Influence of phasic volume feedback on abdominal expiratory nerve activity

Our purpose was to examine the influence of phasic lung volume feedback on the activities of motor nerves innervating the diaphragm and transversus abdominis muscles during hypercapnia and hypoxia. We studied seventeen decerebrate cats that were paralyzed and ventilated with a servo-respirator controlled by the integrated phrenic neurogram. The effects of phasic lung volume feedback were assessed by withholding pulmonary inflation during the central inspiratory period. Withholding lung inflation for a single respiratory cycle under hyperoxic, normocapnic conditions consistently prolonged the durations of the inspiratory and expiratory periods, and caused marked increases in the peak electrical activities of both phrenic and abdominal nerves. Hyperoxic hypercapnia (PaCO2 50-80 mmHg) and isocapnic hypoxia (PaO2 60-35 mmHg) increased peak phrenic and abdominal neural activities, and withholding pulmonary inflation under these conditions caused even greater augmentations of inspiratory and expiratory motor output. The augmentation of expiratory activity by withholding lung inflation was proportionately greater than the concomitant prolongation of the central expiratory period. All responses to non-inflation maneuvers were abolished following bilateral cervical vagotomy. The results indicate that vagally mediated volume feedback during inspiration can attenuate the output of abdominal motoneurons in the subsequent expiratory period. Moreover, hypoxia, which attenuates abdominal motor activity in vagotomized animals, enhances this activity when the vagi are intact.     

Dopaminergic modulation of respiratory timing mechanisms in carotid body-denervated dogs

The role of central dopaminergic mechanisms in ventilatory control was investigated by monitoring phrenic motorneuronal output of anesthetized dogs which were vagotomized, paralyzed and artificially ventilated and in which bilateral carotid body denervation had been performed. Intravenous administration of dopamine (DA) had no effect on phrenic output in these dogs. In contrast, apomorphine (APO), a potent dopaminergic agonist, which unlike dopamine, crosses the blood-brain barrier consistently and significantly prolonged inspiratory duration and shortened expiratory duration without altering phrenic amplitude. The dopaminergic antagonist haloperidol produced a frequency-dependent decrease in basal phrenic minute activity and reversed or abolished APO-induced changes in the phrenic profile. These data verify the specificity of APO for dopamine receptors and further suggest that DA receptors in the central nervous system exert a tonic effect on central respiratory control mechanisms. In contrast, domperidone, a dopaminergic antagonist which poorly penetrates the blood-brain barrier did not alter basal phrenic characteristics. Moreover, with the exception of inspiratory duration, domperidone did not antagonize APO-induced alterations in the phrenic profile. We conclude that dopaminergic mechanisms within the brain or spinal cord modulate timing relationships of central respiratory output.     

Responses of pulmonary slowly adapting receptors to airway occlusion in cat

To determine if phasic pulmonary slowly adapting stretch receptor (SAR) activity is abolished by the no-inflation test, we monitored the discharge patterns of individual SAR during respiratory cycles with and without lung inflation. In spontaneously breathing, anesthetized cats, the airway was occluded at end-expiration at both control functional residual capacity (FRC) and an end-expiratory lung volume elevated with an expiratory threshold load (ETL). We recorded from 67 SAR at FRC and from 32 of these while on the ETL. At FRC, 29 (43%) continued to fire during occluded inspiratory efforts. Of 20 afferents which did not fire during occlusions at FRC, 13 discharged during occlusions on ETL. At FRC, 39% of SAR had modulation indices (MI; difference between peak and minimum discharge frequencies during occlusion expressed as a fraction of the same change during a non-occluded breath) greater than 0.2; on ETL, 72% of SAR had MI greater than 0.2. Identification of medullary inspiratory neurons as ones with (I beta) and without (I alpha) SAR input depends on vagally-mediated respiratory drive to the airway smooth muscle in which SAR are located, the response characteristics of SAR projecting to that neuron, and end-expiratory lung volume.     

Activities of pulmonary stretch receptors during ventilatory cycles without lung inflation

When lung inflation is temporarily withheld in paralyzed, ventilated cats with intact vagi, the activities of inspiratory motor nerves are greater during the second cycle without inflation than during the first. This response is not easily attributable to increasing drive from chemoreceptors as it is abolished by vagotomy. We examined the hypothesis that the increasing inspiratory activity is the result of decreasing inhibitory feedback from pulmonary stretch receptors (PSRs). Decerebrate, paralyzed cats were ventilated by a servo-respirator in accordance with their own phrenic nerve activity. Afferent activities from individual PSRs were recorded from a few cut fibers of one vagus nerve; the vagi were otherwise intact. When lung inflation was withheld, phrenic and hypoglossal nerve activities and the durations of inspiration and expiration all increased and were significantly greater during the second cycle without inflation than during the first. The frequency of PSR discharge was also greater during the second cycle and thus did not account for the responses recorded from the motor nerves. We conclude that the latter responses probably reflect neural processes within the brain stem, involving a persistent inhibitory influence from lung inflation, which outlasts the inflation itself.     

The effect of the phase relationship between the arterial blood gas oscillations and central neural respiratory activity on phrenic motoneurone output in cats

The aim of the present experiments in artificially ventilated, anesthetized cats was to investigate in which circumstances the timing of the arterial blood gas oscillations within the respiratory cycle can be of importance in determining phrenic motoneurone output. The phase relationship phi was defined as the relative position of the peak of the phrenic bursts within the current continuously measured PaO2 oscillations. It was judged breath by breath whether there was a relationship between phi and neural tidal volume, and neural inspiratory and expiratory duration. Within cats, PETCO2 was kept constant at about 1.5-2% above apneic threshold. It was found that phi indeed partly determined these ventilatory parameters provided the oscillations were large enough. This was evident in normoxia; in moderate hypoxia the influence of phi was demonstrable more easily, i.e. at smaller oscillation amplitudes. In both conditions the effect of phi on neural tidal volume was most pronounced. Neural tidal volume was maximal when peak inspiration coincided with the expiratory trough of the PaO2 oscillations. A 1:1 phase lock between phrenic activity and the ventilatory only occurred when the pump frequency was close to the cats own breathing frequency. Bilateral carotid sinus nerve section abolished the effects of phi.     

Influence of lung volume on phrenic, hypoglossal and mylohyoid nerve activities

In decerebrate, paralyzed cats, ventilated by a servo-respirator in accordance with phrenic nerve activity, we examined the influence of lung volume on the activities of the phrenic, hypoglossal and mylohyoid nerves. When lung inflation was briefly withheld, the durations of inspiration (TI) and expiration (TE) and the activities of all three nerves increased. The relative increase in hypoglossal activity greatly exceeded that of phrenic activity and was apparent earlier in the course of inspiration. This hypoglossal response was enhanced by hypercapnia and isocapnic hypoxia. The responses of mylohyoid activity were quite variable: withholding lung inflation augmented inspiratory activity in some cats, but expiratory discharge in others. Sustained increases in end-expiratory lung volume were induced by application of 3-4 cm H2O of positive end-expiratory pressure (PEEP). Steady-state PEEP did not influence nerve activities or the breathing pattern. Bilateral vagotomy increased TI, TE, and the activities of all three nerves. No response to withoholding lung inflation could be discerned after vagal section. The results provide further definition of the influence of vagally mediated, lung volume dependent reflexes on the control of upper airway muscles. These reflexes are well suited to relieve or prevent upper airway obstruction.     

The effect of hyperinflation on respiratory muscle work in acute induced asthma

To examine the relationship between end-expiratory lung volume and respiratory muscle work during acute bronchoconstriction, we measured the work of breathing in nine asthmatic subjects, in whom bronchoconstriction was induced with histamine aerosol. When the forced expiratory volume in one second (FEV1) fell below 60% of the control value, work was measured at the spontaneously hyperinflated lung volume (VLS), at a volume equivalent to the control functional residual capacity (FRC) and at a volume 30% of vital capacity (VC) above the control FRC. Hyperinflation to VLS caused a 39% decrease in the total positive work per breath from 2.8 +/- 0.4 to 1.7 +/- 0.1 J, entirely due to a decrease in expiratory work per breath from 1.6 +/- 0.4 to 0.10 +/- 0.05 J. Inspiratory work did not change at any lung volume, because the increase in inspiratory elastic work due to hyperinflation was offset by the decrease in flow resistive work. Breathing above VLS did not alter the total positive muscle work, but did increase the negative work of the inspiratory muscles from 0.4 +/- 0.1 to 0.8 +/- 0.1 J.breath. We conclude that during induced asthma spontaneous hyperinflation minimizes the total respiratory muscle work and may constitute a mechanism for minimizing energy expenditure.     

Characterization of respiratory-related activity of the facial nerve

Activities of the facial, hypoglossal and phrenic nerves were recorded in decerebrate and paralyzed cats. These animals were ventilated with a servo-respirator which produced lung inflations in parallel with phrenic activity. Peak inspiratory phrenic, hypoglossal and facial activities increased in hypercapnia or hypoxia. When pulmonary inflation was prevented, hypoglossal and facial activities increased more than phrenic. Responses to withholding lung inflation differed from those following vagotomy. These differences were observed in expiratory facial and hypoglossal activities and in hypercapnia- and hypoxia-induced changes in facial activity. Administration of pentobarbital or hyperventilation to hypocapnia caused greater suppressions of hypoglossal than facial activity; the latter declined more than phrenic activity. The results support the hypothesis that influences from the brainstem reticular formation and from pulmonary stretch receptors are differentially distributed to motoneurons innervating upper airway muscles compared to those of the bulbospinal-phrenic system. The concept that ventilatory activity is influenced by tonic, as well as phasic discharge of pulmonary receptors is discussed.     

Responses of early and late onset phrenic motoneurons to lung inflation

In anesthetized or decerebrate cats that were paralyzed and ventilated with a cycle-triggered pump, we produced changes in activity of the whole phrenic nerve and of individual phrenic motoneurons (fibers or cells in the spinal cord) by withholding lung inflation during the inspiratory (I) phase. The neurons were classified into early- and late-onset types (discharge onset less or greater than 80 msec, respectively, after whole phrenic onset). Both unit and whole phrenic activity exhibited a variety of responses to inflation (excitation, depression, or no effect); but there were no consistent differences between responses of early- and late-onset neurons. The distribution of responses was quite different from that of dorsal respiratory group (DRG) I neurons (Cohen and Feldman, 1984); in particular there was no group of phrenic neurons corresponding to the late-onset I-beta neurons (I neurons excited by inflation). We conclude that the inputs to late-onset phrenic neurons are not predominantly or exclusively from late-onset DRG neurons.     

Effects of hypercapnia on phrenic and stretch receptor responses to lung inflation

To determine if hypercapnia and reflex bronchoconstriction attenuate lung inflation effects on ventilatory activity by indirect effects on intrapulmonary stretch receptors (PSR), phrenic nerve activity and single unit PSR were monitored at controlled levels of static airway pressure (Paw) and arterial PCO2 in 15 anesthetized dogs. Paw in a vascularly isolated lung was varied between 2 and 14 cm H2O at levels of PaCO2 between 35 and 85 mm Hg. PSR activity (n = 38) in fine strands dissected from an otherwise intact vagus nerve and the integrated phrenic neurogram were recorded. The response to Paw varied from one PSR to another, but was consistent in a given unit; PaCO2 had no consistent effect on individual responses. Selected PSR (n = 15) were averaged to yield a population response to Paw; the selection criteria were: phrenic activity responded briskly to Paw and measurements were made at three levels of PaCO2. Average PSR discharge increased linearly with Paw but was unaffected by PaCO2. On the other hand, phrenic burst frequency decreased as Paw increased and hypercapnia attenuated the slope of this relationship. These results suggest that effects on the relationship between PSR activity and Paw cannot account for attenuation of the relationship between phrenic frequency and Paw in hypercapnia. The effect of PaCO2 on the phrenic frequency vs Paw relationship probably arises from integrative mechanisms in the central nervous system.     

Effects of focal cooling of the ventral medullary surface on breathing pattern and blood pressure in dogs

We assessed the effect of focal graded cooling of the ventral medullary surface (VMS) on breathing pattern and blood pressure in 15 anesthetized, vagotomized and artificially ventilated dogs. Diaphragmatic electromyogram or phrenic neurogram, referred to as Ec, and blood pressure (BP) were obtained during localized (2 x 2 mm2) cooling of the VMS. Greatest depression of both Ec and BP was obtained by cooling in the areas located 4-9 mm caudal to the foramen cecum (Fc) and lateral to the pyramids. Mild cooling in these intermediate areas decreased both inspiratory duration (Ti) and the rate of rise of Ec (Ec/Ti), but respiratory rate was unchanged. Cooling of the rostral areas (0-3 mm from Fc) induced mild depression of Ec amplitude due to reduction in Ec/Ti without changing Ti, and prolonged expiratory duration (Te) significantly. Cooling of the caudal areas (12-18 mm from Fc) reduced Ec amplitude mildly due to reduction in Ti without affecting Ec/Ti, and shortened Te greatly. Cooling of the rostral areas produced mild fall in BP, but cooling of the caudal areas did not affect BP significantly. It is suggested that rostral and intermediate parts of the VMS participate in the shaping of inspiratory drive, whereas wide areas of the VMS including caudal part are involved in the determination of respiratory timing. It is also suggested that the rostral and intermediate parts, and not the caudal part, of the VMS are important in the regulation of vasomotor tone.     

Effect of blocking medial area of nucleus retrofacialis on respiratory rhythm

Experiments were performed on anaesthetized, vagotomized rabbits. Respiratory movement and phrenic rhythmical discharge were reversibly abolished by the symmetrical injection of 1% procaine into the medial area of the nucleus retrofacialis (mNRF). Blocking other areas of the medulla had no obvious effect on respiratory rhythm, with the exception of the rostral portion of the ventral respiratory group (VRG), which overlaps with the mNRF. When the mNRF was blocked, most inspiratory and expiratory neurons recorded in the VRG and DRG (dorsal respiratory group) gradually started to fire continuously, and no longer exhibited respiratory rhythm. A minority of respiratory neurons was inactivated during apnea. Stimulation of the caudal portion of the DRG and VRG evoked only a short cluster of phrenic discharges instead of rhythmical firing, indicating that the respiratory neurons situated in these areas cannot generate rhythmic activity by themselves. This suggests that the mNRF plays an important role in the genesis and maintenance of basic respiratory rhythm.     

Central and peripheral neural respiratory activity in the mature sheep foetus and newborn lamb.

Activity from respiratory neurones in the medulla, the phrenic and intercostal nerves was recorded in 25 foetal sheep, exteriorized a few days before term from ewes given a spinal anaesthetic, and from nine newborn lambs, anaesthetized with an allobarbitone-urethane mixture. In 12 foetuses, there was little or no sustained respiratory activity, central activity consisting of tonically discharging expiratory and other neurones and silent inspiratory neurones. In the remaining 13 foetuses, respiratory activity was periodic or continuous and it was possible to confirm that the motor component of the respiratory reflex was mature, that apnoea was not due to medullary depression, that foetal respiration was unaffected by chemoreceptor stimulation, by noise, by light, by electrical stimulation of the sciatic nerve and only slightly by inflation or deflation of the lungs. All these stimuli were effective shortly after birth. Occlusion of the umbilical cord caused poorly sustained gasps in the "non-breathing" foetuses and in the "breathing" foetuses, abolition of inspiratory and expiratory activity in the medulla and the onset of gasps and flattening of the electro-corticogram. Rhythmic respiration resumed after release of the cord with a latency which varied with the duration and severity of the asphyxia. This type of respiratory depression was not reflex but due to a direct, central action of hypoxia. The sequence of respiratory events at birth is discussed.     

Activity of medullary respiratory neurones during reflexes from the lungs in cats.

We have studied in cats the discharge pattern in response to lung inflation and deflation of 283 medullary respiratory neurones, 173 being inspiratory and 110 expiratory. The ventral respiratory nucleus, near the nucleus ambiguus, was particularly investigated. The neurones were classified into bulbo-spinal neurones, laryngeal motoneurones and propriobulbar neurones by antidromic invasion from the spinal cord or the vagus nerve (collision test). The bulbo-spinal neurones responded in the same direction as spinal motoneurones in the Hering-Breuer reflexes: depression of inspiratory neurones and facilitation of expiratory neurones by inflation of the lungs. All the expiratory laryngeal motoneurones and some inspiratory laryngeal motoneurons responded in the opposite direction to the Hering-Breuer reflexes: depression of expiratory motoneurones and facilitation of inspiratory motoneurones. The function of propriobular neurones could be inferred from their response to Hering-Breuer reflexes: one group of propriobulbar neurones responded in such a manner as to be linked to the activity of the bulbo-spinal neurones; the other group responded in accordance with the activity of the laryngeal motoneurones.     

Changes in neural drive (EMGd) and neuromuscular coupling during histamine-induced bronchoconstriction in patients with asthma

This study was undertaken in order to assess the neural drive to the respiratory muscles and the inspiratory neuromuscular coupling in patients with bronchial asthma during histamine-induced bronchoconstriction. Bronchoconstriction was produced in a graded fashion, with histamine phosphate aerosol of increasing dose, in twelve asymptomatic asthmatic patients and was measured by FEV1. Inspiratory drive was measured by electromyographic activity of the diaphragm (EMGd) and the coupling of the neural drive to the respiratory muscles was assessed by the relationship of mouth occlusion pressure (P0.1) to EMGd. During the test we also measured electromyographic activity of the inspiratory intercostal (EMGint), sternomastoid (EMGsm) and expiratory abdominal (EMGab) muscles. Histamine caused a significant decrease in FEV1, a significant increase in P0.1, EMGd, EMGint, and a relevant increase in EMGsm, with no substantial increase in EMGab. An inverse significant relationship between the change in FEV1 and changes in P0.1, EMGd and EMGint and a significant correlation between the change in FEV1 and in the P0.1/EMGd ratio were observed. We conclude that a progressive increase in bronchospasm is accompanied by a progressive increase in respiratory neural drive and decrease in neuromuscular coupling. This could be caused both by an increase in lung volume and a lack of abdominal expiratory muscle recruitment.     

Chemosensitivity and breathing pattern regulation of the coatimundi and woodchuck.

An analysis of breathing pattern regulation was carried out on the coatimundi and woodchuck who represent two different volume-time patterns. It was found that the coati, with a short expiratory time as a fraction of total breath time, TE/TTOT, has a greater sensitivity to CO2 as represented by the slope and threshold of its ventilatory response. Breathing air the coati maintains post-inspiratory inspiratory activity (PIIA) of the posterior cricoarytenoid (PCA) through 51% of expiration, while the woodchuck, who is less sensitive to CO2 and has a long TE/TTOT, exhibits no PIIA of the PCA. The woodchuck also has a greater incidence and duration of end-expiratory pauses (or delayed inspiratory onset). The woodchuck does not demonstrate the usual inverse relationship between VT and TE in response to 5% CO2 and does not recruit PIIA of the PCA at this level of CO2. These data confirm the importance of CO2 chemosensitivity in regulation of TE. It is further demonstrated that interspecific differences in chemosensitivity among three mammals of the same size are reflected in regulation of TE but not in inspiratory 'drive' (as indicated by mean inspiratory flow, VT/TI).     

Activity of abdominal muscle motoneurons during hypercapnia.

Our purpose was to examine the influence of hypercapnia on the activity of motoneurons innervating the transversus abdominis and internal oblique abdominal muscles, and of integrated phrenic and abdominal motor nerve activities. Studies were done in nine adult cats that were decerebrated, vagotomized, thoracotomized, paralyzed and ventilated mechanically. Of 42 motoneurons examined, 24 showed strong respiratory modulation (RM neurons), with the discharge confined primarily to the central expiratory period. The remaining 18 motoneurons discharged tonically, and failed to show respiratory modulation even at increased levels of central respiratory drive. Hyperoxic hypercapnia augmented the activities of the phrenic and abdominal nerves and increased the early expiratory discharge frequency of the RM neurons. The hypercapnia-induced increase in firing frequency during early expiration was accompanied by a corresponding decline in late expiration, and a virtual abolition of the inspiratory activity in the few neurons that discharged in this phase under normocapnic conditions. Finally, hypercapnia induced an increase in the number of spikes generated during each expiratory period in about half of the RM neurons, whereas the remaining cells showed a decrease. Thus, the increased peak activity of the integrated whole abdominal nerve burst with hypercapnia was brought about by a shift in the temporal pattern of motoneuron firing, or by an increase in the number of spikes generated during the expiratory period. The steep rate of rise and the pronounced early expiratory peak observed in the integrated abdominal nerve burst during hypercapnia in this preparation are consistent with the increase in motoneuron firing frequency during the early stages of the expiratory phase.     

The effects of acute bronchoconstriction on respiratory activity in patients with chronic obstructive pulmonary disease

Attacks of acute airway obstruction often complicate the course of chronic obstructive pulmonary disease (COPD). In asthmatic subjects, bronchospasm triggers an increase in respiratory drive, which results in hyperventilation and hypocapnia. In the present study, we assessed the effects of acute bronchoconstriction induced by aerosolized methacholine on breathing and lung mechanics in 12 patients with stable COPD. Even low doses of methacholine markedly increased airway resistance and caused hyperinflation and decreased inspiratory muscle performance in the patients. Increasing airway obstruction produced a progressive rise in PCO2 despite an increase in minute ventilation. Breathing frequency and average inspiratory flow were greater, but tidal volume decreased because of shortening of the inspiratory duration. The magnitude of CO2 retention during acute bronchoconstriction was inversely related to the changes in tidal volume and inspiratory time (p less than 0.01 for each). In subjects with COPD, the occlusion pressure response to progressive hypercapnia failed to increase during bronchoconstriction. These results show that patients with COPD retain CO2 during acutely increasing airway obstruction induced by bronchoconstriction partly because of a rapid shallow breathing pattern that reduces alveolar ventilation.     

Effects of bronchoconstriction on breathing during normoxia and hypoxia in anesthetized cats

The effect of an increase in bronchomotor tone on control of breathing during both normoxia and hypoxia, and the role of vagal afferents in regulating these responses were studied in 15 anesthetized cats. Minute ventilation (VE) was measured with a pneumotachograph connected in series with a tracheal cannula. Total diaphragmatic EMG activity per minute (means p X f, peak EMG moving average X respiratory frequency) was measured to assess the central inspiratory drive. Bronchoconstriction was generated by inhalation of methacholine aerosol (10-30 breaths, 0.5% solution) which increased total lung resistance to approximately 400% of the control value. Transient hypoxia was induced by allowing the cats to rebreathe a hypoxic gas mixture (4.5% O2 balanced N2) for approximately 1 min. During normoxia, bronchoconstriction increased VE from a baseline of 100 to 129 +/- 7% (mean +/- SEM; P less than 0.05) and increased (means p X f) from 100 to 174 +/- 16% (P less than 0.01). During hypoxia, the response of (means p X f) to bronchoconstriction (404 +/- 40%) was still greater than without bronchoconstriction (306 +/- 35%; P less than 0.01), but the responses of VE were not significantly different between these two conditions (P greater than 0.05). After sectioning both vagus nerves the bronchoconstriction-induced increase in central inspiratory drive was either reduced (during normoxia) or abolished (during hypoxia). These results suggest that stimulation of vagal bronchopulmonary afferents are involved in regulating the ventilatory responses to bronchoconstriction. Other non-vagal factors, such as intrinsic properties and reflex responses of the respiratory muscles, may also contribute, in part, to the observed responses.     

Contribution of hypercapnic stimuli and of vagal afferents to the timing of breathing in anesthetized cats.

In tracheotomized, anesthetized cats, the authors studied the role of phasic and tonic vagal discharge and of hypercapnic stimuli on the timing of breathing. The effect of tonic vagal discharge was separated from that of the other two parameters by comparing the duration of inspiration and of expiration of control breaths with those obtained during occlusions of the airways at FRC (bulbo-pontine activity). The effect of tonic vagal discharge was then separated from that of hypercapnic stimuli by comparing the bulbo-pontine activity before and after vagotomy. Hypercapnia caused shortening of inspiratory and expiratory duration set by the bulbo-pontine pacemaker and increased sensitivity of the respiratory centers for a given phasic vagal input (displacement to the left of the tidal volume vs inspiratory duration relationship). Vagotomy did not modify the bulbo-pontine duration of inspiration nor its possibility to shorten in hypercapnia; by contrast it caused a lengthening of the expiratory time which did not shorten any more in hypercapnia, suggesting that tonic vagal discharge mainly influences the expiratory duration.