmonary C-fibers abolished a reflex-induced increase in respiratory frequency but did not significantly affect the reductions in tidal volume or lung compliance. Terbutaline treatment in combination with C-fiber blockade abolished the reductions in tidal volume and lung compliance induced by histamine. In three separate alpha-chloralose anesthetized, open-chest, mechanically ventilated dogs, we recorded an increase in the inspiratory activity of rapidly adapting pulmonary stretch receptors (RARs) induced by the inhalation of histamine aerosol. Selective C-fiber blockade abolished histamine-induced increases in RAR activity while only partially attenuating reductions in lung compliance. We conclude that the increase in RAR activity induced by histamine depends on intact C-fibers and not on a direct effect of histamine on RARs or an indirect effect of histamine reducing lung compliance. In addition, our data illustrate the multiple interactions that occur between the various vagal afferents and their roles in the reflexes induced by histamine inhalation.

Cough in motor neuron disease: a review of mechanisms.

For patients with neuromuscular diseases which affect breathing and swallowing, coughing and choking are frightening and distressing symptoms sometimes perceived (correctly) as life-threatening. Cough is an important function of the larynx and respiratory system which allows an individual to clear the airway of foreign material and secretions and prevent aspiration of food and fluid. Choking is the feeling of strangulation or suffocation which may result from the presence of foreign material in the airway, often accompanied by airway obstruction so that there is an inability to draw breath. Motor neuron disease (MND) is a progressive degenerative disorder of the nervous system affecting the anterior horn cells of the spinal cord, the motor nuclei of the brain stem, and the corticospinal tracts. For MND patients, airway obstruction, aspiration and pneumonia are major causes of morbidity and mortality; episodes of coughing and choking are commonly reported by patients, and presumably represent episodes of decompensation of bulbar and respiratory mechanisms as progressive dysfunction develops. Such patients have, on the one hand, an increased need to cough but, on the other, a reduced capacity to do so effectively. To try to develop a clearer clinical approach to dealing with these symptoms, we review some aspects of cough and, subsequently, its pathophysiology in MND. The cough reflex is divided into three main elements: the sensory limb, the central control, and the efferent limb (Figure 1). Figure 1. The cough reflex. ### Sensory limb The epithelium of the larynx, trachea, and larger bronchi contains sensory nerves that are responsible for triggering cough. There are two main categories of cough receptors: the rapidly-adapting pulmonary stretch receptors (RAR) with small-diameter myelinated fibres, and the pulmonary and bronchial C fibre receptors with non-myelinated afferent fibres.1 The pattern of cough depends on the stimulus and on the part of the respiratory tract stimulated. Receptors … Dr S. Hadjikoutis, Department of Neurology, University Hospital of Wales, Heath Park, Cardiff CF4 4XN

Inspiratory inhibition of pulmonary rapidly adapting receptor relay neurons in the rat

Second-order relay neurons (referred to as rapidly adapting pulmonary stretch receptors (RARs)-cells) activated by vagal afferents originating from RARs were identified electrophysiologically in Nembutal-anesthetized, paralyzed and artificially ventilated rats. Their location in the commissural subnucleus of the nucleus tractus solitarii (NTS) and firing properties in response to lung inflations and deflations were studied in detail for the first time in the rat. Importantly, in all the RAR-cells examined, their firing was suppressed to various extent during a period from inspiration to early expiration. This means that the information from the RARs to the central nervous system is gated by the central respiratory system at the level of RAR-cells in the NTS.

EFFECTS OF SUSTAINED CONSTANT ARTIFICIAL VENTILATION ON RAPIDLY ADAPTING PULMONARY STRETCH RECEPTORS AND LUNG MECHANICS IN RABBITS

After hyperinflation to produce maximal dynamic lung compliance (Cdyn), the effects of artificial ventilation at constant frequency (f) and tidal volume (V T) for over a 2-hour period on rapidly adapting pulmonary stretch receptor (RAR) activity and lung mechanics were investigated in anesthetized rabbits. At a 20 min from maximal Cdyn the RARs began to significantly increase their activity, and this increase coincided with the increase in tracheal pressure (P T). Afterward, the increases in RAR activity and P T developed more slowly. Throughout the sustained constant artificial ventilation, the values of V T and respiratory airflow were not significantly different from controls. At 2 hours after maximal Cdyn, atropine (2 mg/kg) did not significantly alter either the increases in RAR activity and total lung resistance (R L) or the decrease in Cdyn, but hyperinflation reverted those responses to the control levels. These results suggest that the sustained artificial ventilation increases lung stiffness to invariably stimulate RARs, but that the response is not involved in vagally mediated bronchoconstriction.

Effects of vagal and carotid chemoreceptor afferents on the frequency and pattern of spontaneous augmented breaths in rabbits.

We investigated the effects of vagal afferents and carotid chemoreceptors on the frequency and pattern of spontaneous augmented breaths in anesthetized rabbits by analyzing the changes in the phrenic nerve discharge. Blockade of vagal C-fiber conduction by capsaicin treatment greatly reduced the frequency of spontaneous augmented breaths but had no significant effect on the pattern of the augmented breaths. Inhalation of sulfur dioxide, which abolished the Hering-Breuer inflation reflex, suppressed the frequency of spontaneous augmented breaths but did not significantly alter the pattern of the augmented breaths. Carotid sinus denervation diminished both the frequency and amplitude of spontaneous augmented breaths. The occurrence of spontaneous augmented breaths was not observed in rabbits after bilateral vagotomy. In other experiments we examined the relationship between rapidly adapting pulmonary stretch receptors (RARs) and dynamic lung compliance during the spontaneous augmented breath. The stimulation of RARs occurred at the first phase of spontaneous augmented breaths, and augmentation of transpulmonary pressure seen at the second phase coincided with vigorous stimulation of the receptor activity. These results suggest that spontaneous augmented breaths may be mediated by the summation of several facilitatory inputs from vagal and carotid chemoreceptor afferents.

The response of rapidly adapting pulmonary stretch receptors elicited by sodium cyanide is augmented by vagotomy in the rabbit

The responses of rapidly adapting pulmonary stretch receptor (RAR) activity, tidal volume ( V T), inspiratory airflow ( V I), transpulmonary pressure ( P trans) and dynamic lung compliance ( C dyn) to administration of NaCN (20 and 40 μg/kg) were compared before and after vagal section in anesthetized, spontaneously breathing rabbits. The responses of RARs were recorded from a partially dissected branch of the left vagus nerve (LVN). Before vagal section, hyperpnea following NaCN administration led to increases in RAR activity, V T, V I and P trans, but caused a decrease in C dyn. Those responses obtained became more prominent by increasing the dose of NaCN. Under these conditions the increased receptor activity fired throughout the whole respiratory cycle. The responses of RAR activity, V T and P trans to NaCN administration were augmented by a vagal section that was produced by denervating the rest of the LVN still intact and right vagus nerve, and the discharge of receptors showed a predominantly inspiratory pattern that corresponded to augmentation of both P trans and V T. Vagal section, however, had no significant effect on the changes of V I and C dyn induced by NaCN. In addition, mean percent changes of increased V T and P trans produced by NaCN administration after vagal section were similar to those before vagal section. Furthermore, augmentation of V T and elevation in baseline V T, when NaCN after bilateral vagotomy was administered i.v., were preceded by simultaneously increased P trans and RAR activity. These results suggest that augmentation of NaCN-induced RAR stimulation in animals without intact vagus nerves is related to concomitant changes in the respiratory mechanics such as P trans and V T, probably involving the increased sensitivity of receptors to these two factors.

Effects of thromboxane A2 agonist STA2 on rapidly adapting pulmonary stretch receptors in vagotomized rabbits.

We investigated the responses of rapidly adapting pulmonary stretch receptors (RARs) and tracheal pressure (PT) to right atrial injections of the thromboxane A2 (TXA2) stable analogue STA2 (0.3, 1.0, and 3.0 microgram/kg) before and after administration of atropine sulfate (1 mg/kg), isoprenaline (200 micrograms/kg), indomethacin (1 mg/kg), or S-145 (0.5 mg/kg) in artificially ventilated, bilaterally vagotomized rabbits. The RARs increased their activity after STA2 administration, and the increase was dose-dependent. However, intraatrial injections of STA2 at all the doses examined had no significant effect on PT. The excitatory responses of RAR activity to STA2 (0.3-3.0 micrograms/kg) were not significantly altered by administration of atropine sulfate (anticholinergic agent), isoprenaline (bronchodilator), or indomethacin (cyclooxygenase inhibitor). However, S-145 treatment (TXA2 antagonist) blocked the STA2-induced RAR stimulation. To determine whether or not administration of STA2 causes release of acetylcholine (ACh), we also examined the effects of vagal efferent stimulation (10-15 V, 10 Hz, 1 ms), STA2 administration (3.0 micrograms/kg), and their combination on PT in rabbits associated with both artificial ventilation and bilateral vagotomy. The vagally mediated bronchoconstriction that led to an increase in PT was not enhanced by simultaneous administration of STA2 at 3.0 micrograms/kg in all of the tested animals. These results suggest that the stimulation of RARs by STA2 is not mediated by the release of ACh from the nerve endings but is probably due to a local inflammatory bronchoconstriction that does not significantly alter the value of PT.

Effects of veratridine and nifedipine on ammonia-induced rapidly adapting pulmonary stretch receptor stimulation in vagotomized rabbits

We studied the effects of aerosol administration of veratridine (a sodium channel opener) or nifedipine (a calcium channel blocker) on the responses of rapidly adapting pulmonary stretch receptors (RARs) and dynamic lung compliance (Cdyn) to aerosols of 2 and 4% ammonia solutions in anesthetized spontaneously breathing rabbits without intact vagi. The RARs increased their activity following ammonia aerosol, and the increase was concentration-dependent. However, ammonia aerosol did not significantly alter the value of Cdyn. The RARs following aerosol administration of veratridine (about 200 μg) showed their characteristic firing pattern with several phases; each phase was characterized by the long high-frequency continuous discharges. Under these conditions, the response was not associated with any significant change in Cdyn. Even though the change in receptor activity produced by veratridine was restored to control level, subsequent aerosol application of ammonia led to similar firing patterns, as veratridine was given by aerosol, but had no significant effect on Cdyn. Following aerosol administration of nifedipine (about 1 and 2 mg) the RAR activity and Cdyn were similar to those during control. Furthermore, the ammonia-induced RAR stimulation was not significantly affected by nifedipine aerosol. These results suggest that the stimulation of RARs by ammonia in vagotomized rabbits is independent of changes in Cdyn and speculate that their excitatory effect is at least in part related to the activation of Na + influx to the receptive terminals but is not involved in the secondary entry of Ca 2+ ions to the receptor membrane, through voltage-dependent calcium channels.

Substance P antagonist does not block the stimulation of rapidly adapting pulmonary stretch receptors by ammonia.

We investigated the effects of the substance P (SP) blocker [D-Pro2,D-Trp7,9]-SP on the response of rapidly adapting pulmonary stretch receptors (RARs) to SP administered into the right atrium, or ammonia vapor inhaled into the lungs in anesthetized, spontaneously breathing rabbits. Right atrial administration of SP (0.3, 1.0, and 3.0 micrograms/kg) caused an increase in the RAR activity, and this increase became more prominent as the dose of SP was increased. The RARs increased their activity following inhalation of vapor from 5 and 10% ammonia solutions, and the increase was concentration dependent. The excitatory responses of RAR activity to SP at different doses were greatly diminished or completely blocked by administration of the selective SP antagonist (300 and 500 micrograms/kg). However, the ammonia-induced RAR stimulation was not significantly altered by prior treatment with the SP blocker (300 and 500 micrograms/kg). These results suggest that the stimulation of RARs by ammonia does not occur as a result of the release of SP from sensory nerves in the airways and lungs.

Effects of atropine on the responses of rapidly adapting pulmonary stretch receptors and dynamic lung compliance to sodium cyanide-induced hyperpnea

The responses of tracheal pressure (P T) and heart rate (HR) to electrical stimulation of the peripheral cut-ends of the vagus nerves (10–15 V, 10 Hz, 1 ms) to activate both myelinated and non-myelinated fibers were examined before and after administration of atropine (1 mg/kg) in artificially ventilated, bilaterally vagotomized rabbits. Vagal stimulation caused an increase in P T and a decrease in HR. The P T response to vagal stimulation was completely blocked by atropine which significantly reduced the bradycardia evoked by the stimulation. In other series of experiments, we also examined the responses of rapidly adapting pulmonary stretch receptors (RARs) and dynamic lung compliance (Cdyn) to intravenous injections of sodium cyanide (NaCN, 20 and 30 μg/kg) before and after administration of atropine (1 mg/kg) in spontaneously breathing rabbits with vagal efferent activities. Administration of NaCN led to an increase in RAR activity associated with a decrease in Cdyn, and these two effects became more prominent by increasing the dose of NaCN. Atropine treatment did not significantly alter the responses of RARs and Cdyn to the injections of NaCN with different doses. These results suggest that the changes of RAR activity and Cdyn produced by hyperpnea due to NaCN administration are not influenced by the vagally mediated bronchoconstriction.

H 1- and H 2-receptor influences of histamine and ammonia on rapidly adapting pulmonary stretch receptor activities

Studies were designed to establish the difference of the excitatory mecha- nisms between histamine and ammonia on rapidly adapting pulmonary stretch receptors (RARs). We therefore examined the responses of RARs to histamine administered as an aerosol and amminia inhaled as a vapor before and after aerosol administration of mequitazine or cimetidine in spontaneously breathing rabbits. The excitatory responses of RARs to aerosols of histamine at different concentrations were completely blocked by administration of aerosol mequitazine but potentiated by aerosol cimetidine. However, the increases of RAR activity produced by inhalation of ammonia vapor at different concentrations were not significantly affected by aerosol administration of either a H 1-receptor blocker or a H 2-receptor antagonist. These results suggest that the stimulation of RARS by aerosol histamine occurs as a result of the interaction between H 1 (excitatory)- and H 2 (inhibitory)-receptor effects, whereas these two receptor effects do not contribute to the ammonia-induced RAR stimulation.

Influences of Lung Mechanoreceptors and Carotid Chemoreceptors on the Response of Respiratory Muscle Activity to Tracheal Occlusion.

We examined the responses of respiratory muscle electromyograms (EMGs) from internal (IIC) and external intercostal (EIC) muscles and diaphragm (DIAP) to three successive occluded breaths in anesthetized spontaneously breathing rabbits. Both inspiratory and expiratory muscle EMGs progressively increased in the course of tracheal occlusion. An increase in these muscle EMGs was still observed after release of tracheal occlusion, but those effects were short-lasting. In a separate series of experiments, for assessment of possible reflex effects involved, the responses of slowly adapting pulmonary stretch receptor (SAR), rapidly adapting pulmonary stretch receptor (RAR), and carotid chemoreceptor activities to tracheal occlusion lasting for three respiratory efforts were also examined. The inspiratory discharge of SARs decreased but the expiratory discharge of SARs increased during tracheal occlusion. Although carotid chemoreceptors increased their activity in the latency of 3-6s after the onset of tracheal occlusion, the activity of RARs was greatly reduced throughout the period of tracheal occlusion. A transient increase in both carotid chemoreceptors and RARs was still observed after release of tracheal occlusion. These results suggest that alterations of inspiratory and expiratory muscle EMGs produced by tracheal occlusion would appear to be mediated by the afferent inputs from lung mechanoreceptors and carotid chemoreceptors.

Effects of ammonia and histamine on lung irritant receptors in the rabbit

The effects of ammonia and histamine on the responses of rapidly adapting pulmonary stretch receptor (RAR) activity before and after administration of isoprenaline or atropine were studied in spontaneously breathing rabbits. Inhalation of vapor from 15% ammonia solution increased the activity of RARs and this increased activity was not significantly altered by isoprenaline (50 μg/kg) or atropine (0.3 mg/kg). The RARs increased their activity following intravenous injections of histamine (20, 40 and 60 μg/kg). The excitatory responses to histamine at different doses were blocked by prior treatment with isoprenaline (50 μg/kg). In 8 of the tested 11 different RAR preparations on 11 rabbits, atropine (0.3 mg/kg) greatly diminished the increases of RAR activity produced by histamine at different doses. These results suggest that the ammonia-induced RAR stimulation results in a direct action of the endings whereas the activation of RARs by histamine is probably due to the combined influence of both local airway constriction and postganglionic parasympathetic pathway-mediated bronchoconstriction.