Reflexes from airway rapidly adapting receptors.

Rapidly adapting receptors (RARs) occur throughout the respiratory tract from the nose to the bronchi. They have thin myelinated nerve fibres, an irregular discharge and adapt rapidly to a maintained volume stimulus, but often slowly to a chemical stimulus. They are polymodal, responding to mechanical and chemical irritant stimuli, and to many inflammatory and immunological mediators. RARs show very varied sensitivities to different stimuli, and diverse reflex responses. Those in the larynx are usually called 'irritant' receptors. They probably cause cough, the expiration reflex and other laryngeal reflexes: cardiovascular, mucus secretion, bronchoconstrictor and laryngoconstrictor. Those in the trachea and larger bronchi are very mechanosensitive; they cause cough, bronchoconstriction and airway mucus secretion. Those in the larger bronchi are more chemosensitive; they may cause cough, but also stimulate hyperventilation, augmented breaths, mucus secretion, bronchoconstriction and laryngeal closure. Most of the stimuli to RARs also affect other airway receptors, especially those with C-fibre afferents, and the total reflex response will be the additive affect of all these reflexes.

Vagal esophageal receptors in anesthetized dogs: mechanical and chemical responsiveness.

This study was performed to evaluate the characteristics of esophageal receptors in anesthetized and artificially ventilated dogs. The electrical activity of the esophageal afferents was recorded from the peripheral cut end of the cervical vagus nerve. A cuffed catheter was inserted into the esophagus at the level of the third tracheal ring and was used to establish the esophageal location of the endings. Most of the receptors were localized in the intrathoracic portion of the esophagus. The majority of the receptors studied (36 of 43) showed a slow adaptation to a maintained stretch of the esophageal wall. Vagal cooling blocked receptor activity at temperatures ranging from 3.5 to 25 degrees C. Twenty-eight of 43 receptors, including 4 rapidly adapting endings (RAR), were challenged with saline, HCl + pepsin (HCl-P; pH 1) and distilled water (8 ml, 37 degrees C). HCl-P solutions specifically stimulated only three receptors; saline or water did not. Five slowly adapting receptors and two RARs were also challenged with topically applied capsaicin; only one RAR was stimulated. To ascertain a possible effect of smooth muscle contraction, 17 receptors were tested with intravenous injections of ACh and/or asphyxia; only 4 were stimulated. These characteristics do not support an important reflexogenic role of the esophagus in response to chemical stimuli.

Larynx vs. esophagus as reflexogenic sites for acid-induced bronchoconstriction in dogs.

Bronchoconstriction in asthmatic patients is frequently associated with gastroesophageal reflux. However, it is still unclear whether bronchoconstriction originates from the esophagus or from aspiration of the refluxate into the larynx and larger airway. We compared the effect of repeated esophageal and laryngeal instillations of HCl-pepsin (pH 1.0) on tracheal smooth muscle activity in eight anesthetized and artificially ventilated dogs. Saline was used as control. We used pressure in the cuff of an endotracheal tube (Pcuff) as a direct index of smooth muscle activity at the level of the larger airways controlled by vagal efferents. The Pcuff values of the first 60 s after instillations were averaged, and the difference from the baseline values was evaluated. Changes in Pcuff were significantly greater with laryngeal than with esophageal instillations (P = 0.0166). HCl-pepsin instillation into the larynx evoked greater responses than did saline (P = 0.00543), whereas no differences were detected with esophageal instillations. Repeated laryngeal exposure enhanced the responsiveness significantly (P < 0. 001). Our data indicate that the larynx is more important than the esophagus as a reflexogenic site for the elicitation of reflex bronchoconstriction in response to acidic solutions.

Endotracheal cuff pressure as an index of airway smooth muscle activity: comparison with total lung resistance.

Pressure changes in the cuff of an endotracheal tube (Pcuff) were measured as an index of the tracheal smooth muscle activity and compared with total lung resistance (RL) in anesthetized, paralyzed and artificially ventilated dogs. After obtaining passive pressure-volume relationships of the cuff in situ, we activated the airway smooth muscle by electrical stimulation of the right vagus nerve, intravenous acetylcholine, and airway mechanical stimulation. The responses elicited by vagal stimulation and airway probing affected predominantly the tracheal smooth muscle, whereas acetylcholine administration caused homogeneous responses in Pcuff and RL, suggesting involvement of the smooth muscle of the entire airway. Pcuff cannot represent the whole airway smooth muscle activity, but it is more sensitive than RL for detecting vagally mediated smooth muscle responses. We conclude that the combination of Pcuff and RL may provide a better evaluation of smooth muscle response to various stimuli.

Asymmetry in reflex responses of nasal muscles in anesthetized guinea pigs.

Nasal reflexes elicited by mechanical or electrical stimulation of nasal afferents were studied in anesthetized guinea pigs. Probing the nasal cavity of one side evoked a greater activation of the contralateral than the ipsilateral nasal muscles and, occasionally, sneezing. Similarly, electrical stimulation of the ethmoidal nerve often caused sneezing, with a greater activation of the nasal muscles and a greater increase in resistance on the contralateral side. Asymmetrical activation of the nasal muscles in response to mechanical stimuli induces asymmetrical airflows, especially during sneezing, between the two sides of the nasal cavity. Most of the expired air is forcibly blown out through the ipsilateral nostril, thus improving the elimination of irritants from the nose.

Effects of HCl-pepsin laryngeal instillations on upper airway patency-maintaining mechanisms.

Gastroesophageal reflux has been indicated as an etiopathological factor in disorders of the upper airway. Upper airway collapsing pressure stimulates pressure-responsive laryngeal receptors that reflexly increase the activity of upper airway abductor muscles. We studied, in anesthetized dogs, the effects of repeated laryngeal instillations of HCl-pepsin (HCl-P; pH = 2) on the response of laryngeal afferent endings and the posterior cricoarytenoid muscle (PCA) to negative pressure. The effect of negative pressure on receptor discharge or PCA activity was evaluated by comparing their response to upper airway (UAO) and tracheal occlusions (TO). It is only during UAO, but not during TO, that the larynx is subjected to negative transmural pressure. HCl-P instillation decreased the rate of discharge during UAO of the 10 laryngeal receptors studied from 56.4 +/- 10.9 (SE) to 38.2 +/- 9.2 impulses/s (P < 0.05). With UAO, the peak PCA moving time average, normalized by dividing it by the peak values of esophageal pressure, decreased after six HCl-P trials from 4.29 +/- 0.31 to 2.23 +/- 0.18 (n = 6; P < 0.05). The responses to TO of either receptors or PCA remained unaltered. We conclude that exposure of the laryngeal mucosa to HCl-P solutions, as it may occur with gastroesophageal reflux, impairs the patency-maintaining mechanisms provided by laryngeal sensory feedback. Inflammatory and necrotic alterations of the laryngeal mucosa are likely responsible for these effects.

Action of moguisteine on the activity of tracheobronchial rapidly adapting receptors in the dog.

We have studied the effects of moguisteine, a new non-narcotic, peripherally acting antitussive compound, on tracheobronchial rapidly adapting irritant receptors (RARs). Experiments were carried out on dogs anaesthetized with a mixture of urethane and alpha-chloralose, paralysed with gallamine, vagotomized and artificially ventilated. Single unit action potentials identified as originating from tracheobronchial RARs were recorded from the peripheral cut end of the right vagus nerve. The activity of these receptors was recorded together with oesophageal pressure and arterial blood pressure. Fourteen RARs were challenged with moguisteine (200 microg x kg[-1] i.v.) in 0.4% dimethylsulphoxide (DMSO) or 0.4% DMSO alone (vehicle). Receptor activity was recorded before (control) and at 2, 5, 10, 15, 20, 30 and 45 min after administration of the challenging compounds. When the results at intervals of 2, 5, 10, 15 and 20 min were averaged for each dog, it was found that moguisteine decreased the mean activity of the 14 receptors to 75% of the control value (p<0.05); the greatest inhibition occurred 10-20 min after moguisteine administration. DMSO did not significantly affect the activity of these endings. Oesophageal pressure, arterial blood pressure and cardiac frequency were not altered during the experimental procedures. The overall results indicate the presence of an inhibitory effect of moguisteine on rapidly adapting irritant receptors that could account for the antitussigenic effect of this compound.

Activation of intrinsic laryngeal muscles during cough.

We studied the pattern of discharge of the posterior cricoarytenoid (PCA), cricothyroid (CT), thyroarytenoid (TA), and arytenoideus transversus (AR) muscles during cough in 12 anesthetized dogs. Diaphragm electromyographic (EMG) activity was also recorded, together with subglottic and esophageal pressures. Trains of repetitive coughs were induced by mechanically stimulating the tracheobronchial airway. Trials with the upper airway isolated from and connected to the lower airway were performed before and following bilateral sectioning of the internal branch of the superior laryngeal nerve (SLN). The immediate effect of tracheal stimulation was an "apneic" period at FRC, during which the PCA, a laryngeal abductor, showed a progressive increase in activity accompanied by small, variable increases in the activity of the CT and the laryngeal adductors, the TA and AR. The subsequent cough efforts were divided into three phases: inspiration, glottic narrowing, and forced expiration. PCA activity was greatest during the inspiratory phase and CT activity was greatest during the expiratory phase. Peak subglottic pressure occurred during glottic narrowing and coincided with the greatest activation of the TA and AR during the cough effort, and suppression of the PCA and CT. The patterns of EMG activation were not affected by the route of breathing or SLN section. The results suggest the presence of a uniquely central process controlling laryngeal muscles during cough, independent of laryngeal sensory feedback.

Effect of airway surface liquid composition on laryngeal muscle activation.

The effects of aerosolized distilled water and isosmolal dextrose in the isolated larynx on laryngeal muscle activity were studied in eight anesthetized dogs. Water aerosol was associated with an increase in peak posterior cricoarytenoid activity but no change in thyroarytenoid activity. Saline or isosmolal dextrose aerosols did not have any effect on the activity of either muscle. The reflex increase in posterior cricoarytenoid activity due to laryngeal negative pressure was enhanced when the negative pressure challenge was repeated following distilled water aerosol. The results suggest that alteration in laryngeal surface liquid composition modifies the response of pressure-responsive laryngeal receptors and, thereby, the reflex activation of airway patency maintaining muscles.

Role of laryngeal afferents in cough.

The superior laryngeal nerve (SLN) is the main source of laryngeal afferent activity. A clear respiratory modulation can be noted when recording from the peripheral cut end of this nerve in several mammalian species. This modulation is due to three types of sensory endings: cold, pressure and 'drive' receptors. Although respiratory-modulated receptors play an important role in the function of the upper airway, they are not generally viewed as a primary factor in the elicitation of cough. Other more likely candidates for this role are thought to be the so-called 'irritant' endings. These are receptors that do not discharge in close association with the breathing cycle, but are usually silent or randomly active in control conditions. However, they are promptly recruited when the laryngeal mucosa is exposed to mechanical and/or chemical irritation. In fact, these receptors respond to well recognized tussigenic stimuli and are therefore thought to provide the triggering mechanisms for the cough reflex from the larynx. Endings with similar characteristics are also found in the most proximal areas of the tracheo-bronchial tree. On the basis of their response to irritants, these receptors are identified under the common denomination of 'irritant receptors'. However, within this category of endings we find a wide range of distinctive characteristics, be this in terms of responsiveness to water solutions of various osmolarity and composition or to particular responses to substances produced within the body (autacoids) or experimentally administered.

Sensory information from the upper airway: role in the control of breathing.

The functional integrity of extrathoracic airways critically depends on the proper orchestration of the activities of a set of patency-maintaining muscles. Recruitment and control of these muscles is regulated by a laryngeal and trigeminal affects that originate from pressure sensing endings. These sensors are particularly numerous among laryngeal receptors and, indeed, they constitute the main element in the respiration-modulated activity of the superior laryngeal nerve. Considering that the most compliant region of the upper airway, and thus more vulnerable to inspiratory collapse, lies cranially to the larynx, the laryngeal pressure-sensing endings seem to be ideally located for detecting collapsing forces and initiating reflex mechanisms for the preservation of patency. This process operates by activating upper airway dilating muscles and by decreasing inspiratory drive: both actions limit t he effect of the collapsing forces. Cold reception is differently represented in various mammalian species within nasal and laryngeal segments. Cooling of the upper airway has an inhibitory influence on breathing, especially in newborns, and a depressive effect on upper airway dilating muscles. The latter response is presumably mediated through the inhibitory effect of cooling on laryngeal pressure endings. These responses could be harmful during occlusive episodes. Powerful defensive responses with distinct characteristics can be elicited through the simulation of laryngeal and nasal irritant type receptors. Sneezing is elicited through the stimulation of trigeminal afferents, cough through the stimulation of laryngeal vagal endings. Changes in osmolality and ionic composition of the mucosal surface liquid can lead to conspicuous alterations in receptor activity and related reflexes.

Effect of changes in airway surface liquid on laryngeal receptors and muscles.

The effects of aerosolizing distilled water and isosmolal dextrose in the isolated larynx on the activity of pressure-responsive receptors and laryngeal muscles were studied in anesthetized dogs. Following water aerosolization, the mean discharge of pressure-responsive laryngeal mechanoreceptors during upper airway breathing and occlusion was 151% and 138% respectively of that present after saline aerosolization. During delivery of water aerosol, the peak activity of the posterior cricoarytenoid muscle increased to 229 +/- 56% of control; no effects were present on the thyroarytenoid muscle activity. Saline or isosmolal dextrose aerosols did not have any effect on the activity of either muscle. The reflex increase in posterior cricoarytenoid muscle activity due to laryngeal negative pressure was enhanced (163%) when the negative pressure challenge was repeated following distilled water aerosol. These results suggest that alteration in laryngeal surface liquid composition modifies the response of pressure-responsive laryngeal receptors and thereby the reflex activation of airway patency maintaining muscles.

Laryngeal and tracheobronchial cough in anesthetized dogs.

Tussigenic sensitivity of laryngeal and tracheobronchial regions to mechanical and chemical stimuli was compared in 22 urethan-alpha-chloralose-anesthetized dogs. In addition, the contribution of myelinated and unmyelinated vagal fibers in mediating laryngeal and tracheobronchial cough was investigated. The intensity of cough was evaluated from changes in esophageal pressure. Whereas all mechanical stimulations and citric acid inhalations into tracheobronchial region elicited cough, only 56.7% of mechanical stimulation and 33.3% of citric acid challenges to larynx were effective. The intensity of tracheobronchial cough was significantly higher than that of laryngeal cough. When mechanical stimulation was conducted under visual control (bronchofiberscope), cough elicitability was found to be higher from tracheal bifurcation and main stem bronchi (62.5-87.5%) than from any laryngeal structure (0-42.9%). During partial block of vagal conduction (cooling to 6 degrees C), mechanical and citric acid tracheobronchial stimulations failed to elicit cough and mechanical laryngeal stimulation was effective only in 1 of 10 dogs. Intensity of cough was strongly decreased when mechanical stimulation followed capsaicin administration into trachea (0.3 ml; 100 micrograms/ml) or intravenously (10 micrograms/kg). We conclude that, in anesthetized dogs, stimulation of tracheobronchial region is more effective and prompt in eliciting cough than stimulation of larynx, myelinated vagal afferent fibers play an important role in mediating mechanically and citric acid-induced tracheobronchial cough and mechanically induced laryngeal cough, and stimulation of tracheobronchial and pulmonary capsaicin-sensitive receptors strongly inhibits mechanically induced cough.

Responses of tracheobronchial receptors to halothane, enflurane, and isoflurane in anesthetized dogs.

We investigated the effects of halothane, enflurane, and isoflurane on the activity of 43 tracheobronchial slowly adapting stretch receptors (SARs) and 16 rapidly adapting irritant receptors (RARs) in 5 anesthetized, vagotomized, paralyzed, and artificially ventilated dogs. The 43 SARs were classified into 2 subtypes: (i) 17 low-threshold SARs with an expiratory discharge at FRC that were active throughout the respiratory cycle and (ii) 26 high-threshold SARs active only in inspiration. Ventilating the lungs with 5% of each anesthetic caused a significant increase in the inspiratory discharge of low-threshold SARs, whereas the expiratory discharge was inhibited or altogether silenced. While the activity of the majority of high-threshold SARs increased during the administration of the three volatile anesthetics, it decreased in those with a particularly high recruitment threshold. There was, however, a consistent increase in the pressure threshold at which all SARs were recruited. Ventilating the lungs with 5% of each anesthetic caused a significant decrease in activity of RARs. Our results indicate that all three halogenated anesthetics inhibit RARs at concentrations ranging from 1% to 5%.

Cardiorespiratory responses elicited by right atrial injections of iodinated contrast media. Comparative evaluation of four agents.

RATIONALE AND OBJECTIVES: The purpose of this study is three-fold: 1) to quantify the cardiorespiratory responses to rapid right atrial injections of meglumine/sodium diatrizoate, ioxaglate, iotrolan, and iopamidol; 2) to compare the effects of each contrast medium to that of its corresponding vehicle and saline; and 3) to evaluate the role of the vagus nerve in the cardiorespiratory responses. METHODS: Seventeen anesthetized dogs, breathing spontaneously, were used. Injections of 2.0 mL/kg were given into the right atrium in 2 seconds. Each contrast medium, along with its vehicle and saline, was tested on 4 dogs (5 dogs for diatrizoate). Blood pressure, air flow, tidal volume, upper airway pressure, esophageal pressure, mean arterial pressure and heart rate, breathing frequency, dynamic lung compliance, upper airway resistance, and total lung resistance were recorded or calculated. RESULTS: Diatrizoate and its vehicle caused a significant increase in blood pressure, tidal volume, esophageal pressure, and a decrease in mean arterial pressure with an increase in heart rate. These responses were not mediated by vagal afferents. Ioxaglate and iotrolan, but not their vehicles, increased breathing frequency; this response was abolished by vagal block. Ioxaglate decreased mean arterial pressure and increased heart rate; the decrease in mean arterial pressure was still present during vagal block. Iopamidol and its vehicle did not alter respiratory parameters. Iopamidol, but not its vehicle, caused only a minimal and transient increase in mean arterial pressure before and during vagal block. None of the contrast media changed upper airway resistance, total lung resistance, and dynamic lung compliance. CONCLUSION: Both diatrizoate and its vehicle elicited the largest changes in respiratory and cardiovascular functions, not mediated by vagal afferents and caused by osmolality of the solution. Ioxaglate, iotrolan, and iopamidol induced smaller cardiorespiratory changes, mediated by vagal afferents. Their respective vehicles did not cause any effects, which suggests that the chemical structure plays a role. Nonionic contrast media elicited only minor and transient cardiorespiratory alterations.

Effect of furosemide on the response of laryngeal receptors to low-chloride solutions.

Laryngeal irritant receptors are stimulated by water and solutions lacking chloride ions, such as isotonic dextrose. It has been reported that furosemide (frusemide) reduces cough evoked by inhalation of low-chloride solutions. We studied the effect of furosemide on the response of laryngeal receptors to isotonic dextrose. Experiments were performed on nine dogs anaesthetized, spontaneously breathing through a tracheostomy, and with the upper airway functionally isolated. We recorded the activity of 13 laryngeal irritant receptors. Isotonic dextrose (4 ml) was instilled into the laryngeal lumen, before and after administration of a furosemide solution (3.75 mg.ml-1) into the upper airway. Before furosemide, dextrose increased the activity of the 13 receptors from 1.0 +/- 0.5 to 25.0 +/- 3.5 impulses (imp).s-1 (average discharge in the first 10 s of activation) and, 1-2 min after furosemide, from 0.3 +/- 0.2 to 13.4 +/- 3.2 imp.s-1; the difference between the stimulation by dextrose before and after furosemide was statistically significant. In contrast, the response to distilled water of four respiratory-modulated mechano-receptors (known to be activated by low-osmolality solutions) was not modified by furosemide. These results suggest that the furosemide-mediated inhibition of cough induced by inhalation of low-chloride solutions is, at least in part, due to the inhibitory effect of this substance on irritant receptor stimulation.

Respiratory and cardiovascular effects of inhaled and intravenous bradykinin, PGE2, and PGF2 alpha in dogs.

Prostaglandins (PGs) and bradykinin act as potent respiratory irritants in both normal and asthmatic subjects, but their sites of action are unknown. We compared the cardiorespiratory effects of bradykinin, PGE2, and PGF2 alpha nebulized into the isolated "in situ" larynx, inhaled into the tracheobronchial tree, and injected intravenously in anesthetized spontaneously breathing dogs. Laryngeal administration only resulted in a brief burst of rapid shallow breaths produced by bradykinin (1,000 micrograms/ml) in one of five dogs. Tracheobronchial administration of bradykinin (1,000 micrograms/ml) increased breathing rate and tidal volume (VT) in four of seven dogs without changing cardiovascular parameters, whereas PGE2 (500 micrograms/ml) caused similar effects in two of six dogs. Lower concentrations of both agents were essentially without effect. PGF2 alpha (50-500 micrograms/ml) inhaled into the lower airway increased breathing rate, reduced VT, and caused a concentration-dependent bronchoconstriction that was significantly reduced by atropine. Inhaled PGF2 alpha only slightly increased arterial blood pressure (5.8 +/- 2.8%) and heart rate (12.0 +/- 6.4%). Intravenous PGF2 alpha (5 micrograms/kg) increased upper and lower airway resistances, which were accompanied by a decrease in breathing rate and VT, hypertension, and bradycardia. Bradykinin (1 micrograms/kg) and PGE2 (1 and 3 micrograms/kg) produced apnea followed by rapid shallow breathing, bradycardia, and hypotension. These results indicate that the tracheobronchial tree is considerably more responsive to aerosolized bradykinin, PGE2, and PGF2 alpha than the laryngeal region. Moreover, the stronger effects produced by intravascular administration suggest a greater accessibility of rapidly adapting stretch receptors and C-fiber endings from the vascular bed than from the airway lumen.