Central Inspiratory Activity Research Articles

In vivo evidence for the cellular basis of central hypoventilation of Rett syndrome and pharmacological correction in the rat model.

Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by mutations in the MECP2 gene. RTT patients show periodical hypoventilation attacks. The breathing disorder contributing to the high incidence of sudden death is thought to be due to depressed central inspiratory (I) activity via unknown cellular processes. Demonstration of such processes may lead to targets for pharmacological control of the RTT-type hypoventilation. We performed in vivo recordings from medullary respiratory neurons on the RTT rat model. To our surprise, both I and expiratory (E) neurons in the ventral respiratory column (VRC) increased their firing activity in Mecp2-null rats with severe hypoventilation. These I neurons including E-I phase-spanning and other I neurons remained active during apneas. Consistent with enhanced central I drive, ectopic phrenic discharges during expiration as well as apnea were observed in the Mecp2-null rats. Considering the increased I neuronal firing and ectopic phrenic activity, the RTT-type hypoventilation does not seem to be caused by depression in central I activity, neither reduced medullary I premotor output. This as well as excessive E neuronal firing as shown in our previous studies suggests inadequate synaptic inhibition for phase transition. We found that the abnormal respiratory neuronal firing, ectopic phrenic discharge as well as RTT-type hypoventilation all can be corrected by enhancing GABAergic inhibition. More strikingly, Mecp2-null rats reaching humane endpoints with severe hypoventilation can be rescued by GABAergic augmentation. Thus, defective GABAergic inhibition among respiratory neurons is likely to play a role in the RTT-type hypoventilation, which can be effectively controlled with pharmacological agents.

CYCLOOXYGENASE MECHANISMS IN THE REGULATION OF RESPIRATORY EFFECTS OF TUMOR NECROSIS FACTOR

Introduction. It is known that the systemic level of the major pro-inflammatory cytokine increases in many respiratory diseases such as asthma, COPD and sleep apnea [1, 2]. The lung ventilation changes and the pathological types of breathing are typical in these diseases. By the reason, the research of the respiratory effects of cytokine is actual. The aim of this study was to compare the respiratory effects of tumor necrosis factor - α (TNF-α) before and after pretreatment with diclofenac, a nonspecific cyclooxygenase (COX) inhibitor. Materials and methods. Тhe experiments were performed in tracheostomized anaesthetized with urethane rats. A respiratory flow head connected to a pneumotachometer (AD Instruments ML141 Spirometer, Dunedin, New Zealand) was used to measure peak airflow and respiratory rate. The hypoxic ventilatory response was measured by using rebreathing with hypoxic gas mixture before and after the tail vein injection of TNF-α (10 μg/rat). In order to determine the role of the cyclooxygenase pathway in the ventilatory effects of TNF-α, introperitoneal administration of diclofenac, a nonspecific COX inhibitor, was used (0.5 mg/rat). Results and discussion. We have shown that the increase in level of TNF-α in blood increased the parameters of respiration such as minute ventilation (by 40%), tidal volume (by 18%), and the mean inspiratory flow (by 33%). The slope of the hypoxic ventilatory response decreased from 6.06 ± 0.91 to 3.48 ± 0.38 ml/min-1 mmHg-1 (by 40%) 40 min after administration of TNF-α (p < 0.05), the slope of tidal volume and mean inspiratory flow also decreased (by 27%) (p < 0.05). After pretreatment with diclofenac, the influence of TNF-α on breathing was dampened, as no significant changes were observed. Conclusion. We concluded that the elevation of inflammatory cytokine level in blood intensifies ventilation during the resting breathing that may be associated with increased central inspiratory activity. At the same time TNF-α reduces the chemoreflex sensitivity to hypoxia, thereby worsening the compensatory capabilities of the respiratory system. Thus, the results of our study suggest participation of inflammatory cytokines in mechanisms of central breathing control and chemoreception. Diclofenac pretreatment eliminated the respiratory effects of TNF-α. The data indicate that the ability of TNF-α to enhance basal ventilation and to reduce the ventilatory hypoxic response is mediated by the COX pathway.

Central inspiratory activity rhythmically activates synaptic currents of airway vagal preganglionic neurons in neonatal rats

The airway vagal preganglionic neurons (AVPNs) in the external formation of the nucleus ambiguus (eNA) can be separated into inspiratory-activated AVPNs (IA-AVPNs) and inspiratory-inhibited AVPNs (II-AVPNs). IA-AVPNs are activated by excitatory presynaptic inputs during inspiratory bursts, but the composition and the roles of these excitatory inputs still remain obscure. II-AVPNs are inhibited by inhibitory presynaptic inputs but whether these inhibitory inputs are regulated by excitatory inputs is also unclear. In the current study, AVPNs were retrogradely fluorescent labeled. The IA-AVPNs were discriminated from II-AVPNs by their different synaptic inputs during inspiratory bursts. The excitatory inputs to IA-AVPNs and the presynaptic regulation of II-AVPNs were examined by whole-cell patch clamping. Topical application of 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX) to the recorded IA-AVPNs almost abolished the tonic EPSCs during inspiratory intervals, inhibited the phasic excitatory currents during inspiratory bursts and attenuated the phasic inspiratory inward currents (PIICs) driven by central inspiratory activity. Blockade of α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) respectively inhibited PIICs in some IA-AVPNs. Carbenoxolone, a gap junction uncoupler, partly inhibited the PIICs of IA-AVPNs. Focal application of CNQX to the II-AVPNs significantly inhibited the frequency, peak amplitude and area of the phasic inspiratory outward currents (PIOCs). These findings demonstrated that glutamatergic non-NMDA receptors played a predominant role in the excitatory drive to the IA-AVPNs, and that α4β2, α7 nAChRs and gap junctions were also rhythmically activated by central inspiratory activity. Additionally, glycinergic neurons making inhibitory inputs to the II-AVPNs were pre-synaptically facilitated by excitatory glutamatergic synaptic inputs.

Mecp2 Disruption in Rats Causes Reshaping in Firing Activity and Patterns of Brainstem Respiratory Neurons

People with Rett Syndrome (RTT), a neurodevelopmental disorder caused by mutations in the MECP2 gene, have breathing abnormalities manifested as periodical hypoventilation with compensatory hyperventilation, which are attributable to a high incidence of sudden death. Similar breathing abnormalities have been found in animal models with Mecp2 disruptions. Although RTT-type hypoventilation is believed to be due to depressed central inspiratory activity, whether this is true remains unknown. Here we show evidence for reshaping in firing activity and patterns of medullary respiratory neurons in RTT-type hypoventilation without evident depression in inspiratory neuronal activity. Experiments were performed in decerebrate rats in vivo. In Mecp2-null rats, abnormalities in breathing patterns were apparent in both decerebrate rats and awake animals, suggesting that RTT-type breathing abnormalities take place in the brainstem without forebrain input. In comparison to their wild-type counterparts, both inspiratory and expiratory neurons in Mecp2-null rats extended their firing duration, and fired more action potentials during each burst. No changes in inspiratory or expiratory neuronal distributions were found. Most inspiratory neurons started firing in the middle of expiration and changed their firing pattern to a phase-spanning type. The proportion of post-inspiratory neurons was reduced in the Mecp2-null rats. With the increased firing activity of both inspiratory and expiratory neurons in null rats, phrenic discharges shifted to a slow and deep breathing pattern. Thus, the RTT-type hypoventilation appears to result from reshaping of firing activity of both inspiratory and expiratory neurons without evident depression in central inspiratory activity.

New insights into a decerebrate feline model of swallow‐breathing coordination

In the medulla, the swallow and respiratory central pattern generators (CPGs) interact to coordinate swallow initiation and permit swallow execution during the expiratory phase of breathing. Disruption of swallow‐breathing coordination can result in dysphagia, which is a major cause of morbidity and mortality in many neuro‐muscular diseases, especially stroke. Despite extensive study, the precise mechanisms of swallow‐breathing coordination are not known. We tested the hypothesis that both central inspiratory activity and vagal feedback from the lungs are key elements for effective swallow‐breathing coordination. Swallows were triggered by electrical stimulation of the superior laryngeal nerves (SLN) or by injection of water into the pharyngeal cavity in decerebrate, paralyzed and artificially ventilated cats while motor activities were recorded from phrenic, hypoglossal, lumbar and vagal nerves. Mechanical ventilation was either triggered by central inspiratory activity or set independently from the phrenic activity to alter the timing of bronchopulmonary vagal afferent input and allow analysis of its influence on swallow‐breathing coordination. We observed two types of swallows that produced opposite effects on central respiratory‐rhythm resetting across all conditions: post‐Inspiratory type swallows disrupted central I activity without affecting expiration, whereas expiratory type swallows prolonged expiration without affecting central inspiratory activity. Repetitive swallows observed during apnea reset the E2 phase of central respiration and produced facilitation of swallow motor output. Moreover, swallow initiation was negatively modulated by vagal feedback and was reset by lung inflation. Collectively, these findings support a reciprocal inhibition between central inspiration and the swallow CPG and they are consistent with a role for pulmonary stretch receptors in the coordination between brainstem CPGs for breathing and swallowing. They may also prove relevant for healthcare management of dysphagia.Support or Funding InformationOT2OD023854‐01, HL109025This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The temporal relationship between non‐respiratory burst activity of expiratory laryngeal motoneurons and phrenic apnoea during stimulation of the superior laryngeal nerve in rat

A striking effect of stimulating the superior laryngeal nerve (SLN) is its ability to inhibit central inspiratory activity (cause ‘phrenic apnoea'), but the mechanism underlying this inhibition remains unclear. Here we demonstrate, by stimulating the SLN at varying frequencies, that the evoked non-respiratory burst activity recorded from expiratory laryngeal motoneurons (ELMs) has an intimate temporal relationship with phrenic apnoea. During 1–5 Hz SLN stimulation, occasional absences of phrenic nerve discharge (PND) occurred such that every absent PND was preceded by an ELM burst activity. During 10–20 Hz SLN stimulation, more bursts were evoked together with more absent PNDs, leading eventually to phrenic apnoea. Interestingly, subsequent microinjections of isoguvacine (10 mm, 20–40 nl) into ipsilateral Bötzinger complex (BötC) and contralateral nucleus tractus solitarii (NTS) significantly attenuated the apnoeic response but not the ELM burst activity. Our results suggest a bifurcating projection from NTS to both the caudal nucleus ambiguus and BötC, which mediates the closely related ELM burst and apnoeic response, respectively. We believe that such an intimate timing between laryngeal behaviour and breathing is crucial for the effective elaboration of the different airway protective behaviours elicited following SLN stimulation, including the laryngeal adductor reflex, swallowing and cough.

Loading and unloading breathing during exercise: respiratory responses and compensatory mechanisms

To characterize the ventilatory responses to resistive loading or unloading, we studied the effects of breathing 79% helium-21% oxygen (He-O2), 79% argon-21% oxygen (Ar-O2) and 79% SF6-21% oxygen (SF6-O2) on the volume-time parameters, end-tidal partial pressure of CO2 (PETCO2), mouth pressure (PIm), work of breathing (WI), central inspiratory activity (dP/dtI), and electromyographic activity of parasternal inspiratory muscles (EMGps) in 10 normal subjects at rest and during short-time steady-state exercise. There were no significant changes in tidal volume (VT), breathing frequency (f), inspiratory (TI) and expiratory (TE) durations, minute ventilation (VE), and PETCO2 when air was replaced by He-O2 or SF6-O2 at rest. VE and PETCO2 were not significantly different after replacement of air by He-O2 or SF6-O2 during exercise. However, inhalation of He-O2 decreased in VT and increased in f, whereas inhalation of SF6-O2 led to the opposite effects compared with air during exercise. Both at rest and exercise, PIm, WI, dP/dtI and EMGps were significantly less during He-O2 breathing and higher during SF6-O2 breathing (P < 0.01) from the first respiratory cycle after room air was replaced by He-O2 or SF6-O2. Ar-O2 breathing did not affect the time-volume parameters both at rest and during exercise compared with air. The increase in PIm, WI, and dP/dtI was observed at Ar-O2 inhalation during exercise relatively to air conditions (P < 0.05). We conclude that internal resistive loaded (SF6-O2) or unloaded (He-O2) breathing changes the neuromuscular output required to maintain constant ventilation. The mechanisms of load or unload compensation seem to be mediated by afferent information from lung and respiratory muscle receptors as well as by segmentary reflexes and properties of muscle fibers.

Neurally Adjusted Ventilatory Assist Increases Respiratory Variability and Complexity in Acute Respiratory Failure

Neurally adjusted ventilatory assist (NAVA) is a partial ventilatory support mode where positive pressure is provided in relation to diaphragmatic electrical activity (EAdi). Central inspiratory activity is normally not monotonous, but it demonstrates short-term variability and complexity. The authors reasoned that NAVA should produce a more "natural" or variable breathing pattern than other modes. This study compared respiratory variability and complexity during pressure support ventilation (PSV) and NAVA. Flow and EAdi were recorded during routine PSV (tidal volume approximately 6-8 ml/kg) and four NAVA levels (1-4 cm H2O/microVEAdi) in 12 intubated patients. Breath-by-breath variability of flow and EAdi-related variables was quantified by the coefficient of variation (CV) and autocorrelation analysis. Complexity of flow and EAdi was described using noise titration, largest Lyapunov exponent, Kolmogorov-Sinai entropy, and three-dimensional phase portraits. Switching from PSV to NAVA increased the CV and decreased the autocorrelation for most flow-related variables in a dose-dependent manner (P < 0.05, partial eta for the CV of mean inspiratory flow 0.642). The changes were less marked for EAdi. A positive noise limit was consistently found for flow and EAdi. Largest Lyapunov exponent and Kolmogorov-Sinai entropy for flow were greater during NAVA than PSV and increased with NAVA level (P < 0.05, partial eta 0.334 and 0.312, respectively). Largest Lyapunov exponent and Kolmogorov-Sinai entropy for EAdi were not influenced by ventilator mode. Compared with PSV, NAVA increases the breathing pattern variability and complexity of flow, whereas the complexity of EAdi is unchanged. Whether this improves clinical outcomes remains to be determined.

Galanin microinjection into the PreBötzinger or the Bötzinger Complex terminates central inspiratory activity and reduces responses to hypoxia and hypercapnia in rat

Respiratory rhythm is generated and shaped by the synaptic interaction of neurons in the Bötzinger Complex (BötC) and PreBötzinger Complex (PreBötC) located in the ventral respiratory column of the medulla. Metabotropic receptors are important modulators of fast neurotransmission in the generation and shaping of respiratory rhythm. Microinjection of the neuropeptide galanin (1mM, 50 nL, 50 pmol) into functionally identified BötC or PreBötC in urethane anesthetized, mechanically ventilated and vagotomized rats caused severe dysrhythmia or persistent apnea. In the BötC and PreBötC, galanin reduced the ventilatory response to hypercapnia (5% CO(2)) by 21% (P<0.001) and 38% (P<0.01) respectively. In the BötC and PreBötC, galanin reduced the ventilatory response to hypoxia (10% O(2)) by 15% (P<0.05) and 23% (P<0.01) respectively. These results indicate that microinjection of galanin into the BötC or PreBötC depresses a neural substrate required for the generation of respiratory motor output and reflex responses to hypercapnea and hypoxia.

Compensatory airway dilation and additive ventilatory augmentation mediated by dorsomedial medullary 5-hydroxytryptamine 2 receptor activity and hypercapnia

5-HT2 receptor activity in the hypoglossal nucleus and hypercapnia is associated with airway dilation. 5-HT neurons in the medullary raphe and hypercapnia are responsible for tidal volume change. In this study, the effects of 5-HT2 receptors in the dorsomedial medulla oblongata (DMM), which receives projections from the medullary raphe, and hypercapnia on airway resistance and respiratory variables were studied in mice while monitoring 5-HT release in the DMM. A microdialysis probe was inserted into the DMM of anesthetized adult mice. Each mouse was placed in a double-chamber plethysmograph. After recovery from anesthesia, the mice were exposed to stepwise increases in CO(2) inhalation (5%, 7%, and 9% CO(2) in O(2)) at 8-min intervals with a selective serotonin reuptake inhibitor, fluoxetine, or fluoxetine plus a 5-HT2 receptor antagonist, LY-53857 in the DMM. In response to fluoxetine plus LY-53857 coperfusion, specific airway resistance was increased, and tidal volume and minute ventilation were decreased. CO(2) inhalation with fluoxetine plus LY-53857 coperfusion in the DMM largely decreased airway resistance and additively increased minute ventilation. Thus, 5-HT2 receptor activity in the DMM increases basal levels of airway dilation and ventilatory volume, dependent on central inspiratory activity and the volume threshold of the inspiratory off-switch mechanism. Hypercapnia with low 5-HT2 receptor activity in the DMM largely recovers airway dilation and additively increases ventilatory volume. Interaction between 5-HT2 receptor activity in the DMM and CO(2) drive may elicit a cycle of hyperventilation with airway dilation and hypoventilation with airway narrowing.

The airway‐related parasympathetic motoneurones in the ventrolateral medulla of newborn rats were dissociated anatomically and in functional control

The respiratory-related synaptic control of the airway-related preganglionic parasympathetic motoneurones (APPMs) has not been investigated, and whether differently targeted APPMs receive differential respiratory-related synaptic modulation is unknown. In this study, putative APPMs in the ventrolateral medulla of newborn rats were retrogradely traced with fluorescent tracer and were examined using the patch-clamp method in brainstem slices with respiratory rhythm. The results indicate that tracer application directly to the recurrent laryngeal nerve only labelled the putative APPMs within the compact portion of nucleus ambiguus (cNA), while tracer injection into the trachea wall labelled the putative APPMs both in cNA and in the area ventral/ventrolateral to cNA (vNA). The putative APPMs within cNA received mainly inhibitory inputs, which in some (9 of 20) neurones showed an inspiratory-related attenuation and in others (7 of 20) showed an inspiratory-related augmentation. At least some putative APPMs within cNA, of which the inhibitory synaptic inputs showed inspiratory-related changes, might be related to the control of laryngeal muscles. The putative APPMs in vNA receive both excitatory and inhibitory inputs, and central inspiratory activity excited some (11 of 19) neurones via augmentation of their excitatory inputs and inhibited others (8 of 19) via augmentation of their inhibitory inputs. At least some putative APPMs in vNA might be trachea-related motoneurones. These results provide evidence that APPMs controlling different segments of the airway might be dissociated in the ventrolateral medulla both anatomically and in functional control.

Spectral Parameters of Phrenic Nerve Activity in Mature Rats during Electrical Stimulation of Retrotrapezoid Nucleus

In mature rats, electrical stimulation of the retrotrapezoid nucleus increased the amplitude and frequency of the high-frequency peak in the firing spectrum of the phrenic nerve, while the amplitude of medium-frequency peak and the amplitude ratio of medium- to high-frequency peaks decreased. These changes in spectral parameters were associated with accelerated increase in central inspiratory activity, decreased amplitude of phrenic nerve firing, and increased frequency of respiratory rhythm. It is hypothesized that being a relay structure of central chemosensitive mechanism, the retrotrapezoid nucleus regulates parameters of medium- and high-frequency spectral peaks of efferent electrical activity in the respiratory center together with the dorsal and ventral respiratory groups.

Hypercapnia induces long-term changes in postganglionic renal nerve activity in the piglet

In developing swine, time and frequency domain analyses were used to compare changes in discharge features of efferent phrenic and postganglionic renal nerve activities evoked by prolonged (1 h) exposure to severe hypercapnia (10% CO 2, balance O 2), before and after combined carotid sinus and aortic depressor nerve (CSN–AOD) sectioning. With intact CSN–AOD innervation, respiration-related activity in renal nerve discharge was rare (3 of 11 animals) during baseline periods with intact innervation, but was observed in most cases (10 of 11 animals) during baseline following denervation. Renal nerve respiration-related activity was recruited by hypercapnic stimulation in animals with intact CSN–AOD innervation, and was augmented in denervated animals with ongoing respiratory activity. Phrenic nerve discharge was markedly augmented during hypercapnia, whether CSN–AOD innervation was intact or not, and it did not exhibit a post-hypercapnic depression. Autopower spectra of renal nerve activity revealed the presence of two coexisting rhythms, 2–6 and 7–13 Hz, which were present whether CSN–AOD innervation was intact or not. The hypercapnic-induced increases of activity in the 2–6 and 7–13 Hz bands were not comparable, with the latter region exhibiting a much more robust response to hypercapnia, especially following CSN–AOD denervation. Thus, prolonged exposure to hypercapnia evoked changes in renal nerve discharge that involved increased coupling to neuronal ensembles shaping central inspiratory activity and those generating central sympathetic outflows, especially to networks generating 7–13 Hz rhythm. Such changes may permit more efficient modulation of innervated structures during exposure to stressors.

Inhibition of baroreflex vagal bradycardia by activation of the rostral ventrolateral medulla in rats.

In stressful conditions, baroreflex vagal bradycardia (BVB) is often suppressed while blood pressure is increased. To address the role of the rostral ventrolateral medulla (RVL), a principal source of sympathetic tone, in inhibition of BVB, we microinjected DL-homocysteic acid (DLH, 6 nmol) into the RVL of chloralose-urethan-anesthetized, sinoaortic-denervated rats to examine the effect on BVB. The BVB was provoked by electrical stimulation of the aortic depressor nerve ipsilateral to the injection sites. DLH microinjection was found to suppress BVB while increasing blood pressure. The inhibition of BVB was observed even during the early phase in which DLH transiently suppressed central inspiratory activity. The inhibition was not affected either by upper spinal cord transection or suprapontine decerebration. Similar results were obtained by microinjection of bicuculline methiodide (160 pmol), a GABA antagonist, into the RVL of carotid sinus nerve-preserved rats due to withdrawal of a tonic GABA-mediated, inhibitory influence including the input from arterial baroreceptors. In conclusion, activation of the RVL inhibits BVB at brain stem level independently of central inspiratory drive.

Electrophysiological and pharmacological analysis of synaptic inputs to pulmonary rapidly adapting receptor relay neurons in the rat.

The information from pulmonary rapidly adapting stretch receptors (RARs) to the central nervous system (CNS) is relayed in the nucleus tractus solitarii (NTS). The second-order neurons in the NTS referred to as RAR cells have recently been shown to receive rhythmic inputs from the central respiratory system in addition to the main inputs from RAR afferents. The present study analyzed these synaptic inputs by intracellular recordings from RAR cells, and by extracellular recordings combined with local applications of neuroactive drugs to RAR cells, in Nembutal-anesthetized, paralyzed, and artificially ventilated rats. The intracellular analysis identified both excitatory postsynaptic potentials (EPSPs) elicited presumably by RAR afferents and inhibitory postsynaptic potentials (IPSPs) synchronous with central inspiratory activity. This inhibitory input, called I suppression, was the origin of respiratory modulation of RAR cell firing, and its time course suggested that some unidentified inspiratory neurons with an augmenting firing pattern were the source of the inhibition. The pharmacological analysis suggested the types of neurotransmitters used in these synaptic events. First, glutamate was shown to be the primary neurotransmitter at the synapse between RAR afferents and RAR cells. Iontophoretic applications of the non-NMDA glutamate antagonist, CNQX, abolished RAR cell firing almost completely in response to lung inflation and deflation and to electrical stimulation of the vagus nerve. Second, glycinergic inputs which inhibited RAR cells in the inspiratory phase were revealed by applications of the glycine antagonist, strychnine. That is, the I suppression was greatly diminished by applications of strychnine. Third, although applications of the GABA(A) receptor antagonist, bicuculline, had little effect on I suppression, bicuculline markedly increased the baseline firing of RAR cells. These results imply that the information path from RARs to the CNS is regulated at the level of RAR cells by phasically-acting glycinergic inhibition in the inspiratory phase and tonically-acting GABAergic inhibition; the results also provide new insights into the neuronal mechanisms of RAR-induced reflexes.

The involvement of rostral ventromedullary neuronal structures in regulating the mechanism of formation of the respiratory rhythm in rats.

The role of neuronal structures in the rostral parts of the ventral surface of the medulla oblongata of the rat in regulating the central inspiratory activity of the respiratory center was analyzed. It is suggested that neuronal structures of the subretrofascial area, located close to the ventral surface of the medulla oblongata have direct associations with the mechanisms generating and regulating the respiratory rhythm. These have excitatory effects on neurons of the respiratory center which generate inspiratory activity.

Implementation of a respiratory drive monitor on a Servo Ventilator.

To design and evaluate a clinical monitor of respiratory drive (P0.1) and other respiratory variables in a simple way, using a commercial ventilator. Nine healthy males were studied as they were breathing spontaneously in a Servo 900C Ventilator, at rest and during light exercise (50 W). The ventilator was slightly modified to improve its mechanical performance during spontaneous breathing, and was used as a measuring instrument. All the relevant information was retrieved, calculated and monitored by a PC. Respiratory drive was assessed as occlusion pressures from the inspiratory airway pressure signal. The equipment was compared with a two-way non-rebreathing laboratory system. Furthermore, negative and positive inspiratory pressures were applied from the ventilator, to study respiratory responses to mechanical loads. At rest, the ventilator introduced a minor influence on inspiratory time and P0.1, but not in ventilation, tidal volume, expiratory duration and respiratory frequency. During exercise, the influence was more evident. This effect could also be noticed in the coefficients of variation. The responses to mechanical loads were easily recorded and can be used as a simple test of central load-compensating mechanisms. CONCLUSIONS. The ventilator, with limitations, may be an alternative to conventional techniques, especially in clinical studies of the central inspiratory activity with and without respiratory loading.

Responses of respiratory drive and breathing pattern to inspiratory loading during nitrous oxide and isoflurane sedation

Increased inspiratory resistance in combination with mild gas narcosis is common during recovery after a general anesthesia, but there are only few previous studies on inspiratory loading during subanesthetic gas narcosis. Responses of respiratory drive (central inspiratory activity, P0.1) and ventilatory pattern to an inspiratory threshold load of -6 cm H2O were studied in 16 healthy subjects during mild subanesthetic gas narcosis. One group (n = 9) was exposed to 13, 26 and 39% nitrous oxide (N2O) and air control (Group N). Another group (n = 7) was exposed to 0.1, 0.2 and 0.3% isoflurane and air control (Group I). Measurements were done after 1 min adaptation to the load. Nitrous oxide and isoflurane had no effect on respiratory drive and VT either during unloaded breathing or during inspiratory threshold loading. Across all gas concentrations (including 0% control), inspiratory threshold loading resulted in significant P0.1 increases, amounting to 62% in group N and 38% in group I. At the same time VT decreased by 11 and 12%, respectively. A significantly increased end-expired CO2 and decreased minute volume compared to air control was found during isoflurane inhalation but could be ascribed to normalization of the hyperventilation in the control situation. It is concluded that the steady-state ventilatory responses to loading, consisting of increased P0.1 and decreased VT, are maintained during inhalation of subanesthetic doses of N2O (0.13-0.38 MAC) and isoflurane (0.09-0.26 MAC).

Responses of distinct types of sympathetic neuron to stimulation of the superior laryngeal nerve in the cat

Stimulation of afferents in the superior laryngeal nerve (SLN) leads to apnea and evokes reflexes in sympathetic neurons. It is not clear whether these reflexes are secondary to changes in the brainstem respiratory network or due directly to the afferent input on neurons belonging to central sympathetic pathways. To clarify this question, single thoracic preganglionic sympathetic neurons projecting into the cervical sympathetic trunk (CST) were classified as described previously and then tested for their responses to electrical stimulation of the superior laryngeal nerve (SLN) in chloralose-anesthetized, paralysed and artificially ventilated cats. SLN stimulation was performed with intensities sufficient to suppress central inspiratory activity detected by phrenic and recurrent laryngeal nerve recordings. Sympathetic neurons were tested under different levels of respiratory drive. Thirteen group I (putative muscle vasoconstrictor) neurons were mostly activated by SLN stimulation when respiratory drive was low, but depressed when it was high; this was due to the change in inspiration-related activity. Ten of eleven group II (putative cutaneous vasoconstrictor) neurons were depressed during SLN stimulation. This inhibition was independent of central respiratory drive. Inhibition also occurred in those neurons which predominantly discharged during postinspiration. Eight group III neurons which showed a discharge confined to inspiration were inhibited but mostly not silenced by SLN stimulation. Group IV (functionally unclassified) neurons either showed no response ( n=5) or were slightly inhibited ( n=2). The responses of group I neurons, but not the responses of group II and group III neurons, showed a significant positive correlation with those of systemic blood pressure. The observed responses corroborate the classification made previously. The results also demonstrate that the responses of sympathetic neurons to SLN stimulation are not merely due to the respiratory modulation of their activity, but rather consist of two components, one occurring independently of and the other secondary to, the changes in respiration.

Alterations of phrenic nerve activity caused by stimulation of neuronal structures in rostral area of ventral surface of the medulla oblongata

Electrical stimulation of neuronal structures in a rostral area of the ventral bulbar surface alters central inspiratory activity in anesthetized rats, augmenting the amplitude and velocity of this activity during the periods of its increase and plateau. The reactions are more pronounced in rats with transected vagal nerves. Blockade of pulmonary mechanoreceptors eliminates the influence of rostral neuronal structures only on the temporal parameters of the plateau. Bilateral cooling of neuronal structures to 20°C results in complete block of central inspiratory activity.