Pulmonary Stretch Receptor Feedback Research Articles

Inhaled furosemide for relief of air hunger versus sense of breathing effort: a randomized controlled trial

BackgroundInhaled furosemide offers a potentially novel treatment for dyspnoea, which may reflect modulation of pulmonary stretch receptor feedback to the brain. Specificity of relief is unclear because different neural pathways may account for different components of clinical dyspnoea. Our objective was to evaluate if inhaled furosemide relieves the air hunger component (uncomfortable urge to breathe) but not the sense of breathing work/effort of dyspnoea.MethodsA randomised, double blind, placebo-controlled crossover trial in 16 healthy volunteers studied in a university research laboratory. Each participant received 3 mist inhalations (either 40 mg furosemide or 4 ml saline) separated by 30–60 min on 2 test days. Each participant was randomised to mist order ‘furosemide-saline-furosemide’ (n- = 8) or ‘saline-furosemide-saline’ (n = 8) on both days. One day involved hypercapnic air hunger tests (mean ± SD PCO2 = 50 ± 3.7 mmHg; constrained ventilation = 9 ± 1.5 L/min), the other involved work/effort tests with targeted ventilation (17 ± 3.1 L/min) and external resistive load (20cmH2O/L/s). Primary outcome was ratings of air hunger or work/effort every 15 s on a visual analogue scale. During saline inhalations, 1.5 mg furosemide was infused intravenously to match the expected systemic absorption from the lungs when furosemide is inhaled. Corresponding infusions of saline during furosemide inhalations maintained procedural blinding. Average visual analogue scale ratings (%full scale) during the last minute of air hunger or work/effort stimuli were analysed using Linear Mixed Methods.ResultsData from all 16 participants were analysed. Inhaled furosemide relative to inhaled saline significantly improved visual analogues scale ratings of air hunger (Least Squares Mean ± SE − 9.7 ± 2%; p = 0.0015) but not work/effort (+ 1.6 ± 2%; p = 0.903). There were no significant adverse events.ConclusionsInhaled furosemide was effective at relieving laboratory induced air hunger but not work/effort in healthy adults; this is consistent with the notion that modulation of pulmonary stretch receptor feedback by inhaled furosemide leads to dyspnoea relief that is specific to air hunger, the most unpleasant quality of dyspnoea.FundingOxford Brookes University Central Research Fund.Trial registrationClinicalTrials.gov Identifier: NCT02881866. Retrospectively registered on 29th August 2018.

Role of pulmonary stretch receptors and sympathetic system in the inhibition of reflex bradycardia produced by chemical stimulation of the periaqueductal gray matter of the rat

The present study examined the role of the sympathetic system and pulmonary afferent feedback in the baroreflex inhibition by chemical stimulation of the dorsal periaqueductal gray matter (DPAG) of the anesthetized rat. The baroreflex bradycardia was induced by phenylephrine infusions (PHE, 50 μg/ml/min, i.v.) given either alone or combined with glutamate microinjections (GLU, 10 nmol/100 nl) into the DPAG. GLU microinjections alone produced marked increases in respiratory amplitude (67±19%), but barely changed the respiratory frequency (15±3 cpm) and blood pressure (14±2 mm Hg), and did not affect the heart rate. In contrast, the same injections produced a 92% inhibition of PHE-induced bradycardia (from −62 to −5 bpm). Because GLU microinjections per se had little effects on blood pressure, the baroreflex inhibition should be credited to the deactivation of both the vagal and sympathetic reflex pathways at the medulla. Indeed, the baroreflex was inhibited in only 47% following the DPAG stimulation of atenolol-treated rats. The GLU-evoked inhibition of baroreflex was also correlated with concomitant increases in respiratory amplitude. The role of pulmonary feedback in baroreflex inhibition was thus examined before and after the neuromuscular blockade of atenolol-treated rats. In spontaneously breathing rats, GLU microinjections reversed PHE-induced bradycardia to tachycardia, thereby producing a 153% inhibition of reflex bradycardia (from −38 bpm to +20 bpm). In contrast, the baroreflex inhibition was attenuated in only 53% after neuromuscular blockade (from −34 to −16 bpm). Data are the first evidence of the contribution of pulmonary stretch receptor feedback in DPAG-evoked inhibition of reflex bradycardia.

Pulmonary mechano-receptors strongly affect the breathing pattern in surfactant-depleted animals

Objective: We hypothesized that pulmonary mechano-receptors influence the breathing pattern also in a lung condition similar to RDS in neonates. Vagal cooling experiments suggest that the deep slow breathing observed after vagotomy is not only a result of loss of pulmonary stretch receptor feedback, but also a result of blocked input from C-fibers (unmyelinated fibers). If these effects on breathing change after surfactant depletion/replacement is not known. To study the influence of vagal afferents on breathing pattern, gas exchange, and lung mechanics in young cats with normal, surfactant-depleted and surfactant-treated lungs.

Pulmonary mechano-receptors strongly affect the breathing pattern in surfactant-depleted animals

Objective: We hypothesized that pulmonary mechano-receptors influence the breathing pattern also in a lung condition similar to RDS in neonates. Vagal cooling experiments suggest that the deep slow breathing observed after vagotomy is not only a result of loss of pulmonary stretch receptor feedback, but also a result of blocked input from C-fibers (unmyelinated fibers). If these effects on breathing change after surfactant depletion/replacement is not known. To study the influence of vagal afferents on breathing pattern, gas exchange, and lung mechanics in young cats with normal, surfactant-depleted and surfactant-treated lungs.

Pulmonary mechano-receptors strongly affect the breathing pattern in surfactant-depleted animals

Objective: We hypothesized that pulmonary mechano-receptors influence the breathing pattern also in a lung condition similar to RDS in neonates. Vagal cooling experiments suggest that the deep slow breathing observed after vagotomy is not only a result of loss of pulmonary stretch receptor feedback, but also a result of blocked input from C-fibers (unmyelinated fibers). If these effects on breathing change after surfactant depletion/replacement is not known. To study the influence of vagal afferents on breathing pattern, gas exchange, and lung mechanics in young cats with normal, surfactant-depleted and surfactant-treated lungs.

Phasic pulmonary stretch receptor feedback modulates both eupnea and gasping in an in situ rat preparation

The perfused in situ juvenile rat preparation produces patterns of phrenic discharge comparable to eupnea and gasping in vivo. These ventilatory patterns differ in multiple aspects, including most prominently the rate of rise of inspiratory activity. Although we have recently demonstrated that both eupnea and gasping are similarly modulated by a Hering-Breuer expiratory-promoting reflex to tonic pulmonary stretch, it has generally been assumed that gasping was unresponsive to afferent stimuli from pulmonary stretch receptors. In the present study, we recorded eupneic and gasplike efferent activity of the phrenic nerve in the in situ juvenile rat perfused brain stem preparation, with and without phrenic-triggered phasic pulmonary inflation. We tested the hypothesis that phasic pulmonary inflation produces reflex responses in situ akin to those in vivo and that both eupnea and gasping are similarly modulated by phasic pulmonary stretch. In eupnea, we found that phasic pulmonary inflation decreases inspiratory burst duration and the period of expiration, thus increasing burst frequency of the phrenic neurogram. Phasic pulmonary inflation also decreases the duration of expiration and increases the burst frequency during gasping. Bilateral vagotomy eliminated these changes. We conclude that the neural substrate mediating the Hering-Breuer reflex is retained in the in situ preparation and that the brain stem circuitry generating the respiratory patterns respond to phasic activation of pulmonary stretch receptors in both eupnea and gasping. These findings support the homology of eupneic phrenic discharge patterns in the reduced in situ preparation and eupnea in vivo and disprove the common supposition that gasping is insensitive to vagal afferent feedback from pulmonary stretch receptor mechanisms.

Tonic pulmonary stretch receptor feedback modulates both eupnea and gasping in an in situ rat preparation.

The perfused in situ juvenile rat preparation produces phrenic discharge patterns comparable to eupnea and gasping in vivo. These ventilatory patterns of eupnea and gasping differ in multiple aspects, including most prominently the rate of rise of inspiratory activity. Because gasping, but not eupnea, appeared similar after vagotomy in spontaneous breathing preparations, it has been assumed that gasping was unresponsive to afferent stimuli from pulmonary stretch receptors. In the present study, efferent activity of the phrenic nerve was recorded during eupnea and gasping in the in situ juvenile rat preparation. Gasping was induced in hypoxic-hypercapnia or ischemia. An increase in the pressure of tonic lung inflation from 1 to 10 cmH2O caused a prolongation of the duration between phrenic bursts in both eupnea or gasping. Bilateral vagotomy eliminated these changes. We conclude that the neural substrate mediating the Hering-Breuer reflex is retained in the in situ preparation and that the brain stem circuitry generating the respiratory patterns responds to tonic activation of pulmonary stretch receptors in a similar manner in eupnea and gasping. These findings support the homology of eupnea-like phrenic discharge patterns in the reduced in situ preparation and eupnea in vivo and disprove the common supposition that gasping is insensitive to vagal afferent feedback from pulmonary stretch receptor mechanisms.

Effect of pulmonary stretch receptor feedback and CO(2) on upper airway and respiratory pump muscle activity in the rat.

1. Our purpose was to examine the effects of chemoreceptor stimulation and lung inflation on neural drive to tongue protrudor and retractor muscles in the rat. 2. Inspiratory flow, tidal volume, transpulmonary pressure, compliance and electromyographic (EMG) activity of genioglossus (GG), hyoglossus (HG) and inspiratory intercostal (IIC) muscles were studied in 11 anaesthetized, tracheotomized and spontaneously breathing rats. Mean EMG activity during inspiration was compared with mean EMG activity during an occluded inspiration, at each of five levels of inspired CO(2) (0, 3, 6, 9 and 12 %). 3. Lung inflation suppressed EMG activity in all muscles, with the effect on both tongue muscles exceeding that of the intercostal muscles. Static elevations of end-expiratory lung volume evoked by 2 cmH(2)O positive end-expiratory pressure (PEEP) had no effect on tongue muscle activity. 4. Despite increasing inspiratory flow, tidal volume and transpulmonary pressure, the inhibition of tongue muscle activity by lung inflation diminished as arterial PCO2 (P(a),CO(2)) increased. 5. The onset of tongue muscle activity relative to the onset of IIC muscle activity advanced with increases in P(a),CO(2) but was unaffected by lung inflation. This suggests that hypoglossal and external intercostal motoneuron pools are controlled by different circuits or have different sensitivities to CO(2), lung inflation and/or anaesthetic agents. 6. We conclude that hypoglossal motoneuronal activity is more strongly influenced by chemoreceptor-mediated facilitation than by lung volume-mediated inhibition. Hypoglossal motoneurons driving tongue protrudor and retractor muscles respond identically to these stimuli.

Development of gill and lung breathing in amphibia

In the 25 morphological stages of larval bullfrog development there exists a gradual transition from gill to lung ventilation associated with a developmental decrease in the contribution of the skin in gas exchange. Bath application of GABA and/or glycine inhibited gill but not lung burst activities of cranial nerve (CN) VII in the premetamorphic (stages 16–19) in vitro tadpole brainstem preparation [1]. It was proposed that the neural basis of gill rhythmogenesis involved network inhibition, whereas lung rhythmicity was pacemaker driven [1]. Bath application of a bicuculline/strychnine solution abolished gill and enhanced lung bursting in stages 16–19 in vitro [1]. Bath application of the GABAB receptor antagonist 2-hydroxy-saclofen disinhibited the lung central pattern generator (CPG) resulting in precocious lung bursting patterns as early as developmental stage 6 [2]. We recorded efferent activity from CNVII and spinal nerve (SN)II in the in vitro tadpole brainstem preparation in three successive developmental groups (3–9; 10–15; 16–19) before and after bath application of a 10 μM bicuculline and 5 μM strychnine solution. We also exposed the brainstem to bath pH7.4, 7.8, and 8.2 before and after bath application of bicuculline/strychnine. Bicuculline/strychnine produced lung ventilatory bursts in all developmental stages tested, indicating the presence of the lung CPG as well as excitatory synapses to respiratory motor neurons as early as stage 3. We also designed an experiment to examine the importance of lung ventilation on the developmental shift from gill to lung bursting. Two groups of tadpoles were hatched from eggs. Control tadpoles had free access to the air-water interface throughout development, whereas tadpoles were denied access to the air-water interface via the placement of Plexiglas 2.5 cm below the surface of the water. CNVII and SNII efferent activities were recorded in vitro at bath pH7.4, 7.8, and 8.2 before and after bath application of 10 μM bicuculline and 5 μM strychnine. Postmetamorphic barrier tadpoles exhibited different motor patterns than stage-matched controls. Tadpoles reared in the barrier condition to stages 20–25 possessed fictive gill and lung ventilatory activities of premetamorphic tadpoles. All barrier tadpole preparations exhibited robust, spontaneous lung burst activity following bath application of bicuculline/strychnine. We propose that developmentally dependent GABA- and glycinergic mechanisms lead to disinhibition of the lung CPG such that early in development gill motor patterns are the dominant respiratory rhythm, whereas in late development the lung CPG is the dominant respiratory rhythm. Denying the tadpole the ability to practice lung breathing during metamorphosis produces a morphologically correct postmetamorphic tadpole with an immature, or premetamorphic respiratory rhythm. We propose that prevention of lung inflation in barrier tadpoles leads to premetamorphic levels of GABA- and glycinergic inhibition, and that this inhibition may be altered by pulmonary stretch receptor feedback in control tadpoles.

Modulation of breathing pattern by pulmonary stretch receptor feedback in the periodically breathing amphibian, Bufo marinus.

Modulation of breathing pattern by pulmonary stretch receptor feedback in the periodically breathing amphibian, Bufo marinus.

Similarities in reflex control of laryngeal and cardiac vagal motor neurones

We sought to test the hypothesis that laryngeal adductor and cardiac vagal motor neurones respond similarly to the activation of certain afferent inputs. Experiments were performed on a working heart–brainstem preparation of rat devoid of pulmonary stretch receptor feedback. Upper airway negative pressure receptors (UANPR), peripheral arterial chemoreceptors and receptors at the junction of the pharynx and oesophagus were stimulated selectively while recording heart rate, recurrent laryngeal, phrenic and hypoglossal motor outflows, subglottic pressure during constant translaryngeal airflow (as an index of laryngeal resistance), and single unit respiratory neurone activity. Stimulation of all three receptor types produced bradycardia, evoked discharges in the recurrent laryngeal and hypoglossal motor outflows during the post-inspiratory period and caused swallowing. Stimulation of pharyngoesophageal receptors and peripheral chemoreceptors evoked an increase in laryngeal resistance during the post-inspiratory phase indicative of laryngeal adductor motoneurone activation. Although this reflex response cannot be evaluated during UANPR stimulation, some post-inspiratory neurones were powerfully activated suggesting that UANPR probably drive laryngeal adductor muscles. Our data show that motor outflows controlling cardiac rate and laryngeal patency are concurrently activated by these sensory inputs. This may constitute the basis for a stereotyped defensive reflex response which maintains end expiratory lung volume, thus conserving oxygen in conditions of upper airway obstruction. Our observations lend further support to models of cardiorespiratory control which propose close coupling and shared central mechanisms for the regulation of the cardiovascular and respiratory systems.

The role of the nucleus isthmi in respiratory pattern formation in bullfrogs.

The nucleus isthmi (NI) is a mesencephalic structure of the amphibian brain located between the roof of the midbrain and the cerebellum. From a neuroanatomical perspective, the NI can be compared with the pons which, in mammals, contributes to the control of breathing pattern. This study tested the hypothesis that the NI plays a critical role in breathing pattern formation in the bullfrog. More specifically, we postulated that this nucleus was the site responsible for clustering breaths into distinct episodes of breathing. This hypothesis was tested by comparing the respiratory motor output of decerebrate, paralyzed and artificially ventilated bullfrogs before and after bilateral lesions of the NI by pressure microinjections of lidocaine or kainic acid (KA) into this area. Bilateral microinjections of lidocaine or KA into the NI transformed the breathing pattern from episodic (many breaths per episode) to one of evenly spaced single breaths, without affecting the amplitude of the fictive breaths. These changes in breathing pattern were associated with an overall decrease in breathing frequency and a reduction in CO2-chemosensitivity. Breathing episodes of more than one breath reappeared during hypercarbia (3.5% CO2 in air) after KA lesioning. Bilateral lesions to the NI did not affect the changes in the timing or the amplitude of the respiratory-related bursts elicited by pulmonary stretch receptor feedback, indicating that mechanoreflexes do not require NI input. We conclude that the NI is not responsible for the genesis of breathing episodes, but provides a tonic excitatory input to respiratory centers in the lower brainstem. The NI also plays an important role in either CO2 chemodetection or, more probably, integration of CO2 chemoreceptor information. This, in turn, contributes to the production of episodes of more than one breath.

Role of pulmonary stretch receptor feedback in control of episodic breathing in the bullfrog.

This study compared the "fictive" breathing patterns of decerebrate, paralyzed, unidirectionally ventilated bullfrogs in which pulmonary stretch receptor (PSR) feedback was either absent bilateral vagotomy), maintained constant at different levels (tonic) or oscillated with each fictive breath (phasic) under different levels of hypoxic or CO2-related respiratory drive. Tonic and phasic PSR feedback had identical effects on the fictive breathing pattern; decreasing PSR feedback increased the peak integrated trigeminal electroneurogram recordings and decreased breathing frequency. The effects of bilateral vagotomy and lung deflation to 0 cmH2O on breathing pattern were identical. Although hypoxia (fractional concentration of O2 in air = 0.06) had no significant effect on fictive breathing, ventilating frogs with increasing CO2 levels (fractional CO2 concentration in inspired air range: 0.00-0.03) increased the number of breaths in each fictive breathing episode, and this effect was potentiated by PSR feedback. Whenever respiratory drive was increased, regardless of the method (increase in PSR feedback or chemoreceptor drive), occasional single breaths were replaced by breathing episodes, indicating that the mechanisms responsible for the clustering of the breaths and the onset/termination of breathing episodes are not dependent on either input alone.

Vagal input enhances responsiveness of respiratory discharge to central changes in pH/CO2 in bullfrogs

This study investigated the interaction between vagal afferent input and central chemosensitivity in modulating the respiratory motor output of in vitro brain stem-spinal cord preparations from adult bullfrogs. With this preparation, the spatiotemporal distribution of respiratory-related motor output emulated that of intact bullfrogs; that is, the fictive breathing pattern was mostly episodic. Recordings from cranial motor nerves (V and X) showed that, without peripheral feedback, increasing the PCO2 of the mock cerebrospinal fluid (thereby reducing pH from 8.3 to 7.7) caused a modest increase in respiration-related burst frequency. When the pulmonary branch of a vagus nerve was stimulated phasically (2 V, 20 Hz, 0.2 ms) during each fictive breath to simulate afferent pulmonary stretch receptor feedback 1) the responsiveness of the preparation to the same changes in pH was augmented nearly threefold and 2) the breathing pattern remained episodic. It appears, therefore, that episodic breathing is an intrinsic property of the central nervous system in bullfrogs. It is concluded that there is a strong interaction between vagal feedback and central chemodetection in controlling the temporal relationships that characterize this episodic breathing pattern.

Background activity in pulmonary vagal C-fibers and its effects on breathing

Vagal cooling experiments suggest that the deep show breathing observed after vagotomy results not only from loss of pulmonary stretch receptor feedback, but also from loss of some unidentified vagal input. To investigate this possibility we cooled the vagus nerves in anesthetized dogs. In dogs breathing spontaneously, the Hearing-Breuer reflex was abolished at 7 °C, but average expiratory time was unchanged and lengthened only on cooling below 3 °C,. In artificially ventilated dogs the pulmonary vargus nerves were cooled in the chest and phrenic activity was recorded. Entrainment of phrenic bursts to the ventillator cycle ceased at 7 °C, and expiratory pauses shortened; they lengthened again on cooling below 3 °C. Cervical vagotomy did not change breathing pattern after the pulmonary vagus nerves were cut. Recording of afferent impulses during cooling showed that at 5 °C or less pulmonary vagal input was confined largely to nonmyelinated fibers; at 3 °C, background activity in pulmonary C-fibers was still 78% of control whereas myelinated afferents were virtually silent. We suggest that in eupnea low frequency, background activity in pulmonary afferent C-fibes shortens expiratory time.

Role of pulmonary stretch receptors during breathing in rabbits, cats and dogs

In order to mimic and then modify the input to the respiratory centre from pulmonary stretch receptors, the central ends of the cut cervical vagus nerves were electrically stimulated with a frequency determined by transpulmonary pressure through a voltage to frequency converter. At appropriate end-expiratory stimulation frequency and gain of the voltage to frequency converter, such stimulation restored the pre-vagotomised patterns of breathing in rabbits, eats and dogs. Mimicking the changes in activity from pulmonary stretch receptors that would be produced by such manoeuvres as hypercapnia, inflations and deflations, reproduced the responses in inspiratory duration that occurred with natural stimuli in the same animals with vagi intact. There were some differences between the responses of expiratory durations to the natural and mimicked interventions; these may be related to the presence of increased expiratory muscle activity in the former. The results demonstrate that transpulmonary pressure-controlled stimulation of the afferent vagus nerves is a satisfactory method of mimicking and controlling the pulmonary stretch receptor feedback mechanism in studies on the control of breathing.

Vagal control of breathing pattern independent of lung inflation in conscious dogs.

ArticleVagal control of breathing pattern independent of lung inflation in conscious dogs.E A PhillipsonE A PhillipsonPublished Online:01 Aug 1974https://doi.org/10.1152/jappl.1974.37.2.183MoreSectionsPDF (2 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByPhasic pulmonary stretch receptor feedback modulates both eupnea and gasping in an in situ rat preparationMichael B. Harris, and Walter M. St.-John1 August 2005 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 289, No. 2Unrestrained plethysmography is an unreliable measure of airway responsiveness in BALB/c and C57BL/6 miceAndy Adler, Greg Cieslewicz, and Charles G. Irvin1 July 2004 | Journal of Applied Physiology, Vol. 97, No. 1Tonic pulmonary stretch receptor feedback modulates both eupnea and gasping in an in situ rat preparationMichael B. Harris, and Walter M. St.-John1 July 2003 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 285, No. 1Differences in respiratory patterns after acute and chronic pulmonary denervationRespiration Physiology, Vol. 70, No. 2The effect of vagal blockade on the variability of ventilation in the awake dogRespiration Physiology, Vol. 49, No. 3Control of breathing during acute hemorrhage in anesthetized catsRespiration Physiology, Vol. 41, No. 3Behavior of expiratory neurons in response to mechanical and chemical loadingRespiration Physiology, Vol. 36, No. 3Control of Respiration in the NewbornClinics in Perinatology, Vol. 5, No. 2The mechanism of rapid shallow breathing due to histamine and phenyldiguanide in cats and rabbitsRespiration Physiology, Vol. 32, No. 2Vagal control of diaphragm timing in cat while breathing at elevated lung volumesRespiration Physiology, Vol. 30, No. 1-2Effect of rib cage or abdomen compression at iso-lung volume on breathing patternRespiration Physiology, Vol. 28, No. 2Respiratory frequency control during hypercapnia in vagotomized, anesthetized catsRespiration Physiology, Vol. 27, No. 3Pattern of breathing during hypoxia or hypercapnia of the awake or anesthetized catRespiration Physiology, Vol. 27, No. 2Airway occlusion pressures in awake and anesthetized goatsRespiration Physiology, Vol. 27, No. 1The effect of varying tidal volume on the associated phrenic motoneurone output: Studies of vagal and chemical feedbackRespiration Physiology, Vol. 25, No. 2Contribution of hypercapnic stimuli and of vagal afferents to the timing of breathing in anesthetized catsRespiration Physiology, Vol. 25, No. 1Tonic vagal influences on inspiratory durationRespiration Physiology, Vol. 24, No. 3 More from this issue > Volume 37Issue 2August 1974Pages 183-9 https://doi.org/10.1152/jappl.1974.37.2.183PubMed4855364History Published online 1 August 1974 Published in print 1 August 1974 Metrics