Diaphragm Electromyogram Activity Research Articles

Diaphragm EMG activity during hyperbaric oxygen exposure in spinal injured rats

Cervical spinal cord injury can cause significant respiratory dysfunction and in severe cases necessitates mechanical ventilation. Accumulating evidence indicates that hyperbaric oxygen (HBO) therapy, initiated shortly after spinal cord injury (SCI), can mitigate spinal cord pathology. Further, a recent study from our group demonstrated that HBO therapy can attenuate diaphragm atrophy after SCI. The primary purpose of the present investigation was to evaluate diaphragm electromyogram (EMG) activity during HBO therapy in rats with cervical SCI. HBO therapy has not been widely adopted after SCI, and if HBO is to be translated to human use, we reasoned that it is important to determine how breathing is impacted during HBO exposure. Adult female Sprague‐Dawley rats were implanted with chronic indwelling EMG electrodes in the mid‐costal diaphragm two weeks prior to SCI. Following hemicontusion injury of the C4 spinal cord, one experimental group was treated with HBO (n=3), and another group was left untreated (n=3). The HBO treatment consisted of a one hour exposure to 100% O2 at 3 atmospheres (ATA). In all experiments, diaphragm EMG activity was recorded in freely moving rats, without anesthesia. Recordings were made for 10 minutes prior to treatment, throughout the HBO exposure, and for 10 minutes after. Diaphragm EMG recordings in the normobaric normoxia control group conditions were completed for the same duration of time as the treated group. Daily HBO treatment and EMG recordings were done until 10‐days post‐SCI. Peak diaphragm EMG burst amplitude was quantified before SCI, over the 10 days of treatment, and at 1 and 2 weeks post‐treatment. Prior to SCI, body weight was similar between groups (control: 227±4 g; HBO: 228±3 g). All rats with tolerated HBO treatment with no evidence of adverse events or impact on weight gain over the 10 day period (10 day body weight: control: 198 ± 14 g; HBO: 197 ± 13 g). The acute HBO exposure caused an increase in the area under the curve of the rectified and integrated inspiratory burst amplitude of the diaphragm recording made ipsilateral to the lesion. This increase averaged 126 ± 18% of baseline across the 10 HBO treatments. The ipsilateral EMG burst amplitude also remained elevated at 10 min post‐HBO exposure (115 ± 32%) compared to pre HBO exposure. At the conclusion of the 10 day treatment paradigm, ipsilateral diaphragm EMG output during quiet breathing was elevated in HBO (156 ± 50% of post‐injury baseline) as compared to the control group (111 ± 6% of baseline). However the ipsilateral diaphragm EMG burst amplitude of the two groups were similar when evaluated 2 weeks after the daily HBO sessions concluded. This ongoing study indicates that acute exposure to HBO therapy is associated with an increase in diaphragm EMG activity, and 10 days of HBO therapy accelerates the recovery of diaphragm activation following cervical contusion injury.

Accessory Muscle Support of Breathing in Young Dystrophin‐deficient mdx Mice

Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disorder that occurs due to the absence of the structural protein dystrophin and secondary consequences. DMD is characterized by severe and progressive skeletal muscle weakness, which extends to the respiratory muscles. In young dystrophin‐deficient mdx mice, peak inspiratory pressure‐generating capacity is preserved despite diaphragm muscle weakness and reduced electromyogram (EMG) activitya. Our overarching hypothesis is that accessory muscle compensation limits ventilatory deficit in early dystrophic disease. Four‐month‐old male wild‐type (n=39) and mdx (n=41) mice were studied. Breathing was assessed in conscious mice using whole body plethysmography during normoxia and chemochallenge (10% O2/6% CO2). Thoracic oesophageal pressure and obligatory (diaphragm and external intercostal) respiratory muscle EMG activities were recorded in urethane (1.7g/kg i.p.) anaesthetised spontaneously breathing mice during baseline and sustained tracheal occlusion (maximal muscle activation). Diaphragm and scalene (accessory respiratory muscle) force output were examined ex vivo. Data were statistically compared using unpaired Student’s t test or two‐way ANOVA with Bonferroni post hoc test. Peak diaphragm force ex vivo (P < 0.0001) and baseline diaphragm EMG activity (P = 0.01) were significantly lower in mdx compared with wild‐type. Minute ventilation was equivalent in age‐matched wild‐type and mdx mice during baseline and chemochallenge (P = 0.1). Peak diaphragm (P < 0.0001) and external intercostal (P = 0.01) EMG activities during obstruction were significantly lower in mdx mice compared to wild‐type, while peak inspiratory pressure was equivalent (P = 0.4). Interestingly, peak scalene muscle force ex vivo was preserved in 4‐month‐old mdx mice (P = 0.8). Despite a decline in diaphragm muscle performance (decreased EMG activity and mechanical weakness) at baseline, ventilatory capacity is preserved in mdx mice. Furthermore, despite lower peak electrical activation of the obligatory muscles of breathing and diaphragm muscle functional deficit, peak inspiratory pressure is preserved in 4‐month‐old mdx mice, confirming our previous findings in 2‐month‐old micea. Our finding of preserved scalene muscle force suggests that compensation may be provided by accessory muscles to support ventilatory and non‐ventilatory behaviours in early dystrophic disease. Current studies are examining the EMG activity of accessory respiratory muscles (e.g. scalene, sternomastoid, cleidomastoid and trapezius) in early and advanced dystrophic disease in mdx mice.References a Burns DP, Murphy KH, Lucking EF, O'Halloran KD. Inspiratory pressure‐generating capacity is preserved during ventilatory and non‐ventilatory behaviours in young dystrophic mdx mice despite profound diaphragm muscle weakness. J. Physiol. 2019;597(3):831‐848.

Diaphragm and Intercostal Muscle Activity after Mid-Cervical Spinal Cord Contusion in the Rat.

The present study was designed to investigate the diaphragm and intercostal muscle activity after unilateral mid-cervical spinal cord contusion in rats. Electromyogram (EMG) activity of the bilateral diaphragm and T2 intercostal muscle was measured in anesthetized and spontaneously breathing rats. Unilateral mid-cervical contusion caused an immediate reduction in inspiratory bursting in the bilateral diaphragm and intercostal muscles. From 3 days to 8 weeks post-contusion, contused animals displayed significantly lower tidal volume than uninjured animals, regardless of the time point after injury. The burst amplitude of the contralateral diaphragm EMG was augmented in contused animals at 3 days post-injury. When the data were normalized by the maximal response during hypoxic-hypercapnic challenge (12-13% O2, 3-4% CO2), the ipsilateral diaphragm EMG of contused animals was greater than that of uninjured animals at 3 days and 2 weeks post-injury. Moreover, hypoxia-hypercapnia-induced increases in ipsilateral diaphragm EMG activity were blunted in contused animals at 2 weeks post-injury, but recovered at 8 weeks post-injury. Bilateral diaphragm EMG activity in contused animals was comparable to uninjured animals at 8 weeks post-injury. Notably, intercostal muscle activity was not substantially changed by mid-cervical spinal cord contusion from 3 days to 8 weeks post-contusion. These results suggest that mid-cervical spinal contusion induces a compensatory increase in contralateral diaphragmatic activity and greater utilization of a percentage of maximal inspiratory activity in the ipsilateral diaphragm. The maintenance of intercostal muscle activity may enable the animal to sustain essential breathing capacity after cervical spinal cord injury.

Intermittent hypercapnic hypoxia during sleep does not induce ventilatory long-term facilitation in healthy males.

Intermittent hypoxia-induced ventilatory neuroplasticity is likely important in obstructive sleep apnea pathophysiology. Although concomitant CO2 levels and arousal state critically influence neuroplastic effects of intermittent hypoxia, no studies have investigated intermittent hypercapnic hypoxia effects during sleep in humans. Thus the purpose of this study was to investigate if intermittent hypercapnic hypoxia during sleep induces neuroplasticity (ventilatory long-term facilitation and increased chemoreflex responsiveness) in humans. Twelve healthy males were exposed to intermittent hypercapnic hypoxia (24 × 30 s episodes of 3% CO2 and 3.0 ± 0.2% O2) and intermittent medical air during sleep after 2 wk washout period in a randomized crossover study design. Minute ventilation, end-tidal CO2, O2 saturation, breath timing, upper airway resistance, and genioglossal and diaphragm electromyograms were examined during 10 min of stable stage 2 sleep preceding gas exposure, during gas and intervening room air periods, and throughout 1 h of room air recovery. There were no significant differences between conditions across time to indicate long-term facilitation of ventilation, genioglossal or diaphragm electromyogram activity, and no change in ventilatory response from the first to last gas exposure to suggest any change in chemoreflex responsiveness. These findings contrast with previous intermittent hypoxia studies without intermittent hypercapnia and suggest that the more relevant gas disturbance stimulus of concomitant intermittent hypercapnia frequently occurring in sleep apnea influences acute neuroplastic effects of intermittent hypoxia. These findings highlight the need for further studies of intermittent hypercapnic hypoxia during sleep to clarify the role of ventilatory neuroplasticity in the pathophysiology of sleep apnea.NEW & NOTEWORTHY Both arousal state and concomitant CO2 levels are known modulators of the effects of intermittent hypoxia on ventilatory neuroplasticity. This is the first study to investigate the effects of combined intermittent hypercapnic hypoxia during sleep in humans. The lack of neuroplastic effects suggests a need for further studies more closely replicating obstructive sleep apnea to determine the pathophysiological relevance of intermittent hypoxia-induced ventilatory neuroplasticity.

Heme oxygenase-1-dependent central cardiorespiratory adaptations to chronic intermittent hypoxia in mice.

Chronic intermittent hypoxia (CIH) increases sympathetic tone and respiratory instability. Our previous work showed that chronic hypoxia induces the oxygen-sensing enzyme heme oxygenase-1 (HO-1) within the C1 sympathoexcitatory region and the pre-Bötzinger complex (pre-BötC). We therefore examined the effect of CIH on time course of induced expression of HO-1 within these regions and determined whether the induction of HO-1 correlated with changes in respiratory, sigh frequency, and sympathetic responses (spectral analysis of heart rate) to acute hypoxia (10% O2) during 10 days of exposure to CIH in chronically instrumented awake wild-type (WT) and HO-1 null mice (HO-1-/-). HO-1 was induced within the C1 and pre-BötC regions after 1 day of CIH. There were no significant differences in the baseline respiratory parameters between WT and HO-1-/- Prior to CIH, acute hypoxia increased respiratory frequency in both WT and HO-1-/-; however, minute diaphragm electromyogram activity increased in WT but not HO-1-/- The hypoxic respiratory response after 1 and 10 days of CIH was restored in HO-1-/- CIH resulted in an initial significant decline in 1) the hypoxic sigh frequency response, which was restored in WT but not HO-1-/-, and 2) the baseline sympathetic activity in WT and HO-1-/-, which remained stable subsequently in WT but not in HO-1-/- We conclude that 1) CIH induces expression of HO-1 in the C1 and pre-BötC regions within 1 day and 2) HO-1 is necessary for hypoxia respiratory response and contributes to the maintenance of the hypoxic sigh responses and baseline sympathetic activity during CIH.

Inactivity‐Induced Phrenic Motor Facilitation underlies Spontaneous Recovery of Ventilation and Diaphragm EMG activity Following Cervical Spinal Injury

Cervical spinal injury disrupts neural pathways to phrenic motor neurons, thereby causing diaphragm paresis and paralysis and diminished breathing capacity. Some spontaneous functional recovery in the capacity to generate phrenic nerve or diaphragm activity is observed days‐to‐months post‐injury via mechanisms that not understood. We have previously found that prolonged reductions in spinal synaptic inputs to phrenic motor neurons in uninjured rats results in a PKCz‐dependent, rebound enhancement of phrenic burst amplitude, a form of spinal plasticity known as inactivity‐induced phrenic motor facilitation (iPMF). Little is known regarding the role for iPMF in the control of breathing. Here, we tested the hypothesis that mechanisms giving rise to iPMF underlie spontaneous recovery of ventilation and diaphragm EMG activity following a high cervical spinal injury. Sprague Dawley rats (Harlan colony 217, 12–16 weeks old) chronically instrumented with radiotelemetry for bilateral diaphragm electromyogram (EMG) recordings received small interfering RNAs directed against PKCz or non‐targeting siRNAs in the interpleural space (100pg/side) three days prior to a C3 midline contusion. Three days following contusion, EMG and plethysmography were recorded in unanesthetized rats breathing room air (FIO2/FICO2=0.21/0.0, NX) or with maximal chemoreceptor stimulation (FIO2/FICO2= 0.105/0.07, MCS). In injured rats receiving control injections, tidal volume under both inspired gas concentrations and diaphragm EMG during MCS showed minimal change from baseline conditions (TV NX: 99%, TV MCS: 90%, diaphragm EMG right: 95%, left: 100%). By contrast, in injured rats receiving siPKCz, tidal volume during normoxia and MCS (63% NX, 90% MCS) and electrical activity of the diaphragm during MCS (right: 85%, left: 80%) were reduced from pre‐injury levels, suggesting that impairment of iPMF prevented spontaneous recovery of phrenic motor output (and hence, diaphragm EMG activity) following spinal injury. Thus, we speculate that iPMF is a form of compensatory plasticity that senses and responds to reductions in spinal synaptic inputs to phrenic motor neurons to maintain stable phrenic motor output following spinal injury.Support or Funding InformationSupported by NIH R01‐HL105511, DoD SC120226 and NIH T32‐OD010423‐09

Relation Between Diaphragm EMG and Ventilation in Rats Acclimatized to Hypobaric Sustained Hypoxia

Exposure to chronic sustained hypoxia in healthy subjects, for example during acclimatization to high altitude, increases ventilation in normoxia and increases the ventilatory response to acute hypoxia or hypercapnia. Laboratory rodents have proved to be a useful model for studying the mechanisms of such ventilatory acclimatization to hypoxia. However, it is not known if all respiratory muscles contribute similarly to increases in ventilatory drive and chemoreflexes with acclimatization. Here we tested the hypothesis that the diaphragm contributes to increases in ventilatory responses to hypoxia and hypercapnia equally before and after acclimatization. Therefore, we measured diaphragm electromyogram activity and related the amplitude of the rectified and integrated signal (EMGdia) to tidal volume (Vt) in rats exposed to one week of sustained hypoxia. We made an abdominal incision in male Sprague‐Dawley rats and implanted a two‐electrode transmitter to telemeter EMG activity from the diaphragm muscle. After recovery, we simultaneously measured ventilation with barometric pressure plethysmography and EMGdia with telemetry in awake, unrestrained rats before and after 7 days of exposure to hypobaric hypoxia (PO2 = 80 Torr). EMGdia positively correlated with Vt when breathing was stimulated by hypoxia, hypercapnia or both, and this relationship was not changed after chronic hypoxia. This shows that ventilatory acclimatization to hypoxia does not change the contribution of the diaphragm to ventilatory drive and chemoreflexes.
 Supported by NIH RO1 HL‐081823.

Tidal volume and diaphragm muscle activity in rats with cervical spinal cord injury

[Purpose] The purpose of this study was to make an experimental model of cervical spinal cord injury (CSCI) using Wistar rats, in order to analyze the influence of CSCI on the respiratory function. [Subjects] Thirty-two male 12-week-old Wistar rats were used. [Methods] The CSCI was made at the levels from C3 to C7, and we performed pneumotachography and electromyography (EMG) on the diaphragm. Computed tomography was used to determine the level of spinal cord damage. [Results] After the operation, the tidal volume of the rats with a C3 level injury decreased to approximately 22.3% of its pre-injury value. In addition, in the same rats, the diaphragmatic electromyogram activity decreased remarkably. Compared with before CSCI, the tidal volume decreased to 78.6% of its pre-injury value in CSCI at the C5 level, and it decreased to 94.1% of its pre-injury value in CSCI at the C7 level. [Conclusion] In the rats that sustained a CSCI in this study, the group of respiratory muscles that receive innervation from the thoracic spinal cord was paralyzed. Therefore, the EMG signal of the diaphragm increased. These results demonstrate that there is a relationship between respiratory function and the level of CSCI.

Effect of hypoxia on expiratory muscle activity in fetal sheep

The fetal respiratory response to acute hypoxia is characterized by depression, often to apnea. This study examined the effect of hypoxia on the electromyogram (EMG) of the thyroarytenoid (TA) muscle. Under anesthesia catheters were placed in the fetal sheep carotid artery, fourth cerebral ventricle, trachea and amniotic fluid and wires sewn into the diaphragm and TA muscle. During normoxic episodes of slow fetal breathing (<40 breaths per min) TA EMG activity was phasic beginning immediately after diaphragmatic EMG bursts and ending well before the next burst. This timing is consistent with the post-inspiratory (post-I) phase of the respiratory cycle. Lowering fetal arterial Pa O(2) from approximately 20mm Hg to approximately 13 mm Hg resulted in arrest of diaphragm EMG and tonic TA activity. Instillation of the (R,S)- -amino-3- hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) ionotrophic glutamate receptor antagonist 2,3-dihydro-6-nitro-7-sulphamoyl-benzo(f) quinoxaline (NBQX) into the cerebrospinal fluid (CSF) of the fourth ventricle abolished tracheal pressure deflections and diaphragmatic EMG activity. Tonic TA activity, however, could still be evoked by hypoxia. These results indicate that fetal post-I motoneurons are not inhibited by moderate hypoxia and that their tonic activity may be due to a loss of inhibitory input.

Responses of the Rat Medullary Neurons to Central Penicillin Microinjection

Background: The microinjection of penicillin in the medulla oblongata caused different alterations in the global respiratory output. The purpose of this paper was to study the involvement of impulse activity and the functional relationship of bulbar neurons in mechanisms underlying experimentally induced respiratory arrhythmias. Methods: Extracellular activity of neurons and diaphragmatic electromyogram activity were recorded and analyzed. Results: Penicillin microinjection increased the mean discharge rate of bulbar neurons and caused the prolongation of discharge of inspiratory neurons. Cross-correlation analysis revealed new excitatory connections between neurons and a high level of positive synchronization of neuronal activity. Conclusion: The local blockage of synaptic inhibition by penicillin within respiratory areas leads to drastic changes in the functioning of neuronal elements of the single respiratory network.

Low-Dose Mirtazapine Increases Genioglossus Activity in the Anesthetized Rat

To examine the effects of mirtazapine on genioglossus and diaphragmatic electromyogram activity in the anesthetized rat. Parallel-group study. Sprague-Dawley adult male rats, 10 in each of 3 groups were studied. After anesthesia with 1.2 g/kg of urethane, a tracheostomy and bilateral vagotomy were performed. Femoral arterial and venous lines were placed, and fine wire hook electrodes were implanted into the genioglossus and diaphragm muscles. After a baseline period of measurement, either saline, 0.5 mg/kg of mirtazapine, or 5.0 mg/kg of mirtazapine was injected via the intraperitoneal route, and measurements were made for the next 3 hours. The average peak and tonic values of the moving time average of the genioglossus and diaphragm electromyogram for hours 1, 2, and 3 were determined and expressed as a percentage of the corresponding average value during the baseline (preinjection) monitoring period. At 0.5 mg/kg of mirtazapine, the peak genioglossus electromyogram was significantly higher than in control conditions over hours 2 and 3. At 5.0 mg/kg of mirtazapine, the genioglossus electromyogram was significantly lower than in control conditions for the first 2 hours of monitoring. The peak diaphragmatic electromyogram was slightly but significantly lower in the mirtazapine 5.0-mg/kg group than in controls. Mirtazapine, at a dose similar to one used clinically, increased genioglossus activity. We hypothesize that, at this dose, the ability of mirtazapine to increase serotonin and norepinephrine or block type-3 serotonin receptors predominated. At the higher dose of mirtazapine, the type-2 blockade effect predominated and genioglossus activity decreased.

Cobalt injections into the pedunculopontine nuclei attenuate the reflex diaphragmatic responses to muscle contraction in rats.

Previous studies have suggested that neurons in the pedunculopontine nucleus (PPN) are activated during static muscle contraction. Furthermore, activation of the PPN, via electrical stimulation or chemical disinhibition, is associated with increases in respiratory activity observed via diaphragmatic electromyogram recordings. The present experiments address the potential for PPN involvement in the regulation of the reflex diaphragmatic responses to muscle contraction in chloralose-urethane anesthetized rats. Diaphragmatic responses to unilateral static hindlimb muscle contraction, evoked via electrical stimulation of the tibial nerve, were recorded before and subsequent to bilateral microinjections of a synaptic blockade agent (CoCl2) into the PPN. The peak reflex increases in respiratory frequency (9.0 +/- 1.0 breaths/min) and minute integrated diaphragmatic electromyogram activity (14.6 +/- 3.3 units/min) were attenuated after microinjection of CoCl2 into the PPN (2.6 +/- 0.9 breaths/min and 4.6 +/- 2.1 units/min, respectively). Consistent diaphragmatic responses were observed in the subset of animals that were barodenervated. Control experiments suggest no effects of PPN synaptic blockade on the cardiovascular responses to muscle contraction. The results are discussed in terms of a potential role for the PPN in modulation of the reflex respiratory adjustments that accompany muscular activity.

GABA-mediated neurotransmission in the ventrolateral NTS plays a role in respiratory regulation in the rat.

Our purpose was to determine whether endogenously released GABA in the ventrolateral nucleus of the solitary tract (vlNTS) of the rat influences respiration. Experiments were carried out in anesthetized, vagotomized and spontaneously breathing rats, and diaphragm electromyogram activity was measured while drugs affecting GABAergic neurotransmission were microinjected into the vlNTS and medial NTS (mNTS). Bilateral microinjection of nipecotic acid, 5 or 25 nmol, into the vlNTS (but not in the mNTS) produced dose-dependent increases in inspiratory duration (Ti) frequently culminating in apneustic breathing. Neither unilateral microinjection of bicuculline nor CGP-35348 (GABA(B) receptor antagonist) reversed this response; however, a combination of both GABA receptor antagonists effectively reversed apneustic breathing. Bilateral microinjection of either muscimol or baclofen into the vlNTS mimicked the effect of nipecotic acid. Microinjection of the bicuculline produced apnea, whereas microinjection of CGP-35348 produced a decrease in Ti and an increase in expiratory duration. Immunohistochemical analysis of the vlNTS region revealed GABA(A) receptors densely localized to processes, whereas GABA(B) immunoreactivity was localized to cell bodies. Our data indicate that GABA activity in the vlNTS is important for respiratory function.

Effects of GABA A and glycine receptor agonists on the medullary inspiratory neuronal activity during spontaneous augmented breaths in anesthetized rats

To clarify whether GABAergic or glycinergic transmission alters the activity of inspiratory neurons during spontaneous augmented breaths, we recorded the single unit activity from inspiratory neurons in the dorsal and ventral respiratory groups in the medulla of pentobarbital anesthetized rats and applied GABA A and glycine receptor agonists by iontophoresis using multibarrel microelectrodes. The spontaneous augmented breath was divided into two different phases; the first phase (phase I) resembled a normal inspiration but the second phase (phase II) indicated a marked increase in diaphragm electromyogram activity. During application of either muscimol or glycine, the discharge of inspiratory neurons during the phase I of spontaneous augmented breaths was suppressed, but the augmenting discharge of the phase II did not change significantly in any cell type of the neurons (I-augmenting, I-decrementing and I-other). These results suggested that the excitatory inputs to inspiratory neurons during the phase II of augmented breaths may not be significantly influenced by the activation of either GABA A receptors or glycine receptors.

Chronic Intermittent Asphyxia Impairs Rat Upper Airway Muscle Responses to Acute Hypoxia and Asphyxia

Obstructive sleep apnea (OSA) is a major clinical disorder that is characterized by multiple episodes of upper airway obstruction due to the failure of the upper airway dilator muscles to maintain upper airway patency. This results in chronic intermittent asphyxia (CIA) due to repetitive apneas, but very little is known about the effects of CIA on upper airway muscle function. To test the hypothesis that CIA affects upper airway muscle activity and electromyogram (EMG) responses to acute hypoxia and asphyxia. Record upper airway EMG responses to acute hypoxia and asphyxia in control and CIA-treated rats. Department of Physiology, Royal College of Surgeons in Ireland, Dublin, Ireland. Sternohyoid (SH) muscle and diaphragm (DIA) muscle EMG activities were recorded in both groups during normoxia, hypoxia (7.5% O(2) in N(2)), and asphyxia (7.5% O(2) and 3% CO(2)) under pentobarbitone anesthesia. Baseline SH EMG activity was significantly elevated in the CIA-treated rats compared to the controls, whereas DIA EMG activity was similar in the two groups. In addition, CIA significantly reduced SH EMG but not DIA EMG responses to acute hypoxia and asphyxia. The elevated upper airway muscle activity associated with OSA in humans during wakefulness is due at least in part to CIA. We propose that a reduction in the response of upper airway dilator muscles to acute asphyxia following upper airway obstruction is likely to cause further asphyxic insult, leading to a vicious feed-forward cycle exacerbating the condition. Our results suggest that CIA contributes to the pathophysiology of sleep-disordered breathing.

Specific subnuclei of the nucleus tractus solitarius play a role in determining the duration of inspiration in the rat

Our previous data obtained in the cat suggest that the neurons of the ventrolateral subnucleus of the tractus solitarius (vlNTS) act as an inspiratory off-switch and terminate the inspiratory phase of the respiratory cycle (Berger et al., Eur. J. Pharmacol. 277 (1995) 195–208; Gillis et al., Neurosci. Abstr. 23 (1997) 725). The purpose of the present study was to determine whether inhibition of the region of the vlNTS of the rat using drugs that hyperpolarize, disfacilitate or block both axonal conduction and action potential generation would alter the inspiratory phase of the respiratory cycle. Experiments were conducted in anesthetized, vagotomized and spontaneously breathing rats while monitoring diaphragmatic electromyogram activity. Vagus nerves were sectioned in order to rule out prolongation of inspiration evoked by microinjection of agents into the vlNTS which block excitatory drive from lung afferent inputs. Bilateral microinjection of the inhibitory amino acid γ-aminobutyric acid (GABA) 25 nmol/45 nl produced an immediate prolongation of inspiratory duration (484±18 to 1291±84 ms) and an apneustic pattern of breathing. Other effects observed were a significant shortening of expiratory duration (778±36 to 432±38 ms), rise in blood pressure (83±4 to 108±6 mmHg) and a small but significant increase in heart rate (439±17 to 452±18 beats/min). Bilateral microinjection of the ionotropic glutamate receptor antagonist kynurenic acid (1 nmol) and the Na + channel blocker tetrodotoxin (10 pmol) into the region of the vlNTS consistently produced a similar prolongation of inspiratory duration and an apneustic pattern of breathing. These results support the hypothesis that neurons in the region of the vlNTS promote the transition from inspiration to expiration and function as part of the ‘Inspiratory Off Switch’.

Differential effects of clonidine on upper airway abductor and adductor muscle activity in awake goats.

The purpose of this study was to determine the extent to which alpha(2)-adrenoceptor (alpha(2)-AR) pathways affect the central motor output to upper airway muscles that regulate airflow. Electromyogram (EMG) measurements were made from posterior cricoarytenoid (PCA), cricothyroid (CT), thyroarytenoid (TA), and middle (MPC) and inferior (IPC) pharyngeal constrictor muscles in awake standing goats. Systemic administration of the alpha(2)-AR agonist clonidine induced a highly dysrhythmic pattern of ventilation in all animals that was characterized by alternating episodes of tachypnea and slow irregular breathing patterns, including prolonged and variable expiratory time intervals. Periods of apnea were commonly observed. Dysrhythmic ventilatory patterns induced by clonidine were associated with differential recruitment of upper airway muscles. alpha(2)-AR stimulation preferentially decreased the activity of the PCA, CT, and IPC muscles while increasing TA and MPC EMG activities. Clonidine-induced apneas were associated with continuous tonic activation of laryngeal (TA) and pharyngeal (MPC) adductors, leading to airway closure and arterial oxygen desaturation. Tonic activation of the TA and MPC muscles was interrupted only during the first inspiratory efforts after central apnea. Laryngeal abductor, diaphragm, and transversus abdominis EMG activities were completely silenced during apneic events. Ventilatory and EMG effects were reversed by selective alpha(2)-AR blockade with SKF-86466. The results demonstrate that alpha(2)-AR pathways are important modulators of central respiratory motor outputs to the upper airway muscles.

Apneic threshold for CO2 in the anesthetized rat: fundamental properties under steady-state conditions.

Experiments were performed to measure the apneic threshold for CO2 and its fundamental properties in anesthetized rats under steady-state conditions. Breathing was detected from diaphragmatic electromyogram activity. Mechanical hyperventilation resulted in apnea once arterial PCO2 (PaCO2) had fallen far enough. Apnea was not a reflex response to lung inflation because it did not occur immediately, was not prevented by vagotomy, and was reversed by raising PaCO2 without changing mechanical hyperventilation. The apneic threshold was measured by hyperventilating rats mechanically with O2 until apnea had occurred and then raising PaCO2 at constant hyperventilation until breathing reappeared. The mean PaCO2 level of the apneic threshold in 42 rats was 32.8 +/- 0.4 Torr. The level of the threshold did not depend on the volume at which the lungs were inflated. The level of the threshold, under steady-state conditions, was the same when approached from hypocapnia as from eupnea. The level of the threshold could be raised by 9 Torr by chronic elevation of the eupneic PaCO2 level by 18 Torr.

Effects of NMDA and non-NMDA receptor antagonists on the medullary inspiratory neuronal activity during spontaneous augmented breaths in anesthetized rats

To elucidate whether there is a difference between the effects of iontophoretically applied N-methyl- d-aspartate (NMDA) and non-NMDA receptor antagonists on the activity of inspiratory neurons during spontaneous augmented breaths, extracellular single unit recording of inspiratory neurons (I-augmenting, I-decrementing and I-other) was performed in pentobarbital anesthetized rats. The spontaneous augmented breath was divided into two different phases; the first phase (phase I) resembled a normal inspiration, but the second phase (phase II) consisted of a marked increase in diaphragm electromyogram activity. The mean firing frequency of I-aug type neurons was significantly decreased after 50 nA application of both d-2-amino-5-phosphonopentanoic acid (AP-5) (NMDA receptor antagonist) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (non-NMDA receptor antagonist). The mean firing frequency of both I-dec and I-other neurons was significantly decreased by both AP-5 and CNQX applications (70 nA). After AP-5 application, relative changes in the discharge rates during inspiratory phases I and II of spontaneous augmented breaths were significantly suppressed in all types of neurons, but CNQX application had no significant effect on the response changes during phase II. In all cell types of neurons, a significant difference between the iontophoretic AP-5 and CNQX applications in the relative mean firing rate was observed. These results suggested that activation of the NMDA receptor-induced neurotransmission can modify the discharge rate of medullary inspiratory neurons, irrespective of the cell types, during the inspiratory phase II of spontaneous augmented breaths, but that non-NMDA receptor blockade may not significantly influence their discharge rate.

Comparative Physiologic Effects of Noninvasive Assist-Control and Pressure Support Ventilation in Acute Hypercapnic Respiratory Failure

To compare the effects of noninvasive assist-control ventilation (ACV) and pressure support ventilation (PSV) by nasal mask on respiratory physiologic parameters and comfort in acute hypercapnic respiratory failure (AHRF). A prospective randomized study. A medical ICU. Fifteen patients with COPD and AHRF were consecutively and randomly assigned to two noninvasive ventilation (NIV) sequences with ACV and PSV mode, spontaneous breathing (SB) via nasal mask being used as control. ACV and PSV settings were always subsequently adjusted according to patient's tolerance and air leaks. Fraction of inspired oxygen did not change between the sequences. ACV and PSV mode strongly decreased the inspiratory effort in comparison with SB. The total inspiratory work of breathing (WOBinsp) expressed as WOBinsp/tidal volume (VT) and WOBinsp/respiratory rate (RR), the pressure time product (PTP), and esophageal pressure variations (deltaPes) were the most discriminant parameters (p<0.001). ACV most reduced WOBinsp/VT (p<0.05), deltaPes (p<0.05), and PTP (0.01) compared with PSV mode. The surface diaphragmatic electromyogram activity was also decreased >32% as compared with control values (p<0.01), with no difference between the two modes. Simultaneously, NIV significantly improved breathing pattern (p<0.01) with no difference between ACV and PSV for VT, RR, minute ventilation, and total cycle duration. As compared to SB, respiratory acidosis was similarly improved by both modes. The respiratory comfort assessed by visual analog scale was less with ACV (57.23+/-30.12 mm) than with SB (75.15+/-18.25 mm) (p<0.05) and PSV mode (81.62+/-25.2 mm) (p<0.01) in our patients. During NIV for AHRF using settings adapted to patient's clinical tolerance and mask air leaks, both ACV and PSV mode provide respiratory muscle rest and similarly improve breathing pattern and gas exchange. However, these physiologic effects are achieved with a lower inspiratory workload but at the expense of a higher respiratory discomfort with ACV than with PSV mode.