Reflex Apnea Research Articles

Trigeminal reflex regulation of the glottis depends on central glycinergic inhibition in the rat.

In an unanesthetized decerebrate in situ arterially perfused brain stem preparation of mature rat, strychnine (0.05-0.2 microM) blockade of glycine receptors caused postinspiratory glottal constriction to occur earlier, shifting from early expiration to inspiration. This resulted in a paradoxical inspiratory-related narrowing of the upper airway. Stimulation of the trigeminal ethmoidal nerve (EN5; 20 Hz, 100 micros, 0.5-2 V) evoked a diving response, which included a reflex apnea, glottal constriction, and bradycardia. After strychnine administration, this pattern was converted to a maintained phrenic nerve discharge and a reduced glottal constriction that was interrupted intermittently by transient abductions. The onset of firing of postinspiratory neurons shifted from early expiration into neural inspiration in the presence of strychnine, but neurons maintained their tonic activation during EN5 stimulation, as observed during control. Inspiratory neurons that were hyperpolarized by EN5 stimulation in control conditions were powerfully excited after loss of glycinergic inhibition. Thus the integrity of glycinergic inhibition within the pontomedullary respiratory network is critical for the coordination of cranial and spinal motor outflows during eupnea but also for protective reflex regulation of the upper airway.

Bradycardic response during submersion in infant swimming.

The diving response involves reflex bradycardia, apnoea and peripheral vasoconstriction and is known to exist in human infants. The response diminishes with increasing age and has been reported to disappear by the age of 6 mo. This study was performed to analyse the physiological events during natural diving of full-term healthy infants and describe how these events alter with maturation. Thirty-six infants were studied during diving exercises in infant swimming. All of the infants who participated showed an immediate decrease in heart rate when submerged. On average, the heart rate decreased by 25% (range -5.0% to -50.7%, p <0.0001). The bradycardia was sustained during the dive and for some seconds afterwards. The response was often followed by a tachycardia as the bradycardia ceased. A decline of reflex bradycardia was observed with increasing age (p = 0.03), but the response was still clearly evident in infants over the age of 6 mo. This study demonstrates the existence of a diving response in infants, which includes an immediate bradycardic response, suggesting vagal mediation. Although the bradycardic response gradually decreases, the study shows that a clear-cut response exists in children older than has previously been reported.

Bradycardic response during submersion in infant swimming

The diving response involves reflex bradycardia, apnoea and peripheral vasoconstriction and is known to exist in human infants. The response diminishes with increasing age and has been reported to disappear by the age of 6 mo. This study was performed to analyse the physiological events during natural diving of full‐term healthy infants and describe how these events alter with maturation. Thirty‐six infants were studied during diving exercises in infant swimming. All of the infants who participated showed an immediate decrease in heart rate when submerged. On average, the heart rate decreased by 25% (range –5.0% to –50.7%, p &lt; 0.0001). The bradycardia was sustained during the dive and for some seconds afterwards. The response was often followed by a tachycardia as the bradycardia ceased. A decline of reflex bradycardia was observed with increasing age (p= 0.03), but the response was still clearly evident in infants over the age of 6 mo. Conclusion: This study demonstrates the existence of a diving response in infants, which includes an immediate bradycardic response, suggesting vagal mediation. Although the bradycardic response gradually decreases, the study shows that a clear‐cut response exists in children older than has previously been reported.

Gastroesophageal reflux and pediatric otolaryngologic disease: the role of antireflux surgery.

To determine the role of antireflux surgery in the treatment of gastroesophageal reflux-induced otolaryngologic disease (GEROD). A retrospective medical record analysis was performed. Patient demographics, otolaryngologic disease secondary to gastroesophageal reflux (GER), method of GER diagnosis, medical treatment used before antireflux surgery, and response to surgical intervention were considered. Tertiary care children's hospital. Among patients undergoing antireflux surgery between January 1, 1996, and December 31, 1999, children with GEROD were included in the study. Children with GEROD who failed medical therapy underwent antireflux surgery. The demographics of patients requiring antireflux surgery for treatment of their otolaryngologic disease and their clinical response to surgery were reviewed. Fourteen (17%) of 82 children, ranging in age from 48 days to 3 years (mean age, 9.7 months), who underwent antireflux surgery for GER at our institution between 1996 and 1999 were diagnosed as having GEROD. Twelve (86%) of the 14 patients were found to have upper airway abnormalities, including subglottic edema, fixed subglottic stenosis, reflex apnea, and recurrent croup. Two patients (14%) had severe chronic sinusitis and otitis media. Nine (64%) of the 14 had normal neurologic function for their age vs 5 (36%) who had neurologic impairment. After antireflux surgery, all 14 patients with GEROD had complete resolution of clinical symptoms. Gastroesophageal reflux has an important role in the cause of numerous otolaryngologic disorders. Although medical management should remain the mainstay of GER therapy, antireflux surgery provided definitive and successful treatment of potentially life-threatening manifestations of GEROD.

The role of gastro-oesophageal reflux in the aetiology of SIDS.

Gastro-oesophageal reflux (GOR) has been identified as a possible cause of SIDS. Several features of GOR unique to infants presenting with apparent life-threatening events (ALTEs) have led to its 'pathogenic' definition. One is that the life-threatening apnoea itself is initiated by GOR, another is that the ALTE relates to prolonged reflux during sleep, in a vulnerable sleep-state, and finally that the ALTE relates to excessive quantities of GOR. The presumption of GOR 'pathology' as a cause of SIDS however, is questionable in these susceptible infants for three reasons: firstly, GOR is physiological and occurs in most infants; secondly, there is no general consensus on what constitutes normal physiological reflux, and thirdly, variation in the recording technique and methods of data analysis and interpretation may account for the differences between study groups. It seems likely therefore if GOR is implicated in SIDS, additional factors are involved. Under certain circumstances, physiological GOR may trigger life-threatening apnoea in apparently healthy infants, that leads to SIDS. One mechanism that could explain such a death is reflex apnoea by stimulation of laryngeal chemoreceptors (LCR) during sleep. The conditions under which this could be fatal are the occurrence of gastric contents refluxed to the level of the pharynx during sleep, in the young infant who has depressed swallowing and arousal. That is, the occurrence of GOR to the level of the pharynx during sleep, an infrequent event that is usually innocuous, could be converted to a fatal event if swallowing is impaired and arousal depressed, by a variety of mediating factors such as prone sleeping, prematurity, sedatives, seizures or upper respiratory tract infections. The identification of LCR responses, particularly in prone sleeping and premature infants provide further evidence that this mechanism may be implicated in the aetiology of SIDS in apparently healthy infants.

Laryngeal C-fiber afferents are not involved in the apneic response to laryngeal wood smoke in anesthetized rats

Laryngeal exposure to wood smoke in rats evokes a reflex apnea which is mediated through superior laryngeal afferents ( J. Appl. Physiol. 83: 723–730, 1997). To study the role of laryngeal C-fiber afferents in eliciting this response, capsaicin aerosol (0.05 – 0.2 μg ml ) and 5 ml of wood smoke were delivered separately into a functionally isolated larynx of anesthetized Sprague-Dawley rats at a constant flow rate of 1.4 ml s , while animals breathed spontaneously. Studies were repeated after either an intravenous injection of ruthenium red (2 mg kg ; n = 8), a perineural capsaicin treatment (200 μg ml for 5 min; n = 8) of the superior laryngeal nerves, or a perineural sham treatment (n = 8); Ruthenium red inhibits the stimulation of afferent C-fiber nerve endings by capsaicin, whereas perineural capsaicin treatment selective blocks the conduction of C-fiber afferents. Either ruthenium red or perineural capsaicin treatment abolished the apneic response to laryngeal capsaicin, but did not significantly affect the apneic response to laryngeal wood smoke. Furthermore, the apneic responses to both types of irritants were not significantly altered by perineural sham treatment, yet were completely eliminated by a subsequent denervation of superior laryngeal nerves. Our results suggest that superior laryngeal C-fiber afferents are not involved in eliciting the reflex apneic response to laryngeal wood smoke in anesthetized rats. It is speculated that this response may result mainly from the stimulation of myelinated afferents, possibly laryngeal irritant receptors.

Congenital vascular anomalies and persistent respiratory symptoms in children

Congenital cardiovascular anomalies are a rare but treatable cause of stridor in the paediatric population. Despite this, we and the authors of other series have found a delay in referral for endoscopic diagnosis. The duration of symptoms prior to endoscopic diagnosis ranged from 6 weeks to 10 years. It has been estimated that up to 3% of the population have congenital anomalies of the aortic arch complex and we feel that many patients currently being diagnosed as having recurrent croup or atypical asthma must be excluded from this group. We had 16 cases of congenital vascular anomalies causing tracheobronchial compression. Fifteen were due to innominate artery compression and one was due to a double aortic arch. Presenting symptoms included stridor (100%), persistent cough (75%), chronic dyspnoea (75%), reflex apnoea (60%), recurring respiratory tract infections (56%) and dysphagia (25%). Direct laryngoscopy and bronchoscopy was diagnostic in all cases and is our investigation of choice. Eleven underwent aortopexy (69%), one had division of the non-dominant aortic arch (6%) and four were managed conservatively (25%). They were followed for up to 9 years post-operatively and 75% had complete resolution of their symptoms. We feel that only a high clinical index of suspicion will enable these potentially fatal anomalies to be diagnosed.

Respiratory control during upper airway infection mechanism for prolonged reflex apnoea and sudden infant death with special reference to infant sleep position.

The mortality rate of sudden infant death syndrome (SIDS) has been dramatically reduced after the supine sleeping position was recommended by health authorities. Concomitant with the decline in overall mortality rate, a marked attenuation of the seasonal distribution has been observed. So far, neither a satisfactory explanation of the previously noted seasonal variation, nor a generally accepted explanation for the preventive effect of supine sleeping position has been presented. Conceivably either the effect of some yet unidentified risk factor for sudden unexpected death in infancy was more prevalent during the dark and cold months of the year during the period when infants generally slept prone, or the effect of the risk factor(s) was more potent in the prone sleeping infant. Prolonged apnoea in infancy may lead to hypoxia, bradycardia and circulatory collapse. Reflex apnoea can be elicited by stimulation of chemoreceptors in the upper airway. The cardio-respiratory response to receptor stimulation is reinforced during a respiratory tract infection. Based on our own and others' experimental data, it is suggested that the reduction in sudden infant mortality rate and in particular the attenuation of the seasonal variation is in part an effect of the reduced likelihood of laryngeal chemoreceptors being stimulated by stagnated airway secretions during upper airway tract infection in the supine sleeping infant.

Respiratory control during upper airway infection: Mechanism for prolonged reflex apnoea and sudden infant death with special reference to infant sleep position

The mortality rate of sudden infant death syndrome (SIDS) has been dramatically reduced after the supine sleeping position was recommended by health authorities. Concomitant with the decline in overall mortality rate, a marked attenuation of the seasonal distribution has been observed. So far, neither a satisfactory explanation of the previously noted seasonal variation, nor a generally accepted explanation for the preventive effect of supine sleeping position has been presented. Conceivably either the effect of some yet unidentified risk factor for sudden unexpected death in infancy was more prevalent during the dark and cold months of the year during the period when infants generally slept prone, or the effect of the risk factor(s) was more potent in the prone sleeping infant. Prolonged apnoea in infancy may lead to hypoxia, bradycardia and circulatory collapse. Reflex apnoea can be elicited by stimulation of chemoreceptors in the upper airway. The cardio-respiratory response to receptor stimulation is reinforced during a respiratory tract infection. Based on our own and others’ experimental data, it is suggested that the reduction in sudden infant mortality rate and in particular the attenuation of the seasonal variation is in part an effect of the reduced likelihood of laryngeal chemoreceptors being stimulated by stagnated airway secretions during upper airway tract infection in the supine sleeping infant.

Trigeminal and carotid body inputs controlling vascular resistance in muscle during post-contraction hyperaemia in cats.

1. In anaesthetized cats, the effects of stimulation of the receptors in the nasal mucosa and carotid body chemoreceptors on vascular resistance in hindlimb skeletal muscle were studied to see whether the responses were the same in active as in resting muscle. The measurements of vascular resistance were taken, first, in resting muscle, and second, in the immediate post-contraction hyperaemic phase that followed a 30 s period of isometric contractions. 2. Stimulation of the receptors in the nasal mucosa caused reflex apnoea and vasoconstriction in muscle. The latter response was attenuated when the test was repeated during post-contraction hyperaemia. 3. Stimulations of the carotid bodies were made during a period of apnoea evoked reflexly by electrical stimulation of both superior laryngeal nerves. This apnoea prevented any effects of changes in respiration on the carotid body reflex vascular responses. Stimulation of the carotid bodies evoked hindlimb muscle vasoconstriction. In the post-contraction hyperaemic period, the response was reduced or abolished. A similar attenuation of the reflex vasoconstrictor responses occurred in decentralized muscles stimulated through their motor roots in the cauda equina. 4. Evidence is presented that the attenuation of the vasoconstrictor responses evoked by the two reflexes is a phenomenon localized to the contracting muscles themselves resulting from an interaction between sympathetic neuronal activity and the local production of metabolites. 5. The results are discussed in relation to the metabolic needs of tissues in relation to asphyxial defence mechanisms such as occur in the diving response.

Modulation of the vagal bradycardia evoked by stimulation of upper airway receptors by central 5-HT1 receptors in anaesthetized rabbits.

1. The effects of central application of 5-HT1A and 5-HT1B/1D receptor ligands on the reflex bradycardia, apnoea, renal sympathoexcitation and pressor response evoked by stimulating upper airway receptors with smoke in atenolol-pretreated anaesthetized rabbits were studied. 2. Intracisternal administration of the 5-HT1A receptor antagonists WAY-100635 (100 microg kg(-1)) and (-)pindolol (100 microg kg(-1)) significantly reduced the smoke-induced bradycardia, attenuated the pressor response and in the case of (-)pindolol, sympathetic nerve activity. The same dose of WAY-100635 i.v. was without effect. 3. Buspirone (200 microg kg(-1), i.c.) potentiated the reflex bradycardia. This action was prevented if the animals were pretreated with WAY-100635 (100 Hg kg(-1), i.v.) 4. (+)8-OH-DPAT (25 microg kg(-1), i.c.) attenuated the evoked bradycardia, pressor response, apnoea and renal sympathoexcitation. The attenuation of the apnoea and renal sympathoexcitation, but not the bradycardia or pressor response was prevented in animals pretreated with WAY-100635 (100 microg kg(-1), i.v.). The attenuation of the reflex bradycardia and the reduction in the renal sympathoexcitation were reduced by pretreatment with the 5-HT1B/1D receptor antagonist GR127935 (100 microg kg(-1), i.v.). 5. In WAY-100635 (100 microg kg(-1), i.v.) pretreated animals, sumatriptan (a 5-HT1B/1D receptor agonist) reduced the reflex bradycardia and the pressor response. The 5-HT1B/1D receptor antagonist GR127935 (20 microg kg(-1), i.c. or 100 microg kg(-1), i.v.) had no effect on the reflex responses. 6. In conclusion, the present data are consistent with the hypothesis that activation of central 5-HT1A receptors potentiate whilst activation of 5-HT1B/1D receptors attenuate the reflex activation of cardiac preganglionic vagal motoneurones evoked by stimulation of upper airway receptors with smoke in rabbits.

Indian red scorpion ( Buthus tamulus) venom-induced augmentation of cardiac reflexes is mediated through the mechanisms involving kinins in urethane anaesthetized rats

The mechanism underlying the action of Indian red scorpion ( Buthus tamulus; BT) venom on cardiac reflexes was examined in urethane anaesthetized adult albino rats of either sex. Intravenous injection of phenyldiguanide (PDG) produced reflex hypotension, bradycardia and apnea lasting for >60 s. The PDG-induced reflex responses (blood pressure, heart rate and respiration) were augmented greatly (magnitude and time period) after exposure to BT venom (100 μg/kg, i.v., for 30 min). However, there were no great alterations in resting blood pressure, heart rate and respiratory rate. Pretreatment with kallikrein–kinin inhibitor (aprotinin; 6000 kallikrein inactivating unit, i.v.) blocked the BT venom-induced augmentation of PDG reflex response. Further, pretreatment with indomethacin (prostaglandin synthetase inhibitor; 10 mg/kg) and heparin (1000 units/kg) also blocked the venom-induced potentiation of the reflex. Captopril (15 mg/kg), an agent known to increase endogenous kinins, also augmented the PDG induced-reflex to the same extent as in BT envenomed rats. The captopril-induced augmentation of the reflex was blocked by aprotinin and heparin, but not by indomethacin. The results indicate that kinins and prostaglandins are involved in the BT venom-induced augmentation of the cardiac reflexes.

Role of vagal fibers in the hypoxia-induced increases in end-expiratory lung volume and diaphragmatic activity.

The possible role of pulmonary C fibers in the hypoxia-induced concomitant increases in end-expiratory lung volume (EELV) and in the activity of the diaphragm at the end of expiration (DE) were evaluated by measuring the effects of hypoxia (10% O2) on ventilation, EELV, and DE in eight chloralose-urethan anesthetized rats. Recordings were made before and after blocking vagal C fibers and after bilateral vagotomy. C-fiber conduction was blocked by applying capsaicin perineurally to the cervical vagi. The efficiency of C-fiber blockade was tested with intravenous capsaicin and its selectivity by the Hering-Breuer reflex. Perineural capsaicin abolished the reflex apnea induced by intravenous capsaicin and transiently reduced Hering-Breuer reflex. Perineural capsaicin affected neither ventilation, DE, and EELV in air nor the hypoxia-induced increases in these parameters. Vagotomy caused the typical changes of breathing pattern in air, but the ventilatory response to hypoxia was unchanged. Vagotomy performed during hypoxia resulted in large decreases in DE and EELV. Hypoxia increased DE and EELV in vagotomized rats but less than in intact rats. We conclude that the hypoxia-induced increases in EELV and diaphragmatic activity are probably not mediated by vagal C fibers and that vagal afferents are involved but not fully responsible for this phenomenon.

Laryngeal reflex apnea is blunted during and after hindlimb muscle contraction in sheep.

This study was carried out on seven chloralose-anesthetized sheep and was designed to investigate the role of muscular afferent fiber stimulation on the duration of reflex apnea triggered by laryngeal stimulation (LS). In six animals, injection of distilled water onto the laryngeal mucosa provoked a 15.7 +/- 1.0 s (mean +/- SE) apnea associated with a rise in systemic blood pressure (+7 +/- 0.8 Torr). Electrically induced contractions (EIC) of the hindlimb muscles doubled the metabolic rate and ventilation and reduced the duration of the apnea produced by LS to 7.4 +/- 1.0 s (P < 0.01). Apnea duration was still reduced during the first minute after the cessation of EIC (7.2 +/- 1.1 s, P < 0.01) but returned to control after a 5-min recovery period (16.7 +/- 1.6 s). The apnea triggered by LS was also reduced during EIC when the venous return was impeded by occluding the inferior vena cava (5.2 +/- 1.1 s, P < 0.01), despite a profound hypocapnia (20.7 +/- 0.3 Torr). The duration of apnea was not significantly affected (14.2 +/- 1.4 s) by breathing a 6% CO2-14% O2 in N2 gas mixture that roughly mimicked the alveolar gas composition when the apnea turned off. These results suggest that chemical drive has a negligible role in the fast reinitiation of breathing after LS during muscular stimulation. Stimulation of muscle afferent fibers does, however, appear to be a potent source of ventilatory reflexes capable of counteracting the inhibition of breathing resulting from laryngeal stimulation. Conversely, it is postulated that any reduction in somatic afferent traffic during this type of reflex apnea, including that resulting from the LS-induced systemic vasoconstriction, may delay the termination of apnea.

Respiratory syncytial virus infection enhances the response to laryngeal chemostimulation and inhibits arousal from sleep in young lambs.

To evaluate the effect of respiratory syncytial virus (RSV) infection on the response to laryngeal chemostimulation (LCS) with water, five lambs were inoculated with human RSV and three lambs were given control media at an age of 3-5 days. During RSV infection, LCS resulted in increased inhibition of minute ventilation and delayed recovery of regular breathing. Sleep further increased the response, and arousal was less likely to occur in active sleep. Two of the five infected lambs needed resuscitation after LCS when arousal was absent. Histological studies showed bronchiolitis and pneumonitis. Laryngeal tastebud morphology was unchanged at 8 days after inoculation. However, infected lambs had disrupted tastebuds 4-6 weeks after infection. Failure to arouse and to terminate reflex apnea may play a role in the pathogenesis of the sudden infant death syndrome associated with respiratory tract infection.

Reflex apnoea response and inflammatory mediators in infants with respiratory tract infection.

The reflex apnoea response to water stimulation was evaluated in infants with respiratory syncytial virus (RSV) infection and compared to the response in non-infected infants who had sustained an apparent life-threatening event (ALTE) or were siblings of infants who had died of sudden infant death syndrome (SIDS). RSV-infected infants had a significantly (p < 0.05) reinforced reflex apnoea response compared with non-infected infants. There was a significant negative correlation between the concentration of interleukin 1 beta (IL-I beta) in pharyngeal secretions and the duration of apnoea (p < 0.01). Increased clinical severity was, however, associated with high (> 5.000 pg ml-1) concentrations of IL-1 beta. There was no correlation between apnoea and interleukin 6. These findings may be relevant for the understanding of why apnoea may be the presenting symptom of RSV infection, and offer an explanation of why a proportion of SIDS cases has a history of mild respiratory tract symptoms prior to death.

Central chemosensitivity affects respiratory muscle responses to laryngeal stimulation in the piglet

Stimulation of laryngeal afferent fibers triggers reflex apnea, which can be very long in the neonatal period. The purpose of this study was twofold: 1) to determine the effect of superior laryngeal nerve (SLN) stimulation on expiratory as well as inspiratory muscle activity and 2) to compare the respiratory response to SLN stimulation under conditions that would appear to alter the level of central chemosensitivity in anesthetized spontaneously breathing piglets. In protocol 1, we measured electromyogram (EMG) responses from the diaphragm (DIA), triangularis sterni, and transversus abdominis muscles to graded SLN stimulation; in protocol 2, we compared the DIA response to different levels of SLN stimulation during normocapnia, hypercapnia, and cooling of the ventrolateral medullary surface (VMS). SLN stimulation performed during normocapnia caused significantly greater inhibition of both expiratory muscles (triangularis sterni and transversus abdominis) than of the DIA. During hypercapnia, laryngeal stimulation-induced inhibition of all three muscles was significantly diminished, and the degree of inhibition for the three muscles became equivalent. Inhibition of the DIA EMG was significantly greater with SLN stimulation during VMS cooling than with a VMS temperature of 38 degrees C. We conclude that the magnitude of respiratory inhibition induced by laryngeal stimulation during early postnatal life is inversely related to the level of central chemical input and speculate that functional deficiency of structures located in the VMS may contribute to potentially life-threatening apnea in infants.

Nonvagal reflex apnea in the newborn kitten and during the early postnatal period.

The aim of this work was to study the nonvagal mechanisms which might induce apneic reflexes in kittens. Experiments were performed on spontaneously breathing animals (19 kittens at different postnatal ages). Animals were anesthetized (halothane) or decerebrated by transcollicular section of the brainstem. Weakly nociceptive cutaneous stimulations and various oral stimulations were administered in all animals. In 10 kittens, one of the lingual nerves was stimulated electrically. In 3 decerebrate kittens the effects of serotonin on respiratory activity and on muscles innervated by the hypoglossal nerve were studied. All the stimulations produced apneas of variable duration, and expiratory reinforcement was associated with activation of pretracheal muscles. Similar effects were observed after applying serotonin to the floor of the 4th ventricle. Thus serotonin may be involved in the mechanisms that cause some apneas.

Prolonged hypoxemia enhances and acute hypoxemia attenuates laryngeal reflex apnea in young lambs.

To determine the influence of an altered carotid body function on the laryngeal chemoreflex (LCR) response, reflex apnea was induced by laryngeal water stimulation during normoxia or acute hypoxia in unanesthetized awake lambs in which the ventilatory response to acute hypoxia was attenuated by prolonged postnatal hypoxemia. Prolonged hypoxemia (H) was induced in seven lambs for 12 d after birth through exposure to 0.10 fraction of inspired oxygen. Five control lambs were kept in 0.21 fraction of inspired oxygen. Studies were performed repeatedly during the first 7 wk after birth. The ventilatory response to LCR stimulation, expressed as a percent decrease in minute ventilation, was tested in 0.21, 0.14, and 0.10 fraction of inspired oxygen. H after birth resulted in a markedly increased inhibition of ventilation in response to LCR stimulation and postponed the age-related decrease in LCR response. A potential failure to recover from apnea occurred only in the H lambs, and in these lambs there was a significantly greater requirement for mechanical ventilation after LCR stimulation. Acute hypoxemia preceding LCR stimulation significantly attenuated the ventilatory response in both control and H lambs, with a stronger effect in the H lambs. There was no difference between the two groups in heart rate response to LCR stimulation. Acute hypoxemia significantly augmented reflex bradycardia in the H lambs. These results show that there is a relationship between H immediately after birth--which is known to delay resetting of carotid chemoreceptors--and augmented ventilatory inhibition in response to LCR stimulation. They do not confirm the theory that acute hypoxia reinforces reflex apnea.

Pulmonary stretch receptor afferents activate excitatory amino acid receptors in the nucleus tractus solitarii in rats.

1. The goal of the present study was to identify potential neurotransmitter candidates in the Breuer-Hering (BH) reflex pathway, specifically at synapses between the primary afferents and probable second-order neurones (pump cells) within the nucleus tractus solitarii (NTS). We hypothesized that if activation of specific receptors in the NTS is required for production of the BH reflex, then (1) injection of the receptor agonist(s) would mimic the reflex response (apnoea), (2) injection of appropriate antagonists would impair the apnoea produced by either lung inflation or agonist injection, and (3) second-order neurones in the pathway would be excited by either lung inflation or agonists while antagonists would prevent the response to either. 2. Studies were carried out either in spontaneously breathing or in paralysed, thoracotomized and ventilated rats in which either diaphragm EMG or phrenic nerve activity, expired CO2 concentration and arterial pressure were continuously monitored. The BH reflex was physiologically activated by inflating the lungs. 3. Pressure injections (0.03-15 pmol) of selective excitatory amino acid (EAA) receptor agonists, quisqualic acid (Quis) and N-methyl-D-aspartic acid (NMDA) into an area of the NTS shown previously to contain neurones required for production of the BH reflex produced dose-dependent apnoeas that mimicked the response to lung inflation. Injection of substance P (0.03-4 pmol) did not alter baseline respiratory pattern. 4. Injections of the EAA antagonists, kynurenic acid (Kyn; 0.6-240 pmol), 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) or 6,7-dinitroquinoxaline-2,3-dione (DNQX) into the BH region of the NTS reversibly impaired the apnoea produced by lung inflation. All three antagonists reduced or abolished the apnoeas resulting from injection of Quis or NMDA, and slowed baseline respiratory frequency. In contrast, injections of the highly selective NMDA receptor antagonist, D-2-amino-5-phosphonovaleric acids (AP5), in doses sufficient to block the apnoeic response to NMDA, neither altered the reflex apnoea evoked by lung inflation nor the baseline respiratory pattern. 5. Pump cells located within the BH region were excited by pressure injections of the broad spectrum EAA agonist, DL-homocysteic acid (DLH). Kyn reversibly blocked the excitation of pump cells in response to either lung inflation or DLH injection. 6. These findings suggest that EAAs mediate primary afferent excitation of second-order neurones in the Breuer-Hering reflex pathway, primarily through the activation of non-NMDA EAA receptor subtypes.