Pulmonary C-fiber Activity Research Articles

Pulmonary C-fiber activation attenuates respiratory-related tongue movements

The functional impact of pulmonary C-fiber activation on upper airway biomechanics has not been evaluated. Here, we tested the hypothesis that pulmonary C-fiber activation alters the respiratory-related control of tongue movements. The force produced by tongue movements was quantified in spontaneously breathing, anesthetized adult rats before and after stimulation of pulmonary C fibers via intrajugular delivery of capsaicin (0.625 and 1.25 μg/kg). Brief occlusion of the trachea was used to increase the respiratory drive to the tongue muscles, and hypoglossal (XII) nerve branches were selectively sectioned to denervate the protrusive and retrusive tongue musculature. Tracheal occlusion triggered inspiratory-related tongue retrusion in rats with XII nerves intact or following section of the medial XII nerve branch, which innervates the genioglossus muscle. Inspiratory-related tongue protrusion was only observed after section of the lateral XII branch, which innervates the primary tongue retrusor muscles. The tension produced by inspiratory-related tongue movement was significantly attenuated by capsaicin, but tongue movements remained retrusive, unless the medial XII branch was sectioned. Capsaicin also significantly delayed the onset of tongue movements such that tongue forces could not be detected until after onset of the inspiratory diaphragm activity. We conclude that altered neural drive to the tongue muscles following pulmonary C-fiber activation has a functionally significant effect on tongue movements. The diminished tongue force and delay in the onset of tongue movements following pulmonary C-fiber activation are potentially unfavorable for upper airway patency.

Inhalation of isoflurane alters the pulmonary C‐fiber‐mediated respiratory responses in anesthetized rats

This study is aimed to explore the effect of inhaling isoflurane, a commonly used volatile anesthetic, on pulmonary C-fiber (PCF)-mediated respiratory responses. We recorded ventilatory (Study Series I) and nodose ganglion neuronal responses (Study Series II) to right atrial bolus injection of phenylbiguanide (PBG, 20μg/kg), a selective PCF's stimulant, before and during 5% isoflurane exposure for 8 s in anesthetized spontaneously breathing and paralyzed rats, respectively. Isoflurane initially caused a remarkable increase in respiratory frequency (f) during the first 3–5 s exposure, and this response gradually disappeared during the following exposure without significant change in tidal volume. PBG evoked an apnea which was markedly reduced by isoflurane. Correspondingly, isoflurane also increased baseline firing rate of all C-type neurons (n = 17) extracellularly recorded in the nodose ganglia by 136% and attenuated the PBG-induced C-type neuronal excitation by 52%. In sharp contrast, the firing rate of pump-neurons (n = 5) and rapid adapting type neurons (n = 2) was not be affected by PBG injection, but decreased by isoflurane. Our result suggests that isoflurane can stimulate PCFs to produce tachypnea and depress PBG-induced PCF's activity probably through different mechanisms.

Serotonin regulates the cardiopulmonary effects of pulmonary embolism through vagal C‐fiber activation

We have addressed the hypothesis that the tachypnea, tachycardia and pulmonary hypertension evoked by pulmonary embolism (PE) occur secondary to platelet activation/degranulation followed by serotonin-dependent pulmonary C-fiber activation. In anesthetized guinea pigs, intravenously administered equine collagen induced immediate, sustained (>20 minutes) and pronounced (~200%) increases in respiratory rate, transient falls in blood pressure and sustained increases in right ventricular pressure (n=10). These effects were mimicked by 5-HT and the P2Y receptor agonist and platelet stimulant ADP (n=5/treatment group), and prevented by prior platelet depletion (>90% reduction) with busulfan (n=5). The serotonin reuptake inhibitor fluoxetine (1mg/kg iv) rendered ADP challenges lethal (n=5). Vagotomy prevented the tachypnea and systemic hypotension evoked by PE (n=4). The 5-HT3 receptor antagonist ondansetron (1 mg/kg iv) nearly abolished the responses to 5-HT and prevented the lethal effects of ADP challenge following fluoxetine (n=5/treatment group). Ondansetron also markedly attenuated the tachypnea and hypotension accompanying PE (n=8). Based on these results we speculate that the cardiopulmonary reflexes evoked by PE depend upon platelet serotonin release and subsequent activation of pulmonary C-fibers via 5-HT3 receptors.

Inhibition of respiratory‐related activity of the facial nerve by pulmonary vagal C‐fiber activation in the rat

We have previously reported that respiratory-related facial nerve activity can be modulated by hypercapnia, lung inflation, and positive end-expired pressure (PEEP). Whether respiratory-related rhythmic activities of the facial nerve could be modulated by pulmonary C-fiber activation is unclear. Activity of the facial and phrenic nerve was recorded simultaneously in the anesthetized and ventilated adult rat. Activation pulmonary C-fiber by intra-jugular injection of capsaicin produced a dose-dependent reduction of amplitude and onset of the facial nerve activity. Furthermore, uncoupled facial activity (persistent rhythmic activity during phrenic cessation) evoked by increasing PEEP could be also suppressed by capsaicin injection. Single fiber recording from the facial nerve revealed that capsaicin treatment produced inhibition on activity of expiratory-inspiratory (EI) motoneuron during expiration such that became inspiratory motoneurons and of pre-inspiratory motoneurons. In addition, capsaicin injection could attenuate the uncoupled activity of EI from the phrenic burst caused by PEEP manipulation. These results implied that capsaicin might differentially inhibit pre-inspiratory than inspiratory facial activity.

Neural drive to tongue protrudor and retractor muscles following pulmonary C-fiber activation

Hypoglossal (XII) nerve recordings indicate that pulmonary C-fiber (PCF) receptor activation reduces inspiratory bursting and triggers tonic discharge. We tested three hypotheses related to this observation: 1) PCF receptor activation inhibits inspiratory activity in XII branches innervating both tongue protrudor muscles (medial branch; XIImed) and retractor muscles (lateral branch; XIIlat); 2) reduced XII neurogram amplitude reflects decreased XII motoneuron discharge rate; and 3) tonic XII activity reflects recruitment of previously silent motoneurons. Phrenic, XIImed, and XIIlat neurograms were recorded in anesthetized, paralyzed, and ventilated rats. Capsaicin delivered to the jugular vein reduced phrenic bursting at doses of 0.625 and 1.25 mug/kg but augmented bursting at 5 mug/kg. All doses reduced inspiratory amplitude in XIImed and XIIlat (P < 0.05), and these effects were eliminated following bilateral vagotomy. Single-fiber recordings indicated that capsaicin causes individual XII motoneurons to either decrease discharge rate (n = 101/153) or become silent (n = 39/153). Capsaicin also altered temporal characteristics such that both XIImed and XIIlat inspiratory burst onset occurred after the phrenic burst (P < 0.05). Increases in tonic discharge after capsaicin were greater in XIImed vs. XIIlat (P < 0.05); single-fiber recordings indicated that tonic discharge reflected recruitment of previously silent motoneurons. We conclude that PCF receptor activation reduces inspiratory XII motoneuron discharge and transiently attenuates neural drive to both tongue protrudor and retractor muscles. However, tonic discharge appears to be selectively enhanced in tongue protrudor muscles. Accordingly, reductions in upper airway stiffness associated with reduced XII burst amplitude may be offset by enhanced tonic activity in tongue protrudor muscles.

Stimulatory effect of CO2 on vagal bronchopulmonary C-fiber afferents during airway inflammation

This study investigated 1) whether pulmonary C fibers are activated by a transient increase in the CO2 concentration of alveolar gas; and 2) if the CO2 sensitivity of these afferents is altered during airway inflammation. Single-unit pulmonary C-fiber activity was recorded in anesthetized, open-chest rats. Transient alveolar hypercapnia (HPC) was induced by administering a CO2-enriched gas mixture (25-30% CO2, 21% O2, balance N2) for five to eight breaths, which increased alveolar CO2 concentration progressively to near or above 13% for 3-5 s and lowered the arterial pH transiently to 7.10 +/- 0.05. Our results showed the following. 1) HPC evoked only a mild stimulation in a small fraction (4/47) of pulmonary C fibers, and there was no significant change in fiber activity (change in fiber activity = 0.22 +/- 0.16 imp/s; P > 0.1, n = 47). 2) In sharp contrast, after airway exposure to poly-L-lysine, a cationic protein known to induce mucosal injury, the same challenge of transient HPC activated 87.5% of the pulmonary C fibers tested and evoked a distinct stimulatory effect on these afferents (change in fiber activity = 6.59 +/- 1.78 imp/s; P < 0. 01, n = 8). 3) Similar potentiation of the C-fiber response to HPC was also observed after acute exposure to ozone (n = 6) and during a constant infusion of inflammatory mediators such as adenosine (n = 15) or prostaglandin E2 (n = 12). 4) The enhanced C-fiber sensitivity to CO2 after poly-L-lysine was completely abrogated by infusion of NaHCO3 (1.82 mmol.kg(-1).min(-1)) that prevented the reduction in pH during HPC (n = 6). In conclusion, only a small percentage (<10%) of the bronchopulmonary C fibers exhibit CO2 sensitivity under control conditions, but alveolar HPC exerts a consistent and pronounced stimulatory effect on the C-fiber endings during airway inflammation. This effect of CO2 is probably mediated through the action of hydrogen ions.

Response of Respiratory-Related Hypoglossal Nerve Activity to Capsaicin-Induced Pulmonary C-Fiber Activation in Rats

This study was designed to examine respiratory-related hypoglossal nerve activity in response to activation of pulmonary C-fibers by capsaicin. Rats were anesthetized with urethane (1.2 g/kg, i.p.). Tracheostomy was performed. Catheters were introduced into the femoral vein and artery. Another catheter was placed near the entrance of the right atrium via the right jugular vein. Rats were paralyzed with gallamine triethiodide (5 mg/kg, i.v.), and ventilated artificially. Activities of the phrenic nerve (PNA) and the hypoglossal nerve (HNA) were recorded simultaneously. Varied doses of capsaicin (0.625, 1.25, and 5 µg/kg) were delivered into the right atrium to activate pulmonary C-fibers. Before bilateral vagotomy, apnea, decreases in PNA and HNA were observed in response to pulmonary C-fiber activation by the low and moderate doses of capsaicin. The high dose of capsaicin evoked an increase in PNA, an immediate tonic discharge of the hypoglossal nerve, and a decrease in phasic HNA. The onset time of HNA preceding PNA was abolished and replaced by a time lagged pattern as pulmonary C-fibers were activated. Raising CO₂ concentration did not attenuate the inhibitory effect of pulmonary C-fiber activation upon PNA and HNA. After bilateral sectioning of the vagi, administration of the moderate dose of capsaicin to activate non-vagal C-fibers produced increases in PNA and HNA. These results suggest that pulmonary vagal C-fiber activation may narrow the diameter at the oropharyngeal level by a decrease in phasic HNA, which may be disadvantageous for the maintenance of a patent upper airway.

Response of respiratory-related hypoglossal nerve activity to capsaicin-induced pulmonary C-fiber activation in rats

Response of respiratory-related hypoglossal nerve activity to capsaicin-induced pulmonary C-fiber activation in rats

Alveolar hypercapnia augments pulmonary C-fiber responses to chemical stimulants: role of hydrogen ion.

To determine whether the excitabilities of pulmonary C fibers to chemical and mechanical stimuli are altered by CO(2)-induced acidosis, single-unit pulmonary C-fiber activity was recorded in anesthetized, open-chest rats. Transient alveolar hypercapnia (HPC) was induced by administering CO(2)-enriched gas mixture (15% CO(2), balance air) via the respirator inlet for 30 s, which rapidly lowered the arterial blood pH from a baseline of 7.40 +/- 0.01 to 7.17 +/- 0.02. Alveolar HPC markedly increased the responses of these C-fiber afferents to several chemical stimulants. For example, the C-fiber response to right atrial injection of the same dose of capsaicin (0.25-1.0 microg/kg) was significantly increased from 3.07 +/- 0.70 impulses/s at control to 8.48 +/- 1.52 impulses/s during HPC (n = 27; P < 0.05), and this enhanced response returned to control within approximately 10 min after termination of HPC. Similarly, alveolar HPC also induced significant increases in the C-fiber responses to right atrial injections of phenylbiguanide (4-8 microg/kg) and adenosine (0.2 mg/kg). In contrast, HPC did not change the response of pulmonary C fibers to lung inflation. Furthermore, the peak response of these C fibers to capsaicin during HPC was greatly attenuated when the HPC-induced acidosis was buffered by infusion of bicarbonate (1.36-1.82 mmol. kg(-1). min(-1) for 35 s). In conclusion, alveolar HPC augments the responses of these afferents to various chemical stimulants, and this potentiating effect of CO(2) is mediated through the action of hydrogen ions on the C-fiber sensory terminals.

The changes in pulmonary C-fiber activity and lung mechanics induced by vagal stimulation in rabbits

The effect of unilateral stimulation of the vagus nerve on pulmonary C-fiber activity, total lung resistance (R L) and dynamic lung compliance (Cdyn) was studied in anesthetized, artificially ventilated rabbits. Vagal stimulation (4–30 Hz) increased both pulmonary C-fiber activity and R l but decreased Cdyn, and these changes were frequency-dependent. Atropine (2 mg kg ) blocked the responses of pulmonary C-fiber, R L and Cdyn to vagal stimulation at 4–30 Hz. Stimulation of pulmonary C-fiber activity by the higher volume-induced lung inflation was not significantly altered by atropine (2 mg kg ). A selective SP antagonist [D-Pro 2, D-Try 7,9]-SP (0.5 mg kg ) inhibited bronchoconstrictor responses to vagal stimulation at 30Hz but had no significant effect on those to the stimulation at 4–17 Hz. These results suggest that excitation of the rabbit pulmonary C-fiber activity by unilateral vagus nerve stimulation would occur as a result of the mechanical stimuli via a cholinergic neurotransmission and that during the stimulation at 30 Hz this excitation partly involves the local release of substance P (SP) to promote acetylcholine outflow.

Pulmonary C-fiber activation before and after peptidase inhibition in rats

Inhibition of peptidases within the lungs not only potentiates the effects of neuropeptides released from C-fibers but also the effects of bradykinin and capsaicin both of which stimulate C-fibers. To determine if peptidase inhibition potentiates C-fiber activation, we challenged pulmonary C-fibers in rats with capsaicin or bradykinin before and after inhibition of neutral endopeptidase (NEP) or angiotensin converting enzyme (ACE). Inhibition of NEP by phosphoramidon (10 mg/kg, i.v.) potentiated the effect of capsaicin (0.5–1 μg, i.v.) on C-fiber activity but did not change the response to bradykinin (1–2 μg, i.v.). Inhibition of ACE by captopril (5 mg/kg, i.v.) potentiated C-fiber activation by either bradykinin or capsaicin. Aerosol administration of either phosphoramidon (1×10 −5 M, 2 min) or captopril (4.6×10 −3 M, 2 min) potentiated C-fiber activation by capsaicin aerosol (1.6×10 −4 M, 1 min) but not by bradykinin aerosol (9.4×10 −5 M, 1 min). Therefore, inhibition of NEP or ACE may potentiate airway obstructive mechanisms initiated by C-fiber stimulation.

Pulmonary chemoreflexes elicited by intravenous injection of lactic acid in anesthetized rats.

Experiments were carried out to characterize the cardiorespiratory reflex responses to intravenous injection of lactic acid and to determine the involvement of vagal bronchopulmonary C-fiber afferents in eliciting these responses in anesthetized rats. Bolus injection of lactic acid (0.2 mmol/kg i.v.) immediately elicited apnea, bradycardia, and hypotension, which were then followed by a sustained hyperpnea. The immediate apneic and bradycardiac responses to lactic acid were completely abolished by bilateral vagotomy and were absent when the same dose of lactic acid was injected into the left ventricle. The subsequent hyperpneic response was substantially attenuated by denervation of carotid body chemoreceptors. After a perineural capsaicin treatment of both vagus nerves to block the conduction of C fibers, lactic acid no longer evoked the immediate apnea and bradycardia, whereas the hyperpneic response became more pronounced and sustained, presumably because of the removal of the inhibitory effect on breathing mediated by pulmonary C-fiber activation. Single-unit electrophysiological recording showed that intravenous injection of lactic acid consistently evoked an abrupt and intense burst of discharge from the vagal C-fiber afferent endings in the lungs. In conclusion, the cardiorespiratory depressor responses induced by lactic acid are predominantly elicited by activation of vagal pulmonary C fibers.

Pulmonary C-fibers elicit both apneusis and tachypnea in the rabbit

The effects of phenylbiguanide (PBG) on phrenic nerve and pulmonary C-fibers were studied in anesthetized spontaneously breathing rabbits with unilateral vagotomy. Right atrial injections of PBG at low (10 μg/kg) and high (100 μg/kg) dose resulted in a shallow tachypnea and apneusis followed by tachypnea, respectively, and these effects were blocked by procaine treatment of the vagus nerve. Also, the injection of PBG (100 μg/kg) still evoked the rapid shallow breathing preceded by apneusis in carotid chemoreceptor-denervated animals. Vigorous stimulation of pulmonary C-fibers by PBG (100 μg/kg) coincided with apneusis and the response was followed by a more modest increase in activity associated with tachypnea. Administration of PBG (10 μg/kg) into the right atrium caused an increase in pulmonary C-fiber activity associated with tachypnea. However, a small dose of PBG injected into the aortic circulation had no effect on the C-fiber activity but did inhibit respiration. These results suggest that the stimulation of pulmonary C-fibers via PBG injection can produce both inspiratory apnea and tachypnea.

Stimulation of pulmonary vagal afferent C-fibers by lung edema in dogs.

In anesthetized, open-chest dogs we examined the effect of pulmonary edema on the firing frequency of afferent vagal fibers arising from the lung. We recorded impulses from slips of the cervical vagus nerves and infused isotonic Krebs-Henseleit solution (20% of body weight) intravenously to increase net filtration pressure in the lung microvasculature. Measurement of extravascular lung water (6.0 +/- 0.4 g/g dry lung), and morphological examination of lung tissue (revealing various degrees of perivascular and peribronchial cuffing) confirmed that edema was present. At the end of the infusion when the lungs were congested (lung microvascular pressure, 37 cm water) and edematous, the impulse frequency of pulmonary and bronchial C-fibers and rapidly adapting receptors had increased 5-6 times. The only significant change in slowly adapting receptor activity was an increase during deflation. When lung water was still elevated but lung microvascular pressure had been restored to control by withdrawal of blood, impulse activity of rapidly and slowly adapting receptors reverted to or below control. Pulmonary C-fiber activity, although less than during congestion, remained significantly above control, several C-fibers being stimulated by interstitial edema in the absence of alveolar edema. Bronchial C-fibers were stimulated in severely edematous lung showing pronounced peribronchial cuffing and alveolar edema, but were not stimulated in milder grades of edema. Our results support the hypothesis (Paintal, 1969) that pulmonary C-fibers (J-receptors) are stimulated by an increase in interstitial pressure secondary to edema.