RESUMEN
The neural networks controlling vital functions such as breathing are embedded in the brain, the neural and chemical environment of which changes with state, i.e., wakefulness, non-rapid eye movement (non-REM) sleep and REM sleep, and with commonly administered drugs such as anaesthetics, sedatives and ethanol. One particular output from the state-dependent chemical brain is the focus of attention in this paper; the motor output to the muscles of the tongue, specifically the actions of state-dependent modulators acting at the hypoglossal motor pool. Determining the mechanisms underlying the modulation of the hypoglossal motor output during sleep is relevant to understanding the spectrum of increased upper airway resistance, airflow limitation, hypoventilation and airway obstructions that occur during natural and drug-influenced sleep in humans. Understanding the mechanisms underlying upper airway dysfunction in sleep-disordered breathing is also important given the large and growing prevalence of obstructive sleep apnea syndrome which constitutes a major public health problem with serious clinical, social and economic consequences.
Asunto(s)
Nervio Hipogloso/fisiología , Neuronas Motoras/fisiología , Músculos Faríngeos/fisiología , Fases del Sueño/fisiología , Lengua/fisiología , Resistencia de las Vías Respiratorias/efectos de los fármacos , Resistencia de las Vías Respiratorias/fisiología , Animales , Humanos , Hipnóticos y Sedantes/farmacología , Bulbo Raquídeo/citología , Bulbo Raquídeo/fisiología , Neuronas Motoras/efectos de los fármacos , Vías Nerviosas/fisiología , Apnea Obstructiva del Sueño/patología , Apnea Obstructiva del Sueño/fisiopatología , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Several epidemiological studies have identified obstructive sleep apnea (OSA) as a risk factor for systemic hypertension, but a direct etiologic link between the two disorders has not been established definitively. Furthermore, the specific physiological mechanisms underlying the association between OSA and systemic hypertension have not been identified. The purpose of this study was to systematically examine the effects of OSA on daytime and nighttime blood pressure (BP). We induced OSA in four dogs by intermittent airway occlusion during nocturnal sleep. Daytime and nighttime BP were measured before, during, and after a 1-3-mo long period of OSA. OSA resulted in acute transient increases in nighttime BP to a maximum of 13.0+/-2.0 mmHg (mean+/-SEM), and eventually produced sustained daytime hypertension to a maximum of 15.7+/-4.3 mmHg. In a subsequent protocol, recurrent arousal from sleep without airway occlusion did not result in daytime hypertension. The demonstration that OSA can lead to the development of sustained hypertension has considerable importance, given the high prevalence of both disorders in the population.
Asunto(s)
Presión Sanguínea/fisiología , Hipertensión/complicaciones , Hipertensión/etiología , Síndromes de la Apnea del Sueño/complicaciones , Animales , Perros , Femenino , Masculino , Privación de Sueño , Vigilia/fisiologíaRESUMEN
Brainstem respiratory neurons innervate the hypoglossal motor nucleus which in turn transmits this respiratory drive signal to the genioglossus muscle of the tongue. The mechanism of this transmission is important to help maintain an open airspace for effective breathing, and is thought to rely almost exclusively on non-N-methyl-d-aspartate (non-NMDA) glutamate receptor activation during respiration. However those studies were performed in slices of medulla from neonatal animals in vitro which may have led to an underestimation of the contribution of NMDA glutamate receptors that may normally operate in intact preparations. The current study tests the hypothesis that both NMDA and non-NMDA receptors contribute to respiratory drive transmission at the hypoglossal motor nucleus in vivo. Experiments were performed in urethane-anesthetized and tracheotomized adult Wistar rats in which vagus nerves were either intact or sectioned. In the presence of augmented genioglossus activity produced by vagotomy, microdialysis perfusion of either an NMDA receptor antagonist (D-2-amino-5-phosphonovaleric acid, 0.001-10 mM) or a non-NMDA receptor antagonist (6-cyano-7-nitroquinoxaline-2, 3-dione disodium salt, 0.001-1 mM) to the hypoglossal motor nucleus reduced respiratory-related genioglossus activity in a dose-dependent manner (P < 0.001) indicating that both NMDA and non-NMDA glutamate receptors are necessary for transmission of the respiratory drive signal to genioglossus muscle in vivo. Similar effects were observed in the vagus nerve intact rats. Further experiments demonstrated that each delivered antagonist had effects that were specific to its respective receptor. Regression analysis also revealed that the activity of both NMDA and non-NMDA receptors at the hypoglossal motor nucleus is related to levels of the prevailing respiratory drive. These results show that both NMDA and non-NMDA glutamate receptors at the hypoglossal motor nucleus are involved in transmission of the respiratory drive signal to genioglossus muscle in vivo.
Asunto(s)
Nervio Hipogloso/fisiología , Bulbo Raquídeo/fisiología , Neuronas Motoras/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Fenómenos Fisiológicos Respiratorios/efectos de los fármacos , Lengua/inervación , 2-Amino-5-fosfonovalerato/farmacología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Animales , Antagonistas de Aminoácidos Excitadores/farmacología , Líquido Extracelular/efectos de los fármacos , Líquido Extracelular/metabolismo , Ácido Glutámico/metabolismo , Nervio Hipogloso/efectos de los fármacos , Masculino , Bulbo Raquídeo/efectos de los fármacos , Microdiálisis , Microinyecciones , Neuronas Motoras/efectos de los fármacos , Músculo Esquelético/inervación , Músculo Esquelético/fisiología , Ratas , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Vagotomía , Nervio Vago/cirugía , Traumatismos del Nervio VagoRESUMEN
Microinjection of a cholinergic agonist, carbachol, into the pontine reticular formation of chronically instrumented intact or acutely decerebrate rats and cats has been used extensively to study rapid eye movement sleep mechanisms. In this study, we sought to develop a reduced carbachol model of rapid eye movement sleep-like neural events exhibiting multiple physiological markers of this state, and allowing for the use of invasive electrophysiological techniques. Accordingly, we investigated whether pontine carbachol could produce rapid eye movement sleep-like motor atonia and electrocortical changes in urethane-anaesthetized rats. We recorded cortical and hippocampal electroencephalograms and genioglossus and inspiratory intercostal muscle activities in 13 urethane-anaesthetized, spontaneously breathing, tracheotomized and vagotomized rats. In steady-state periods with high-voltage/low-frequency electroencephalogram activity, carbachol microinjections (15-40 nl, 10 mM) were placed in the medial pontine reticular formation. In 12 rats, carbachol elicited episodes of stereotyped hypotonia of genioglossus but not intercostal muscle activity, typical of rapid eye movement sleep, with a latency and duration of 2.2+/-0.3min (mean+/-S.E.M.) and 11.0+/-2.9 min, respectively. In four of these rats, also similar to rapid eye movement sleep, the major suppression of genioglossus activity (-74+/-9%) was accompanied by electroencephalogram desynchronization, appearance of hippocampal theta rhythm, and a respiratory rate increase (+ 14+/-3%). In the remaining eight rats, the stereotyped suppression of genioglossus activity (-48+/-3%) occurred without electroencephalogram desynchronization and hippocampal theta, and was accompanied by a respiratory rate decrease (-6+/-2%); a pattern of response typical of decerebrate animals. Within a rat, similar patterns of response to repeated carbachol injections at the same anatomical site were obtained. Pontine atropine prevented responses to subsequent carbachol injections. Thus, in urethane-anaesthetized rats, pontine carbachol consistently produced a differential suppression of pharyngeal versus respiratory pump muscle activity, and in a subset of animals, this was also accompanied by cortical and hippocampal electrographic changes typical of rapid eye movement sleep. This shows that complex and stereotyped neuronal events underlying both ascending and descending signs of rapid eye movement sleep can be pharmacologically activated under general anaesthesia. Such a reduced preparation may be useful for studies into the central neuronal mechanisms underlying generation of rapid eye movement sleep; particularly for studies requiring techniques that are difficult to implement in intact, naturally sleeping animals. The acceleration of the respiratory rate observed only when carbachol induced electroencephalogram desynchronization suggests that neural events associated with electrocortical changes contribute to the respiratory rate increases observed in natural rapid eye movement sleep.
Asunto(s)
Carbacol/farmacología , Agonistas Muscarínicos/farmacología , Puente/fisiología , Sueño REM/efectos de los fármacos , Anestesia , Animales , Atropina/farmacología , Carbacol/administración & dosificación , Sincronización Cortical/efectos de los fármacos , Electroencefalografía/efectos de los fármacos , Masculino , Microinyecciones , Movimiento/efectos de los fármacos , Agonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/farmacología , Puente/anatomía & histología , Puente/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Mecánica Respiratoria/efectos de los fármacos , UretanoRESUMEN
The genioglossus muscle is involved in the maintenance of an open airway for effective breathing. Inhibitory neurotransmitters may be responsible for the major suppression of hypoglossal motor output to genioglossus muscle that occurs in certain behaviours such as rapid-eye-movement sleep. There is evidence for GABA(A) receptor-mediated inhibition of hypoglossal motoneurons in vitro. However, comparable studies have not been performed in vivo and the interactions of such mechanisms with integrative reflex respiratory control have also not been determined. Urethane-anaesthetised, tracheotomized and vagotomized rats were studied whilst diaphragm and genioglossus muscle activities, blood pressure and the electroencephalogram were recorded. Microdialysis probes were implanted into the hypoglossal motor nucleus, with sites verified by histology. Genioglossus responses to microdialysis perfusion of muscimol (GABA(A) agonist: 0, 0.1, 1 and 10 microM in artificial cerebrospinal fluid) were recorded at inspired CO(2)s of 0, 5 and 7.5% in six rats. Responses to bicuculline (GABA(A) antagonist, 0, 1, 10, 100 and 1000 microM) were also studied in six rats with and without CO(2) stimulation. Genioglossus activity decreased with muscimol (P<0.0001), with major suppression at 1 and 10 microM during air breathing (decreases=70.2% and 92.8%, P<0.005). Genioglossus activity increased with CO(2) (P=0.003), but genioglossus activation with 5 and 7.5% CO(2) were almost abolished with 10-microM muscimol. Responses were specific to genioglossus muscle as there were no changes in diaphragm, respiratory rate or blood pressure with muscimol (P>0.144). Antagonism of GABA(A) receptors increased genioglossus activity (P<0.001). These results show that GABA(A) receptor stimulation at the hypoglossal motor nucleus suppresses both genioglossus muscle tone and activity in the presence of reflex stimulation produced by hypercapnia. Recruitment of such mechanisms may contribute to the major suppression of genioglossus activity observed with and without CO(2) stimulation in behaviours such as rapid-eye-movement sleep.
Asunto(s)
Diafragma/fisiología , Hipercapnia , Nervio Hipogloso/fisiología , Neuronas Motoras/fisiología , Receptores de GABA-A/fisiología , Músculos Respiratorios/fisiología , Animales , Bicuculina/farmacología , Presión Sanguínea/efectos de los fármacos , Electroencefalografía , Electromiografía , Agonistas del GABA/farmacología , Antagonistas del GABA/farmacología , Nervio Hipogloso/efectos de los fármacos , Masculino , Microdiálisis , Neuronas Motoras/efectos de los fármacos , Muscimol/farmacología , Ratas , Ratas Wistar , Reflejo/fisiología , Respiración/efectos de los fármacos , Músculos Respiratorios/efectos de los fármacos , Traqueotomía , VagotomíaRESUMEN
Obstructive sleep apnea is a common breathing problem that results in recurrent episodes of nighttime hypoxemia, hypercapnia, bradytachycardia, and hypertension, as well as sleep disturbance and daytime hypersomnolence. The obstruction is located in the oropharynx and is caused by hypotonia of the pharyngeal dilator muscles. In this paper, the various mechanisms affecting motor output to the upper airway muscles are reviewed. In particular, the respiratory function of the pharyngeal dilator muscles, the various reflex mechanisms underlying their control, and the effects of sleep on these mechanisms are discussed. The literature relevant to the central neuronal circuits and neurotransmitters that may be involved in the state-dependent activity of the pharyngeal dilator muscles is also reviewed. In addition to an examination of these basic mechanisms, consideration is given throughout this review as to how these mechanisms may relate to the normal control of pharyngeal patency awake and asleep and how they may be involved in the pathogenesis of obstructive sleep apnea.
Asunto(s)
Músculos Faríngeos/fisiopatología , Síndromes de la Apnea del Sueño/fisiopatología , Carbacol/farmacología , Células Quimiorreceptoras/fisiología , Humanos , Presorreceptores/fisiología , Ventilación Pulmonar , Núcleos del Rafe/efectos de los fármacos , Sueño REM/efectos de los fármacos , Ventiladores de Presión Negativa , VigiliaRESUMEN
Normal spontaneous arousals from sleep are associated with transient increases in blood pressure, heart rate, and ventilation caused by large transient changes in autonomic output. These autonomic changes are out of proportion to obvious physiological need and are in excess of those observed in later periods of quiet wakefulness. This paper discusses some of the mechanisms underlying the cardio-respiratory consequences of arousal from sleep, and discusses why the normal onset of wakefulness may be associated with such large changes in autonomic output.
Asunto(s)
Nivel de Alerta , Sueño REM , Sistema Nervioso Autónomo/fisiología , Presión Sanguínea , Electroencefalografía , Frecuencia Cardíaca , Humanos , Respiración/fisiología , Síndromes de la Apnea del Sueño , VigiliaRESUMEN
This paper summarizes evidence for reflex genioglossus muscle activation by stimuli of negative airway pressure in normal, awake human subjects. Stimuli of negative airway pressure (range -5 to -35 cm H2O) caused activation of the genioglossus muscle. The larger values of negative pressure gave larger responses. Response latencies (median = 34 milliseconds) were much faster than the time for voluntary muscle activation (median = 184 milliseconds), suggesting that the responses were reflex in origin. The reflex nature of the responses was confirmed by studies with local anesthetics. The trigeminal, superior laryngeal and the glossopharyngeal nerves all mediated a component of the responses observed from the upper airway.
Asunto(s)
Presión del Aire , Músculos Faríngeos/inervación , Faringe/fisiología , Reflejo , Vigilia , Electromiografía , Humanos , Faringe/inervación , Ventilación PulmonarRESUMEN
Obstructive sleep apnea (OSA) causes recurrent sleep disruption that is thought to contribute to excessive daytime sleepiness in patients with this disorder. The purpose of this study was to determine the specific effects of OSA on overall sleep architecture in a canine model of OSA. The advantage of this model is that sleep during long-term OSA can be compared to both normal sleep before OSA and recovery sleep after OSA. Studies were performed in four dogs in which sleep-wake state was monitored continuously by a computer that received telemetered EEG and EMG signals. Whenever sleep was detected, the computer sent a signal to close a valve through which the dog breathed; when the dog awoke the occlusion was released. In each dog, data were analyzed from 4 consecutive nights in three phases: a control phase before induction of OSA, a phase during long-term OSA (mean = 85 days, apnea index = 59/hour), and a recovery phase after cessation of OSA. During recovery there was a significant increase in the amount of rapid-eye-movement (REM) sleep compared to the OSA phase (p < 0.01), as well as significant increases in sleep efficiency and decreases in wakefulness (p < 0.01), similar to that reported in OSA patients. The REM rebound during recovery, however, could not be attributed to overall REM deprivation since the amount of REM sleep during the OSA phase was not different from the control phase (p = 0.708). This finding suggests that REM rebound during recovery from OSA is not the result of an overall REM sleep deficit per se. Rather, repeated sleep disruption due to the effects of repetitive apneas and hypoxia may lead to an increased REM sleep drive that manifests itself as a REM sleep rebound during recovery sleep after OSA.
Asunto(s)
Síndromes de la Apnea del Sueño/diagnóstico , Sueño REM/fisiología , Animales , Modelos Animales de Enfermedad , Perros , Electroencefalografía , Electromiografía , Femenino , Masculino , Respiración con Presión Positiva/métodos , Síndromes de la Apnea del Sueño/terapiaRESUMEN
Sleep-disordered breathing is associated with adverse clinical consequences such as daytime sleepiness and hypertension. The mechanisms behind these associations have been studied in animal models, especially rats, but intermittent stimuli such as hypoxia have been applied without reference to sleep-wake states. To determine mechanisms underlying the adverse physiological consequences of stimuli associated with sleep-disordered breathing requires criteria for detection of sleep-wake states on-line to trigger stimuli only in sleep. This study aimed to develop such a system for freely behaving rats. Twelve rats with implanted electroencephalogram and neck electromyogram electrodes were studied in the light and dark phases. Electroencephalogram frequencies in the high (20-30 Hz) and low (2-4 Hz) frequency bands distinguished non-rapid eye movement (REM) sleep, whereas neck electromyogram distinguished REM. Using these parameters in a simple algorithm led to detection accuracies of 94.5 +/- 1.0 (SE) % for wakefulness, 96.2 +/- 0.8% for non-REM sleep, and 92.3 +/- 1.6% for REM compared with blinded human judgment. The algorithm was then used to trigger hypoxic stimuli only in sleep. Because frequency and amplitude analysis is readily performed using a variety of commercial systems, incorporation of these parameters into such an algorithm will facilitate studies investigating mechanisms underlying the physiological consequences of sleep-related respiratory stimuli in a fashion that more effectively models clinical disorders.
Asunto(s)
Hipoxia/fisiopatología , Sueño/fisiología , Vigilia/fisiología , Algoritmos , Animales , Electroencefalografía , Electromiografía , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
This study was designed to determine whether a chemoreceptor-mediated tonic respiratory drive exists below the apneic threshold. Expiratory (triangularis sterni) and inspiratory (diaphragm and parasternal intercostal) electromyographic activities were recorded in three awake relaxed dogs breathing through an endotracheal tube inserted into a permanent tracheostomy. The cervical vagus nerves were cold blocked to avoid the complicating effects of vagal inputs on respiratory activity. During hypocapnia produced by mechanical hyperventilation, expiratory muscle activity converted from rhythmic to tonic discharge when inspiratory muscle activity and spontaneous breathing movements were abolished. In hypocapnia, changes in arterial PCO2 (in hyperoxia) were produced by changing the ventilator rate for steady-state (> 6 min) CO2 stimuli and by disconnecting the ventilator for transient CO2 stimuli. By use of either method, a CO2-mediated drive to the expiratory muscle was consistently observed during hypocapnic apnea. At a constant level of hypocapnia, inhalation of 5% O2 consistently caused the onset of spontaneous breathing; the onset of phasic inspiratory activity was associated with reciprocal inhibition of the tonic expiratory activity. However, inhalation of 10 and 15% O2 caused an inhibition of the tonic expiratory activity, even without the onset of breathing. These results suggest that the response threshold of the respiratory chemoreceptors is lower than the apneic threshold and that a chemoreceptor-mediated tonic respiratory drive persists during apnea.
Asunto(s)
Apnea/fisiopatología , Periodicidad , Respiración/fisiología , Animales , Arterias , Dióxido de Carbono/sangre , Perros , Electromiografía , Hiperventilación/fisiopatología , Hipocapnia/sangre , Hipocapnia/fisiopatología , Bloqueo Nervioso , Presión Parcial , Respiración Artificial , Músculos Respiratorios/fisiología , Nervio VagoRESUMEN
To determine the immediate effects of arousal from non-rapid-eye-movement (non-REM) sleep on cardiac sympathetic and parasympathetic activities, six dogs were studied breathing through an endotracheal tube inserted into a chronic tracheostomy. Mean heart rates (HRs) during non-REM sleep were compared with 1) awake periods immediately after spontaneous arousals (ARs) and 2) later periods of stable relaxed wakefulness (RW). During spontaneous breathing, HR increased after AR (mean = 31.0%; P < 0.001) and in RW (mean = 7.6%; P < 0.001). To avoid the confounding influence of changes in breathing pattern, lung volume, and blood gases accompanying AR on HR, further studies were performed during constant mechanical hyperventilation that eliminated spontaneous breathing. In this condition, HR still increased after AR (mean = 29.9%; P < 0.001) and in RW (mean = 5.7%; P < 0.001), suggesting that the HR increases could be mediated by an effect of the state change per se on autonomic activity. This interpretation was confirmed when the HR increases were essentially abolished by combined cardiac sympathetic and parasympathetic block. In contrast, parasympathetic block alone did not prevent the HR increases after AR (mean = 12.2%; P < 0.001) or in RW (mean = 12.3%; P < 0.001), whereas sympathetic block alone almost abolished the HR increases in RW (mean = 3.6%) but did not prevent the HR increases during AR (mean = 30.2%; P < 0.001). The results show that, compared with non-REM sleep, AR is associated with acute cardiac sympathetic activation and parasympathetic withdrawal, whereas stable RW is associated mainly with sympathetic activation. These effects may have clinical relevance to the cardiovascular sequelae of breathing disorders that cause repetitive arousals from sleep.
Asunto(s)
Apnea/fisiopatología , Nivel de Alerta/fisiología , Sistema de Conducción Cardíaco/fisiopatología , Sueño , Animales , Perros , Frecuencia Cardíaca , Bloqueo Nervioso , Ruido , Sistema Nervioso Parasimpático/fisiología , Respiración , Respiración Artificial , Fases del Sueño , Sistema Nervioso Simpático/fisiología , VigiliaRESUMEN
The aim of this study was to determine the mechanism(s) responsible for the persistence of respiratory sinus arrhythmia (RSA) during central apnea. In five awake dogs, heart rate (HR) was recorded during constant mechanical ventilation (MV) and during central apneas produced by cessation of MV. For each of 10 control ventilator cycles before MV was stopped, instantaneous HR was plotted against the time from the onset of lung inflation; the fundamental and first harmonic of a sine wave (at the ventilator frequency) was then fitted to the HR data. For the control cycles, the mean r2 from the curve fits was 0.57 +/- 0.07, showing that a significant component of the HR variability was linked to the ventilator cycle. After MV was stopped, RSA persisted and only by the third "phantom" ventilator cycle during apnea had the degree of fit consistently decreased compared with control dogs (P < 0.02). The persistence of ventilator-linked RSA at the onset of central apnea supports the concept of a "memory" in the respiratory system. Toward the end of central apnea, HR variability reappeared and had the periodicity and rhythmic profile of RSA on 81% of occasions. The presence of RSA-like activity toward the end of central apnea suggests that subthreshold rhythmic respiratory-related activity may be present even before the onset of detectable lung volume changes.
Asunto(s)
Arritmia Sinusal/fisiopatología , Frecuencia Cardíaca/fisiología , Síndromes de la Apnea del Sueño/fisiopatología , Animales , Perros , Hipocapnia/fisiopatología , Respiración/fisiología , Factores de TiempoRESUMEN
Recurrent sleep-related hypoxia occurs in common disorders such as obstructive sleep apnea (OSA). The marked changes in sleep after treatment suggest that stimuli associated with OSA (e.g., intermittent hypoxia) may significantly modulate sleep regulation. However, no studies have investigated the independent effects of intermittent sleep-related hypoxia on sleep regulation and recovery sleep after removal of intermittent hypoxia. Ten rats were implanted with telemetry units to record the electroencephalogram (EEG), neck electromyogram, and body temperature. After >7 days recovery, a computer algorithm detected sleep-wake states and triggered hypoxic stimuli (10% O2) or room air stimuli only during sleep for a 3-h period. Sleep-wake states were also recorded for a 3-h recovery period after the stimuli. Each rat received an average of 69.0 +/- 6.9 hypoxic stimuli during sleep. The non-rapid eye movement (non-REM) and rapid-eye-movement (REM) sleep episodes averaged 50.1 +/- 3.2 and 58.9 +/- 6.6 s, respectively, with the hypoxic stimuli, with 32.3 +/- 3.2 and 58.6 +/- 4.8 s of these periods being spent in hypoxia. Compared with results for room air controls, hypoxic stimuli led to increased wakefulness (P < 0.005), nonsignificant changes in non-REM sleep, and reduced REM sleep (P < 0.001). With hypoxic stimuli, wakefulness episodes were longer and more frequent, non-REM periods were shorter and more frequent, and REM episodes were shorter and less frequent (P < 0.015). Hypoxic stimuli also increased faster frequencies in the EEG (P < 0.005). These effects of hypoxic stimuli were reversed on return to room air. There was a rebound increase in REM sleep, increased slower non-REM EEG frequencies, and decreased wakefulness (P < 0.001). The results show that sleep-specific hypoxia leads to significant modulation of sleep-wake regulation both during and after application of the intermittent hypoxic stimuli. This study is the first to determine the independent effects of sleep-related hypoxia on sleep regulation that approximates OSA before and after treatment.
Asunto(s)
Hipoxia/fisiopatología , Sueño/fisiología , Vigilia/fisiología , Animales , Temperatura Corporal/fisiología , Calibración , Electroencefalografía , Electromiografía , Masculino , Polisomnografía , Ratas , Ratas Sprague-Dawley , Síndromes de la Apnea del Sueño/fisiopatología , TelemetríaRESUMEN
This report describes a canine model of obstructive sleep apnea (OSA) developed in our laboratory and the results of its preliminary short-term application. Healthy adult dogs were prepared with a tracheostomy and with implanted electroencephalographic and nuchal electromyographic recording electrodes. A silent occlusion valve was attached to the outer end of the endotracheal tube. The electroencephalogram and electromyogram were monitored continuously by a computer that determined sleep-wake state using software developed in our laboratory. At a predetermined time (e.g., 12 s) after each sleep onset, a signal was transmitted from the computer to the valve controller, resulting in airway occlusion. When the dog aroused from sleep, the occlusion was released. These events therefore mimic those that occur in human OSA. Successful operation of the model was confirmed during 5-day continuous trials in two dogs. During the trials, the dogs became increasingly somnolent both by behavioral observation and objective measurement. The frequency of occlusions increased, and measures of apnea severity, including apnea duration and end-apneic arterial oxygen saturation, worsened. We conclude that this experimental model of repeated airway occlusion during sleep provides a potentially powerful tool for investigating the sequelae of OSA.
Asunto(s)
Obstrucción de las Vías Aéreas/fisiopatología , Síndromes de la Apnea del Sueño/fisiopatología , Obstrucción de las Vías Aéreas/psicología , Animales , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Perros , Electrodos Implantados , Electroencefalografía , Electromiografía , Consumo de Oxígeno/fisiología , Sueño/fisiología , Síndromes de la Apnea del Sueño/psicología , Sueño REM/fisiología , TelemetríaRESUMEN
We have used an implanted telemetry system to continuously monitor blood pressure (BP) in three dogs for durations ranging from 28 to 75 wk after implantation. Measurements of BP obtained by telemetry were compared every 3-12 wk, with measurements of BP recorded with a manometer-tipped catheter that was inserted into a femoral artery. Over a wide range of both physiological and pharmacologically manipulated pressures (40-200 mmHg), the values of BP obtained by the two methods were highly correlated (all r > 0.966; all P < or = 0.0001). However, the mean differences between the values obtained by the two systems were different from zero (range +29.6 to -1.5 mmHg; P < or = 0.0001), indicating an offset in the BP values recorded from the implanted system. Furthermore, this offset was dependent on the absolute level of the BP. The findings indicate that, for a period of at least 28 wk and up to 75 wk after implantation, the telemetry system accurately measures acute changes in BP and can reliably measure absolute BP provided that the system is properly validated.
Asunto(s)
Monitoreo Ambulatorio de la Presión Arterial/instrumentación , Monitoreo Ambulatorio de la Presión Arterial/métodos , Telemetría/instrumentación , Telemetría/métodos , Animales , Presión Sanguínea/fisiología , Calibración , Perros , Electroencefalografía , Electromiografía , Femenino , Frecuencia Cardíaca/fisiología , Reproducibilidad de los ResultadosRESUMEN
In contrast to the many neural studies into the mechanisms of sleep onset and maintenance, few studies have focused specifically on awakening from sleep. However, the abrupt electrographic changes and large brief cardio-respiratory activation at awakening suggest that a distinct, transiently aroused, awake state may exist compared to later wakefulness. To test this hypothesis we utilized the acoustic startle reflex, a standard un-conditioned reflex elicited by a sudden loud noise. This reflex is modulated under specific conditions, one being a diminution of startle when a quieter pre-stimulus is presented immediately before the loud stimulus. This pre-pulse inhibition (PPI) is used as a measure of sensorimotor gating, with smaller PPI indicating less filtering of sensory inputs and increased responsiveness to external stimuli. Eight rats with electrodes for recording sleep-wake state were studied. An accelerometer measured startle responses. The startle reflex was elicited by 115 dB, 40 ms tones. PPI was produced by 74 dB, 20 ms tones preceding the 115 dB tone by 100 ms. Responses within 100 ms were measured. Stimuli were applied either 3-10 s after spontaneous awakenings, or in established wakefulness (> 30 s). Responses to the startle stimuli alone were similar in the different awake states (P = 0.821). However, PPI was smaller at awakening from non-REM sleep compared to established wakefulness (45.4 +/- 7.5% vs. 74.3 +/- 6.1%, P = 0.0002). PPI after awakening from REM sleep (52.8 +/- 17.9%) was not significantly different than established wakefulness (P = 0.297). Reduced PPI of the startle reflex at awakening from non-REM sleep supports the hypothesis that wakefulness immediately after spontaneous sleep episodes is neurophysiologically distinct from later wakefulness and associated with reduced gating of motor responses to sensory inputs. Spontaneous activation of this distinct, transiently aroused, state upon awakening may serve a protective function, preparing an animal to respond immediately to potentially threatening stimuli.
Asunto(s)
Nivel de Alerta/fisiología , Reflejo de Sobresalto/fisiología , Sueño/fisiología , Vigilia/fisiología , Estimulación Acústica , Análisis de Varianza , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/fisiologíaRESUMEN
Adenosine, an endogenous modulator of synaptic transmission, has been implicated in regulation of sleep and arousal. The effect of adenosine on neuronal excitability depends on its concentration in the extracellular space. The present study shows that the state of activity of laboratory rats determines the level of tonic inhibition by adenosine in hippocampal slices prepared from these animals. Thus, slices taken at the end of the active period showed significantly more inhibition by adenosine, as determined by the effects of the A1 receptor blocker 8-CPT, in comparison to slices taken in the inactive state. The results support the proposed role of adenosine in regulation of sleep and arousal and point to the importance of the time of day at which slices for electrophysiological experiments are prepared.
Asunto(s)
Adenosina/fisiología , Ritmo Circadiano , Hipocampo/fisiología , Transmisión Sináptica/fisiología , Animales , Potenciales Postsinápticos Excitadores , Técnicas In Vitro , Masculino , Ratas , Ratas WistarRESUMEN
This paper describes some of the anatomical and physiological factors affecting the maintenance of upper airway patency in man. Such factors have particular relevance to the mechanisms responsible for maintaining upper airway patency during sleep, and the failure of these mechanisms in patients with the clinical syndrome of obstructive sleep apnoea: a condition in which repeated episodes of sleep-related inspiratory oropharyngeal collapse lead to recurrent hypoxaemia, disturbed sleep patterns and other clinical sequelae. The relationships between upper airway geometry, negative intrapharyngeal pressure, activation of upper airway dilator muscles, and sleep state are important factors affecting the maintenance of upper airway patency. The aim of this paper is not to consider such factors in isolation but to consider their interaction in affecting the adequacy of the upper airspace as a conduit for airflow.