Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model.

Several epidemiological studies have identified obstructive sleep apnea (OSA) as a risk factor for systemic hypertension, but a direct etiologic link between the two disorders has not been established definitively. Furthermore, the specific physiological mechanisms underlying the association between OSA and systemic hypertension have not been identified. The purpose of this study was to systematically examine the effects of OSA on daytime and nighttime blood pressure (BP). We induced OSA in four dogs by intermittent airway occlusion during nocturnal sleep. Daytime and nighttime BP were measured before, during, and after a 1-3-mo long period of OSA. OSA resulted in acute transient increases in nighttime BP to a maximum of 13.0+/-2.0 mmHg (mean+/-SEM), and eventually produced sustained daytime hypertension to a maximum of 15.7+/-4.3 mmHg. In a subsequent protocol, recurrent arousal from sleep without airway occlusion did not result in daytime hypertension. The demonstration that OSA can lead to the development of sustained hypertension has considerable importance, given the high prevalence of both disorders in the population.

Sleep architecture in a canine model of obstructive sleep apnea.

Obstructive sleep apnea (OSA) causes recurrent sleep disruption that is thought to contribute to excessive daytime sleepiness in patients with this disorder. The purpose of this study was to determine the specific effects of OSA on overall sleep architecture in a canine model of OSA. The advantage of this model is that sleep during long-term OSA can be compared to both normal sleep before OSA and recovery sleep after OSA. Studies were performed in four dogs in which sleep-wake state was monitored continuously by a computer that received telemetered EEG and EMG signals. Whenever sleep was detected, the computer sent a signal to close a valve through which the dog breathed; when the dog awoke the occlusion was released. In each dog, data were analyzed from 4 consecutive nights in three phases: a control phase before induction of OSA, a phase during long-term OSA (mean = 85 days, apnea index = 59/hour), and a recovery phase after cessation of OSA. During recovery there was a significant increase in the amount of rapid-eye-movement (REM) sleep compared to the OSA phase (p < 0.01), as well as significant increases in sleep efficiency and decreases in wakefulness (p < 0.01), similar to that reported in OSA patients. The REM rebound during recovery, however, could not be attributed to overall REM deprivation since the amount of REM sleep during the OSA phase was not different from the control phase (p = 0.708). This finding suggests that REM rebound during recovery from OSA is not the result of an overall REM sleep deficit per se. Rather, repeated sleep disruption due to the effects of repetitive apneas and hypoxia may lead to an increased REM sleep drive that manifests itself as a REM sleep rebound during recovery sleep after OSA.

Tonic respiratory drive in the absence of rhythm generation in the conscious dog.

This study was designed to determine whether a chemoreceptor-mediated tonic respiratory drive exists below the apneic threshold. Expiratory (triangularis sterni) and inspiratory (diaphragm and parasternal intercostal) electromyographic activities were recorded in three awake relaxed dogs breathing through an endotracheal tube inserted into a permanent tracheostomy. The cervical vagus nerves were cold blocked to avoid the complicating effects of vagal inputs on respiratory activity. During hypocapnia produced by mechanical hyperventilation, expiratory muscle activity converted from rhythmic to tonic discharge when inspiratory muscle activity and spontaneous breathing movements were abolished. In hypocapnia, changes in arterial PCO2 (in hyperoxia) were produced by changing the ventilator rate for steady-state (> 6 min) CO2 stimuli and by disconnecting the ventilator for transient CO2 stimuli. By use of either method, a CO2-mediated drive to the expiratory muscle was consistently observed during hypocapnic apnea. At a constant level of hypocapnia, inhalation of 5% O2 consistently caused the onset of spontaneous breathing; the onset of phasic inspiratory activity was associated with reciprocal inhibition of the tonic expiratory activity. However, inhalation of 10 and 15% O2 caused an inhibition of the tonic expiratory activity, even without the onset of breathing. These results suggest that the response threshold of the respiratory chemoreceptors is lower than the apneic threshold and that a chemoreceptor-mediated tonic respiratory drive persists during apnea.

Role of upper airway in ventilatory control in awake and sleeping dogs.

We examined the role of the upper airway in the regulation of the pattern of breathing in six adult dogs during wakefulness and sleep. The dogs breathed through a fenestrated endotracheal tube inserted through a tracheostomy. The tube was modified to allow airflow to be directed either through the nose or through the tracheostomy. When airflow was diverted from nose to tracheostomy there was an abrupt increase in the rate of expiratory airflow, resulting in prolongation of the end-expiratory pause but no change in overall expiratory duration or respiratory frequency. Furthermore, electromyogram recordings from implanted diaphragmatic and laryngeal muscle electrodes did not show any changes that could be interpreted as an attempt to delay expiratory airflow or increase end-expiratory lung volume. The effects of switching from nose to tracheostomy breathing could be reversed by adding a resistance to the endotracheal tube so as to approximate upper airway resistance. The findings indicate that under normal conditions in the adult dog upper airway receptors play little role in regulation of respiratory pattern and that the upper airway exerts little influence on the maintenance of end-expiratory lung volume.

Immediate effects of arousal from sleep on cardiac autonomic outflow in the absence of breathing in dogs.

To determine the immediate effects of arousal from non-rapid-eye-movement (non-REM) sleep on cardiac sympathetic and parasympathetic activities, six dogs were studied breathing through an endotracheal tube inserted into a chronic tracheostomy. Mean heart rates (HRs) during non-REM sleep were compared with 1) awake periods immediately after spontaneous arousals (ARs) and 2) later periods of stable relaxed wakefulness (RW). During spontaneous breathing, HR increased after AR (mean = 31.0%; P < 0.001) and in RW (mean = 7.6%; P < 0.001). To avoid the confounding influence of changes in breathing pattern, lung volume, and blood gases accompanying AR on HR, further studies were performed during constant mechanical hyperventilation that eliminated spontaneous breathing. In this condition, HR still increased after AR (mean = 29.9%; P < 0.001) and in RW (mean = 5.7%; P < 0.001), suggesting that the HR increases could be mediated by an effect of the state change per se on autonomic activity. This interpretation was confirmed when the HR increases were essentially abolished by combined cardiac sympathetic and parasympathetic block. In contrast, parasympathetic block alone did not prevent the HR increases after AR (mean = 12.2%; P < 0.001) or in RW (mean = 12.3%; P < 0.001), whereas sympathetic block alone almost abolished the HR increases in RW (mean = 3.6%) but did not prevent the HR increases during AR (mean = 30.2%; P < 0.001). The results show that, compared with non-REM sleep, AR is associated with acute cardiac sympathetic activation and parasympathetic withdrawal, whereas stable RW is associated mainly with sympathetic activation. These effects may have clinical relevance to the cardiovascular sequelae of breathing disorders that cause repetitive arousals from sleep.

Respiratory-related heart rate variability persists during central apnea in dogs: mechanisms and implications.

The aim of this study was to determine the mechanism(s) responsible for the persistence of respiratory sinus arrhythmia (RSA) during central apnea. In five awake dogs, heart rate (HR) was recorded during constant mechanical ventilation (MV) and during central apneas produced by cessation of MV. For each of 10 control ventilator cycles before MV was stopped, instantaneous HR was plotted against the time from the onset of lung inflation; the fundamental and first harmonic of a sine wave (at the ventilator frequency) was then fitted to the HR data. For the control cycles, the mean r2 from the curve fits was 0.57 +/- 0.07, showing that a significant component of the HR variability was linked to the ventilator cycle. After MV was stopped, RSA persisted and only by the third "phantom" ventilator cycle during apnea had the degree of fit consistently decreased compared with control dogs (P < 0.02). The persistence of ventilator-linked RSA at the onset of central apnea supports the concept of a "memory" in the respiratory system. Toward the end of central apnea, HR variability reappeared and had the periodicity and rhythmic profile of RSA on 81% of occasions. The presence of RSA-like activity toward the end of central apnea suggests that subthreshold rhythmic respiratory-related activity may be present even before the onset of detectable lung volume changes.

Effect of inspiratory muscle unloading on arousal responses to CO2 and hypoxia in sleeping dogs.

Chemical respiratory stimuli can induce arousal from sleep, but the specific mechanisms involved have not been established. Therefore, we tested the hypothesis that mechanoreceptor stimuli arising in the ventilatory apparatus have a role in the arousal responses to progressive hypercapnia and hypoxia by comparing arousal responses during spontaneous ventilation with those obtained when the inspiratory muscles were unloaded by mechanical ventilatory assistance. Studies were performed in three trained dogs in which the adequacy of inspiratory muscle unloading was verified by diaphragmatic electromyographic (EMG) recordings. In rapid-eye-movement (REM) sleep the arousal threshold during progressive hypercapnia increased from 68.4 +/- 0.5 (SE) mmHg during spontaneous runs to 72.3 +/- 0.8 mmHg during mechanically assisted runs (P < 0.01). In contrast there were no changes in arousal responses to hypercapnia during non-REM (NREM) sleep or to hypoxia in either NREM or REM sleep. However, during the assisted hypoxic runs, EMG activity of the transversus abdominis muscle was increased compared with the unassisted runs; therefore, the effects on arousal threshold of unloading the inspiratory muscles may have been offset by increased loading of the expiratory muscles. The findings indicate that even in the absence of added mechanical loads, mechanoreceptor stimuli probably arising in the respiratory muscles contribute to the arousal response to hypercapnia during REM sleep.

Canine model of obstructive sleep apnea: model description and preliminary application.

This report describes a canine model of obstructive sleep apnea (OSA) developed in our laboratory and the results of its preliminary short-term application. Healthy adult dogs were prepared with a tracheostomy and with implanted electroencephalographic and nuchal electromyographic recording electrodes. A silent occlusion valve was attached to the outer end of the endotracheal tube. The electroencephalogram and electromyogram were monitored continuously by a computer that determined sleep-wake state using software developed in our laboratory. At a predetermined time (e.g., 12 s) after each sleep onset, a signal was transmitted from the computer to the valve controller, resulting in airway occlusion. When the dog aroused from sleep, the occlusion was released. These events therefore mimic those that occur in human OSA. Successful operation of the model was confirmed during 5-day continuous trials in two dogs. During the trials, the dogs became increasingly somnolent both by behavioral observation and objective measurement. The frequency of occlusions increased, and measures of apnea severity, including apnea duration and end-apneic arterial oxygen saturation, worsened. We conclude that this experimental model of repeated airway occlusion during sleep provides a potentially powerful tool for investigating the sequelae of OSA.

Validation of a telemetry system for long-term measurement of blood pressure.

We have used an implanted telemetry system to continuously monitor blood pressure (BP) in three dogs for durations ranging from 28 to 75 wk after implantation. Measurements of BP obtained by telemetry were compared every 3-12 wk, with measurements of BP recorded with a manometer-tipped catheter that was inserted into a femoral artery. Over a wide range of both physiological and pharmacologically manipulated pressures (40-200 mmHg), the values of BP obtained by the two methods were highly correlated (all r > 0.966; all P < or = 0.0001). However, the mean differences between the values obtained by the two systems were different from zero (range +29.6 to -1.5 mmHg; P < or = 0.0001), indicating an offset in the BP values recorded from the implanted system. Furthermore, this offset was dependent on the absolute level of the BP. The findings indicate that, for a period of at least 28 wk and up to 75 wk after implantation, the telemetry system accurately measures acute changes in BP and can reliably measure absolute BP provided that the system is properly validated.

Abdominal muscle activation by respiratory stimuli in conscious dogs.

The responses of the diaphragm, external oblique, and transversus abdominis muscles to hyperoxic hypercapnia and isocapnic hypoxia were studied in four awake dogs to test the hypothesis that central and peripheral chemoreceptor inputs result in different patterns of respiratory muscle activation. The dogs were trained to lie quietly in place, and electromyographic (EMG) discharges of the diaphragm (EMGdi), external oblique (EMGeo), and transversus abdominis (EMGta) were recorded from chronically implanted electrodes. Both hypercapnia and hypoxia recruited EMGeo and EMGta activity, but at comparable levels of minute volume of ventilation the EMG activity of the abdominal muscles was greater during hypercapnia than during hypoxia. However the two chemical stimuli also resulted in different tidal volume (VT) and respiratory frequency responses at any given minute volume of ventilation. When EMG activity was reanalyzed as a function of VT, EMGeo and EMGta were the same for a given VT whether induced by hypercapnia or hypoxia, but EMGdi was consistently greater during hypoxia than during hypercapnia. When the vagus nerves were blocked by cooling exteriorized cervical vagal loops, all abdominal muscle EMG activity was abolished. The findings support the concept that stimulation of the central and peripheral chemoreceptors results in asymmetric activation of the inspiratory and expiratory respiratory muscles. The findings also indicate that afferent vagal stimuli play an important facilitatory role in activation of the abdominal expiratory muscles.

Effect of aging on metabolic respiratory control in sleeping dogs.

We examined the effects of aging on the metabolic respiratory control system by measuring changes with time in steady-state minute volume of ventilation (VI), alveolar carbon dioxide pressure (PACO2), and ventilatory and arousal responses to hypercapnia and hypoxia during slow-wave sleep (SWS). Studies were performed longitudinally in six healthy dogs over a span of 3 to 7 yr, corresponding biologically to 12 to 24 human yr. In each of the dogs aging was associated with a decrease in steady state VI during SWS, from 6.53 +/- 1.08 (mean +/- SEM) to 5.56 +/- 0.90 L/min (p < 0.01), and with an increase in PACO2 from 36.2 +/- 1.0 to 38.5 +/- 1.1 mm Hg (p < 0.01). However, ventilatory and arousal responses to hyperoxic hypercapnia (four dogs) remained unchanged. In contrast there was a decrement in the response of VI to isocapnic hypoxia during SWS (five dogs), from 1.22 +/- 0.12 to 0.70 +/- 0.07 L/min/% fall in arterial O2 saturation (SaO2) (p < 0.02), and a decrease in arousal SaO2, from 83.3 +/- 3.2 to 73.5 +/- 2.3 percent (p < 0.001). The findings indicate that aging is accompanied by impairment of ventilatory and arousal responses to hypoxia during SWS, and point to a specific effect of aging on the carotid-body chemoreceptors, as opposed to the brainstem respiratory controller or the ventilatory pump.

Regulation of respiration in sleeping dogs.

We have examined the respiratory changes that occur during physiological sleep in three dogs with exteriorized cervical vagal loops. Sleep stage was determined by behavioral and EEG criteria. During non-REM (NREM) sleep breathing was slower (mean change, 23%),deeper (mean change, 18%), and less variable (coefficients of variation, 0.05-0.10) than during wakefulness (W); minute volume of ventilation (Ve) decreased (mean change, 14%) and alveolar CO2 pressure (PAco2) increased slightly (mean change, 1.3 mmHg). In addition, the rate of O2 consumption and ventilatory response to hypercapnia were decreased. In contrast, REM sleep was characterized by rapid, shallow, and considerably more irregular (coefficients of variation, 0.18-0.30) breathing; Ve increased markedly and PAco2 decreased (mean change, 5.2 mmHg). Blockade of both cervical vagus nerves produced comparable changes in each stage of sleep (W, NREM, REM): breathing became slower and deeper, but the differences between stages and the marked irregularity in REM sleep persisted. In contrast, the Hering-Breuer inflation reflex (HBIR) was strong in W and NREM sleep, but weak in REM sleep. The results indicate that changes in respiratory control and stability during sleep are not due to fluctuations in vagal influence despite the fact that one vagal reflex (HBIR) was sleep-state dependent.

Respiratory load compensation in awake and sleeping dogs.

We have investigated immediate and progressive ventilatory responses to external elastic loads in five dogs with cervical vagal loops. Three dogs were studied while awake (W) and during non-REM sleep (S); the other two during barbiturate anesthesia (A). Elastic loads were applied at the end expiration for 1-6 breaths by having the dogs breathe from a rigid container (partial load) or against an occluded airway (infinite load). "Effective" elastance (EE) was determined from the tidal volume (VT)-tracheal pressure relationships of the unloaded, partially loaded, and infinitely loaded breaths. Passive thoracic elastance during W and S averaged 16.7 cmH2O/1. EE averaged 55.8 cmH2O/1 during W, 54.7 during S, and 59.5 during A. Vagal blockade (VB) induced large changes in VT but no change in EE in W or S; during A, EE decreased 37.5%. With sustained loading (partial) there was a progressive increase in VT but a corresponding increase in chemical (primarily hypoxic) respiratory drive, so that EE remained constant during five loaded breaths. VB augmented the progressive increase in VT during W or S but virtually abolished the increase in A. Thus the responses to elastic loads in W and S are similar and independent of conscious reactions or vagal influence; responses during A differ considerably. "Progressive load compensation" is a reflection of increasing of increasing chemical drive and not of progressive changes in EE.

Waking and ventilatory responses to laryngeal stimulation in sleeping dogs.

We studied waking and ventilatory responses to laryngeal stimulation during sleep in three dogs. The dogs breathed through an endotracheal tube inserted caudally into the trachea through a tracheostomy. Laryngeal stimulation was produced either by inflating a small balloon that was positioned in the rostral tracheal segment, or by squirting water onto the larynx through a catheter inserted through the tracheostomy. Airflow was measured with a pneumotachograph, and sleep state was determined by behavioral, electroencephalographic, and electromyographic criteria. We found that the degree of laryngeal stimulation required to produce arousal and coughing was higher in rapid-eye-movement (REM) sleep than in slow-wave sleep (SWS). Stimuli that failed to cause arousal from SWS often produced a single expiratory effort, or brief apnea (1--2 s) and bradycardia. In contrast, during REM sleep subarousal stimuli often resulted in prolonged apnea (greater than 10 s) and marked bradycardia. We conclude that during REM sleep arousal responses to laryngeal stimulation are depressed, but ventilatory and cardiac responses are intact.

Respiratory muscle activation by chemical stimuli in awake and sleeping dogs.

The present findings in awake and sleeping dogs confirm the early observations in anesthetized cats (Bainton et al., 1978; Sears et al., 1982), and more recent studies in awake and sleeping humans (Takasaki et al., 1989), that suggest an asymmetry in pattern of respiratory motoneuron and muscle activation by central and peripheral chemoreceptor stimulation, with central chemoreceptor stimulation driving both inspiratory and expiratory mechanisms, and peripheral chemoreceptor stimulation driving inspiratory and inhibiting expiratory mechanisms. Because REM sleep inhibits the nondiaphragmatic muscles, which include the expiratory muscles, there is a reduction in CO2 response during this sleep stage. In contrast because the response to hypoxia is mediated predominantly by the diaphragm, which is not generally inhibited by REM sleep, there is less effect of REM sleep on the overall response to hypoxia. In addition to being of basic importance, these concepts may have important clinical implications.

Interaction of chemical and mechanical respiratory stimuli in the arousal response to hypoxia in sleeping dogs.

The role of respiratory mechanoreceptor stimuli in the arousal response to hypoxia was studied in three trained dogs. The dogs breathed through a cuffed endotracheal tube inserted through a chronic tracheostomy, and resistive loads of 8 to 49 cm H2O/L/s were added to the expiratory circuit. Arterial O2 saturation (SaO2) was measured with an ear oximeter, and isocapnic progressive hypoxia was induced by a rebreathing technique. Arousal from sleep was determined by electroencephalographic and behavioral criteria. SaO2 at arousal from non-rapid eye movement (NREM) sleep increased progressively from 67.5 +/- 4.6% (mean +/- SEM), with no added resistance to 85.2 +/- 0.5% with the highest resistance (p less than 0.01), and from 60.6 +/- 0.6 to 81.6 +/- 0.4% during REM sleep (p less than 0.01). The added resistances also increased the steady-state (normoxic) level of alveolar PCO2 (PACO2). However, when PACO2 was increased to comparable levels by the addition of dead space rather than expiratory resistance to the breathing circuit, SaO2 at arousal from hypoxia was significantly lower than during expiratory resistive loading (p less than 0.05). We therefore conclude that mechanoreceptor stimuli arising from the ventilatory apparatus may contribute substantially to the arousal response to hypoxia.

Effects of sleep on the tonic drive to respiratory muscle and the threshold for rhythm generation in the dog.

1. The present study was designed to determine the effect of sleep on the tonic output to respiratory muscle and on the level of chemical respiratory stimulation required to produce rhythmic respiratory output. 2. Chronically implanted electrodes recorded expiratory (triangularis sterni) and inspiratory (diaphragm and parasternal intercostal) electromyographic (EMG) activities in three trained dogs during wakefulness and sleep. The dogs were mechanically hyperventilated via an endotracheal tube inserted into a permanent tracheostomy. During the studies, a cold block of the cervical vagus nerves was maintained to avoid the complicating effects of vagal inputs on respiratory drive and rhythm. 3. During wakefulness, steady-state hypocapnia (partial pressure of CO2, PCO2 = 30 mmHg) abolished inspiratory EMG activity, resulting in apnoea, but the expiratory muscle became tonically active. Compared to wakefulness, the level of the tonic expiratory EMG activity was decreased in non-REM (non-rapid eye movement) sleep (median decrease = 34%, P = 0.005) and was further decreased in REM sleep (median decrease = 78%, P < 0.0001). During REM sleep, the tonic expiratory EMG activity was highly variable (mean coefficient of variation = 39% compared to 7% awake, P < 0.0001) and in some periods of REM, bursts of inspiratory EMG activity and active breathing movements were observed despite the presence of hypocapnia. 4. During constant mechanical hyperventilation, progressive increases in arterial PCO2 (in hyperoxia) were produced by rebreathing. Measurement of the CO2 threshold for the onset of spontaneous breathing showed that this threshold was not different between wakefulness and non-REM sleep (mean difference = 0.1 mmHg from paired observations, 95% confidence interval for the difference = -1.0 to +1.1 mmHg, P = 0.898). 5. The results show that sleep reduces the tonic output to respiratory muscles but does not increase the CO2 threshold for the generation of rhythmic respiratory output. These observations suggest that changes in the tonic drives to the respiratory motoneurones may be a principal mechanism by which changes in sleep-wake states produce changes in respiratory output.

Respiratory activity of laryngeal muscles in awake and sleeping dogs.

Experiments were conducted in adult dogs to determine the respiratory activity of laryngeal muscles during wakefulness and sleep. We studied the EMG activity of three laryngeal muscles in five trained dogs, two of which were completely intact, and three of which had a previously-formed side-hole tracheal stoma. Pairs of electrodes were implanted chronically into the posterior cricoarytenoid muscle (PCA), a laryngeal dilator, cricothyroid (CT), and thyroarytenoid (TA), a laryngeal adductor. EMG electrodes were also inserted into the costal portion of the diaphragm. In wakefulness (W), slow wave sleep (SWS) and rapid eye movement (REM) sleep the EMGs of the PCA and CT muscles increased in intensity during diaphragm activation, with varying levels of basal activity during expiration. However, the greatest levels of inspiratory activity in PCA and CT during sleep were found in REM sleep, usually in the absence of augmented diaphragm EMG activity. This laryngeal muscle activity was associated with laryngeal dilation. There were also marked state-related changes in the level of activity of CT during expiration, suggestive of changes in the degree of expiratory adduction of the larynx. The adductor muscles (TA) were not active during expiration, except during alert W. There were no consistent differences in respiratory activity of the laryngeal muscles between the two intact dogs and those with a tracheal stoma (whether or not an endotracheal tube was in place), nor was laryngeal muscle activity affected by the subsequent creation of a tracheal stoma in the two intact dogs. The findings indicate that sleep-wakefulness state exerts important influences on the respiratory activity of laryngeal muscles in the adult dog.

The ventilatory response to arousal from sleep is not fully explained by differences in CO(2) levels between sleep and wakefulness.

1. Arousal from sleep is associated with transient stimulation of ventilation above normal waking levels that predisposes to subsequent breathing instability and central apnoea. The transient hyperpnoea at arousal is normally explained by differences in arterial partial pressure of CO(2) (P(a,CO2)) between sleep and wakefulness, with a higher P(a,CO2) in sleep leading to stimulation of ventilation at arousal according to the awake ventilatory response to CO(2). Surprisingly, however, the validity of this current model in fully explaining the increased ventilation at arousal from sleep has not been directly tested. 2. This study tests the hypothesis that the level of ventilation at arousal from non-rapid eye movement (non-REM) sleep is greater than that produced by elevating P(a,CO2) in wakefulness to the sleeping level, i.e. the ventilation predicted by the current model. 3. Studies were performed in five dogs. Inspired CO(2) was used to increase end-tidal partial pressure of CO(2) (P(ET,CO2)) in wakefulness and measure the ventilatory response. The same P(ET,CO2) was then maintained in non-REM sleep. Ventilation was measured for 10 breaths before and after arousal from non-REM sleep induced by a 72 dB tone. 4. Arousal from sleep produced a transient surge in ventilation of 1.42 +/- 0.35 l min(-1) (P = 0.005). This increased ventilation was due to arousal from sleep per se as the tone alone produced no change in awake ventilation. In support of the hypothesis, ventilation at wake onset from sleep was greater by 0.83 +/- 0.28 l min(-1) (P = 0.031) than the ventilation elicited in wakefulness by raising P(ET,CO2) to the sleeping level. 5. The results show that > 50 % of the increase in ventilation at wake onset from sleep is not attributable to the awake ventilatory response to the elevated P(a,CO2) that was previously present in sleep. This result leads to important modifications of the physiological model currently used to explain the ventilatory consequences of arousal from sleep.

Role of vagal stimuli in exercise ventilation in dogs with experimental pneumonitis.

We have investigated the possibility that afferent vagal stimuli may be responsible for the excessive ventilatory drive during exercise characteristic of many diffuse pulmonary parenchymal diseases. Studies were performed on four conscious dogs with cervical vagal loops, in whom experimental pneumonitis was induced by the intravenous administration of complete Freund's adjuvant. Control measurements were made over a 3-mo interval prior to induction of disease which then ran a course of 6 wk. The disease was characterized histologically by a diffuse interstitial pneumonitis during the first week, and by a proliferative granulomatosis during the subsequent 4-5 wk. Physiologic disturbances at rest included decreased total lung and functional residual capacities; increased lung elastic recoil; and decreased carbon monoxide diffusing capacity. During mild-to-moderate steady-state exercise, the minute volume of ventilation (VE) and respiratory frequency (f) were increased significantly compared to control values; tidal volume (VT) was decreased significantly; and exercise tolerance (ET) was impaired. Complete cervical vagal blockade abolished the abnormally high VE, decreased f, and increased VT in all dogs, and improved ET in at least two dogs. The results indicate that afferent vagal stimuli were responsible for the excessive ventilation during exercise and contributed to the abnormal pattern of breathing.