Motor nucleus of the V-th nerve and the control of breathing. Breuer-Hering reflexes and apneustic breathing

Earlier studies from this department have demonstrated that neurones of the V-th nerve motor nucleus (NVmt) have oligosynaptic, inhibitory output to the inspiratory motoneurone themselves under the influence of a polysynaptic input from vagal afferents. To check the hypothesis that NVmt is a part of the pneumotaxic mechanism, we studied the effects of pharmacological microblockade of the NVmt on Breuer-Hering reflexes in halothane-anesthetized, paralyzed and artificially ventilated rabbits. Activities of NVmt neurones and phrenic nerve firing were recorded. Acid-base balance was controlled and histologic examinations were routinely performed. Expiratory activities were regulatory found in NVmt. Its blockade elicited a typical apneustic breathing. During the blockade the Breuer-Hering reflexes gave "paradoxical" effects: an increase in central respiratory frequency following inflation, inspiratory apneusis in response to deflation. We conclude that the NVmt is an important component of the pneumotaxic mechanism or even the anatomical substrate of the pneumotaxic "centre".     

Breuer-Hering reflexes in ketamine-induced apneustic breathing in the rabbit

The effects of ketamine on the activities of the mylohyoid nerve (a branch of the Vth nerve) and of both phrenic nerves were investigated in rabbits anaesthetized with halothane, paralyzed and artificially ventilated. Intravenous administration of ketamine elicited a marked prolongation of the phrenic inspiratory discharge (without significantly affecting its amplitude) and a depression of the mylohyoid expiratory activity. An elimination of the volume-related input from the lungs ("no-inflation manoeuvre") or deflation elicited under these conditions typical apneustic pattern of breathing. The response to tracheal occlusion at peak-inspiration was "classical". We conclude that ketamine inhibits the Vth nerve motor nucleus which is not only an important component of the central inspiratory-inhibitory neurones but also a "relay station" between the vagal and the central inspiratory "off-switch" mechanisms.     

Recovery of breathing pattern after 15 min of cerebral ischemia in rabbits

The study was undertaken to ascertain the neural control of breathing and vagal reflexes during and after cerebral ischemia. The experiments were performed on anesthetized, paralyzed, and artificially ventilated rabbits. Cerebral ischemia was induced by reversible intrathoracic occlusion of the brachiocephalic trunk and the left subclavian and both internal thoracic arteries for 15 min. The effect of cerebral ischemia on breathing pattern was assessed by monitoring the integrated activities of phrenic and recurrent laryngeal nerves. Ischemia produced enhancement of breathing followed by apnea and gasping. During enhanced breathing as well as during gasping, the inspiratory-inhibiting effect of lung inflation (Breuer-Hering reflex) was abolished. When brain circulation was restored, respiratory activity started with gasps, which later were intermingled with eupneic type of inspirations. During the onset of a eupneic breath, lung inflation produced inspiratory facilitation but never an inhibition. However, after 30 min of recovery from cerebral ischemia, the Breuer-Hering reflex was restored. Results show that precise analysis of vagal reflexes and respiratory pattern during ischemia and resuscitation may be used as an indicator of resumption of autonomic activity in the brain stem.     

Medullary neurons mediating the inhibition of inspiration by intercostal muscle tendon organs?

Studies were conducted to test the hypothesis that nonrespiratory-modulated units are last-order interneurons mediating the effects of intercostal muscle tendon organs on medullary inspiratory neuron activity. Vagotomized, anesthetized, or decerebrate cats were used. Results show the following. 1) Afferents from different receptor types (i.e., intercostal tendon organs and chest wall cutaneous receptors) that inhibit medullary inspiratory neuron activities evoke the same units. 2) Gastrocnemius muscle group I afferent fibers evoke some of the same units as intercostal afferents but do not alter respiratory activity. 3) The "pneumotaxic center" and laryngeal nerve afferents, which inhibit medullary inspiratory activity, evoke different medullary units than intercostal afferents. 4) Evoked units are not active in spontaneously breathing cats. Additional results suggest that a few respiratory neurons near the retrofacial nucleus may be involved in the mediation of the inspiratory inhibitory effects of intercostal tendon organs. These results do not establish the mechanism by which intercostal muscle tendon organs reduces medullary inspiratory activity.     

Activity of bulbar respiratory neurones during cough and other respiratory tract reflexes in cats

Changes evoked by mechanical stimulation of the relevant parts of the respiratory tract in the activity of inspiratory and expiratory neurones in the ventral respiratory group of the medulla oblongata, and in pleural pressure and the diaphragmatic electromyogram, were determined during cough, sneeze and the aspiration and expiration reflexes in 17 anaesthetized (but not paralysed) cats. The results of 72 tests of elicitation of the given reflexes showed that: Compared with the control inspiration, both the mean and the maximum discharge frequency of spontaneously active inspiratory neurones rose during the inspiratory phase of cough, sneeze and the aspiration reflex. Regular recruitment of new inspiratory units was also observed in the inspiratory phase of cough and the aspiration reflex. Compared with the control expiration, both the mean and the maximum discharge frequency of spontaneously active expiratory neurones rose during the cough, sneeze and expiration reflex effort. Recruitment of latent expiratory neurones was always observed in the expulsive phase of the given respiratory processes. The recruitment of latent expiratory neurones was accompanied by reciprocal inhibition of the activity of inspiratory units and recruitment of latent inspiratory neurones by inhibition of the activity of expiratory units and recruitment of latent inspiratory neurones by inhibition of the activity of expiratory units. Regular recruitment of the same expiratory neurones in all expulsive respiratory processes, together with the similar incidence of inspiratory neurones in the inspiratory phase of sneeze and the aspiration reflex, indicates that they are "nonspecific" in character.     

Reflex responses of respiratory muscles to tilting and positive pressure breathing

We have recorded the action potentials of muscle fibres of External Oblique in anaesthetized rabbits in supine and horizontal position. During head-up tilting the inspiratory activity is inhibited and the abdominal activity is excited. Both these two responses are reflexly mediated through vagal afferent fibres. The positive pressure was chosen as to determine a shift in end-expiratory volume similar to that induced by the head-up tilting. Also at positive pressure breathing (PPB) the abdominal activity increases but less than during head-up tilting. This result seems to indicate the importante of the proprioceptive afferents of the external oblique during the vertical posture. The blockade of vagal nervous conduction markedly reduces the abdominal activity both during tilting and P.P.B. and similar results are obtained either by "total" or "partial" vagal blockade. Therefore it seems possible to conclude that both these two reflexes (introduced by head-up tilting and PPB) be due to the activation of the same receptors (pulmonary stretch receptors).     

Role of phrenic nerve afferents in the control of breathing

A long-held belief is that respiratory-related reflexes mediated by afferents in the diaphragm are weak or absent. However, recent data suggest that diaphragmatic afferents are capable of altering ventilatory motor drive as well as influencing perception of added inspiratory loads in humans. This review describes the sensory elements of the diaphragm, their central projections, and their functional significance in the control of respiratory muscle activation. The reflexes elicited by electrical stimulation of phrenic nerve afferents and the contribution of diaphragmatic afferents in respiratory load compensation and perception are considered. There is growing evidence that phrenic nerve afferents are activated under a variety of conditions. However, the significance of this input to the central nervous system is yet to be discerned.     

Function of different medullary neurons in respiration]

1. We have studied the activity of 162 medullary respiratory neurones in the "encephale isole bas" cat. These neurones were classed into three groups : bulbospinal inspiratory (NBSI : 39) or expiratory (NBSE : 15) neurones whose axons enter the spinal cord ; inspiratory or expiratory laryngeal motoneurones (MLI : 17; MLE : 10) antidromically activated by vagus nerve stimulation ; propriobulbar inspiratory (NPBI : 59) or expiratory (NPBE : 22) neurones whose axons lie perhaps entirely within the medulla. 2. Correlation coefficients between number of spikes delivered in each burst and the duration of the corresponding respiratory phase (inspiration for NBSI, MLI, NPBI ; expiration for NBSE, MLE, NPBE) have been calculated for each neurone. 3. The activity of most of the NBSI and MLI is significantly correlated with the duration of the inspiration. These two groups of neurones are probably homogenous. 4. On the basis of this correlation test, NPBI do not constitute an homogeneous population ; 50% of NPBI are not significantly correlated. The same results are obtained if correlations are calculated between the number of spikes delivered and the amplitude of integrated phrenic nerve acitivty. According to the discharge pattern and correlation test, we can consider three groups of NPBI : early recruited neurones with decreasing frequency and non significantly correlated activity (23,7%); early and late neurones with increasing frequency and significantly correlated activity (32,2%); early and late neurones with increasing frequency and non significantly correlated acitivty (44,1%). 5. The activity of most of the NBSE and NPBE with increasing frequency is significantly correlated with the duration of the expiration. Among the MLE and NPBE with a decreasing frequency, a great number of neurones are not significantly correlated. 6. The functional significantion of the different neuronal types is discussed from these correlation tests and from the pattern of activity and axonal pathways.     

Existence of respiratory interneurons in the cervical spinal cord of the rabbit

A spinal "respiration" generator has been shown to fire phrenic motoneurones in rhythmic bursts. It is very likely driven through bulbo-spinal inspiratory neurones in intact preparations. Although no direct evidence for respiratory interneurones at the C4-C5 spinal levels has been obtained so far (except for Renshaw cells ), it is currently believed that only few inspiratory inputs to the phrenic motoneurones are transmitted monosynaptically from the medulla. We have tried here to record spinal interneuronal respiratory activities in decorticate, unanaesthetized, vagotomized and curarized rabbit preparations. Different functional categories of interneurones could be identified at the C4-C5 spinal levels: inspiratory and expiratory interneurons with various discharge patterns which rather well correspond to the functional categories of inspiratory and expiratory bulbo-spinal neurones described by Bianchi and Richter. In addition, multiunit inspiratory bursting could be followed over several 100 microns during each electrode penetration. The different categories of interneurones were encountered laterally from 700 to 1,000 microns, at depths ranging from 300 to 500 microns dorsally to the phrenic nucleus, down to the nucleus itself. These results indicate that part of the medullary inspiratory drive is channelled via spinal cord interneurones; they also suggest that an inhibition of phrenic motoneurones from the bulbo-spinal expiratory drive takes place via interneurones.     

Tonic activity in inspiratory muscles and phrenic motoneurons by stimulation of vagal afferents

In anesthetized rabbits, direct and integrated phrenic neurogram (Ephr) and electromyograms from the diaphragm (Edi) and intercostal (Eic) (2nd space) and transversus abdominis muscles (Etr) were simultaneously recorded in two protocols. 1) In animals breathing spontaneously, we used infinite inspiratory (RI) or expiratory (RE) resistive load and intravenous injections of carbachol, histamine, or phenyl diguanide (PDG). All circumstances except RE evoked tonic activities in Ephr, Edi, and Eic but never in Etr. Intravenous atropine abolished carbachol-induced bronchoconstriction and associated tonic inspiratory activities, but this effect persisted with RI, histamine, and PDG. Selective procaine block of conduction in thin vagal fibers (with persistence of the Breuer-Hering inflation reflex) reduced or suppressed the tonic response, which was abolished in all cases after vagotomy. 2) In rabbits artificially ventilated with open chest, passive deflation of the lung or intravenous injections of histamine or PDG also produced tonic discharge in Ephr and often in Eic. The present results demonstrate that 1) stimulation of vagal afferents and mostly thin sensory fibers elicits tonic inspiratory discharges, 2) bronchoconstriction is not necessary for the induction of the response, and 3) reflexes from the chest wall do not mediate this response in rabbits.     

Integration of chemoreceptor stimuli by rostral brainstem respiratory areas.

Ventilatory regulation by brainstem sites rostral to the midpontile level was assessed in decerebrate cats by comparing the effects of punctate pneumotaxic center lesions with those of midpontile transection. After either procedure, PACO2 was significantly elevated. Moreover an equal suppression of hypercapnia-induced minute volumes and maintenance, at some PACO2 levels, of minute volume responses to hypoxia was observed. Tidal volume elevations accounted for the maintenance of hypoxia-induced minute volumes. Following pneumotaxic center lesions, hypercapnia-induced tidal volumes were higher than those exhibited subsequent to midpontile transection. After carotid sinus nerve section, PACO2 was elevated and hypoxia-induced alterations were abolished. Bilateral vagotomy resulted in apneusis. These data demonstrate that, in the brainstem area examined, only the pneumotaxic center influences the PACO2 level or set point for respiratory activity. A locus of tidal volume generation is ascribed to rostral brainstem sites outside this pneumotaxic center. Data obtained support the hypothesis of a differential brainstem integration of peripheral and central chemoreceptor afferent stimuli.     

Effects of hypercapnia on Breuer-Hering threshold for inspiratory termination

The effects of CO2 concentration on the timing of inspiratory duration (TI) and expiratory duration (TE) and the responses to lung inflation were studied in decerebrate paralyzed cats. With lung volume held at functional residual capacity during the breath cycle, hypercapnia (fractional concentration of inspired CO2 = 0.04) caused variable changes in TI and significant increases in TE. To obtain the Breuer-Hering threshold relationship [tidal volume (VT) vs. TI] and the timing relationship between TE and the preceding TI (TE vs. TI), ramp inflations of various sizes were used to terminate inspiration at different times in the breath cycle. Hypercapnia caused the VT vs. TI curves to shift in an upward direction so that at higher lung volumes TI was lengthened. Also, the slope of the TE vs. TI relationship was increased. The results suggest that hypercapnia diminished the sensitivity of the Breuer-Hering reflex to the lung volume, thus allowing volume to increase with little effect on TI. In addition, TE appears to become more sensitive to changes in the preceding TI. A model is presented which provides a possible neural mechanism for these responses.     

Morphological and functional characteristics of the inspiratory and expiratory formations of the medial and lateral areas of the respiratory center

The density of the reticular and respiratory neurones in the inspiratory and the exspiratory "points" of medial and lateral zones of the medulla oblongata the electrical stimulation of which is accompanied by the maximum inspiratory and exspiratory effects has been studied in the anesthetized cats. The electrophysiological and morphological data allow to relate the structures studied to the respiratory centre and confirm the correct picking out of two functionally heterogeneous zones - the medial and lateral.     

Inspiratory and expiratory patterns of the pectoralis major muscle during pulmonary defensive reflexes

Experiments wereconducted to determine the discharge pattern of the pectoralis majormuscle during pulmonary defensive reflexes in anesthetized cats(n = 15). Coughs andexpiration reflexes were elicited by mechanical stimulation of theintrathoracic trachea or larynx. Augmented breaths occurredspontaneously or were evoked by the same mechanical stimuli.Electromyograms (EMGs) were recorded from the diaphragm, rectusabdominis, and pectoralis major muscles. During augmented breaths, thepectoralis major had inspiratory EMG activity similar to that of thediaphragm, but during expiration reflexes the pectoralis major also hadpurely expiratory EMG activity similar to the rectus abdominis. Duringtracheobronchial cough, the pectoralis major had an inspiratory patternsimilar to that of the diaphragm in 10 animals, an expiratory patternsimilar to that of the rectus abdominis in 3 animals, and a biphasicpattern in 2 animals. The pectoralis major was active during both the inspiratory and expiratory phases during laryngeal cough. We conclude that, in contrast to the diaphragm or rectus abdominis muscles, thepectoralis major is active during both inspiratory and expiratory pulmonary defensive reflexes.

     

Breathing pattern of anesthetized humans during pancuronium-induced partial paralysis

We investigated the breathing patterns of 17 subjects anesthetized with enflurane before and after partial muscle paralysis produced by pancuronium bromide. In the face of significant muscle weakness produced by pancuronium, breathing patterns are characterized by decreases in both tidal volume and respiratory frequency. The decreased tidal volume corresponded to the decrease in occlusion pressure, indicating that the decreased tidal volume results solely from a decreased contractile force of the respiratory muscles. The decreased respiratory frequency was due to prolongation of both inspiratory and expiratory time without changing the ratio of the inspiratory time to the total breath time. Withdrawal of phasic vagal influence by airway occlusion before partial muscle paralysis revealed that an active Breuer-Hering inflation reflex was operative in only 8 of all 17 subjects. Since the contribution of the Breuer-Hering inflation reflex alone does not seem to account for the consistent decrease in respiratory frequency, some other mechanisms modulating respiratory frequency might be involved in the characteristic breathing patterns during partial muscle paralysis under enflurane anesthesia.     

Inspiratory timing of heart-lung transplant recipients during progressive hypercapnia.

The relationship between tidal volume (VT) and inspiratory duration (TI) displays biphasic characteristics during progressive hypercapnia in humans: an initial phase in which VT increases while TI remains constant (region I) and a subsequent phase with reciprocal decreases of TI as VT continues to increase (region II). Region II behavior is generally attributed, albeit inferentially, to lung volume-mediated inflation inhibition (Breuer-Hering reflex). To investigate this phenomenon, we compared CO2 responses of 10 heart-lung transplant recipients (HL) with normal pulmonary function tests and 13 normal controls. Despite pulmonary denervation, the HL exhibited region II behavior identical to controls. In four additional HL with pulmonary restriction, there were comparative decreases of the region II slope (P less than 0.05), but the absolute VT where the phase change between regions occurred was indistinguishable from the other groups. We conclude that TI shortening in humans during progressive hypercapnia occurs in the absence of pulmonary reflexes. The consistency of the VT associated with phase changes, despite pulmonary denervation, suggests that the stimulus for this behavior is volume displacement of extra-pulmonary respiratory structures.     

Effects of breathing pattern on inspiratory muscle endurance in humans

Endurance of the inspiratory muscles was measured in normal volunteers using a threshold resistance that produced a relatively constant mouth-pressure load, independent of inspiratory flow rate (VTI). Breathing pattern was controlled by visual feedback from an oscilloscope. Endurance was measured as the length of time (Tlim) a target VTI could be maintained with maximum effort. Effects of changes in breathing pattern on Tlim were compared with control measurements made the same day. Increases in VTI or in duty cycle (inspiratory time/total period) shortened Tlim, whereas decreases lengthened Tlim. However, effects of changes in VTI were less than equivalent changes in tidal volume produced by alterations in duty cycle. Furthermore, when two breathing pattern changes were altered simultaneously to keep the rate of external inspiratory work (Winsp) constant, significant effects due to changes in duty cycle were still observed. In conclusion, 1) both VTI and duty cycle have significant effects on measurements of inspiratory muscle endurance and 2) the effects of VTI are less than the effects of duty cycle for the same Winsp.     

The role of lung afferent system in respiratory control during head-down tilt

The role of lung receptors in respiratory control during acute head-down tilt (AHDT, -30 degrees) was investigated in anesthetized, tracheostomized rats. The results show that AHDT increased the mechanical respiratory load, slowed inspiratory flow, reduced the end expiratory lung volume, tidal volume and minute ventilation. On the other hand, during AHDT a significant rise in inspiratory swings of oesophageal pressure was recorded indicated a compensatory increase in inspiratory muscle contraction force. These effects were reduced after transaction of the vagus nerve. It was also shown that respiratory response on added mechanical load was reduced during AHDT as compared with the value in horizontal position. This deference disappeared after vagotomy. The data obtained suggested that afferent information from lung receptors take part in compensation of respiratory effects of AHDT. The cause of reduction in respiratory response to loading during AHDT involves weakness of lung reflexes evoked by volume changes.     

Comparative study of the activity of medullary respiratory neurones during polypnea triggered by hypothalamic electrical stimulation or by hypothalamic heating (author's transl)

We have compared in "encéphale isolé bas" cats the activity of medullary respiratory neurones during polypnea triggered by electrical stimulation (PSt) or by heating (PTh) of the hypothalamus. The medullary respiratory neurones are classified according to:--their anatomical localization (dorsal or ventral respiratory nucleus);--their axon destination (spinal : bulbo-spinal respiratory neurones; non spinal : propriobulbar neurones);--their discharge pattern;--the correlation coefficient between the number of spikes delivered in each burst and the duration of the corresponding respiratory phase (HILAIRE et MONTEAU, 1975). 1. During the two polypneas (PSt and PTh), we observe:--a reduction of activity that preferentially affects some groups of neurones (propriobulbar neurones) (fig. 3);--an inversion of the discharge firing rate, which increases during inspiration in normopnea and decreases in polypnea (fig. 1; fig. 6);--a decrease of the maximal discharge firing rate for the neurones of different groups (Table V). 2. However, two differences exist : during PSt, the maximal discharge firing rate increases for the inspiratory bulbo-spinal neurones of the dorsal nucleus and for the early-burster inspiratory propriobulbar neurones. The recruitment of the bulbo-spinal inspiratory neurones seems to be different; they are activated earlier during PSt than during PTh (Table VI). 3. Some of the observed differences are probably quantitative and we think that polypnea triggered by hypothalamic electrical stimulation is a good model for thermal polypnea.     

Nerves containing substance P,vasoactive intestinal polypeptide,enkephalin or somatostatin in the guinea-pig taenia coli

Summary The guinea-pig taenia coli is rich in peptide-containing nerves. Nerve fibres containing substance P (SP), vasoactive intestinal peptide (VIP), or enkephalin, were numerous in the smooth muscle while somatostatin fibres were very few. Nerve fibres displaying SP or VIP immunoreactivity were numerous in the myenteric plexus. Enkephalin nerve fibres were fairly numerous in the plexus while somatostatin nerve fibres were sparse. Nerve cell bodies containing immunoreactive SP or VIP were regularly seen in the plexus. Delicate varicose elements of the different types of nerve fibres were found to ramify around nerve cell bodies in a manner suggestive of innervation.In the electron microscope the various peptide-storing nerve fibres (i.e., elements containing SP, VIP or enkephalin) were found to contain a varying number of fairly large, electron-opaque vesicles in the varicose swellings. These vesicles represent the storage site of the neuropeptides.The isolated taenia coli responded to electrical nerve stimulation with a contraction. After cholinergic and adrenergic blockade the contractile response was replaced by a relaxation followed by a contraction upon cessation of stimulation. SP contracted the taenia while VIP caused a relaxation. The enkephalins raised the resting tension slightly while somatostatin had no effect. These observations are compatible with a role for SP as an excitatory neurotransmitter and for VIP as an inhibitory one, and with the view that both SP neurones and VIP neurones act as motor neurones. In preparations contracted by SP the electrically induced contractions were reduced in amplitude while the electrically induced relaxations seen after adrenergic and cholinergic blockade were enhanced in amplitude. In preparations relaxed by VIP there was an increased contractile response to electrical stimulation, while in the atropine + guanethidine-treated preparation the electrically induce relaxations were reduced in amplitude. The enkephalins reduced the contractile response to electrical stimulation, while somatostatin induced a very small reduction in the amplitude of such responses. These observations suggest that SP neurones and VIP neurones may play additional roles as interneurones. Somatostatin neurones probably act as interneurones. Enkephalin-containing fibres may serve to modify the release of transmitter from other nerves in the smooth muscle, perhaps through axo-axonal arrangements. Alternatively, the enkephalin nerve fibres in the smooth muscle are afferent elements involved in mediating sensory impulses to the myenteric plexus.