Responses of hypoglossal and phrenic nerves to decreased respiratory drive in cats

Agents which depress respiration, such as alcohol, seem to increase the occurrence of obstructive apneas during sleep. It has been proposed that upper airway obstruction can result from an imbalance in the activity (or forces) produced by the upper airway muscles versus the chest wall muscles so that upper airway passages might be blocked when a disproportionate decrease in upper airway muscle activity occurs. This study examines the hypothesis that depression of respiration affects the activity of the hypoglossal nerve (the motor nerve to the tongue) more than the activity of the phrenic nerve (the motor nerve to the diaphragm). In addition, we examined the role of the putative central chemoreceptor area on the ventrolateral medullary surface (VMS) in maintaining phrenic and hypoglossal discharge. In chloralose-anesthetized, artificially ventilated, paralyzed cats, three methods of reducing respiratory drive were studied: hyperoxic hypocapnia (produced by mechanical hyperventilation), the application to the intermediate area of the ventral medullary surface of the respiratory depressant GABA and its agonist muscimol, and cooling the same area of the VMS (using a water-cooled thermode). All these interventions decreased hypoglossal nerve activity more than phrenic nerve activity (range of p values: p less than 0.001 to p less than 0.01). Moreover, the reduction in hypoglossal activity was greater with GABA and muscimol than with the other two maneuvers; this was statistically significant for both GABA versus VMS cooling (p less than 0.02) and muscimol versus VMS cooling (p less than 0.01). These results show that respiratory depression can differentially affect hypoglossal and phrenic nerve activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential elevation by protriptyline and depression by diazepam of upper airway respiratory motor activity

Effects of systemically administered protriptyline and diazepam on the respiratory activity of the phrenic, hypoglossal, and recurrent laryngeal nerves were investigated in vagotomized, decerebrate cats. Both hypoglossal and recurrent laryngeal nerve activities were consistently increased after protriptyline administration, whereas the phrenic nerve discharge was not systematically altered. Similar changes were observed in cats with bilateral carotid sinus nerve sections. Diazepam induced a reduction of hypoglossal and recurrent laryngeal nerve activities at doses that did not alter phrenic nerve discharge. These results with diazepam were the same in carotid chemodenervated cats. We conclude that neural mechanisms controlling upper airway muscles are much more sensitive to protriptyline and diazepam than are those of the bulbospinal-phrenic system. The selective augmentation of hypoglossal and recurrent laryngeal discharges by protriptyline could account for the reported decrease in the frequency of obstructive sleep apneas in patients receiving this antidepressant. In contrast, diazepam, by depressing motor activity to upper airway muscles, may exacerbate oropharyngeal obstruction during sleep.     

Hypoglossal motoneuron responses to pulmonary and superior laryngeal afferent inputs

In decerebrate, paralyzed cats ventilated with a cycle-triggered pump, the inspiratory discharges of the hypoglossal (whole nerve or single fibers), phrenic, and recurrent laryngeal nerves were compared, and the effects of pulmonary and superior laryngeal afferent inputs were observed. During lung inflations in phase with neural inspiration, hypoglossal and recurrent laryngeal activities differed from phrenic with respect to (a) burst onset times: both preceded the phrenic; (b) overall pattern: phrenic, augmenting; hypoglossal, decrementing; recurrent laryngeal, plateau-like. When inflation was withheld, the phrenic pattern was not markedly changed, but both hypoglossal and recurrent laryngeal became augmenting; the marked increase of hypoglossal activity (both whole nerve and single fiber) indicated strong inhibition by lung afferents. Superior laryngeal electrical stimulation evoked excitation of the contralateral phrenic (latency 4.1 msec) and the ipsilateral whole hypoglossal (latency 5.3 msec), followed by bilateral inhibitions (durations 20-30 msec); most hypoglossal fibers showed only inhibition. We conclude that, although both hypoglossal and phrenic outputs are driven by the inspiratory pattern generator(s), their promotor systems differ with respect to influences from central and peripheral inputs.     

Respiratory-modulated activities of motor units of the facial nerve

The purpose of this work was to characterize the influence of activity of vagal pulmonary receptors upon the discharge pattern of motor units of the facial nerve. Decerebrate and paralyzed cats were ventilated with a servo-respirator which produced pulmonary inflations in parallel with activity of the phrenic nerve. At normocapnia, facial units discharged phasically during neural inspiration, expiration or across both phases or discharged tonically throughout the respiratory cycle. When pulmonary inflation was withheld, the tonic discharge of some units became phasic; others changed the pattern of phasic discharge. In hypercapnia, the number of tonic fiber activities increased and, again, some phasic discharge patterns were altered. Withholding inflation caused similar alterations as in normocapnia. Activities of facial fibers in vagotomized animals differed in that no tonic activities were recorded, and no change in phasic discharge patterns was induced by hypercapnia. We conclude that afferents from pulmonary stretch receptors influence ventilatory activity throughout the entire respiratory cycle. The concept is discussed that the tonic, as well as phasic discharge of these receptors, is important for the regulation of activity of motoneurons to upper airway muscles.     

Influence of extreme hypercapnia on respiratory motor nerve activity in cats

Sedative drugs have been found to depress the respiratory activity of upper airway muscles more than that of the diaphragm. To determine whether CO2 at narcotic levels has a similar action, we recorded phrenic and hypoglossal nerve activities in decerebrate, vagotomized, paralyzed cats. T5 or T6 external intercostal nerve activity was also recorded in some animals. End-tidal CO2 concentration was raised progressively to over 30% or until depression of nerve activity was apparent. Respiratory frequency was reduced by severe hypercapnia in most cats. Hypoglossal nerve activity was consistently decreased more than that of the phrenic nerve. In most cases intercostal nerve activity was also more susceptible than phrenic nerve activity to hypercapnic depression. The results indicate that CO2 at narcotic levels interferes both with the central pattern generator for breathing movements and with the expression of the pattern in specific motor nerves.     

Afferent pathways for hypoglossal and phrenic responses to changes in upper airway pressure

Our purpose was to determine the afferent pathways underlying reflexes by which changes in upper airway pressure induced alterations in hypoglossal and phrenic nerve activities. An isolated upper airway was produced in decerebrate, vagotomized, paralyzed and ventilated cats. Efferent activities of the phrenic and hypoglossal nerves were monitored. Hypoglossal activity significantly increased following pressure changes in the upper airway of -4 to -21 cm H2O; phrenic discharge declined in most trials. Similar alterations of neural activities were induced by positive pressures though changes of +14 to +21 cm H2O were required for significant responses. These changes in hypoglossal and phrenic activities were greatly reduced following bilateral sectionings of the superior laryngeal nerves but were augmented after the pharyngeal branches of the glossopharyngeal nerves were sectioned. Additional bilateral destruction of the trigeminal nerves almost entirely eliminated responses to pressure changes. We conclude that upper airway receptors may serve to maintain patency of the upper airways. These receptors may play a crucial role in promoting release from upper airway obstructions, especially in sleep.     

Characterization of respiratory-related activity of the facial nerve

Activities of the facial, hypoglossal and phrenic nerves were recorded in decerebrate and paralyzed cats. These animals were ventilated with a servo-respirator which produced lung inflations in parallel with phrenic activity. Peak inspiratory phrenic, hypoglossal and facial activities increased in hypercapnia or hypoxia. When pulmonary inflation was prevented, hypoglossal and facial activities increased more than phrenic. Responses to withholding lung inflation differed from those following vagotomy. These differences were observed in expiratory facial and hypoglossal activities and in hypercapnia- and hypoxia-induced changes in facial activity. Administration of pentobarbital or hyperventilation to hypocapnia caused greater suppressions of hypoglossal than facial activity; the latter declined more than phrenic activity. The results support the hypothesis that influences from the brainstem reticular formation and from pulmonary stretch receptors are differentially distributed to motoneurons innervating upper airway muscles compared to those of the bulbospinal-phrenic system. The concept that ventilatory activity is influenced by tonic, as well as phasic discharge of pulmonary receptors is discussed.     

Influence of lung volume on phrenic, hypoglossal and mylohyoid nerve activities

In decerebrate, paralyzed cats, ventilated by a servo-respirator in accordance with phrenic nerve activity, we examined the influence of lung volume on the activities of the phrenic, hypoglossal and mylohyoid nerves. When lung inflation was briefly withheld, the durations of inspiration (TI) and expiration (TE) and the activities of all three nerves increased. The relative increase in hypoglossal activity greatly exceeded that of phrenic activity and was apparent earlier in the course of inspiration. This hypoglossal response was enhanced by hypercapnia and isocapnic hypoxia. The responses of mylohyoid activity were quite variable: withholding lung inflation augmented inspiratory activity in some cats, but expiratory discharge in others. Sustained increases in end-expiratory lung volume were induced by application of 3-4 cm H2O of positive end-expiratory pressure (PEEP). Steady-state PEEP did not influence nerve activities or the breathing pattern. Bilateral vagotomy increased TI, TE, and the activities of all three nerves. No response to withoholding lung inflation could be discerned after vagal section. The results provide further definition of the influence of vagally mediated, lung volume dependent reflexes on the control of upper airway muscles. These reflexes are well suited to relieve or prevent upper airway obstruction.     

Selective depression by ethanol of upper airway respiratory motor activity in cats

We studied the effects of systemically administered ethyl alcohol on the respiratory motor activity of the phrenic, hypoglossal and recurrent laryngeal nerves in unanesthetized, decerebrate cats. Some of the cats were studied after carotid sinus nerve section. In addition, parallel studies were done in intact, awake cats with chronic electromyographic electrodes in the diaphragm, genioglossus, and posterior cricoarytenoid (PCA) muscles. In decerebrate animals, alcohol induced a significant reduction of hypoglossal and recurrent laryngeal nerve activities at doses that had little or no effect on the phrenic nerve discharge. Similar changes were observed in chemodenervated cats. In awake animals, genioglossal and PCA muscle activities were depressed by alcohol, whereas diaphragm activity showed no consistent change. Alcohol caused a significant increase in respiratory frequency in awake cats and reduced the responses of genioglossal and PCA muscle activities to hypercapnia and normocapnic hypoxia. We conclude that alcohol induces a selective reduction in upper airway respiratory motor activity by an action that does not require intact suprapontile structures, vagal afferents, or peripheral chemoreceptors. This reduction may contribute to the alcohol-induced exacerbation of obstructive sleep apnea.     

Responses of recurrent laryngeal motoneurons to changes of pulmonary afferent inputs

In decerebrate, paralyzed cats ventilated with a cycle-triggered pump, the discharges of the recurrent laryngeal (whole nerve or single fibers) and phrenic nerves, and the changes produced by pulmonary afferent inputs (lung inflation), were compared. When lung inflation was in phase with neural inspiration, four types of laryngeal fiber activities were observed: (a) phasic-inspiratory; (b) tonic-inspiratory; (c) expiratory-inspiratory; (d) early-expiratory. The firing patterns during inspiration were plateau-like, whereas the phrenic pattern was augmenting. When inflation was withheld, the plateau patterns usually became augmenting, indicating inhibition of laryngeal inspiratory activity by pulmonary afferents. Secondary effects of withholding inflation were (a) increases of early-expiratory activity (both whole nerve and individual fiber), indicating increased post-inhibitory rebound excitation; (b) decreased activity of tonic-inspiratory and expiratory-inspiratory fibers during early neural expiration, indicating increased inhibition by early-expiratory neurons. The discharge patterns of different types of laryngeal motoneuron, as well as their changes with inflation, are interpreted in relation to the function of regulating airway resistance.     

Influence of morphine on respiratory activities of phrenic and hypoglossal nerves in cats

Anesthetic and sedative drugs have been found to diminish the respiratory motor activity of the hypoglossal nerve more than that of the phrenic nerve. This differential depression of motor activity to the upper airway may contribute to the exacerbation of obstructive sleep apnea by sedative drugs. To determine whether morphine has a similar selective action, we recorded phrenic and hypoglossal nerve activities before and after morphine administration in decerebrate, vagotomized cats, paralyzed with gallamine. Morphine diminished the activities of both nerves in most animals, but the responses were highly variable, and no consistent pattern of differential depression was apparent. The variability of the results may reflect the complex nature of opiate actions on the control of breathing.     

Functions of the retrofacial nucleus in chemosensitivity and ventilatory neurogenesis

The hypothesis was evaluated that neurons within the retrofacial nucleus of medulla integrate afferent stimuli from the central chemoreceptors. In decerebrate, vagotomized, paralyzed and ventilated cats, activity of the phrenic nerve was monitored. Peak integrated phrenic activity increased in hypercapnia; the frequency of phrenic bursts typically declined slightly. The retrofacial nucleus was ablated by radio-frequency lesions or neurons within this nucleus were destroyed by microinjections of kainic acid. Results were similar following lesions or injections. Following unilateral ablations, peak phrenic activity was greatly reduced at normocapnia and hypercapnia; the frequency of phrenic bursts typically rose. Both frequency and peak phrenic activity fell further after the contralateral destruction with a cessation of all phasic phrenic discharge being observed in most animals. Injections of kainic acid in regions rostral, caudal or medial to the retrofacial nucleus produced no consistent changes in phrenic activity. We conclude that neuronal activities in the region of the retrofacial nucleus are important both in the integration of stimuli from the central chemoreceptors and in defining the discharge patterns of respiratory neurons.     

Phrenic afferent input to the lateral medullary reticular formation of the cat

The afferent inputs from phrenic nerve stimulation to the lateral reticular formation of the lower brain stem were studied in anesthetized spontaneously breathing cats. The activity of reticular neurons was recorded by means of extracellular tungsten microelectrodes. Electrical stimulation of the central end of the right phrenic nerve evoked excitatory or inhibitory responses in the lateral reticular nucleus (LRN), in the nucleus ambiguus (AMB) and in a region dorsal to the AMB of ipsi- and contralateral sides. Phrenic afferents belonging to the flexor reflex afferent group were involved in these responses. The discharge pattern of the respiratory related units (RRU) of the AMB were exceptionally affected by phrenic nerve stimulations. It is concluded that high threshold phrenic afferents relay in the LRN before projecting to the cerebellar cortex. The overlapping of respiratory and non-respiratory afferents in the reticular formation may participate to the adaptations of respiratory and somatomotor functions during specific behaviors.     

The effects of hypercapnia and hypoxia on single hypoglossal nerve fiber activity

The respiratory related modulation of hypoglossal nerve activity has been studied at the single fiber level in cats under hyperoxic hypercapnia and hypoxic conditions and their conduction velocities determined. Changes in fiber activity were compared to simultaneous changes occurring in phrenic activity. Three different kinds of discharge patterns were observed: (a) inspiratory, (b) phasic activity during both inspiration and expiration, and (c) continuous random activity with no respiratory modulation. These fibers could be grouped into three categories according to their pattern of discharge during CO2 breathing. Type I fibers, mean conduction velocity of 30.0 m/sec, exhibited only an inspiratory phasic discharge during 100% O2 breathing. Their discharge frequency increased rapidly with higher levels of CO2 and hypoxia. Type II fibers, mean conduction velocity of 36.7 m/sec, had three different kinds of inspiratory-expiratory discharge patterns during 100% O2 breathing. With increasing hypercapnia or hypoxia fibers of this group discharged phasically during inspiration and discharge at low frequency during expiration. Type III fibers had a non phasic discharge pattern at 100% O2 breathing and at all levels of CO2 tested (up to 10%). Discharge frequency rose during CO2 rebreathing and hypoxia, but the rate of increase was much less than Type I and Type II fibers. Their mean conduction velocity was 41.3 m/sec. The inspiratory activity of Type I and II fibers increased their activity more than the phrenic during hypercapnia and hypoxia. Type II and Type III fibers are responsible at least in part for the tonic activity of the nerve.     

Influence of laryngeal CO2 on respiratory activities of motor nerves to accessory muscles.

Intralaryngeal CO2 in decerebrate, vagotomized cats decreases phrenic nerve activity and increases the respiratory activity of the hypoglossal (HG) nerve. These responses are mediated by afferents in the superior laryngeal nerves. To explore the responses of other respiratory motor nerves to this stimulus, we have recorded the activities of the nasolabial (NL) branch of the facial nerve, the posterior cricoarytenoid (PCA) and thyroarytenoid (TA) branches of the recurrent laryngeal nerve and the nerve to triangularis sterni (TS) muscle. In response to 5 and 10% CO2 in the surgically isolated upper airway, we found dose-related decreases in phrenic activity, increases in HG and NL activity and characteristic, but intermittent, exaggeration of early expiratory bursts of TA activity. The activities of the PCA and TS nerves showed no consistent responses. These results broaden the definition of the reflex response to intralaryngeal CO2, revealing components that reflect ventilatory inhibition, upper airway dilation and laryngeal protection.     

Changes in inspiratory muscle electrical activity and upper airway resistance during periodic breathing induced by hypoxia during sleep

We hypothesized that: the balance of electrical activities between the upper airway and chest wall inspiratory muscles affects upper airway inspiratory caliber, and at low levels of central respiratory neural efferent activity, an imbalance between the electrical activities of these 2 inspiratory muscle groups exists that results in a decreased upper airway caliber. These hypotheses were tested during periodic breathing induced by mild hypoxemia in NREM sleep in 9 healthy male subjects. In 6 subjects during periodic breathing as central respiratory neural activity decreased, the tonic and phasic EMG activity of the upper airway inspiratory muscles decreased at a rate greater than that of the chest wall EMG activity. When the ratio of upper airway to chest wall EMG activity decreased below a critical level, which was reproducible across subjects, upper airway inspiratory resistance increased hyperbolically. Resistance at peak inspiratory flow increased from 4.10 +/- 0.97 (mean +/- SEM) to 48.70 +/- 21.00 cmH2O/L/s as tidal volume decreased from 0.79 +/- 0.12 to 0.20 +/- 0.02 L during periodic breathing in these subjects. In the 3 remaining subjects, the ratio of the upper airway to chest wall EMG activity did not decrease below the critical level as the activity of both muscle groups decreased during periodic breathing, and upper airway resistance did not increase. We conclude that within the confines of this study the nonlinear activation of upper airway and chest wall inspiratory muscles contributed to fluctuations in upper airway resistance observed during periodic breathing in sleep.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of reticular mechanisms upon hypoglossal, trigeminal and phrenic activities

Studies were undertaken to evaluate the hypothesis that mechanisms within the reticular formation influence activities of nerves to muscles of the upper airways more than the bulbospinal-phrenic system. In decerebrate, vagotomized, paralyzed and ventilated cats, activities of the phrenic, trigeminal, and the hypoglossal nerves were monitored. Activity of the pontile and medullary reticular formation was increased directly by electrical stimulation within the brainstem and indirectly by stimulating the sciatic nerve. Trigeminal and hypoglossal discharges increased more than phrenic during stimulations at many brainstem loci. Changes were typically maintained for one or more respiratory cycles following termination of stimulation. At some loci, activation of neurons by microinjections of glutamate increased trigeminal and hypoglossal activities more than phrenic. Although responses were extremely variable, activities of the trigeminal and/or hypoglossal nerves usually increased more than phrenic during stimulations of the sciatic nerve or upon termination of stimulation. The results support the conclusion that respiratory-modulated trigeminal and hypoglossal discharges are dependent upon reticular mechanisms for their expression.     

The respiratory activity of the superior laryngeal nerve in the rat.

The aim of this study was to characterize the laryngeal afferent activity of the rat. The animals were anesthetized and breathing spontaneously. Laryngeal afferent activity was recorded from both the whole superior laryngeal nerve (SLN) and from single fibers isolated from this nerve. An overall inspiratory augmenting activity was observed in the whole SLN during tracheostomy breathing, tracheal occlusion and upper airway breathing, but an expiratory augmenting activity was present during upper airway occlusion. The inspiratory modulated activity was abolished by bilateral section of the hypoglossal nerves but not the recurrent laryngeal nerves. A great number of receptors (46/80, 58%) were identified as 'drive' receptors, and others as 'pressure' (22/80, 28%) and 'irritant' type receptors (9/80, 11%). Nineteen pressure receptors were stimulated by positive transmural pressure, while only three stimulated by negative pressure. Nine drive receptors were also stimulated by positive pressure and inhibited by negative pressure. Such response to pressure was further evaluated by applying maintained pressures to the functionally isolated upper airway. These results are essentially consistent with findings obtained in the rabbit, but differ from those reported for the dog.     

Similarities in reflex control of laryngeal and cardiac vagal motor neurones

We sought to test the hypothesis that laryngeal adductor and cardiac vagal motor neurones respond similarly to the activation of certain afferent inputs. Experiments were performed on a working heart-brainstem preparation of rat devoid of pulmonary stretch receptor feedback. Upper airway negative pressure receptors (UANPR), peripheral arterial chemoreceptors and receptors at the junction of the pharynx and oesophagus were stimulated selectively while recording heart rate, recurrent laryngeal, phrenic and hypoglossal motor outflows, subglottic pressure during constant translaryngeal airflow (as an index of laryngeal resistance), and single unit respiratory neurone activity. Stimulation of all three receptor types produced bradycardia, evoked discharges in the recurrent laryngeal and hypoglossal motor outflows during the post-inspiratory period and caused swallowing. Stimulation of pharyngoesophageal receptors and peripheral chemoreceptors evoked an increase in laryngeal resistance during the post-inspiratory phase indicative of laryngeal adductor motoneurone activation. Although this reflex response cannot be evaluated during UANPR stimulation, some post-inspiratory neurones were powerfully activated suggesting that UANPR probably drive laryngeal adductor muscles. Our data show that motor outflows controlling cardiac rate and laryngeal patency are concurrently activated by these sensory inputs. This may constitute the basis for a stereotyped defensive reflex response which maintains end expiratory lung volume, thus conserving oxygen in conditions of upper airway obstruction. Our observations lend further support to models of cardiorespiratory control which propose close coupling and shared central mechanisms for the regulation of the cardiovascular and respiratory systems.     

Comparison of respiratory-related trigeminal, hypoglossal and phrenic activities

In decerebrate, paralyzed and vagotomized cats, we recorded activities of hypoglossal and phrenic nerves and of the mylohyoid branch of the trigeminal nerve. At normocapnia, a respiratory-modulated trigeminal discharge could be discerned in most cats. This discharge was characterized by a diminution of activity during neural inspiration and a peak in expiration. In hypercapnia or hypoxia, peak activity increased and its time of occurrence moved to late inspiration. Augmentations of peak trigeminal, hypoglossal and phrenic activities were proportional. Peak trigeminal and hypoglossal activities increased more than phrenic following administrations of protriptyline, strychnine and, in some cats, cyanide or doxapram. Peak trigeminal activity fell more than phrenic after diazepam. Pentobarbital or halothane reduced peak hypoglossal, but not trigeminal, activity more than phrenic. However, after these anesthetics, trigeminal activity became restricted to the inspiratory-expiratory junction. We conclude that trigeminal and hypoglossal activities are more dependent upon processes within the reticular formation than is the bulbospinal-phrenic system. Central and peripheral chemoreceptor influences are distributed equivalently upon trigeminal, hypoglossal and phrenic motoneurons.