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We tested the hypothesis that barbiturates depress respiratory motor output by actions on the GABAA receptor. We examined the influence of pentobarbital sodium on nerve activity recorded from a fourth cervical (C4) ventral root (phrenic motoneuron output) in the in vitro brainstem-spinal cord preparation of neonatal rats aged 1-3 days. Bath application of pentobarbital slowed the respiratory rhythm but this effect could be reversed by drug washout or by simultaneous application of 8 microM bicuculline methiodide, a GABAA receptor antagonist. Pentobarbital up to a concentration of 80 microM (or 20 mg/l) did not change the magnitude of C4 nerve bursts. The GABAA receptor agonist muscimol evoked similar changes. The results support the hypothesis that respiratory depression by barbiturates is due to GABAA receptor-mediated inhibition, with the principal effects on rhythm generation. In the light of recent studies suggesting that GABAA receptors may be excitatory in the early neonatal period, we examined postnatal changes in the GABAergic slowing of respiratory rhythm. Stimulation of GABAA receptors slowed respiratory rhythm from the first postnatal day, with no change in efficacy over the first 3 days of life., (Copyright 2004 Elsevier B.V.)

Background: Whether or not isolated endurance training of the respiratory muscles improves whole-body endurance exercise performance is controversial, with some studies reporting enhancements of 50% or more, and others reporting no change. Twenty fit (VO2 max 56.0 ml/kg/min), experienced cyclists were randomly assigned to three groups. The experimental group (n = 10) trained their respiratory muscles via 20, 45 min sessions of hyperpnea. The placebo group (n = 4) underwent "sham" training (20, 5 min sessions), and the control group (n = 6) did no training., Results: After training, the experimental group increased their respiratory muscle endurance capacity by 12%. Performance on a bicycle time trial test designed to last about 40 min improved by 4.7% (9 of 10 subjects showed improvement). There were no test-re-test improvements in either respiratory muscle or bicycle exercise endurance performance in the placebo group, nor in the control group. After training, the experimental group had significantly higher ventilatory output and VO2, and lower PCO2, during constant work-rate exercise; the placebo and control groups did not show these changes. The perceived respiratory effort was unchanged in spite of the higher ventilation rate after training., Conclusions: The results suggest that respiratory muscle endurance training improves cycling performance in fit, experienced cyclists. The relative hyperventilation with no change in respiratory effort sensations suggest that respiratory muscle training allows subjects to tolerate the higher exercise ventilatory response without more dyspnea. Whether or not this can explain the enhanced performance is unknown.

Background: We tested the hypothesis that ventilatory drive in hypoxia and hypercapnia is inversely correlated with the number of hypopneas and obstructive apneas per hour of sleep (obstructive apnea hypopnea index, OAHI) in children., Methods: Fifty children, 6 to 12 years of age were studied. Participants had an in-home unattended polysomnogram to compute the OAHI. We subsequently estimated ventilatory drive in normoxia, at two levels of isocapnic hypoxia, and at three levels of hyperoxic hypercapnia in each subject. Experiments were done during wakefulness, and the mouth occlusion pressure measured 0.1 seconds after inspiratory onset (P0.1) was measured in all conditions. The slope of the relation between P0.1 and the partial pressure of end-tidal O2 or CO2 (PETO2 and PETCO2) served as the index of hypoxic or hypercapnic ventilatory drive., Results: Hypoxic ventilatory drive correlated inversely with OAHI (r = -0.31, P = 0.041), but the hypercapnic ventilatory drive did not (r = -0.19, P = 0.27). We also found that the resting PETCO2 was significantly and positively correlated with the OAHI, suggesting that high OAHI values were associated with resting CO2 retention., Conclusions: In awake children the OAHI correlates inversely with the hypoxic ventilatory drive and positively with the resting PETCO2. Whether or not diminished hypoxic drive or resting CO2 retention while awake can explain the severity of sleep-disordered breathing in this population is uncertain, but a reduced hypoxic ventilatory drive and resting CO2 retention are associated with sleep-disordered breathing in 6-12 year old children.

Background: Recent studies in children have demonstrated that frequent occurrence of parasomnias is related to increased sleep disruption, mental disorders, physical harm, sleep disordered breathing, and parental duress. Although there have been several cross-sectional and clinical studies of parasomnias in children, there have been no large, population-based studies using full polysomnography to examine the association between parasomnias and sleep disordered breathing. The Tucson Children's Assessment of Sleep Apnea study is a community-based cohort study designed to investigate the prevalence and correlates of objectively measured sleep disordered breathing (SDB) in pre-adolescent children six to 11 years of age. This paper characterizes the relationships between parasomnias and SDB with its associated symptoms in these children., Methods: Parents completed questionnaires pertaining to their child's sleep habits. Children had various physiological measurements completed and then were connected to the Compumedics PS-2 sleep recording system for full, unattended polysomnography in the home. A total of 480 unattended home polysomnograms were completed on a sample that was 50% female, 42.3% Hispanic, and 52.9% between the ages of six and eight years., Results: Children with a Respiratory Disturbance Index of one or greater were more likely to have sleep walking (7.0% versus 2.5%, p < 0.02), sleep talking (18.3% versus 9.0%, p < 0.006), and enuresis (11.3% versus 6.3%, p < 0.08) than children with an Respiratory Disturbance Index of less than one. A higher prevalence of other sleep disturbances as well as learning problems was observed in children with parasomnia. Those with parasomnias associated with arousal were observed to have increased number of stage shifts. Small alterations in sleep architecture were found in those with enuresis., Conclusions: In this population-based cohort study, pre-adolescent school-aged children with SDB experienced more parasomnias than those without SDB. Parasomnias were associated with a higher prevalence of other sleep disturbances and learning problems. Clinical evaluation of children with parasomnias should include consideration of SDB.

The muscular-hydrostat model of tongue function proposes a constant interaction of extrinsic (external bony attachment, insertion into base of tongue) and intrinsic (origin and insertion within the tongue) tongue muscles in all tongue movements (Kier WM and Smith KK. Zool J Linn Soc 83: 207-324, 1985). Yet, research that examines the respiratory-related effects of tongue function in mammals continues to focus almost exclusively on the respiratory control and function of the extrinsic tongue protrusor muscle, the genioglossus muscle. The respiratory control and function of the intrinsic tongue muscles are unknown. Our purpose was to determine whether intrinsic tongue muscles have a respiration-related activity pattern and whether intrinsic tongue muscles are coactivated with extrinsic tongue muscles in response to respiratory-related sensory stimuli. Esophageal pressure and electromyographic (EMG) activity of an extrinsic tongue muscle (hyoglossus), an intrinsic tongue muscle (superior longitudinal), and an external intercostal muscle were studied in anesthetized, tracheotomized, spontaneously breathing rats. Mean inspiratory EMG activity was compared at five levels of inspired CO2. Intrinsic tongue muscles were often quiescent during eupnea but active during hypercapnia, whereas extrinsic tongue muscles were active in both eupnea and hypercapnia. During hypercapnia, the activities of the airway muscles were largely coincident, although the onset of extrinsic muscle activity generally preceded the onset of intrinsic muscle activation. Our findings provide evidence, in an in vivo rodent preparation, of respiratory modulation of motoneurons supplying intrinsic tongue muscles. Distinctions noted between intrinsic and extrinsic activities could be due to differences in motoneuron properties or the central, respiration-related control of each motoneuron population.

We tested the hypothesis that pharyngeal geometry and soft tissue dimensions correlate with the severity of sleep-disordered breathing. Magnetic resonance images of the pharynx were obtained in 18 awake children, 7-12 yr of age, with obstructive apnea-hypopnea index (OAHI) values ranging from 1.81 to 24.2 events/h. Subjects were divided into low-OAHI (n = 9) and high-OAHI (n = 9) groups [2.8 +/- 0.7 and 13.5 +/- 4.9 (SD) P < 0.001]. The OAHI correlated positively with the size of the tonsils (r2 = 0.42, P = 0.024) and soft palate (r2 = 0.33, P = 0.049) and inversely with the volume of the oropharyx (r2 = 0.42, P = 0.038). The narrowest point in the pharyngeal airway was smaller in the high-compared with the low-OAHI group (4.4 +/- 1.2 vs. 6.0 +/- 1.3 mm; P = 0.024), and this point was in the retropalatal airway in all but two subjects. The airway cross-sectional area (CSA)-airway length relation showed that the high-OAHI group had a narrower retropapatal airway than the low-OAHI group, particularly in the retropalatal region where the soft palate, adenoids, and tonsils overlap (P = 0.001). The "retropalatal air space," which we defined as the ratio of the retropalatal airway CSA to the CSA of the soft palate, correlated inversely with the OAHI (r2 = 0.49, P = 0.001). We conclude that 7- to 12-yr-old children with a narrow retropalatal air space have significantly more apneas and hypopneas during sleep compared with children with relatively unobstructed retropalatal airways.

We examined the relationship between nocturnal respiratory disturbance and learning and compared learning in children with and without nocturnal respiratory disturbance. Subjects were 149 participants in a prospective cohort study examining sleep in children ages 6-12: The Tucson Children's Assessment of Sleep Apnea study (TuCASA). Sleep was assessed via home polysomnography. Intelligence, learning and memory, and academic achievement were assessed. Parents rated attention. Group comparisons were used to test the hypothesis that the group with an apnea/hypopnea index (AHI) of 5 or more (n = 77) would have weaker performance than the group with AHI less than 5 (n = 72). The group with AHI of 5 or more had weaker learning and memory though differences between groups decreased when arousals were taken into account. There was a greater percentage of Stage 1 sleep in the AHI 5 or more group, and Stage 1 percentage was negatively related to learning and memory in the sample (n = 149). There were negative relationships between AHI and immediate recall, Full Scale IQ, Performance IQ, and math achievement. Hypoxemia was associated with lower Performance IQ. Thus, findings suggest that nocturnal respiratory disturbance is associated with decreased learning in otherwise healthy children, that sleep fragmentation adversely impacts learning and memory, and that hypoxemia adversely influences nonverbal skills.

Study Objectives: This report describes clinical outcomes and threshold levels of respiratory disturbance index (RDI) associated with sleep-disordered breathing in children participating in the Tucson Children's Assessment of Sleep Apnea study., Design: A community-based, prospective cohort study designed to assess the severity of sleep-related symptoms associated with sleep-disordered breathing in children aged 6 to 11 years., Setting: Students attending elementary school in the Tucson Unified School District., Participants: Unattended home polysomnograms were completed on 239 children-55.2% boys, 51% Hispanic, and 55% between the ages of 6 and 8 years., Measurements and Results: Based on full home polysomnography, levels of RDI that correspond to a higher prevalence of clinical symptoms of sleep-disordered breathing in children aged 6 to 11 were observed. An RDI of at least 5 was associated with frequent snoring (20.3% vs 9.1%, P<.01), excessive daytime sleepiness (22.9% vs 10.7%, P<.01), and learning problems (8.5% vs 2.5%, P<.04) when no oxygen desaturation accompanied the respiratory event. An RDI of at least 1 was associated with these symptoms when a 3% oxygen desaturation was required, snoring (24.0% vs 10.4%, P<.006), excessive daytime sleepiness (24.0% vs 13.4%, P<.04), and learning problems (10.7% vs 3.0%, P<.02). Hispanic or Caucasian ethnicity, sex, age category, obesity, insomnia, and witnessed apnea were not associated with RDI regardless of event definition., Conclusions: The Tucson Children's Assessment of Sleep Apnea study has shown that there are values of RDI based on polysomnography that correspond to an increased rate of clinical symptoms in children ages 6 to 11 years.

Our hypothesis was that the simultaneous activation of tongue protrudor and retractor muscles (co-activation) would constrict and stiffen the pharyngeal airway more than the independent activation of tongue protrudor muscles. Upper airway stiffness was determined by injecting known volumes of air into the sealed pharyngeal airway of the anaesthetized rat while measuring nasal pressure under control (no-stimulus) and stimulus conditions (volume paired with hypoglossal (XII) nerve stimulation). Stimulation of the whole XII nerves (co-activation) or the medial XII branches (protrudor activation) effected similar increases in total pharyngeal airway stiffness. Importantly, co-activation produced volume compression (airway narrowing) at large airway volumes (P < 0.05), but had no effect on airway dimension at low airway volumes. In comparison, protrudor activation resulted in significant volume expansion (airway dilatation) at low airway volumes and airway narrowing at high airway volumes (P < 0.05). In conclusion, both co-activation and independent protrudor muscle activation increase airway stiffness. However, their effects on airway size are complex and depend on the condition of the airway at the time of activation.

Objective: To obtain normative sleep architecture data from unattended home polysomnography in Caucasian and Hispanic children aged 6-11 years., Design and Subjects: Unattended home polysomnography was performed on a single night in Caucasian and Hispanic children aged 6-11 years as part of the Tucson Children's Assessment of Sleep Apnea Study (TuCASA), a cohort study designed to examine the prevalence and correlates of sleep disordered breathing. A subset of 42 children enrolled in TuCASA who had no symptoms of any sleep disorder and had polysomnograms without technical recording problems., Results: Sleep architecture in preadolescent Caucasian and Hispanic children was not different between boys and girls. However, total sleep time (TST), sleep efficiency (SLE) and time spent in REM sleep declined with increasing age. In addition, the number of sleep to wake stage shifts was slightly higher in younger children. Hispanic children had less Stage 3/4 sleep (18+/-1 vs. 22+/-1%, P

The upper airway respiratory muscles play an important role in the regulation of airway resistance, but surprisingly little is known about their contractile properties and endurance performance. We developed a technique that allows measurement of force and the electromyogram (EMG) of human nasal dilator muscles (NDMs). Endurance performance was quantified by measuring NDM "flaring" force and EMG activity as healthy human subjects performed 10 s maximal voluntary contractions (MVCs), separated by 10 s rest, until the area under the force curve fell to 50% MVC (the time limit of the fatigue task, Tlim), which was reached in 34.2 +/- 3.1 contractions (685.0 +/- 62.3 s). EMG activity was unchanged except at Tlim, where it averaged 78.7 +/- 3.6% of pretest activity (P < 0.01). M-wave amplitude did not change, suggesting that neuromuscular propagation was not impaired. MVC force increased to 80% of the pretest level within 10 min of recovery but twitch force failed to recover, suggesting low-frequency fatigue. The data suggest that a failure of the nervous system to excite muscle could explain at most only a small fraction of the NDM force loss during an intermittent fatigue task, and then only at Tlim. Thus, the majority of the force failure during this task is due to impairment of mechanisms that reside within the muscle fibers., (Copyright 2002 Wiley Periodicals, Inc.)

We tested the hypothesis that abdominal muscles are active during the expiratory phase of the respiratory cycle during exercise. Electromyographic (EMG) activities of external oblique and rectus abdominis muscles were recorded during incremental exercise to exhaustion and during 30 min of constant work rate exercise at an intensity of 85 % of the peak oxygen consumption rate (V(O(2))). High amplitude intramuscular EMG activities of both abdominal muscles could be evoked with postural manoeuvres in all subjects. During cycling, respiratory-related activity of the external obliques was evoked in four of seven subjects, whereas rectus abdominis activity was observed in six of the seven subjects. We measured only the activity that was confined exclusively to the expiratory phase of the respiratory cycle. Expiratory activity of both muscles increased with exercise intensity, although peak values averaged only 10-20 or 20-40 % of the peak activity (obtained during maximal, voluntary expiratory efforts) for the external oblique and rectus abdominis muscles, respectively. To estimate how much of the recorded abdominal muscle activity was supporting leg movements during exercise, we compared the activity at the very end of incremental exercise to that recorded during the first five respiratory cycles after the abrupt cessation of exercise, when ventilation was still very high. Although external oblique activity was reduced after exercise stopped, clear expiratory activity remained. Rectus abdominis activity remained high after exercise cessation, showing a gradual decline that approximated the decline in ventilation. During constant work rate exercise, EMG activities increased to 40-50 and 5-10 % of peak in rectus and external oblique muscles, respectively, and then plateaued for the remainder of the bout in spite of a continual upward drift in (V(O(2))) and pulmonary ventilation. Linear regression analysis showed that the rise in respiratory-related expiratory muscle activity during progressive intensity exercise was significantly correlated with ventilation, although weakly. In constant work rate exercise, expiratory EMG activities increased, but the changes were highly variable and did not change as a function of exercise time, even though ventilation drifted significantly with time. These experiments suggest that abdominal muscles play a role in regulating the ventilatory response to progressive intensity bicycle exercise, although some of the observed activity may support postural adjustments or limb movements. The contribution of abdominal muscles to ventilation during constant work rate exercise is variable, and expiratory activity does not 'drift' significantly with time.

Study Objectives: The Tucson Children's Assessment of Sleep Apnea study (TuCASA) is designed to investigate the prevalence and correlates of objectively measured sleep-disordered breathing in pre-adolescent children. This paper documents the methods and feasibility of attaining quality unattended polysomnograms in the first 162 TuCASA children recruited., Design: A prospective cohort study projected to enroll 500 children between 5 and 12 years of age who will undergo unattended polysomnography, neurocognitive evaluation, and physiological and anatomical measurements thought to be associated with sleep-disordered breathing., Setting: Children are recruited through the Tucson Unified School District. Polysomnograms and anthropometric measurements are completed in the child's home., Participants: Of the 157 children enrolled in TuCASA, there were 100 children (64%) between 5-8 years old and 57 children (36%) between the ages of 9 to 12. There were 74 (47%) Hispanic children, and 68 (43%) female participants., Interventions: N/A., Measurements & Results: Technically acceptable studies were obtained in 157 children (97%). The initial pass rate was 91%, which improved to 97% when 9 children who failed on the first night of recording completed a second study which was acceptable. In 152 studies (97%), greater than 5 hours of interpretable respiratory, electroencephalographic, and oximetry signals were obtained. The poorest signal quality was obtained from the chin electromyogram and from the combination thermister/nasal cannula. Parents reported that 54% of children slept as well as, or better than usual, while 40% reported that their child slept somewhat worse than usual. Only 6% were observed to sleep much worse than usual. Night-to-night variability in key polysomnographic parameters (n=10) showed a high degree of reproducibility on 2 different nights of study using identical protocols in the same child. In 5 children, polysomnograms done in the home were comparable to those recorded in a sleep laboratory., Conclusions: The high quality of data collected in TuCASA demonstrates that multi-channel polysomnography data can be successfully obtained in children aged 5-12 years in an unattended setting under a research protocol.

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

The medial branch (Med) of the hypoglossal nerve innervates the tongue protrudor muscles, whereas the lateral branch (Lat) innervates tongue retractor muscles. Our previous finding that pharyngeal airflow increased during either selective Med stimulation or whole hypoglossal nerve (WHL) stimulation (coactivation of protrudor and retractor muscles) led us to examine how WHL, Med, or Lat stimulation affected tongue movements and nasopharyngeal (NP) and oropharyngeal (OP) airway volume. Electrical stimulation of either WHL, Med, or Lat nerves was performed in anesthetized, tracheotomized rats while magnetic resonance images of the NP and OP were acquired (slice thickness 0.5 mm, in-plane resolution 0.25 mm). NP and OP volume was greater during WHL and Med stimulation vs. no stimulation (P < 0.05). Ventral tongue depression (measured in the midsagittal images) and OP volume were greater during Med stimulation than during WHL stimulation (P < 0.05). Lat stimulation did not alter NP volume (P = 0.39). Our finding that either WHL or Med stimulation dilates the NP and OP airways sheds new light on the control of pharyngeal airway caliber by extrinsic tongue muscles and may lead to new treatments for patients with obstructive sleep apnea.

Repeated electrical or hypoxic stimulation of peripheral chemoreceptors has been shown to cause a persistent poststimulus increase in respiratory motoneuron activity, termed long-term facilitation (LTF). LTF after episodic hypoxia has been demonstrated most consistently in anesthetized, vagotomized, paralyzed, artificially ventilated rats. Evidence for LTF in spontaneously breathing animals and humans after episodic hypoxia is equivocal and may have been influenced by the awake state of the subjects in these studies. The present study was designed to test the hypothesis that LTF is evoked in respiratory-related tongue muscle and inspiratory pump muscle activities after episodic hypoxia in 10 spontaneously breathing, anesthetized, vagotomized rats. The animals were exposed to three (5-min) episodes of isocapnic hypoxia, separated by 5 min of hyperoxia (50% inspired oxygen). Genioglossus, hyoglossus, and inspiratory intercostal EMG activities, along with respiratory-related tongue movements and esophageal pressure, were recorded before, during, and for 60 min after the end of episodic isocapnic hypoxia. We found no evidence for LTF in tongue muscle (genioglossus, hyoglossus) or inspiratory pump muscle (inspiratory intercostal) activities after episodic hypoxia. Rather, the primary poststimulus effect of episodic hypoxia was diminished respiratory frequency, which contributed to a reduction in ventilatory drive.

Our purpose was to determine the influence of posture and breathing route on electromyographic (EMG) activities of nasal dilator (NDM) and genioglossus (GG) muscles during exercise. Nasal and oral airflow rates and EMG activities of the NDM and GG were recorded in 10 subjects at rest and during upright and supine incremental cycling exercise to exhaustion. EMG activities immediately before and after the switch from nasal to oronasal breathing were also determined for those subjects who demonstrated a clear switch point (n = 7). NDM and GG EMG activities were significantly correlated with increases in nasal, oral, and total ventilatory rates during exercise, and these relationships were not altered by posture. In both upright and supine exercise, NDM activity rose more sharply as a function of nasal inspired ventilation compared with total or oral inspired ventilation (P < 0.01), but GG activity showed no significant breathing-route dependence. Peak NDM integrated EMG activity decreased (P = 0.008), and peak GG integrated EMG activity increased (P = 0.032) coincident with the switch from nasal to oronasal breathing. In conclusion, 1) neural drive to NDM and GG increases as a function of exercise intensity, but the increase is unaltered by posture; 2) NDM activity is breathing-route dependent in steady-state exercise, but GG activity is not; and 3) drive to both muscles changes significantly at the switch point, but the change in GG activity is more variable and is often transient. This suggests that factors other than the breathing route dominate drive to the GG soon after the initial changes in the configuration of the oronasal airway are made.

The influence of systemic hypoxia on the endurance performance of tongue protrudor and retractor muscles was examined in anesthetized, ventilated rats. Tongue protrudor (genioglossus) or retractor (hyoglossus and styloglossus) muscles were activated via medial or lateral XII nerve branch stimulation (0.1-ms pulse; 40 Hz; 330-ms trains; 1 train/s). Maximal evoked potentials (M waves) of genioglossus and hyoglossus were monitored with electromyography. Fatigue tests were performed under normoxic and hypoxic (arterial PO(2) = 50 +/- 1 Torr) conditions in separate animals. The fatigue index (FI; %initial force) after 5 min of normoxic stimulation was 85 +/- 6 and 79 +/- 7% for tongue protrudor and retractor muscles, respectively; these values were significantly lower during hypoxia (protrudor FI = 52 +/- 10, retractor FI = 18 +/- 6%; P < 0.05). Protrudor and retractor muscle M-wave amplitude declined over the course of the hypoxic fatigue test but did not change during normoxia (P < 0.05). We conclude that hypoxia attenuates tongue protrudor and retractor muscle endurance performance; potential mechanisms include neuromuscular transmission failure and/or diminished sarcolemmal excitability.

This study was designed to investigate the influence of hypoxia-evoked augmented breaths (ABs) on respiratory-related tongue protrudor and retractor muscle activities and inspiratory pump muscle output. Genioglossus (GG) and hyoglossus (HG) electromyogram (EMG) activities and respiratory-related tongue movements were compared with peak esophageal pressure (Pes; negative change in pressure during inspiration) and minute Pes (Pes x respiratory frequency = Pes/min) before and after ABs evoked by sustained poikilocapnic, isocapnic, and hypercapnic hypoxia in spontaneously breathing, anesthetized rats. ABs evoked by poikilocapnic and isocapnic hypoxia triggered long-lasting (duration at least 10 respiratory cycles) reductions in GG and HG EMG activities and tongue movements relative to pre-AB levels, but Pes was reduced transiently (duration of <10 respiratory cycles) after ABs. Adding 7% CO(2) to the hypoxic inspirate had no effect on the frequency of evoked ABs, but this prevented long-term declines in tongue muscle activities. Bilateral vagotomy abolished hypoxia-induced ABs and stabilized drive to the tongue muscles during each hypoxic condition. We conclude that, in the rat, hypoxia-evoked ABs 1) elicit long-lasting reductions in protrudor and retractor tongue muscle activities, 2) produce short-term declines in inspiratory pump muscle output, and 3) are mediated by vagal afferents. The more prolonged reductions in pharyngeal airway vs. pump muscle activities may lead to upper airway narrowing or collapse after spontaneous ABs.

1. The purpose of these experiments was to examine the mechanisms by which either co-activation or independent activation of tongue protrudor and retractor muscles influence upper airway flow mechanics. We studied the influence of selective hypoglossal (XIIth) nerve stimulation on tongue movements and flow mechanics in anaesthetized rats that were prepared with an isolated upper airway. In this preparation, both nasal and oral flow pathways are available. 2. Inspiratory flow limitation was achieved by rapidly lowering hypopharyngeal pressure (Php) with a vacuum pump, and the maximal rate of flow (VI,max) and the nasopharyngeal pressure associated with flow limitation (Pcrit) were measured. These experimental trials were repeated while nerve branches innervating tongue protrudor (genioglossus; medial XIIth nerve branch) and retractor (hyoglossus and styloglossus; lateral XIIth nerve branch) muscles were stimulated either simultaneously or independently at frequencies ranging from 20-100 Hz. Co-activating the protrudor and retractor muscles produced tongue retraction, whereas independently activating the genioglossus resulted in tongue protrusion. 3. Co-activation of tongue protrudor and retractor muscles increased VI, max (peak increase 44 %, P < 0.05), made Pcrit more negative (peak decrease of 44 %, P < 0.05), and did not change upstream nasopharyngeal resistance (Rn). Independent protrudor muscle stimulation increased VI,max (peak increase 61 %, P < 0.05), did not change Pcrit, and decreased Rn (peak decrease of 41 %, P < 0.05). Independent retractor muscle stimulation did not significantly alter flow mechanics. Changes in Pcrit and VI,max at all stimulation frequencies were significantly correlated during co-activation of protrudor and retractor muscles (r2 = 0.63, P < 0.05), but not during independent protrudor muscle stimulation (r2 = 0.09). 4. These findings indicate that either co-activation of protrudor and retractor muscles or independent activation of protrudor muscles can improve upper airway flow mechanics, although the underlying mechanisms are different. We suggest that co-activation decreases pharyngeal collapsibility but does not dilate the pharyngeal airway. In contrast, unopposed tongue protrusion dilates the oropharynx, but has a minimal effect on pharyngeal airway collapsibility.

1. Our primary purpose was to test the hypothesis that the tongue protrudor (genioglossus, GG) and retractor (styloglossus, SG and hyoglossus, HG) muscles are co-activated when respiratory drive increases, and that co-activation will cause retraction of the tongue. This was addressed by performing two series of experiments using a supine, anaesthetized, tracheotomized rat in which tongue muscle force and the neural drive to the protrudor and retractor muscles could be measured during spontaneous breathing. In the first series of experiments, respiratory drive was increased progressively by occluding the tracheal cannula for thirty respiratory cycles; in the second series of experiments, the animals were subjected to hyperoxic hypercapnia and poikilocapnic hypoxia. 2. Airway occlusion for thirty breaths caused progressive, quantitatively similar increases in efferent motor nerve activity to protrudor and retractor tongue muscles. Net tongue muscle force was always consistent with tongue retraction during occlusion, and peak force rose in parallel with the neural activites. When airway occlusion was repeated following section of the lateral XIIth nerve branch (denervation of retractor muscles) the tongue either protruded (15/21 animals; 10 +/- 2 mN at the 30th occluded breath) or retracted weakly (6/21 animals; 6 +/- 2 mN at 30th occluded breath). 3. To ensure that our findings were not the result of damage to the muscle nerves, occlusion experiments were also done in eight animals in which GG EMG activity was recorded instead of nerve activities. Changes in peak integrated GG electryomyogram (EMG) activity and peak retraction force during occlusion were highly correlated (r2 = 0.86, slope = 1.05). 4. In separate experiments in fourteen rats, we found that hyperoxic hypercapnia and poikilocapnic hypoxia also result in parallel increases in the respiratory-related EMG activity of the GG and HG muscles. Also, as in the occlusion experiments, augmentations of protrudor and retractor muscle EMG activities were associated with parallel changes in tongue retraction force. 5. These studies in anaesthetized rats demonstrate that tracheal occlusion and independent stimulation of central or peripheral chemoreceptors results in inspiratory-related co-activation of the protrudor and retractor muscles, and proportional changes in tongue retraction force. These observations also demonstrate that recording GG EMG activity in isolation could lead to erroneous conclusions about respiratory-related movements of the tongue.

The technique of intramuscular microstimulation was used to activate facial nerve fibers while acquiring simultaneous twitch force measurements to measure the contractile properties and force-frequency responses of human nasal dilator (ND) motor units. Twitch force amplitude (TF), contraction time (CT), half-relaxation time (HRT), and the maximal rate of rise of force normalized to the peak force (maximum contraction rate, MCR) were recorded from 98 ND motor units in 37 subjects. The average CT, HRT, MCR, and TF were 47.9 +/- 1.8 ms, 42.6 +/- 2.1 ms, 28.6 +/- 1.8 s-1, and 1.06 +/- 0.1 mN, respectively. Neither CT nor HRT were significantly correlated with TF. The average CT and HRT were similar to values recorded for small muscles of the hand but were faster than the values recorded from human toe extensor motor units. However the lack of an association between twitch force and CT or HRT was similar to the findings obtained for both human hand and foot muscles. Force-frequency curves were recorded from eight ND motor units. The force produced by the eight motor units was recorded in response to stimuli delivered at 1, 5, 10, 15, 20, 25, 30, 35, and 40 Hz to assess force-frequency relationships. The mean twitch force of the eight motor units was 0.91 +/- 0.3 mN and the average tetanic force was 8.1 +/- 1.8 mN. Therefore the average twitch force was equal to 12.7% of the tetanic force. Fifty percent of the unit tetanic force was achieved at an average frequency of 16. 4 +/- 1.7 Hz, which is greater than the value recorded for human toe extensor motor units (9.6 Hz). Thus the force produced by the ND motor units was more sensitive to changes in discharge frequency over the range of approximately 10-30 Hz and less sensitive to changes in the range of 0-10 Hz because of their fast contractile properties. The mean slope of the regression lines that were fit to the steep portion of each force-frequency curve was 5.15 +/- 0.5% change in force/Hz. This value was greater than the slope measured for human toe extensor muscles (4.2% change in force/Hz). These observations suggest that force gradation by ND motor units is more sensitive to changes in stimulation frequency than human toe extensor motor units. We conclude that most ND motor units have fast contractile properties and that rate coding may play a significant role in the gradation of force produced by the ND muscle. Furthermore, the findings of this investigation have demonstrated that contractile speed and TF in a human facial muscle are not correlated. This supports previous findings obtained from human hand and foot muscles and suggests that there may be a fundamental difference in the contractile speed-twitch force relationship between many human muscles and most muscles of other mammals.

The purpose of this brief report is to introduce new evidence showing that the protrudor and retractor muscles of the tongue are co-activated during inspiration in eupnea and hyperpnea in an anesthetized, tracheotomized rat model. We also review previous work on the respiratory related control of the tongue musculature, and briefly consider the clinical significance of this work. The important new findings are that: (1) Both hypoxia and hypercapnia cause parallel increases in drive to the tongue protrudor and retractor muscles (the genioglossus and hyoglossus muscles, respectively); (2) phasic volume feedback inhibits the peak inspiratory activity of both muscles; and (3) the tongue muscles consistently produce a retraction force when the genioglossus and hyoglossus are co-activated, in both animal and human subjects. This latter observation is consistent with previous work showing that the retractor muscles (hyoglossus and styloglossus) develop up to ten times more force than the genioglossus muscle. The possible mechanical consequences of tongue muscle co-activation are briefly considered.

The primary purpose of the present investigation was to determine whether long-term facilitation (LTF) of upper airway muscle activities occurs in vagotomized and vagally intact cats. Tidal volume and diaphragm, genioglossus, and nasal dilator muscle activities were recorded before, during, and after one carotid sinus nerve was stimulated five times with 2-min trains of constant current. Sixty minutes after stimulation, nasal dilator and genioglossus muscle activities were significantly greater than control in the vagotomized cats but not in the vagally intact cats. Tidal volume recorded from the vagotomized and vagally intact cats was significantly greater than control during the poststimulation period. In contrast, diaphragm activities were not significantly elevated in the poststimulation period in either group of animals. We conclude that 1) LTF of genioglossus and nasal dilator muscle activities can be evoked in vagotomized cats; 2) vagal mechanisms inhibit LTF in upper airway muscles; and 3) LTF can be evoked in accessory inspiratory muscles because LTF of inspired tidal volume was greater than LTF of diaphragm activity.

These experiments were designed to examine the behavior of external oblique motor units in spontaneously breathing cats during hypoxia and to estimate the contribution of recruitment and rate coding to changes in the integrated external oblique electromyogram (iEMG). Motor unit activities in the external oblique muscle were identified while the cats expired against a positive end-expiratory pressure (PEEP) of 1-2.5 cmH2O. After localization of unit activity, PEEP was removed, and recordings were made continuously for 3-4 min during hyperoxia, normoxia, and hypoxia. A total of 35 single motor unit activities were recorded from 10 cats. At each level of fractional concentration of end-tidal O2, the motor unit activity was characterized by an abrupt increase in mean discharge frequency, at approximately 30% of expiratory time, which then continued to increase gradually or remained constant before declining abruptly at the end of expiration. The transition from hyperoxia to normoxia and hypoxia was accompanied by an increase in the number of active motor units (16 of 35, 20 of 35, and 29 of 35, respectively) and by an increase in the mean discharge frequency of those units active during hyperoxia. The changes in motor unit activity recorded during hypoxia were accompanied by a significant increase in the average peak amplitude of the abdominal iEMG. Linear regression analysis revealed that motor unit rate coding was responsible for close to 60% of the increase in peak iEMG amplitude. The changes in abdominal motor unit activity and the external oblique iEMG that occurred during hypoxia were abolished if the arterial PCO2 was allowed to fall. We conclude that external oblique motor units are activated during the latter two-thirds of expiration and that rate coding and recruitment contribute almost equally to the increase in expiratory muscle activity that occurs with hypoxia. In addition, the excitation of abdominal motor units during hypoxia is critically dependent on changes in CO2 and/or tidal volume.

The aim of our study was to describe the endurance capacity of the expiratory muscles and to determine whether it is altered after exhaustive cycling exercise. Subjects performed repeated maximal expiratory efforts against a closed breathing valve, with and without prior exercise performed at a work rate that elicited 75% of the maximum ventilation rate. Each expiratory effort lasted 6 s, was separated by 10 s of rest, and was initiated from the end-expiratory lung volume. Endurance performance was assessed by measuring the decline in area under the pressure*time curve over 39 contractions. Prior exhaustive exercise attenuated the ability to generate and sustain maximal expiratory pressure (P = 0.013) and resulted in significant declines in the integrated electromyogram of the rectus abdominis (P = 0.005) and external oblique (P = 0.036) abdominal muscles. Each subject also performed a handgrip endurance task before and after exhaustive exercise on a separate day. Prior exercise had no effect on handgrip endurance performance, suggesting that the decline in expiratory muscle performance after exercise was not the result of reduced motivation. We conclude that the ability to maximally activate the abdominal expiratory muscles and to generate maximum expiratory pressure is impaired after exhaustive exercise. Declines in the surface integrated electromyogram despite maximal effort is consistent with findings in limb muscles and is thought to be due to a slowing of motoneuron firing rates or to neuromuscular transmission failure.

Our primary aim was to determine whether reducing the activity of nasal airway receptors would influence drive to the nasal dilator muscles (NDMs) during exercise. We used lidocaine (2%) or nasal splints to diminish afferent airway receptor activity and measured the electromyogram (EMG) activity of the NDMs during incremental bicycle exercise in subjects who breathed nasally. NDM EMG activities increased as a function of exercise intensity but were not changed by lidocaine and were only slightly reduced by splinting. Similarly, neither intervention altered the normal decrease in NDM EMG activity associated with reductions in airway resistance evoked by He-O2 breathing. We also compared the NDM EMG response to exercise with that evoked by CO2 rebreathing at rest to determine whether the nature of the ventilatory stimulus influences drive to the NDMs; comparisons were made at constant levels of nasal inspired ventilation and, therefore, constant total ventilatory output. The increase in EMG activity was much higher during exercise compared with hyperoxic hypercapnia. In conclusion, 1) desensitizing the nasal airway does not alter NDM activity significantly during exercise and 2) exercise results in much greater increases in NDM activity compared with hypercapnia, indicating that different ventilatory stimuli can evoke more or less activation of upper airway motoneurons, even when comparisons are made at constant levels of total ventilatory output.

Our aim was to test the following hypotheses: 1) neural drive to the muscles of the alae nasi (AN) is proportional to nasal airflow and is independent of the overall level of central respiratory drive, and 2) the switch from nasal to oronasal breathing corresponds to the onset of marked flow turbulence in the nasal airway. Total and nasal inspired ventilation rates (VI) and the electromyogram (EMG) of the AN muscles were measured in seven subjects during progressive-intensity bicycling exercise. In separate experiments in six subjects the nasal VI corresponding to the transition from laminar to turbulent airflow was determined by measuring the pressure-flow relationship of the nasal airway with anterior rhinomanometry. Nasal VI accounted for 70 +/- 11% of total VI at rest and 27 +/- 8% (SE) at 90% of the maximal attainable power (max). Nasal VI and integrated AN EMG activities increased linearly with exercise intensity up to 60% of the max power, but both variables plateaued at this level even though total VI (and central respiratory drive) began to increase exponentially as exercise intensity increased to 90% max. The onset of the exponential rise in total VI was associated with a sharp increase in oral VI and with the onset of marked flow turbulence in the nasal airway. The results suggest that during incremental exercise 1) changes in AN EMG activities are highly correlated with changes in nasal VI, 2) turbulent flow in the nose may be the stimulus for the switch to oronasal breathing so that total pulmonary resistance is minimized, and 3) the correlation between nasal airflow and neural drive to the AN muscles is probably mediated by mechanisms that monitor airway resistance. Although these mechanisms were not identified, the most likely possibilities are receptors in the upper and/or lower airways that are sensitive to negative transmural pressure, or to effort sensations leading to greater corollary motor discharge to nasal dilator muscle motoneurons.

Voluntary wheel running for 4 or 8 wk was used to assess whether a volitional training stimulus would induce adaptations in the oxidative capacity [citrate synthase activity (CS)], glucose phosphorylation capacity [hexokinase activity (HK)], and glucose transporter protein level (GLUT-4) of rat respiratory muscles. Running distances averaged approximately 10-13 km/day over the final 5 wk of training. Peak oxygen consumption by the trained animals was 17% greater (P < 0.05) than by age-matched sedentary control animals after 8 wk. CS, HK, and GLUT-4 in soleus and plantaris muscles all increased because of exercise training. CS increased in the rectus abdominis (+17%), external oblique (+28%), and internal oblique (+17%) but not in the costal or crural diaphragm after 4 wk of training. However, after 8 wk, CS in the costal diaphragm was 39% greater than control but was unchanged in the crural diaphragm. Whereas HK was significantly greater than control in the costal diaphragm (+18%) and rectus abdominis (+54%) after 4 wk, 8 wk of running were required for increases in HK in the external oblique (+17%) and internal oblique (+14%). HK in the crural diaphragm was not significantly altered by the exercise training. GLUT-4 did not change significantly in any of the respiratory muscles studied. These results indicate that significant adaptations in the glucose phosphorylation capacity and oxidative capacity of both inspiratory and expiratory muscles can take place in response to voluntary exercise. However, this same stimulus is not sufficient to cause an adaptive response in GLUT-4 protein level in these respiratory muscles.

The upper airway muscles play an important role in breathing, swallowing, and speaking, but little is known about the electromyogram (EMG)-force relationship of these muscles. We have measured the peak integrated EMG activity (iEMG) and force of human nasal dilator muscles (NDM) with a custom-designed headpiece that was attached via the forehead and upper lip. The headpiece contains a micromanipulator that holds a rod with a load cell mounted on its tip. The reproducibility of the force measurements was examined by measuring the lateral or "flaring" force of the NDM in multiple trials on two separate occasions in 13 subjects. For these studies the subjects were instructed to perform maximal voluntary contractions (MVCs). Test-retest reproducibility averaged 8.3% (coefficient of variation) for within-day comparisons and 13.7% between days. We also measured iEMG and NDM force during an incremental exercise test in nine of the subjects; they were instructed to breathe nasally throughout one 30-s epoch at rest and at each workload. The iEMG and force during peak exercise (175-275 W) averaged 81 +/- 26% (SD) MVC and 235 +/- 127 mN (approximately 75% MVC), respectively. The iEMG during incremental exercise was linearly related to the peak force (r = 0.90, P < 0.001). Contractile properties were measured in seven of the subjects by application of single supramaximal shocks (0.1-ms pulse) to the facial nerve. Twitch force averaged 9 +/- 6% MVC, and the time to peak force was 62 +/- 13 ms, which is considerably faster than that in human diaphragm or elbow flexors.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Repeated carotid sinus nerve (CSN) stimulation evokes a serotonin-dependent long-term facilitation (LTF) of phrenic nerve activity in cats. To determine whether CSN stimulation-evoked LTF is a general property of spinal inspiratory motoneurones, phrenic and inspiratory internal intercostal (IIC) nerve activities were recorded in nine cats (eight anaesthetized; one decerebrate), which were vagotomized, paralysed, thoracotomized and ventilated with O2; airway CO2 was controlled by means of of a servo-respirator. Baseline conditions were established by setting the arterial CO2 pressure (Pa,CO2) at approximately 2 mmHg above the threshold for IIC activity. One CSN was stimulated (3 times threshold, 25 Hz, 0.5 ms duration) with five (2 min) trains, each separated by 5 min. 2. The peak integrated phrenic activity was elevated by 33% whereas IIC activity was elevated by 226% above baseline, 90 min post-stimulation (P < 0.05). The results were similar when expressed as a percentage of the maximal neural activities (elicited by combined hypercapnia and CSN stimulation), although differences between the nerves were less pronounced. The burst frequency was not change following stimulation. 3. In five additional cats that were pretreated with the serotonin receptor antagonist, methysergide maleate (0.5-1 mg kg-1, I.V.), the CO2 thresholds of the phrenic (12 mmHg) and IIC nerves (22 mmHg) were increased (P < 0.05), and LTF could not be elicited in either neurogram. 4. Successive CSN stimulation episodes evoked a previously undescribed phenomenon. Although the peak integrated phrenic activity was unchanged (90-95% of maximal), IIC activity increased progressively during successive stimulus episodes (66-90% of maximal; P < 0.05). However, after methysergide treatment, the initial stimulus-evoked phrenic response decreased to 58% of maximal and both neurograms exhibited progressive augmentation of the stimulus-evoked response. As stimulus-evoked augmentation does not require serotonin, it is independent of LTF. 5. We conclude that CSN stimulation-evoked LTF of IIC activity exceeds that of phrenic activity. Since LTF requires the neuromodulator serotonin and is expressed predominantly by changes in burst pattern formation versus rhythm generation, serotonin may exert a greater influence on IIC relative to phrenic respiratory motor output. A unique mechanism is described whereby successive CSN stimulus episodes cause progressively increasing responses in both neurograms.

The purpose of this study was to test the hypothesis that hemorrhage-induced hypotension increases the neural drive to the abdominal expiratory muscles in chloralose-urethan-anesthetized cats that are studied under conditions of constant arterial PCO2 (PaCO2) and hyperoxia. A secondary aim was to describe in detail the concomitant changes in inspired pulmonary ventilation (VI) and the pattern of breathing under these conditions. The rectified and integrated electromyogram (EMG) of the external oblique and rectus abdominis muscles and VI were recorded in moderate and severe hemorrhagic hypotension, leading to reductions in mean blood pressure of approximately 30 and 60%, respectively. The PaCO2 was prevented from falling, and the arterial PO2 was maintained at a hyperoxic level (> 200 mmHg) by adding CO2 and O2 to the inspired gas mixture. VI increased by 2.5- and 5-fold in moderate and severe hypotension (P < 0.05). The changes in VI were mediated exclusively by changes in tidal volume, indicating that the reflex did not alter the activity of respiratory rhythm-generating structures. The EMG of external oblique muscles averaged 2, 44, and 100% in control conditions and in moderate and severe hypotension, respectively; corresponding values in rectus abdominis muscles were 10, 28, and 100% (P < 0.05 for both muscles). Bilateral cervical vagotomy caused a one- to three-fold decrease in the ventilatory response to hemorrhage and abolished the increase in abdominal muscle EMG activities. In conclusion, hemorrhagic hypotension reflexly increases pulmonary ventilation and the neural drive to the abdominal muscles. The reflex is vagally mediated, but the location of the receptors was not identified.

Experiments were designed to test two hypotheses regarding the influence of isocapnic hypoxia on the expiratory activity of the abdominal muscles: 1) brain hypoxia attenuates the increased drive to the abdominal muscles that is elicited by hypoxic stimulation of peripheral chemoreceptor afferents, and 2) activation of the abdominal muscles in hypoxia requires vagal afferent feedback. The measurements included inspired ventilation (VI) and the electromyogram (EMG) of the external and internal oblique and transversus abdominis muscles in 12 supine cats that were anesthetized with chloralose (50 mg/kg) and breathed spontaneously. Changes in respiratory drive were evoked with isocapnic hypoxia or electrical stimulation of a carotid sinus nerve. Although both stimuli increased abdominal motor output, carotid sinus nerve stimulation evoked a significantly greater increase in the external and internal oblique EMG than hypoxia when comparisons were made at an equivalent level of VI. Neither stimulus changed the abdominal EMG significantly after bilateral cervical vagotomy. Separate experiments revealed that, at a given level of VI, hypercapnia evoked a significantly greater increase in abdominal activity than isocapnic hypoxia. The results suggest that the increased drive to the abdominal muscles elicited by stimulation of the peripheral and central chemoreceptors can be antagonized by an inhibitory input that is triggered by brain hypoxia. Moreover the decrease in expiratory motor activity often observed during hypoxia in vagotomized animals is due to the removal of an excitatory mechanism that is mediated by vagal afferent feedback.

This study was designed to examine the effect of non-weight-bearing conditions and the systemic influences of simulated microgravity on rat hindlimb muscles. For this purpose, rats were suspended (SUS) in a head-down position (45 degrees) with the left hindlimb non-weight bearing (NWB) and the right hindlimb bearing 20% of presuspension body mass (WB). Weight bearing by the SUS-WB limb was accomplished by using a platform connected to a rod in sleeve, cable, and pulley apparatus to which weight could be added. Rats (250-325 g) were assigned to SUS or cage control (CC) conditions for 14 days. The angle between the foot and leg for SUS-WB and CC remained similar (20-30 degrees) throughout the experiment while the SUS-NWB hindlimbs extended to approximately 140 degrees by day 12. On day 14, the soleus, plantaris, and gastrocnemius muscles from the SUS-NWB limbs exhibited significantly lower (P < or = 0.05) masses than presuspension mass values (29, 11, and 21%, respectively). Weight bearing by the SUS-WB limbs prevented the loss of mass by these muscles. In separate groups of SUS and CC rats, 2-deoxyglucose uptake during hindlimb perfusion was significantly higher in both SUS-NWB and SUS-WB hindlimbs at 24,000 microU/ml of insulin compared with CC for all the muscles examined (21-80%). In addition, extracellular space (ml/g) was significantly greater in the soleus muscles from both the SUS-NWB and SUS-WB hindlimbs (64%) compared with CC muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

Our purpose was to assess the separate effects of nasal airflow and resistance on the activity of the nasal dilator [alae nasi (AN)] muscles. Nasal airflow and the AN electromyogram were recorded at rest and during progressive-intensity exercise at 60, 120, and 150-180 W in 10 healthy subjects who breathed nasally under all conditions. The activity of the AN muscles increased linearly as a function of the increase in nasal minute ventilation evoked by progressive-intensity exercise (r = 0.99, P < 0.002). Reciprocal changes in nasal airflow and resistance were produced by surreptitious substitution of 12-15 breaths of 79% He-21% O2 for air at rest and during exercise. The switch to He-O2 decreased airway resistance (anterior rhinomanometry) by approximately 30% at rest and 40-60% during exercise. He-O2 did not change nasal flow or AN activities significantly under resting conditions. In contrast, He-O2 increased nasal flow and decreased the AN electromyogram by 25-50% during exercise (P < 0.05). The results suggest that AN muscle activities during nasal breathing are regulated by mechanisms that track airway resistance or the level of flow turbulence. The increase in AN activities during exercise probably helps ensure nasal airway patency in the face of the considerable collapsing pressures that prevail under these conditions.

The slope of the relationship between ventilation (VI) and O2 consumption, as derived in progressive-intensity exercise tests, is increased markedly by systemic hypoxia. The mechanisms underlying the hypoxic potentiation of the ventilatory response to exercise have not been established, partly because several factors that can increase respiratory drive (e.g., metabolic rate, cardiac output, circulating catecholamine levels) change significantly and simultaneously under these conditions. In an effort to avoid these confounding changes, we sought to determine whether hypoxia potentiates the ventilatory response to dynamic forearm exercise in humans. Forearm exercise increased the O2 consumption by only 80-90 ml/min; nevertheless, hypoxia resulted in a significant potentiation of VI that was mediated by a marked increase in breathing frequency. These observations led us to hypothesize that the hypoxic potentiation of VI is due to an exaggerated stimulation of chemosensitive afferent nerve endings within the exercising muscles ("muscle chemoreceptors"). We tested this hypothesis in separate experiments under conditions of forearm ischemia so that the stimulus to the muscle chemoreceptors in normoxic and hypoxic exercise would be the same. The magnitude of the change in VI evoked by hypoxic ischemic exercise was significantly greater than the sum of the separate changes evoked by normoxic ischemic exercise and hypoxic ischemic rest. We conclude that the combination of dynamic forearm exercise and hypoxia potentiates VI and that this effect is mediated by neural structures that govern respiratory frequency. Moreover the potentiated ventilatory response cannot be attributed to an exaggerated stimulation of intramuscular chemoreceptors.

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.

Our purpose was to determine if endurance exercise training would increase the oxidative capacity of the abdominal expiratory muscles of the rat. Accordingly, 9 male rats were subjected to an endurance training protocol (1 h/day, 6 days/week, 9 weeks) and 9 litter-mates served as controls. Citrate synthase (CS) activity was used as an index of oxidative capacity, and was determined in the following muscles: soleus, plantaris, costal diaphragm, crural diaphragm, and in all four abdominal muscles: rectus abdominis, transversus abdominis, external oblique, and internal oblique. Compared to their non-trained litter-mates, the trained rats had higher peak whole body oxygen consumption rates (+ 16%) and CS activities in plantaris (+34%) and soleus (+36%) muscles. Thus, the training program caused substantial systemic and locomotor muscle adaptations. The CS activity of costal diaphragm was 20% greater in the trained animals, but no difference was observed in crural diaphragm. The CS activity in the abdominal muscles was less than one-half of that in locomotor and diaphragm muscles, and there were no significant changes with training except in the rectus abdominis where a 26% increase was observed. The increase in rectus abdominis CS activity may reflect its role in postural support and/or locomotion, as none of the primary expiratory pumping muscles adapted to the training protocol. The relatively low levels of CS activity in the abdominal muscles suggests that they are not recruited frequently at rest, and the lack of an increase with training indicates that these muscles do not contribute significantly to the increased ventilatory activity accompanying exercise in the rat.

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)

Our purpose was to test the hypothesis that hypoxia potentiates exercise-induced sympathetic neural activation in humans. In 15 young (20-30 yr) healthy subjects, lower leg muscle sympathetic nerve activity (MSNA, peroneal nerve; microneurography), venous plasma norepinephrine (PNE) concentrations, heart rate, and arterial blood pressure were measured at rest and in response to rhythmic handgrip exercise performed during normoxia or isocapnic hypoxia (inspired O2 concn of 10%). Study I (n = 7): Brief (3-4 min) hypoxia at rest did not alter MSNA, PNE, or arterial pressure but did induce tachycardia [17 +/- 3 (SE) beats/min; P less than 0.05]. During exercise at 50% of maximum, the increases in MSNA (346 +/- 81 vs. 207 +/- 14% of control), PNE (175 +/- 25 vs. 120 +/- 11% of control), and heart rate (36 +/- 2 vs. 20 +/- 2 beats/min) were greater during hypoxia than during normoxia (P less than 0.05), whereas the arterial pressure response was not different (26 +/- 4 vs. 25 +/- 4 mmHg). The increase in MSNA during hypoxic exercise also was greater than the simple sum of the separate responses to hypoxia and normoxic exercise (P less than 0.05). Study II (n = 8): In contrast to study I, during 2 min of exercise (30% max) performed under conditions of circulatory arrest and 2 min of postexercise circulatory arrest (local ischemia), the MSNA and PNE responses were similar during systemic hypoxia and normoxia. Arm ischemia without exercise had no influence on any variable during hypoxia or normoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

The primary aim of this study was to determine the influence of systemic hyperoxia on sympathetic nervous system behavior at rest and during submaximal exercise in humans. In seven healthy subjects (aged 19-31 yr) we measured postganglionic sympathetic nerve activity to skeletal muscle (MSNA) in the leg, antecubital venous norepinephrine concentrations, heart rate, and arterial blood pressure during normoxic rest (control) followed by 3- to 4-min periods of either hyperoxic (100% O2 breathing) rest, normoxic exercise (rhythmic handgrips at 50% of maximum force), or hyperoxic exercise. During exercise, isocapnia was maintained by adding CO2 to the inspirate as necessary. At rest, hyperoxia lowered MSNA burst frequency (12-42%) and total activity (6-42%) in all subjects; the average reductions were 25 and 23%, respectively (P less than 0.05 vs. control). Heart rate also decreased during hyperoxia (6 +/- 1 beats/min, P less than 0.05), but arterial blood pressure was not affected. During hyperoxic compared with normoxic exercise, there were no differences in the magnitudes of the increases in MSNA burst frequency or total activity, plasma norepinephrine concentrations, or mean arterial blood pressure. In contrast, the increase in heart rate during hyperoxic exercise (13 +/- 2 beats/min) was less than the increase during normoxic exercise (20 +/- 2 beats/min; P less than 0.05). We conclude that, in healthy humans, systemic hyperoxia 1) lowers efferent sympathetic nerve activity to skeletal muscle under resting conditions without altering venous norepinephrine concentrations and 2) has no obvious modulatory effect on the nonactive muscle sympathetic nerve adjustments to rhythmic exercise.

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.

For the first time in the rat, we described the effects of exercise on arterial acid-base status and examined the role of chemical stimuli as determinants of the hyperventilatory response in this species. O2 consumption (VO2), CO2 production (VCO2), arterial blood gases, arterial lactate concentration ([LA-]a), and rectal temperature (Tre) were measured in non-trained male rats at rest and during 10 min of treadmill exercise at various intensities. During mild exercise (2.5-fold increase in VCO2), PaCO2 fell 5.5 +/- 0.6 Torr, and despite a small but significant increase in [LA-]a, respiratory alkalosis prevailed [change in arterial pH (delta pHa) = 0.034 +/- 0.006]. Arterial PO2 (PaO2) increased 4.1 +/- 1.5 Torr and Tre increased 0.6 +/- 0.1 degrees C. A progressive hyperventilation occurred from mild to heavy exercise. This response was not attributable to arterial hypoxemia or acidosis and it was not affected by preventing the exercise-induced increase in body temperature. During maximal exercise, VO2 increased 3.4-fold (72 +/- 1.50 ml X kg-1 X min-1) and VCO2 increased 4.5-fold (74 +/- 1.90 ml X kg-1 X min-1), resulting in a 9-fold increase in [LA-]a and a severe metabolic acidosis (pHa 7.31 +/- 0.02). A marked hyperventilation [arterial PCO2 (PaCO2) 28.5 +/- 1.4 Torr] resulted in partial compensation of pHa, but almost all of this hyperventilation occurred before the onset of metabolic acidosis, [i.e., at less than 65% maximum VO2 (VO2max)], and the increased [H+]a with further elevations in VO2 produced no further hypocapnia.(ABSTRACT TRUNCATED AT 250 WORDS)

The conventional view of the healthy pulmonary system during exercise is of a very precise and mechanically efficient homeostatic regulator of ventilation and gas exchange occurring within the reserves of a near ideal architecture of the lung and chest wall. These regulatory and architectural limits may be exceeded in the healthy pulmonary system when extremely high levels of metabolic demand are needed. For example, arterial hypoxemia will often occur at exercise intensities demanding greater than 25 liters/min cardiac output. This may be due to inadequate red cell transit time in the pulmonary capillary bed whose blood volume has been maximally recruited, thereby resulting in alveolar-end-capillary oxygen disequilibrium. At these extreme levels of exercise the hyperventilatory response may be minimal (and clearly inadequate in terms of alveolar oxygenation) despite substantial and progressive metabolic acidosis or hypoxemia or both. This evidence of compromised ventilatory response and inadequate gas exchange in the highly fit human suggests that the pulmonary system may not be reasonably designed or adaptable (with long-term physical training) to the extreme demands imposed on gas transport by a truly adapted cardiovascular system.

We determined the effects of ether, intra-arterial Na+ pentobarbital (SP) and decapitation on arterial [H+] and labile metabolites in plantaris, diaphragm and intercostal muscles of rats at rest and following exhaustive treadmill exercise. 30-60 sec post-analgesia arterial [Lactate] ([LA]a) increased with both anesthetics. SP rats retained CO2 resulting in mixed acidosis, while ether anesthetized rats hyperventilated and maintained pH. During recovery from exercise ether anesthesia had no effect but SP anesthesia caused CO2 retention. Decapitation of resting rats markedly decreased [CP] and elevated [LA] and [G6P] in all three muscles, thereby negating any subsequent exercise effects. The effects of ether differed from those of SP in that with ether anesthesia: [CP]/[Total Creatine] fell and [LA] rose significantly with exercise; resting [LA] was lower and increased with exercise; and metabolite variability was less with ether than with SP. We conclude that: anesthesia obscured the true effects of exercise on acid-base status by increasing [LA]a in the resting state; decapitation is unsuitable for the study of exercise effects on most muscle metabolites; ether anesthesia is most suitable for use in studies aimed at detecting exercise effects on muscle metabolites and for preserving arterial acid-base status closest to the unanesthetized state.

Our purpose was to determine whether the intensity of abdominal expiratory nerve discharge is conditioned by the intensity of the preceding inspiratory phrenic discharge, independent of mechanical and chemical afferent influences. In decerebrate, paralyzed, vagotomized cats with bilateral pneumothoraxes, we recorded phrenic and abdominal (cranial iliohypogastric nerve, L1) nerve activities at hyperoxic normocapnia. We reduced the duration and intensity (i.e., integrated peak height) of phrenic nerve discharge for single cycles by stimulating the cut central end of the superior laryngeal nerve (SLN) during the central inspiratory phase (75 microA, 20-50 Hz, 0.2-ms pulse). Premature termination of inspiration consistently reduced expiratory duration (TE) and abdominal expiratory nerve activity (area of integrated neurogram), but the average reduction in TE was much less than the reduction in abdominal nerve activity (14 vs. 51%). Stimulation of the cut central end of the vagus nerve yielded similar results, as did spontaneous premature terminations of inspiration, which we observed in one cat. SLN stimulation during hyperoxic hypercapnia resulted in more variable responses, and higher stimulation frequencies were usually required to abort inspiration. SLN (or vagal) stimulation during expiration consistently increased abdominal expiratory nerve activity. We speculate that this facilitatory response is gated during inspiration, thereby allowing the inspiratory conditioning effect on the subsequent expiration to be expressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Our purpose was to examine the influence of steady-state changes in chemical stimuli, as well as discrete peripheral chemoreceptor stimulation, on abdominal expiratory motor activity. In decerebrate, paralyzed, vagotomized, and ventilated cats that had bilateral pneumothoraces, we recorded efferent activity from a phrenic nerve and from an abdominal nerve (cranial iliohypogastric nerve, L1). All cats showed phasic expiratory abdominal nerve discharge at normocapnia [end-tidal PCO2 38 +/- 2 Torr], but small doses (2-6 mg/kg) of pentobarbital sodium markedly depressed this activity. Hyperoxic hypercapnia consistently enhanced abdominal expiratory activity and shortened the burst duration. Isocapnic hypoxia caused inhibition of abdominal nerve discharge in 11 of 13 cats. Carotid sinus nerve denervation (3 cats) exacerbated the hypoxic depression of abdominal nerve activity and depressed phrenic motor output. Stimulation of peripheral chemoreceptors with NaCN increased abdominal nerve discharge in 7 of 10 cats, although 2 cats exhibited marked inhibition. Four cats with intact neuraxis, but anesthetized with ketamine, yielded qualitatively similar results. We conclude that when cats are subjected to steady-state chemical stimuli in isolation (no interference from proprioceptive inputs), hypercapnia potentiates, but hypoxia attenuates, abdominal expiratory nerve activity. Mechanisms to explain the selective inhibition of expiratory motor activity by hypoxia are proposed, and physiological implications are discussed.

We sought to determine if chronic endurance training would increase mitochondrial respiration or protein content in rat diaphragm muscle. To this end, 20 male Wistar rats were randomly assigned to control (C) or an 8-week endurance training (T) group, n = 10 per group. At the end of T, VO2 max was 13% greater in T (83.3 vs 73.8 ml X kg-1 X min-1) and peak max power output was 32% greater (2.63 vs 1.98 kg X m X min-1). Mitochondrial specific activities of pyruvate-malate and cytochrome oxidase (expressed per mg mitochondrial protein) in both plantaris and diaphragm were similar in C and T rats, as were ADP/O and respiratory control ratios. When expressed per gram wet weight, whole muscle homogenate oxygen uptake (pyruvate + malate) and cytochrome oxidase activity increased 36 and 23%, respectively (P less than 0.05) in plantaris from T rats but did not change in diaphragm. Control oxidative capacity and mitochondrial protein content in the diaphragm were ca. 2-fold those in control plantaris. Plantaris mitochondrial protein content increased ca. 50% with T while the diaphragm was unaffected. We conclude that: plantaris muscle oxidative capacity adapts to training by increasing mitochondrial protein content, since there was no evidence for functional improvement of existing mitochondria, and in the face of a substantial training effect in whole animal and plantaris, the T stimulus was not sufficient to induce mitochondrial protein changes in the diaphragm. This finding is the result of either a 'pre-adaptation' secondary to the diaphragm's high chronic activity, or a sub-threshold increase in diaphragm recruitment during the exercise conditions studied.

We determined changes in rat plantaris, diaphragm, and intercostal muscle metabolites following exercise of various intensities and durations, in normoxia and hypoxia (FIO2 = 0.12). Marked alveolar hyperventilation occurred during all exercise conditions, suggesting that respiratory muscle motor activity was high. [ATP] was maintained at rest levels in all muscles during all normoxic and hypoxic exercise bouts, but at the expense of creatine phosphate (CP) in plantaris muscle and diaphragm muscle following brief exercise at maximum O2 uptake (VO2max) in normoxia. In normoxic exercise plantaris [glycogen] fell as exercise exceeded 60% VO2max, and was reduced to less than 50% control during exhaustive endurance exercise (68% VO2max for 54 min and 84% for 38 min). Respiratory muscle [glycogen] was unchanged at VO2max as well as during either type of endurance exercise. Glucose 6-phosphate (G6P) rose consistently during heavy exercise in diaphragm but not in plantaris. With all types of exercise greater than 84% VO2max, lactate concentration ([LA]) in all three muscles rose to the same extent as arterial [LA], except at VO2max, where respiratory muscle [LA] rose to less than half that in arterial blood or plantaris. Exhaustive exercise in hypoxia caused marked hyperventilation and reduced arterial O2 content; glycogen fell in plantaris (20% of control) and in diaphragm (58%) and intercostals (44%). We conclude that respiratory muscle glycogen stores are spared during exhaustive exercise in the face of substantial glycogen utilization in plantaris, even under conditions of extreme hyperventilation and reduced O2 transport. This sparing effect is due primarily to G6P inhibition of glycogen phosphorylase in diaphragm muscle. The presence of elevated [LA] in the absence of glycogen utilization suggests that increased lactate uptake, rather than lactate production, occurred in the respiratory muscles during exhaustive exercise.

The purpose was to characterize expiratory-related neural activities in eupnea and gasping. In decerebrate and vagotomized cats, activities were recorded from the phrenic nerve, spinal intercostal and abdominal nerves, and recurrent laryngeal nerve and its branches. Neural inspiration was defined by phrenic discharge. The spinal and laryngeal nerves discharged in inspiration, expiration, or during both phases. Gasping was induced by freezing the brain stem at the pontomedullary junction, exposure to asphyxia or anoxia, or ligation of the basilar artery and its branches. In gasping, peak phrenic activity typically increased as did inspiratory-related activities of laryngeal and spinal nerves. Expiratory activities were greatly reduced in gasping, with some activities being completely eliminated. Reductions of expiratory activity were more prominent for spinal than laryngeal nerves. Similar results were obtained in cats having intact vagi that were ventilated with a servo-respirator so that lung inflation paralleled phrenic activity. The concept that gasping differs fundamentally form other ventilatory patterns is discussed.