On the relation between expiratory duration and subsequent inspiratory duration

To characterize respiratory interphase relationships in dogs, inspiratory duration (TI) or expiratory duration (TE) was systematically altered by electrical activation of vagal afferents, and the effect on subsequent TE or TI values was measured from the phrenic discharge. A linear TI-subsequent TE relationship was found. Following a vagally mediated prolongation of TE, 1) TI was prolonged, and the TE-subsequent TI relationship was curvilinear, 2) the threshold for inspiratory termination by phasic vagal inputs was increased, 3) the amplitude of the time course of the phrenic discharge was reduced so that the peak discharge reached the same level at inspiratory termination independent of TI, 4) the effect on TI prolongation persisted for several breaths whereas the effect was minimal on subsequent TE values, and 5) for tonic inputs the direct shortening of TI was nearly offset by the indirect lengthening of TI. These studies suggest the existence of slow central mechanisms that provide adaptation to elevated levels of vagal input in the control of TI. These mechanisms may also be responsible for the interphase timing relationships.     

Phase resetting of the respiratory cycle before and after unilateral pontine lesion in cat.

The pontine respiratory group (PRG) facilitates the mechanism for terminating the inspiratory phase but may influence other phases in the respiratory cycle as well. We determined the effects of PRG lesions on the response of the respiratory cycle to superior laryngeal nerve stimulation delivered in each phase of the cycle in decerebrate, vagotomized, paralyzed, and ventilated cats (n = 6). We measured the duration of inspiration (TI) and expiration (TE) for three breaths before and in the perturbed breath and TI for three breaths after the perturbation. The delay to next inspiration was plotted against the phase at which the stimulus was delivered. Before lesioning, premature inspiratory termination was followed by phase-dependent shortening of TE. After lesioning, premature inspiratory termination did not systematically change the following TE. Breath-by-breath variability (measured 50 breaths) increased and stimulus after-effects (prolonged TI in the subsequent cycle) were augmented following lesions. These data indicate that the PRG plays an important role in the control of TE after perturbation and in the stability of the respiratory central pattern generator.     

Adaptation to reflex effects of prolonged lung inflation

Adaptation to the reflex effects of sustained changes in lung volume on inspiratory duration (TI), expiratory duration (TE), and the phrenic neurogram was examined. Test inflations in gallamine-paralyzed dogs anesthetized with pentobarbital sodium were made during a 6-min trial while the animal was not ventilated: 2 min at functional residual capacity (FRC), 2 min at elevated airway pressure, and 2 min back at FRC. The dogs were hyperoxygenated and arterial PCO2 was kept constant by an infusion of tris (hydroxymethyl) aminomethane. The maintained inflations produced minimal changes in TI. On return to FRC, TI was prolonged in proportion to the magnitude of the prior inflation. In contrast, inflation produced marked prolongation of TE, which then adapted back toward preinflation values. On return to FRC, TE shortened initially to values below control. This shortening increased with greater prior lung inflations. The times to reestablish steady-state values upon return to FRC differed for TI (14.8 +/- 4.6 s) and TE (33.8 +/- 12.7 s). The magnitude of the phrenic neurogram at a fixed time from onset of inspiration and its slope were unchanged with inflation. These results indicate that respiratory phase durations are influenced not only by pulmonary afferent input within each respiratory cycle but also by prior vagal afferent activity that engages central processes with long, although different, time constants. Afferent input to the slow central process controlling TI is not gated to only one phase of the respiratory cycle.     

Short-term potentiation of breathing in humans.

The purpose of this study was to determine if the increase in ventilation induced by hypoxic stimulation of the carotid bodies (CB) persists after cessation of the stimulus in humans. I reasoned that a short-term potentiation (STP) of breathing, sometimes called an "afterdischarge," could be unmasked by combining hypoxia with exercise, because ventilation increases synergistically under these conditions. Seven young healthy men performed mild bicycle exercise (30% peak power) while breathing O2 for 1.5 min ("control" state), and their CB were then stimulated by 1.5 min of hypoxic exercise (10% O2--balance N2). CB stimulation was then terminated by changing the inspirate back to O2 as exercise continued. Inspiratory and expiratory duration (TI and TE) and inspiratory flow and its time integral [tidal volume (VT)] were measured with a pneumotachometer. Inspired minute ventilation (VI) and mean inspiratory flow (VT/TI) declined exponentially after the cessation of CB stimulation, with first-order time constants of 28.6 +/- 6.7 and 24.6 +/- 1.6 (SD) s, respectively. The slow decay of VI was due primarily to potentiation of both TI and TE, although the effect on the latter predominated. Additional experiments in six subjects showed that brief intense CB stimulation with four to five breaths of N2 during mild exercise induced STP of similar magnitude to that observed in the hypoxic exercise experiments. Finally, the imposition of hyperoxia during air breathing exercise at a level of respiratory drive similar to that induced by the hypoxic exercise did not change VI significantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

PAF and the role of the vagus nerve in the breathing pattern of the pig.

In 14 anesthetized, spontaneously breathing pigs we examined the changes in breathing pattern, in respiratory mechanics and in systemic and pulmonary vascular parameters after i.v. PAF administration. In another 3 pigs, the effects of PAF were also examined after bilateral vagotomy. In intact pigs, PAF induces apnea, bronchoconstriction, pulmonary hypertension and systemic hypotension. Our results also show that administration of PAF alters the phasic vagal activity, modifying the slope of VT vs TI and TE vs TI relationships and the TI0/TI ratio. These effects and apnea are vagus-dependent. The central excitatory timing effect of PAF on inspiratory duration (TI0) was correlated with a decrease in passive compliance but not with active compliance. We postulate that the activation by vagal input strengthens the mechanisms that counteract the bronchoconstrictor effect of PAF.     

Phrenic activity and intercostal muscle emg during inspiratory loading in newborn kittens

The effects of airway occlusions at functional residual capacity (FRC) on both "integrated" phrenic activity (Phr) and intercostal muscle electromyogram (intEMG) were studied in intact and vagotomized spontaneously breathing kittens during the 1st wk of life. Animals were anesthetized im with a mixture of ketamine (30 mg/kg) and acepromazine (1.1 mg/kg). In the intact kittens, inspiratory loading led to a significant increase in peak amplitudes of both Phr and intEMG and prolongation of inspiratory (TI) and expiratory (TE) times. Mean values of rate of rise of Phr and intEMG measured at 200 ms (intEMG200) from the onset of inspiration were unaffected. The results indicated that in newborns the vagal component of the load compensation is of great importance. Following vagotomy, airway occlusion produced a significant increase in mean values of TI and intEMG only. These small but significant changes suggest that most of the load compensation reflex is dependent on prolongation of TI. Increased intEMG200 during loading in the vagotomized kittens, observed during several trials, implies that the intercostal fusion-alpha interaction may operate in newborns.     

Central adaptation to inspiratory-inhibiting expiratory-prolonging vagal input

We reported earlier on the changes in excitability of central respiratory switching mechanisms in the course of a brief inspiratory-inhibiting vagal stimulus (J. Appl. Physiol. 50: 1183-1192, 1981). To further define the dynamics of central processing of such input we studied the changes in the excitability of timing mechanisms in the immediate (less than 1.0 s) and late (1-20 s) periods after stimulus removal. We also examined the changes in respiratory timing in the course of protracted (greater than 20 s) stimulation. Studies were done using pentobarbital-anesthetized cats. For studies involving long-term stimulation or late off responses, cats were paralyzed, vagotomized, carotid denervated, and artificially ventilated. We found that the inspiratory inhibitory influence of a brief stimulus continues, in a declining fashion, for 0.3-10 s after removal of the stimulus. This was followed by a paradoxical response, inspirations were prolonged and expirations were shortened, which was maximal 1-2 s after stimulus removal and which declined gradually over a period of 6-16 s. There was progressive decline in inspiratory-shortening expiratory-prolonging influence in the course of sustained stimuli. These results indicate substantial adaptation in the course of even brief stimuli and provide an explanation for inspiratory-expiratory duration and expiratory-inspiratory duration linkages.     

Interaction between vagal and chemoreceptors afferents in ventilatory response to transient hypercapnia (anaesthetized rabbit).

In rabbits anaesthetized with ethyl-carbamate, stimulation of chemoreceptors afferents was allowed by transient hypercapnia, before and after vagal blockade by DC current. In these relatively fast breathing animals, the transient hypercapnia produced light changes of inspiratory tidal volume (VI), inspiratory (TI) and expiratory durations (TE). Despite the identity of transient hypercapnia, it ensued that: (1) the higher the spontaneous VI and the lower the respiratory frequency (fR), the greater their respective changes (deltaVI and deltafR) during the ventilatory response; (2) after vagal blockade, greater changes in VI, TI, TE and mean inspiratory flow rate (VI/TI) occurred than in control state, while the relation between deltafR and fR was more significant than in control state. Respective roles played by vagal and chemoreceptors afferents in the ventilatory response to transient hypercapnia are discussed.     

Thyroarytenoid muscle activity during loaded and nonloaded breathing in adult humans

Previous fiber-optic studies in humans have demonstrated narrowing of the glottic aperture in expiration during application of expiratory resistive loads. Nine healthy subjects were studied to determine the effect of expiratory resistive loads on the electromyographic activity of the thyroarytenoid (TA) muscle, a vocal cord adductor. Four of the nine subjects also underwent the application of inspiratory resistive loads and voluntary prolongation of either inspiratory (TI) or expiratory (TE) time. TA activity was recorded by intramuscular hooked-wire electrodes. During quiet breathing in all subjects, the TA was phasically active on expiration and often tonically active throughout the respiratory cycle. TA expiratory activity progressively increased with increasing levels of expiratory load. Inspiratory loads resulted in increased TA "inspiratory" activity. Voluntary prolongation of TE to times similar to those reached during loaded breathing induced increases in TA expiratory activity similar to those reached during the loaded state. Voluntary prolongation of TI was associated with an increase in TA inspiratory activity. Similar increases in TI during inspiratory loading or voluntary conditions were associated with comparable increases in TA inspiratory activity in three of the four subjects. In conclusion, increased activation of TA during the application of expiratory resistive loads implies that the reported narrowing of glottic aperture during expiratory loading is an active phenomenon. Changes in activation of the TA with resistive loads appear to be related to changes in respiratory pattern.     

Role of the carotid chemoreceptors in regulation of inspiratory onset

We studied the effect of intermittent tidal breaths of CO2-enriched air (3-9% CO2) on the duration of expiratory time (TE) in five trained dogs, before and after (3 dogs) bilateral surgical denervation of the carotid bodies (CBD). During studies the dogs lay quietly, either awake or in nonrapid-eye-movement sleep, and breathed through a cuffed endotracheal tube inserted via a chronic tracheostomy. Studies were conducted during bilateral blockade of the cervical vagus nerves (VB), achieved by circulating cold alcohol through radiators placed around exteriorized vagal skin loops. Prior to CBD, single breaths of CO2 significantly shortened TE and thus advanced the onset of the subsequent inspiration. Further, the decrease in TE induced by the CO2 stimulus was in direct proportion to the inspired CO2 concentration. Thus 3% CO2 shortened TE by 1.82 +/- 0.93 (SD) s, and 9% CO2 by 3.44 +/- 1.53 s. Changes in TE occurred in the absence of associated changes in either tidal volume or inspiratory time. After CBD, test breaths of CO2 failed to shorten TE during VB. We conclude that the carotid bodies have the ability to mediate changes in the timing of inspiratory onset in response to a transient CO2 stimulus.     

Respiratory effects of brief baroreceptor stimuli in the anesthetized dog

To quantify the immediate isocapnic respiratory response to baroreceptor stimulation, pressure in the isolated externally perfused carotid sinuses (CS) of 24 vagotomized alpha-chloralose-anesthetized dogs was increased selectively during either inspiration or expiration as a step (from time of onset to end of respiratory phase) or a pulse (500 ms). The rise time (150 ms), base-line pressure (80 mmHg), and stimulus magnitude (40 mmHg) were similar for the two stimuli. The time of stimulus onset (delay), expressed as a percent of control time of inspiration (TI) or expiration (TE), was varied. TI, TE, and tidal volume (VT) were expressed as percent changes from control. Stimuli delivered early in inspiration lengthened TI [23.5 +/- 6.4% (SE) for step and 11.7 +/- 6.3% for pulse stimuli at 5% delay] more effectively than late stimuli. VT was essentially unaltered. In contrast, step stimuli delivered during expiration caused a lengthening of TE (32.7 +/- 6.3% at 5% delay) that did not depend on the delay (up to 75%). Very late (85%) pulse stimuli lengthened TE (15.2 +/- 5.7%) more effectively than early stimuli. For both stimuli, the expiratory VT was unaltered. When the responses are compared before and after separation of the blood supply of the carotid bodies from the CS region and when they are compared before and after inhibition of reflex systemic hypotension by ganglionic blockade, the observed responses were shown to be due solely to CS baroreceptor stimulation and not to alterations in carotid body blood flow or reflex changes in systemic cardiovascular variables.     

Termination of inspiration by phase-dependent respiratory vagal feedback in awake normal humans.

Imperceptible levels of proportional assist ventilation applied throughout inspiration reduced inspiratory time (TI) in awake humans. More recently, the reduction in TI was associated with flow assist, but flow assist also reaches a maximum value early during inspiration. To test the separate effects of flow assist and timing of assist, we applied a pseudorandom binary sequence of flow-assisted breaths during early, late, or throughout inspiration in eight normal subjects. We hypothesized that imperceptible flow assist would shorten TI most effectively when applied during early inspiration. Tidal volume, integrated respiratory muscle pressure per breath, TI, and TE were recorded. All stimuli (early, late, or flow assist applied throughout inspiration) resulted in a significant increase in inspiratory flow; however, only when the flow assist was applied during early inspiration was there a significant reduction in TI and the integrated respiratory muscle pressure per breath. These results provide further evidence that vagal feedback modulates breathing on a breath-by-breath basis in conscious humans within a physiological range of breath sizes.     

Interactions between lung stretch and PaCO2 in modulating ventilatory activity in dogs

The effects of changes in airway pressure (Paw) and arterial PCO2 (PaCO2) on ventilatory activity were studied in anesthetized thoracotomized dogs in which both lungs were ventilated separately. Pulmonary artery occlusion on one side and contralateral vagotomy allowed the reflex effects on ventilation of changes in Paw and PaCO2 to be elicited independently of each other. Ventilatory activity was assessed from integrated efferent phrenic activity, analyzed with respect to burst amplitude (Phr), burst frequency (f), and inspiratory TI) and expiratory duration (TE). While Phr increased linearly with PaCO2, it was independent of Paw. Both PaCO2 and Paw affected f in a complex nonadditive way; this response was entirely mediated by effects on TE, TI being unaffected by either stimulus. The analog of ventilation, estimated as Phr x f, increased linearly with PaCO2 and decreased linearly with Paw, but the effects of both stimuli appeared to be additive. It is concluded that the apparently simple effect of Paw and PaCO2 on ventilation results from more complex effects these stimuli exert on its components.     

Effects of spontaneous swallows on breathing in awake goats.

The effects of spontaneous swallows on breathing before, during, and after solitary swallows were investigated in 13 awake goats. Inspiratory (TI) and expiratory (TE) time and respiratory output were determined from inspiratory airflow [tidal volume (VT)] and peak diaphragmatic activity (Dia(peak)). The onset time for 1,128 swallows was determined from pharyngeal muscle electrical activity. During inspiration, the later the swallowing onset, the greater increase in TI and VT, whereas there was no significant effect on TE and Dia(peak). Swallows in early expiration increased the preceding TI and reduced TE, whereas later in expiration swallows increased TE. After expiratory swallows, TI and VT were reduced whereas minimal changes in Dia(peak) were observed. Phase response analysis revealed a within-breath, phase-dependent effect of swallowing on breathing, resulting in a resetting of the respiratory oscillator. However, the shift in timing in the breaths after a swallow was not parallel, further demonstrating a respiratory phase-dependent effect on breathing. We conclude that, in the awake state, within- and multiple-breath effects on respiratory timing and output are induced and/or required in the coordination of breathing and swallowing.     

Effects of acute hyperbaric oxygenation on respiratory control in cats

We studied ventilatory responsiveness to hypoxia and hypercapnia in anesthetized cats before and after exposure to 5 atmospheres absolute O2 for 90-135 min. The acute hyperbaric oxygenation (HBO) was terminated at the onset of slow labored breathing. Tracheal airflow, inspiratory (TI) and expiratory (TE) times, inspiratory tidal volume (VT), end-tidal PO2 and PCO2, and arterial blood pressure were recorded simultaneously before and after HBO. Steady-state ventilation (VI at three arterial PO2 (PaO2) levels of approximately 99, 67, and 47 Torr at a maintained arterial PCO2 (PaCO2, 28 Torr) was measured for the hypoxic response. Ventilation at three steady-state PaCO2 levels of approximately 27, 36, and 46 Torr during hyperoxia (PaO2 450 Torr) gave a hypercapnic response. Both chemical stimuli significantly stimulated VT, breathing frequency, and VI before and after HBO. VT, TI, and TE at a given stimulus were significantly greater after HBO without a significant change in VT/TI. The breathing pattern, however, was abnormal after HBO, often showing inspiratory apneusis. Bilateral vagotomy diminished apneusis and further prolonged TI and TE and increased VT. Thus a part of the respiratory effects of HBO is due to pulmonary mechanoreflex changes.     

Effects of hypercapnia on Breuer-Hering threshold for inspiratory termination

The effects of CO2 concentration on the timing of inspiratory duration (TI) and expiratory duration (TE) and the responses to lung inflation were studied in decerebrate paralyzed cats. With lung volume held at functional residual capacity during the breath cycle, hypercapnia (fractional concentration of inspired CO2 = 0.04) caused variable changes in TI and significant increases in TE. To obtain the Breuer-Hering threshold relationship [tidal volume (VT) vs. TI] and the timing relationship between TE and the preceding TI (TE vs. TI), ramp inflations of various sizes were used to terminate inspiration at different times in the breath cycle. Hypercapnia caused the VT vs. TI curves to shift in an upward direction so that at higher lung volumes TI was lengthened. Also, the slope of the TE vs. TI relationship was increased. The results suggest that hypercapnia diminished the sensitivity of the Breuer-Hering reflex to the lung volume, thus allowing volume to increase with little effect on TI. In addition, TE appears to become more sensitive to changes in the preceding TI. A model is presented which provides a possible neural mechanism for these responses.     

Control of respiratory pattern in conscious dog: effects of heat and CO2

We measured tidal volume (VT) and inspiratory (TI) and expiratory (TE) durations in five conscious tracheostomized dogs breathing air or 5% CO2 in air either at normal (20 degrees C) or elevated (30 degrees C) ambient temperatures. Respiratory frequency ranged between 16 and 333/min due to changes in both TI and TE. During panting TI exceeded TE. During air inhalation instantaneous ventilation (V) spontaneously ranged from 100 to 1,600 ml . kg-1 . min-1. Hypercapnia, heat stress, or both, increased this range of V by increasing maximum V, primarily due to increases in mean inspiratory flow. Under these conditions, changes in TI accounted for more of the spontaneous changes in breath duration. During inhalation of air and 5% CO2, a positive correlation between VT and TI was obtained for TI between 0.13 and 1.05 s; above 1.05 s VT decreased. Heat stress increased VT at a given TI. We suggest that either the decay rate or position of the inspiratory off-switch threshold curve (Clark and von Euler, J. Physiol. London 222: 267, 1972) varies in conscious dogs. Shifts in either the reset (onset) value or decay rate of the curve yield a positive correlation between VT and TI. This modification to the Clark-von Euler model implies that the primary effect of anesthesia on respiratory control is fixation of the inspiratory off-switch threshold curve.     

Breath-by-breath interactions between inspiratory and expiratory duration in occlusive sleep apnea

We examined interactions between inspiratory duration (TI), expiratory duration (TE), and inspiratory (esophageal) pressure (Pes) generation in seven subjects with confirmed occlusive sleep apnea. Breath-by-breath values of TI, TE, and Pes were identified by digital computer during 21 260-s epochs of repetitive occlusive apnea during non-rapid-eye-movement sleep. The control theory of interacting nonlinear oscillators was used to categorize the interaction between TI and TE for each epoch as either 1) synchronization, the strongest possible interaction between biological oscillators; 2) relative entrainment, a moderate interaction between oscillators; or 3) relative coordination, a weak interaction. The latter two interactions were characterized by systemic oscillations in the moving cross-correlation between TI and TE. The relationship between TI and Pes was analyzed in a similar fashion. Significant oscillations were present in all three parameters (P less than 0.0001 for each). We observed significant negative correlations between TI and TE and between TI and Pes (P less than 0.001 for each) when all breaths for all epochs were pooled. In no epoch was there a significant positive correlation between TI and TE or Pes. All three interactions were observed between TI and TE: five epochs of synchronization, nine of relative entrainment, and seven of relative coordination. In contrast, 19 of 21 epochs exhibited synchronization between TI and Pes, with 2 epochs of relative entrainment. The relative frequency of TI vs. Pes synchronization was significantly greater than TI vs. TE synchronization (P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential timing of respiratory muscles in response to chemical stimuli in awake dogs

We assessed changes in respiratory muscle timing in response to hyperpnea and shortened inspiratory and expiratory times caused by chemoreceptor stimuli in six awake dogs. Durations of postinspiratory inspiratory activity of costal and crural diaphragm (PIIA), the delay in diaphragm electromyogram (EMG) after the initiation of inspiratory airflow, postexpiratory expiratory activity of the transversus abdominis (PEEA), and the delay of abdominal expiratory muscle activity after the initiation of expiratory airflow were measured. In control, four out of six dogs showed PIIA [8-10% of expiratory time (TE)]; all showed delay of diaphragm [19% of inspiratory time (TI)], delay of abdominal muscle activation (21% of TE), and PEEA (24% of TI). Hypercapnia decreased PIIA (4-9% of TE), maintained diaphragm delay at near control values (23% of TI), increased PEEA (36% of TI), eliminated delay of abdominal muscle activation (4% of TE), and decreased end-expiratory lung volume (EELV). Hypocapnic hypoxia increased PIIA (24-25% of TE), eliminated diaphragm delay (3% of TI), eliminated PEEA (3% of TI), reduced delay of abdominal muscle activation (14% of TE), and increased EELV. Most of these effects of hypoxic hypocapnia vs. hypercapnia on the within-breath EMG timing parameters corresponded to differences in the magnitude of expiratory muscle activation. These changes exerted significant influences on flow rates and EELV.     

Respiratory responses to aortic and carotid chemoreceptor activation in the dog

Respiratory responses arising from both chemical stimulation of vascularly isolated aortic body (AB) and carotid body (CB) chemoreceptors and electrical stimulation of aortic nerve (AN) and carotid sinus nerve (CSN) afferents were compared in the anesthetized dog. Respiratory reflexes were measured as changes in inspiratory duration (TI), expiratory duration (TE), and peak averaged phrenic nerve activity (PPNG). Tonic AN and AB stimulations shortened TI and TE with no change in PPNG, while tonic CSN and CB stimulations shortened TE, increased PPNG, and transiently lengthened TI. Phasic AB and AN stimulations throughout inspiration shortened TI with no changes in PPNG or the following TE; however, similar phasic stimulations of the CB and CSN increased both TI and PPNG and decreased the following TE. Phasic AN stimulation during expiration decreased TE and the following TI with no change in PPNG. Similar stimulations of the CB and CSN decreased TE; however, the following TI and PPNG were increased. These findings differ from those found in the cat and suggest that aortic chemoreceptors affect mainly phase timing, while carotid chemoreceptors affect both timing and respiratory drive.