Increase In Inspiratory Activity Research Articles

A6 neurons simultaneously modulate active expiration and upper airway resistance in rats.

What is the central question of this study? Do A6 neurons modulate active expiratory and airway responses evoked by hypercapnia/acidosis? What is the main finding and its importance? Acute inhibition of A6 neurons reduced active expiratory, inspiratory and the associated oropharyngeal and laryngeal motor responses to hypercapnia/acidosis. A6 neurons provide excitatory synaptic drive contributing to the central generation of inspiratory and expiratory motor activity as well as the control of upper airway resistance. During rest, inspiration is an active phenomenon, whereas expiration is passive. Under conditions of high chemical drive, such as hypercapnia/acidosis, there is an increase in inspiratory activity, expiration becomes active and upper airway resistance is reduced. The locus coeruleus noradrenergic neurons (A6 neurons) are activated when exposed to elevated CO2 /[H+ ] levels and modulate respiratory brainstem neurons regulating ventilation. However, the role of A6 neurons in the control of upper airway resistance is not fully understood. We tested the hypothesis that A6 neurons contribute to the central generation of active inspiratory and expiratory responses and the associated changes in the motor nerves controlling upper airway resistance during hypercapnia/acidosis in rats. Using a perfused brainstem-spinal cord preparation, we inhibited A6 neurons using pharmacogenetics and evaluated the active expiratory (abdominal nerve), laryngeal (cervical vagus nerve), oropharyngeal (hypoglossal nerve) and inspiratory (phrenic nerve) motor nerve responses to hypercapnia/acidosis. Acute inhibition of A6 neurons did not produce significant changes in the respiratory pattern in normocapnia. However, the hypercapnia/acidosis-induced active expiratory response and the associated changes in the motor nerves responsible for control of oropharyngeal and laryngeal resistance, as well as the inspiratory response were all reduced after inhibition of A6 neurons. Our data demonstrate that A6 neurons exert an important excitatory synaptic drive to the central generation of both active inspiratory and expiratory activities and modulate the control of upper airway resistance during hypercapnia/acidosis.

Ampakine CX717 potentiates intermittent hypoxia-induced hypoglossal long-term facilitation.

Glutamatergic currents play a fundamental role in regulating respiratory motor output and are partially mediated by α-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) receptors throughout the premotor and motor respiratory circuitry. Ampakines are pharmacological compounds that enhance glutamatergic transmission by altering AMPA receptor channel kinetics. Here, we examined if ampakines alter the expression of respiratory long-term facilitation (LTF), a form of neuroplasticity manifested as a persistent increase in inspiratory activity following brief periods of reduced O2 [intermittent hypoxia (IH)]. Current synaptic models indicate enhanced effectiveness of glutamatergic synapses after IH, and we hypothesized that ampakine pretreatment would potentiate IH-induced LTF of respiratory activity. Inspiratory bursting was recorded from the hypoglossal nerve of anesthetized and mechanically ventilated mice. During baseline (BL) recording conditions, burst amplitude was stable for at least 90 min (98 ± 5% BL). Exposure to IH (3 × 1 min, 15% O2) resulted in a sustained increase in burst amplitude (218 ± 44% BL at 90 min following final bout of hypoxia). Mice given an intraperitoneal injection of ampakine CX717 (15 mg/kg) 10 min before IH showed enhanced LTF (500 ± 110% BL at 90 min). Post hoc analyses indicated that CX717 potentiated LTF only when initial baseline burst amplitude was low. We conclude that under appropriate conditions ampakine pretreatment can potentiate IH-induced respiratory LTF. These data suggest that ampakines may have therapeutic value in the context of hypoxia-based neurorehabilitation strategies, particularly in disorders with blunted respiratory motor output such as spinal cord injury.

Role of parafacial nuclei in control of breathing in adult rats.

Contiguous brain regions associated with a given behavior are increasingly being divided into subregions associated with distinct aspects of that behavior. Using recently developed neuronal hyperpolarizing technologies, we functionally dissect the parafacial region in the medulla, which contains key elements of the central pattern generator for breathing that are important in central CO2-chemoreception and for gating active expiration. By transfecting different populations of neighboring neurons with allatostatin or HM4D Gi/o-coupled receptors, we analyzed the effect of their hyperpolarization on respiration in spontaneously breathing vagotomized urethane-anesthetized rats. We identify two functionally separate parafacial nuclei: ventral (pFV) and lateral (pFL). Disinhibition of the pFL with bicuculline and strychnine led to active expiration. Hyperpolarizing pFL neurons had no effect on breathing at rest, or changes in inspiratory activity induced by hypoxia and hypercapnia; however, hyperpolarizing pFL neurons attenuated active expiration when it was induced by hypercapnia, hypoxia, or disinhibition of the pFL. In contrast, hyperpolarizing pFV neurons affected breathing at rest by decreasing inspiratory-related activity, attenuating the hypoxia- and hypercapnia-induced increase in inspiratory activity, and when present, reducing expiratory-related abdominal activity. Together with previous observations, we conclude that the pFV provides a generic excitatory drive to breathe, even at rest, whereas the pFL is a conditional oscillator quiet at rest that, when activated, e.g., during exercise, drives active expiration.

Relationship between respiratory mechanics and postinspiratory muscle activity during muscarinic challenge in rabbits

In six spontaneously breathing New Zealand rabbits (weight 2.36 ± 0.29 kg) anesthetized with pentobarbital sodium (35 mg/kg i.v.) airflow, tidal volume, and tracheal and esophageal pressures were measured. These allowed the determination of breathing pattern parameters, respiratory system and lung resistances, elastances, and time constants, total postinspiratory muscle pressure and its timing parameters. The measurements were performed: (a) under control conditions; (b) after increasing concentrations of aerosolized methacholine (8, 16, 32, and 64 mg/ml); and (c) after aerosolized atropine (1 mg/ml). Methacholine progressively increased intrinsic mechanical load (resistance and elastance) of the respiratory system. Total postinspiratory muscle pressure (Pmus,0) increased in relation to the increase in elastic load. The duration of postinspiratory activity increased mainly because of the decrease in expiratory time. In conclusion, increase in inspiratory activity during expiration is due to two independent mechanisms controlling the amplitude and the relative duration.

Effects of expiratory resistive loading on the sensation of dyspnea

To determine whether an increase in expiratory motor output accentuates the sensation of dyspnea (difficulty in breathing), the following experiments were undertaken. Ten normal subjects, in a series of 2-min trials, breathed freely (level I) or maintained a target tidal volume equal to (level II) or twice the control (level III) at a breathing frequency of 15/min (similar to the control frequency) with an inspiratory load, an expiratory load, and without loads under hyperoxic normocapnia. In tests at levels II and III, end-expiratory lung volume was maintained at functional residual capacity. A linear resistance of 25 cmH2O.1(-1).s was used for both inspiratory and expiratory loading; peak mouth pressure (Pm) was measured, and the intensity of dyspnea (psi) was assessed with a visual analog scale. The sensation of dyspnea increased significantly with the magnitude of expiratory Pm during expiratory loading (level II: Pm = 9.4 +/- 1.5 (SE) cmH2O, psi = 1.26 +/- 0.35; level III: Pm = 20.3 +/- 2.8 cmH2O, psi = 2.22 +/- 0.48) and with inspiratory Pm during inspiratory loading (level II: Pm = 9.7 +/- 1.2 cmH2O, psi = 1.35 +/- 0.38; level III: Pm = 23.9 +/- 3.0 cmH2O, psi = 2.69 +/- 0.60). However, at each level of breathing, neither the intensity of dyspnea nor the magnitude of peak Pm during loading was different between inspiratory and expiratory loading. The augmentation of dyspnea during expiratory loading was not explained simply by increases in inspiratory activity. The results indicate that heightened expiratory as well as inspiratory motor output causes comparable increases in the sensation of difficulty in breathing.

On the central pattern generator for the basic breathing rhythmicity.

Recent advances in several laboratories concerning the respiration-related medullary neurons, their locations, projections, interconnections, morphological and physiological properties, and patterns of inhibitory postsynaptic potentials, excitatory postsynaptic potentials, and discharge rate, on the one hand, and the "systems behavior," on the other, have provided the basis for new hypothesis concerning the neural mechanisms underlying the central pattern generator (CPG) for breathing and its different parts. The onset of the "ramp"-like increase in inspiratory activity is due to an abrupt release of inhibition and a subsequent progressively increasing synaptic excitation of inspiratory premotor neurons. The integration of the excitatory "drive" inputs underlying the ramp inspiratory activity seems to depend on structures in the ventrorostral medulla, including nucleus paragigantocellularis. The termination of this activity by the off-switch mechanisms is actuated when a critical threshold is attained by the excitatory inputs of 1) a slowly increasing inspiration-related activity and 2) the afferent input from the pulmonary stretch receptors. The nature of the former activity is discussed. During the expiratory phase, an inhibitory activity suppresses inspiration-facilitating inputs with a slowly decaying power that controls the expiratory duration. The postinspiration activity, which brakes the rate of exhalation during the first part of the expiratory phase, depends on mechanisms separate from those responsible for the inspiratory ramp activity. The respiratory CPG seems to be organized with considerable amount of redundancy, or "degeneracity."

Volume, flow, and timing of each breath during negative airway pressure in humans.

We have analyzed the effects of 4-6 min of 5, 10 and 15 cmH2O continuous negative airway pressure breathing (NPB) on steady-state end-expiratory lung volume (delta VR) and breathing pattern. Fourteen healthy adults, seated in a full body box, breathed via a mouthpiece on a bag-in-box. Pressure in the body box was elevated to the desired pressure level. Inspiratory (TI) and expiratory (TE) durations, tidal volume (VT), minute ventilation (VI), mean inspiratory flow (VT/TI), and mean expiratory flow (VT/TE) were calculated from pneumotachometer recordings. The effects of NPB are decreases in delta VR, VT, and VT/TI and increases in VT/TE. The responses to NPB are an increase in breathing frequency, due to a shortened TE, and an increase in inspiratory activity. The decrease in delta VR and the increase in VT/TE are limited by an active retardation of expiratory flow. End-tidal CO2 and VI were not altered significantly during NPB, suggesting no alveolar hyperventilation. Thus multiple components of the human response to NPB are not all engaged at the same levels of NPB. The changes in the timing of respiratory events occur at -5 cmH2O, whereas VT compensation is not seen until -15 cmH2O.

Respiratory responses to changes in airflow resistance in conscious man

The time course and magnitude of adjustments in respiratory activity during the application and following the removal of inspiratory resistive loads were determined in conscious men. Changes in airflow resistance were made periodically during rebreathing of a gas mixture of carbon dioxide and oxygen. Ventilation, the ratio of tidal volume to inspiratory duration and the mouth pressure during airway occlusion, 100 ms after the onset of inspiration were used as measures of inspiratory neuromuscular activity. The occlusion pressure was measured during each breath using an electrically activated solenoid shutter which obstructed the airway for only the first 100 ms of each inspiration. During the second breath following the application of the resistive load, there was an increase in inspiratory output which occured independently of changes in P CO 2 and P O 2 . Further increases in inspiratory activity during successive loaded breaths, however, were due exclusively to changing chemical drive. The level of inspiratory neuromuscular activity remained elevated for a single breath following removal of the added resistance. Adjustments in respiratory activity were greater the more severe the load. The results suggest that non-chemically mediated respiratory compensation in conscious individuals develops rapidly and is important in maintaining ventilation when breathing is encumbered.