Slowly Adapting Pulmonary Stretch Receptors Research Articles

Airway Deflation Activated Receptors Are Stimulated by Hypertonic Saline

Recently, deflation activated receptors (DARs) in the lung have been identified as a group of airway sensory receptors. DARs often share their afferents with rapidly adapting receptors (RARs) as well as slowly adapting pulmonary stretch receptors (SARs) to form a sensory unit. However, the afferent properties of DARs have not been well characterized. It has been reported that airway RAR units are stimulated, whereas typical SAR units (units do not respond to lung deflation) are not stimulated by hypertonic saline. Since RAR units are often share afferents with DARs, possibly, it is the DARs that are stimulated by hypertonic saline. The present study determines whether DARs can be stimulated by increased osmolarity. In anesthetized, open‐chest and artificially ventilated rabbits, we recorded single unit activities from typical SAR units and SAR units that respond to lung deflation (units contain DARs). We examined responses of these two groups to injection of hypertonic saline (8.1% sodium chloride, 0.1 ml) into receptive fields in the lung. Hypertonic saline decreased the activity of typical SARs, although not substantially. At baseline, activity of typical SAR units was 40.3 ± 5.4 imp/s (n=12). It decreased to 34.8 ± 4.7 imp/s (p<0.05) at 17.5 seconds after injection of hypertonic saline. On the other hand, hypertonic saline stimulated deflation activated SAR units significantly. Baseline activity increased from 15.9 ± 2.2 imp/s to its speak of 43.4 ± 10.0 imp/s (n=10, p<0.01) at 10.5 seconds after injection. The activity returned to the control level within a minute. Our results show that behavior of deflation activated and typical SAR units was different. The former, but not the latter, was stimulated by hypertonic saline. We conclude that DARs are stimulated by hypertonic saline.Support or Funding Information(Supported by a VA Merit Review Award PULM‐029‐10S)

Airway Mechanosensor Behavior during Application of Positive End-Expiratory Pressure

Background: Positive end-expiratory pressure (PEEP) is commonly used in clinical settings. It is expected to affect the input from slowly adapting pulmonary stretch receptors (SARs), leading to altered cardiopulmonary functions. However, we know little about how SARs behave during PEEP application. Objectives: Our study aimed to characterize the behavior of SARs during PEEP application. Methods: We recorded single-unit activities from 18 SARs in the cervical vagus nerve and examined their response to an increase of PEEP from 3 to 10 cm H₂O for 20 min in anesthetized, open-chest and mechanically ventilated rabbits. Results: The mean activity of the units increased immediately from 35.7 to 80.5 impulses per second at the fifth breath after increasing PEEP (n = 14, p < 0.001) and then gradually returned to 56.5 impulses per second at the end of 20 min of PEEP application (p < 0.001). In the meantime, peak airway pressure increased from 9.3 to 32.7 cm H₂O, and then gradually returned to 29.4 cm H₂O (n = 18; p < 0.05) after 20 min. The remaining four units ceased firing at 34.7 s (range 10-56 s) after their initial increased activity upon 10 cm H₂O PEEP application. The unit activity resumed as the PEEP was returned to 3 cm H₂O. Conclusions: High PEEP stimulates SARs and SAR activity gradually returns towards the baseline via multiple mechanisms including receptor deactivation, neural habituation and mechanical adaptation. Understanding of the sensory inputs during PEEP application will assist in developing better strategies of mechanical ventilation.

RR interval–respiratory signal waveform modeling in human slow paced and spontaneous breathing

Our aim was to model the dependence of respiratory sinus arrhythmia (RSA) on the respiratory waveform and to elucidate underlying mechanisms of cardiorespiratory coupling. In 30 subjects, RR interval and respiratory signal were recorded during spontaneous and paced (0.1Hz/0.15Hz) breathing and their relationship was modeled by a first order linear differential equation.This model has two parameters: a0 (related to the instantaneous degree of abdominal expansion) and a1 (referring to the speed of abdominal expansion). Assuming that a0 represents slowly adapting pulmonary stretch receptors (SARs) and a1 SARs in coordination with other stretch receptors and central integrative coupling; then pulmonary stretch receptors relaying the instantaneous lung volume are the major factor determining cardiovagal output during inspiration.The model's results depended on breathing frequency with the least error occurring during slow paced breathing. The role of vagal afferent neurons in cardiorespiratory coupling may relate to neurocardiovascular diseases in which weakened coupling among venous return, arterial pressure, heart rate and respiration produces cardiovagal instability.

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.

Effects of airway pressure, hypercapnia, and hypoxia on pulmonary vagal afferent activity in the alligator

The American alligator (Alligator mississippiensis) is an aquatic vertebrate that dives and has a periodic breathing pattern. The effects of airway pressure, hypercapnia, and hypoxia on dynamic and static responses of pulmonary stretch receptors (PSR) were studied in juvenile alligators (mean mass = 246 g) at room temperature (24°C). Alligators were initially anesthetized with isoflurane, pithed, tracheotomized and attached to a small animal ventilator. The vagus nerve (cranial nerve X) was exposed, sectioned and submerged in mineral oil. Nerve filaments were teased from the nerve trunk and placed over platinum electrodes for differential nerve recording. Afferent tonic and phasic activity was recorded. The majority of receptors appeared to be slowly‐adapting PSRs (SAR) with varying thresholds and degrees of adaptation and no CO2 sensitivity. Dives were simulated in order to characterize receptor activity during and after prolonged periods of inflation and deflation. Some stretch receptors showed a change in dynamic response, exhibiting inhibition after lung inflation and potentiation after lung deflation. These airway stretch receptors may be involved in buoyancy control and/or recovery of breathing patterns and lung volume during pre– and post‐diving behavior and apneic periods. Supported by NSF CAREER IOS 0845741 (DAC).

Pulmonary stretch receptor spike time precision increases with lung inflation amplitude and airway smooth muscle tension

Slowly adapting pulmonary stretch receptors (SARs) respond to different lung inflation volumes with distinct spike counts and patterns, conveying information regarding the rate and depth of breathing to the cardiovascular and respiratory control systems. Previous studies demonstrated that SARs respond to repetitions of the same lung inflation faithfully, suggesting the possibility of modeling an SAR's discrete response pattern to a stimulus using a statistically based method. Urethane-anesthetized rabbit SAR spike trains were recorded in response to repeated 9-, 12-, and 15-ml lung inflations, and used to construct model spike trains using K-means clustering. Analysis of the statistics of the responses to different lung inflation volumes revealed that SARs fire with more temporal precision in response to larger lung inflations, because the standard deviations of real spikes clustered around the modeled spike times of responses to 15-ml stimuli were smaller than those produced by 12 or 9 ml, even at the same absolute firing frequencies. This implied that the mechanical coupling of SAR endings with pulmonary tissue is critical in determining spike time reliability. To test this, we collected SAR responses during bronchial constriction, compared them with those produced by the same SARs under normal airway resistance, and found that their firing reliability improved during bronchial constriction. These results suggest that airway distension and mechanical coupling of the receptor endings with the airway wall (partially determined by smooth muscle tone) are important determinants of SAR spike time reliability.

Flecainide inhibits the stimulatory effect of veratridine on the response of airway mechanoreceptors to maintained inflations in rats

Aims The purpose of the present study was to investigate (a) whether maintained inflations result in the inhibition of slowly adapting pulmonary stretch receptor (SAR) discharge to elicit an abrupt change in receptor activity and (b) whether pretreatment with veratridine, a Na + channel opener, and/or flecainide, a Na + channel blocker, alters the responses of SAR properties to maintained inflations. Main methods We measured the properties of SAR activity during maintained inflations at different pressures in 31 anesthetized, artificially ventilated rats with unilateral vagotomy. Key findings During maintained inflations (approximately 5, 10 and 15 cmH 2O) for about 5 s, the procedures did not produce the induction of inhibition of either 16 low-threshold SARs (firing during both inflation and deflation) or 15 high-threshold SARs (firing during inflation only). In these preparations, the excitatory responses of SARs to maintained inflations at three different pressures were markedly enhanced after administration of veratridine (50 μg/kg), but under such conditions, the inhibition of SAR discharges was not observed. In the same SAR preparations, after flecainide treatment (9 mg/kg) sufficient for the blockade of veratridine (50 μg/kg)-induced SAR stimulation, maintained inflations at higher pressures (10 and 15 cmH 2O) greatly inhibited SAR discharges. Under these conditions, the inhibition of SAR discharges was not observed during maintained inflations at 5 cmH 2O. Significance These results suggest that neither low-threshold SARs nor high-threshold SARs in the rat lung are deactivated during maintained inflations at higher pressures.

Slowly adapting pulmonary stretch receptor spike patterns carry lung distension information

Slowly adapting pulmonary stretch receptors (SARs) provide the respiratory and cardiovascular control systems with information regarding the rate and depth of breathing. Previous information theoretical analysis demonstrated that SAR spike count provides a reliable representation of lung distension. This study examines whether SAR spike patterns may also provide information about lung distension. To investigate this, artificial spike trains were generated with the same number of spikes (but randomized intervals) as those recorded from SARs in response to three different lung inflation volumes in urethane-anesthetized rabbits. Three different spike train classification methods were applied to estimate which stimulus evoked them, and the accuracy with which artificial spike trains were classified was compared to that of real SAR spike trains using the same methods. Because real SAR spike trains were classified with higher accuracies than artificial ones containing the same number of spikes, we conclude that SAR spike patterns, in addition to spike counts, contain information concerning the amplitude of lung distension.

Joint Probability-Based Neuronal Spike Train Classification

Neuronal spike trains are used by the nervous system to encode and transmit information. Euclidean distance-based methods (EDBMs) have been applied to quantify the similarity between temporally-discretized spike trains and model responses. In this study, using the same discretization procedure, we developed and applied a joint probability-based method (JPBM) to classify individual spike trains of slowly adapting pulmonary stretch receptors (SARs). The activity of individual SARs was recorded in anaesthetized, paralysed adult male rabbits, which were artificially-ventilated at constant rate and one of three different volumes. Two-thirds of the responses to the 600 stimuli presented at each volume were used to construct three response models (one for each stimulus volume) consisting of a series of time bins, each with spike probabilities. The remaining one-third of the responses where used as test responses to be classified into one of the three model responses. This was done by computing the joint probability of observing the same series of events (spikes or no spikes, dictated by the test response) in a given model and determining which probability of the three was highest. The JPBM generally produced better classification accuracy than the EDBM, and both performed well above chance. Both methods were similarly affected by variations in discretization parameters, response epoch duration, and two different response alignment strategies. Increasing bin widths increased classification accuracy, which also improved with increased observation time, but primarily during periods of increasing lung inflation. Thus, the JPBM is a simple and effective method performing spike train classification.

Are ATP and glutamate released from slowly adapting pulmonary stretch receptor afferents in the NTS?

Are ATP and glutamate released from slowly adapting pulmonary stretch receptor afferents in the NTS?

Lung afferent activity: Implications for respiratory sensation

Stimuli within the lung can cause the sensations of pain, ache, irritation and urge-to-cough. In general these are abolished or inhibited by vagal section or vagal anaesthesia, or local anaesthesia within the airways. They are present in patients with functional high cervical spinal cord transaction and after general neuromuscular paralysis. There are at least nine sensors in the bronchopulmonary system, studied almost entirely in animals. It is at present impossible to link any one sensor with any one pattern of sensation. It is reasonable to suppose that urge-to-cough arises from sensors what mediate cough, but there are at least five sensors involved in this reflex, and how they relate to unpleasant sensation is unknown. The problem is that sensation can almost only be studied in humans, and the vagal neural mechanisms almost only in other species. Vagal sensors can also ameliorate the sensation of air hunger, and this is probably due to the action of slowly adapting pulmonary stretch receptors (SARs). The same sensors may give rise to the awareness of lung volume and its changes. Many sensors in the lungs can be sensitized or desensitized by natural or imposed conditions, and this could underlie the sensitization and desensitization of dyspnoeic sensations that have been described.

Sparse firing frequency-based neuron spike train classification

Peri-stimulus time histograms (PSTHs) reveal the temporal distribution of action potentials, averaged over many stimulus presentations. PSTHs have been used as model responses to solve the classification problem, in which a single response (i.e., spike train) is assigned to one of a set of response models evoked by a set of stimuli. In this study, we developed and applied a sparse firing frequency-based method to classify individual spike trains of slowly adapting pulmonary stretch receptors (SARs). Extracellularly recorded individual SAR spike trains were evoked by one of three different lung inflation volumes in anesthetized, paralyzed adult male New Zealand White rabbits. Three different PSTH-based firing frequency response models (i.e., one for each stimulus) were constructed from two-thirds of the responses to the 600 inflations presented at each volume, while the remaining one-third were used as responses to be classified. An instantaneous firing frequency representation of each remaining "test response" was computed from their individual spike trains, using one of two forms: sparse and filled. The sparse format assigned instantaneous firing rate values only in bins that contained spikes, while the filled format assigned values to intervening bins too. Classification was performed by computing the Euclidean distance between the response spike trains and the three PSTH-based models using both sparse and filled representations. When comparing the two representations with regard to classification accuracy, we found that the sparse representation does not diminish performance appreciably, while reducing computational burden significantly.

GABAergic Pump Cells of Solitary Tract Nucleus Innervate Retrotrapezoid Nucleus Chemoreceptors

The retrotrapezoid nucleus (RTN) contains central respiratory chemoreceptors that are inhibited by activation of slowly adapting pulmonary stretch receptors (SARs). Here we examine whether RTN inhibition by lung inflation could be mediated by a direct projection from SAR second-order neurons (pump cells). Pump cells (n = 56 neurons, 13 rats) were recorded in the nucleus of solitary tract (NTS) of halothane-anesthetized rats with intact vagus nerves. Pump cells had discharges that coincided with lung inflation as monitored by the tracheal pressure. Their activity increased when end-expiratory pressure was raised and stopped instantly when ventilation was interrupted in expiration. Many pump cells could be antidromically activated from RTN (12/36). Nine of those were labeled with biotinamide. Of these nine cells, eight contained glutamic acid decarboxylase 67 (GAD67) mRNA and seven were found to reside in the lower half of the interstitial subnucleus of NTS (iNTS). Using the retrograde tracer cholera toxin-B, we confirmed that neurons located in or close to iNTS innervate RTN (two rats). Many such neurons contained GAD67 mRNA and a few contained glycine transporter2 (GLYT2) mRNA. Anterograde tract tracing with biotinylated dextranamide (four rats) applied to iNTS also confirmed that this region innervates RTN by a predominantly GABAergic projection. This work confirms that many rat NTS pump cells are located in and around the interstitial subnucleus at area postrema level. We demonstrate that a GABAergic subset of these pump cells innervates the RTN region. We conclude that these inhibitory neurons probably contact RTN chemoreceptors and mediate their inhibition by lung inflation.

Reflexively inhibiting respiratory drive

Breathing is a voluntary somatomotor activity that depends on the integration of a chemosensory drive, arising from central and peripheral chemoreceptors, with dynamic feedback from airway afferents and with the respiratory rhythm generator. In this issue of The Journal of Physiology, as part of a continuing series of investigations into the chemosensory role of the retrotrapezoid nucleus (RTN; Mulkey et al. 2004; Guyenet et al. 2005), Moreira et al. (2007) provide evidence that RTN neurons integrate chemosensory information with inhibitory afferent input arising in the pathway from slowly adapting pulmonary stretch receptors (SARs). Chemosensory properties of brain regions on or near the ventrolateral surface of the medulla and caudal pons were originally observed in studies by Loeschcke, Schlaefke, Mitchell and their colleagues (Schlaefke, 1981). Subsequently, Smith et al. (1989) identified the RTN as a cluster of neurons close to the brainstem surface just below the facial nucleus (just caudal to the level of the trapezoid body) that projected to medullary regions containing respiratory neurons. The location of the RTN neurons near the ventral surface and their extensive projections to respiratory neurons suggested to Smith et al. (1989) that these neurons could be the chemoreceptors described by the earlier investigations. In the ensuing decades, numerous studies have demonstrated the general importance of this region in chemoreception using a variety of approaches including chemical activation or inactivation and general or neurotransmitter specific lesions (Nattie & Li, 2006). Interactions between central chemoreceptors and peripheral respiratory afferents have also long been recognized. For example, lung inflation activates SARs eliciting a variety of cardiorespiratory responses that includes lengthening expiratory duration. The effectiveness of the expiratory lengthening is, however, inversely related to the magnitude of the central chemoreceptor stimulation (Mitchell et al. 1980). Moreira et al. (2007) show that at least an aspect of SAR and central chemoreceptor interaction can occur in the retrotrapezoid nucleus. This site is significant in that it is upstream of respiratory neurons involved in inspiratory rhythm generation as well as those sculpting the rhythm into patterns of activity on motor nerves to respiratory muscles. Thus, as pointed out by Moreira et al. (2007) this can provide a mechanism for modulating a tonic excitatory drive to the respiratory system. The interaction documented by Moreira et al. (2007) is an inhibition of chemosensitive neurons in the RTN by lung inflation. The authors interpret this as a negative feedback suppression of a central chemoreceptor excitatory drive to inspiratory neurons. Inhibiting the chemoreceptor drive would facilitate the inhibiting effects of SAR activation on inspiratory neurons in rhythm-generating regions of the ventral respiratory column (VRC). Deflation-activated receptors (DARs) are an additional lung volume-related afferent that could also contribute to the modulation of RTN activity. These receptors are particularly prevalent in rats and second order neurons in the DAR afferent pathway are thought to be excitatory and project to the vicinity of the RTN (Otake et al. 2001). DAR can be activated at resting end-expiratory lung volumes in rats (Ho et al. 2001). Consequently they could contribute to the increase in activity of RTN neurons observed by Moreira et al. (2007) between lung inflations. An important related issue is the postulated existence of an expiratory rhythm-generating circuit in the RTN region ventral to the facial nucleus (Onimaru & Homma, 2003; Janczewski & Feldman, 2006). Activation of SARs by lung inflation in juvenile rats excites the expiratory oscillator while DAR receptors inhibit expiration (Janczewski & Feldman, 2006). Thus, the demonstrated effects of SARs (Moreira et al. 2007) and the postulated effects of DAR afferent inputs on RTN chemoreceptive neurons in adult rats appear to be opposite to those on expiratory rhythm-generating neurons demonstrated in neonatal and juvenile rats. The potential coincidence of chemoreceptor neurons and an expiratory oscillator in the RTN region and its persistence into adults will be a continuing hot issue for the neurobiology of breathing. Unravelling this ontogenetic puzzle and understanding the multiple roles neurons in this parafacial region play in the regulation of breathing will be particularly important for the current theoretical debate. This is also significant because developmental abnormalities in chemosensitivity at the ventral surface of human brains are postulated to play a critical role in the aetiology of diseases including sudden infant death syndrome.

Inhibitory input from slowly adapting lung stretch receptors to retrotrapezoid nucleus chemoreceptors

The retrotrapezoid nucleus (RTN) contains CO(2)-activated interneurons with properties consistent with central respiratory chemoreceptors. These neurons are glutamatergic and express the transcription factor Phox2b. Here we tested whether RTN neurons receive an input from slowly adapting pulmonary stretch receptors (SARs) in halothane-anaesthetized ventilated rats. In vagotomized rats, RTN neurons were inhibited to a variable extent by stimulating myelinated vagal afferents using the lowest intensity needed to inhibit the phrenic nerve discharge (PND). In rats with intact vagus nerves, RTN neurons were inhibited, also to a variable extent, by increasing positive end-expiratory pressure (PEEP; 2-6 cmH(2)O). The cells most sensitive to PEEP were inhibited during each lung inflation at rest and were instantly activated by stopping ventilation. Muscimol (GABA-A agonist) injection in or next to the solitary tract at area postrema level desynchronized PND from ventilation, eliminated the lung inflation-synchronous inhibition of RTN neurons and their steady inhibition by PEEP but did not change their CO(2) sensitivity. Muscimol injection into the rostral ventral respiratory group eliminated PND but did not change RTN neuron response to either lung inflation, PEEP increases, vagal stimulation or CO(2). Generalized glutamate receptor blockade with intracerebroventricular (i.c.v.) kynurenate eliminated PND and the response of RTN neurons to lung inflation but did not change their CO(2) sensitivity. PEEP-sensitive RTN neurons expressed Phox2b. In conclusion, RTN chemoreceptors receive an inhibitory input from myelinated lung stretch receptors, presumably SARs. The lung input to RTN may be di-synaptic with inhibitory pump cells as sole interneurons.

Effect of ouabain on the afterhyperpolarization of slowly adapting pulmonary stretch receptors in the rat lung

In anesthetized, artificially ventilated rats with one vagus nerve section, the purposes of the present study were to investigate whether release from phasic consecutive hyperinflations (inflation volume = 3 tidal volumes) results in the afterhyperpolarization (AHP) of the slowly adapting pulmonary stretch receptor (SAR) activity and whether the effect of ouabain, a Na +–K + ATPase inhibitor, alters AHP of the SAR activity seen after release from maintained inflations. Release from 10 consecutive phasic hyperinflations did not cause any significant inhibition of SAR activity. Release from maintained inflations (for approximately 10 and 15 cmH 2O) for 5 s produced the induction of disappearance of SAR activity, corresponding with the AHP. Intravenous administration of ouabain (20 and 40 μg/kg) had no significant effects on the responses of SAR activity and SAR adaptation index (AI) to maintained inflations, but ouabain treatment with at 40 μg/kg resulted in a significant increase in the SAR activity after stopping the respirator and significantly attenuated the AHP of the SAR activity. In the immunohistochemical study, we found Na +–K + ATPase α 3-subunit-isoforms-like immunoreactivity in SAR terminals, forming leaflike extensions in the intrapulmonary bronchioles at different diameters, and those terminals were buried in the smooth muscle. In the same sections, the α 1 subunit immunoreactivity of SAR terminals was not found. These results suggest that the mechanism of generating the AHP of SARs is mainly mediated by the activation of Na +–K + ATPase α 3 subunit isoform.

Regulation of cough by secondary sensory inputs

We have reviewed the role of afferent inputs and blood chemical changes to the central nervous system, and the way in which they modify the cough and expiration reflexes (CR and ER). Slowly adapting pulmonary stretch receptors (SARs) augment the CR, insofar as when their activity is abolished the CRs from the tracheobronchial (TB) tree and larynx are abolished or weakened. However, stimulation of SARs by lung inflation has an inconsistent effect on the CR. Activation of SARs strongly potentiates the ER from the vocal folds, by a reflex mechanism, and inhibition of SARs weakens the ER. Bronchopulmonary C-fibre receptors inhibit the CR, as do capsaicin-sensitive afferents from the heart and splanchnic bed, cutaneous cold receptors and those that respond to chest wall vibration. Nasal receptors responsive to the irritant agent capsaicin potentiate the reflex. Acute hypoxia also augments the CR, and the reflex is down-regulated by carotid body resection. On the other hand, the CR is inhibited by prolonged hypoxia and hyperoxia, and by hypercapnia. Thus different inputs to the cough-controlling mechanism in the brainstem have very varied effects on the CR. We conclude that the sensitivities of the CR and ER can be modified in a large variety of physiological and clinical conditions, and that there is no clear relationship between the reflexes and changes in breathing caused by the interventions.

The inhibitory effect of ouabain on the response of slowly adapting pulmonary stretch receptors to hyperinflation in the rabbit

The combined effects of ouabain (Na +–K + ATPase inhibitor) and hyperinflation (inflation volume = three tidal volumes) on slowly adapting pulmonary stretch receptors (SARs) were studied before and after administration of nifedipine (an L-type Ca 2+ channel blocker) and KB-R7943 (a reverse-mode Na +–Ca 2+ exchanger blocker) in anesthetized, artificially ventilated rabbits after bilateral vagotomy. Before ouabain administration, hyperinflation stimulated SAR activity. After 20 min of ouabain administration (30 μg/kg) the SARs increased discharge rates in normal inflation. Under these conditions, hyperinflation initially stimulated SAR activity but subsequently inhibited the activity at peak inflation. Additional administration of 60 μg/kg ouabain (total dose = 90 μg/kg) caused a further stimulation of SAR activity, but 20 min later both normal inflation and hyperinflation resulted in a greater inhibition of the receptor activity. The hyperinflation-induced SAR inhibition in the presence of ouabain (30 μg/kg) was not significantly altered by administration of either nifedipine (2 and 4 mg/kg) or KB-R7943 (1 and 3 mg/kg). In another series of experiments, we further examined the combined effects of ouabain and hyperinflation in veratridine (a Na + channel opener, 40 μg/kg)-treated animals. After recovery from the veratridine effect on SAR activity, which vigorously stimulated the receptor activity, ouabain treatment (30 μg/kg) that silenced the receptor activity at peak inflation greatly inhibited hyperinflation-induced SAR stimulation. These results suggest that hyperinflation-induced SAR inhibition in the presence of ouabain may be related to a Na + overload, but not to a Ca 2+ influx via activation of L-type Ca 2+ channels, in the SAR endings.

Effects of acetazolamide and 4-aminopyridine on CO2-induced slowly adapting pulmonary stretch receptor inhibition in rats.

Inhibitory responses of slowly adapting pulmonary stretch receptor (SAR) activity to CO(2) inhalation (maximal tracheal CO(2) concentration ranging from 9.5 to 12.5%) for approximately 60 s were examined before and after administration of acetazolamide (a carbonic anhydrase inhibitor) or 4-aminopyridine (4-AP, a K(+) channel blocker). The experiments were performed in 35 anesthetized, artificially ventilated rats after unilateral vagotomy. Sixty-eight of eighty-four SARs were inhibited by CO(2) inhalation. The SAR inhibition was attenuated by pretreatment with either acetazolamide (20 mg/kg, n = 10) or 4-AP (0.7 and 2.0 mg/kg, n = 10). In other series of experiments, stainings to show the existence of carbonic anhydrase (CA) enzymatic reaction were not found in the smooth muscle of either extrapulmonary or intrapulmonary bronchi. Protein gene product 9.5 (PGP 9.5)-immunoreactive SAR terminals to form leaflike extensions were found in the bronchioles at different diameters and were smooth-muscle-related receptors. But in the same sections, CA isozyme II-like (erythrocyte CA) immunoreactive SAR terminals were not identified. These results suggest that CO(2)-induced inhibition of SARs may be involved in the CA-dependent CO(2) hydration in addition to the activation of 4-AP sensitive K(+) currents.

A single pulmonary mechano-sensory unit possesses multiple encoders in rabbits

Morphological studies have shown that axons of slowly adapting pulmonary stretch receptors (SARs) may supply more than one receptor structure. Thus, a single-unit of SARs may contain multiple encoders. We recorded SAR activities and searched for multiple receptive fields (MRFs) by probing the lung in anesthetized, open-chest and mechanically ventilated rabbits. One-third of SARs had clear MRFs. Selectively blocking fields with lidocaine, we found that each has its own encoder and discharge characteristics. Unit activity of SARs results from encoder interactions and undergoes significant integration before reaching the central nervous system.