Contributions of passive mechanical loads and active neuromuscular compensation to upper airway collapsibility during sleep.
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Continuous Positive Airway Pressure↗
Biomedical subjects
Richard L Horner
Publications and source records attributed to Richard L Horner.
Endogenous excitatory drive modulating respiratory muscle activity across sleep-wake states.
RATIONALE: The concept of a tonic drive activating respiratory muscle in wakefulness but not sleep has been an important and enduring notion in respiratory medicine, not least because it is useful in modeling sleep effects on breathing and understanding the pathogenesis of sleep-related breathing disorders such as obstructive sleep apnea. However, a neurotransmitter substrate mediating respiratory muscle activation across sleep-wake states has not been identified. OBJECTIVES: We determined if alpha1 receptor antagonism at the hypoglossal motor nucleus (HMN) decreases genioglossus (GG) activity consistent with a role for an endogenous noradrenergic drive contributing to GG activation across sleep-wake states. We also determined if alpha1 receptor stimulation could counteract reduced endogenous noradrenergic drive and increase sleeping GG activity. METHODS: Thirty-five rats were implanted with electroencephalogram and neck electrodes to record sleep-wake states and GG and diaphragm electrodes for respiratory muscle recordings. Microdialysis probes were inserted into the HMN. MEASUREMENTS AND MAIN RESULTS: Microdialysis perfusion of the alpha1 receptor antagonist terazosin into the HMN significantly decreased GG activity in wakefulness and nonrapid eye movement (non-REM) sleep but not REM sleep. The alpha1 receptor agonist phenylephrine increased GG activity in wakefulness and sleep, but periods of motor inactivity persisted in REM sleep; there was no potentiating effect of combined alpha1 and 5-HT2 receptor stimulation. CONCLUSIONS: Identification of an endogenous noradrenergic drive contributing to GG activation in wakefulness and non-REM sleep, but not REM sleep, is important given the prevalence and clinical significance of sleep-induced hypoventilation and obstructive sleep apnea in humans and the potential for pharmacologic treatment.
Adrenergic alpha-Antagonists↗
Update in sleep and control of ventilation 2005.
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Animals↗
The effect of time of day on apnoea index in the sleeping rat.
This study tested the hypothesis that apnoea index would be greater during daytime sleep than nighttime sleep in the rat. Electroencephalogram and electromyogram were monitored via biotelemetry implant and respiration was measured using whole body plethysmography in six male rats in two separate 34h recording sessions per animal. Apnoeas were classified as "spontaneous" or "post-sigh". Daily average spontaneous apnoea index was 35 times greater (p<0.0001) during rapid eye movement (REM) sleep than in non-REM (NREM) sleep. In contrast, daily average post-sigh apnoea index was not significantly greater in REM sleep than in non-REM (NREM) sleep (p=0.39). There was a greater post-sigh apnoea index during daytime REM than during nighttime REM (p=0.043) but REM-related spontaneous apnoea index was unaffected by time of day. There was no day to night difference in spontaneous apnoea index or post-sigh apnoea index during NREM sleep. Respiratory variability (coefficient of variation for breath duration and tidal volume) was not affected by time of day in REM or NREM sleep. We conclude that the circadian timing system has no effect on apnoea index during NREM sleep in the rat, but it may influence the propensity for post-sigh apnoea during REM sleep.
Animals↗
Inhibition of serotonergic medullary raphe obscurus neurons suppresses genioglossus and diaphragm activities in anesthetized but not conscious rats.
Although exogenous serotonin at the hypoglossal motor nucleus (HMN) activates the genioglossus muscle, endogenous serotonin plays a minimal role in modulating genioglossus activity in awake and sleeping rats (Sood S, Morrison JL, Liu H, and Horner RL. Am J Respir Crit Care Med 172: 1338-1347, 2005). This result therefore implies that medullary raphe neurons also play a minimal role in the normal physiological control of the HMN, but this has not yet been established because raphe neurons release other excitatory neurotransmitters onto respiratory motoneurons in addition to serotonin. This study tests the hypothesis that inhibition of medullary raphe serotonergic neurons with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) suppresses genioglossus and diaphragm activities in awake and sleeping rats. Ten rats were implanted with electrodes to record sleep-wake states and genioglossus and diaphragm activities. Microdialysis probes were also implanted into the nucleus raphe obscurus (NRO). Experiments in 10 anesthetized and vagotomized rats were also performed using the same methodology. In anesthetized rats, microdialysis perfusion of 0.1 mM 8-OH-DPAT into the NRO decreased genioglossus activity by 60.7+/-9.0% and diaphragm activity by 13.3+/-3.4%. Diaphragm responses to 7.5% CO2 were also significantly reduced by 8-OH-DPAT. However, despite the robust effects observed in anesthetized and vagotomized rats, there was no effect of 0.1 mM 8-OH-DPAT on genioglossus or diaphragm activities in conscious rats awake or asleep. The results support the concept that endogenously active serotonergic medullary raphe neurons play a minimal role in modulating respiratory motor activity across natural sleep-wake states in freely behaving rodents. This result has implications for pharmacological strategies aiming to manipulate raphe neurons and endogenous serotonin in obstructive sleep apnea.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Cyclic nucleotides modulate genioglossus and hypoglossal responses to excitatory inputs in rats.
RATIONALE: Previous studies modulating pharyngeal muscle activity with pharmacologic approaches have targeted membrane receptors on pharyngeal motoneurons. Whether modulation of intracellular pathways can increase pharyngeal muscle activity, however, has not been investigated but is relevant to pharmacologic treatments of obstructive sleep apnea. OBJECTIVES: To determine if modulating the second messenger cyclic adenosine-3'-5'-monophosphate (cAMP) at the hypoglossal motor nucleus (HMN) will increase genioglossus activity across sleep- wake states. METHODS: Forty-eight rats were implanted with electroencephalogram and neck electrodes to record sleep-wake states and genioglossus and diaphragm electrodes for respiratory muscle recordings. Microdialysis probes were inserted into the HMN to perfuse artificial cerebrospinal fluid and (1) forskolin (500 microM, adenylyl cyclase activator to increase cAMP), (2) a cAMP analog (500 microM), (3) iso-butyl-methylxanthine (IBMX; 300 microM, phosphodiesterase inhibitor), or (4) a cyclic guanosine-3'-5'-monophosphate (cGMP) analog (500 microM, 8-Br-cGMP). MEASUREMENTS AND MAIN RESULTS: Forskolin and the cAMP analog at the HMN increased respiratory-related and tonic genioglossus activities in wakefulness and non-REM sleep but not REM sleep. IBMX did not affect genioglossus activity in awake or sleeping rats. However, IBMX abolished the robust excitatory responses to serotonin and phenylephrine at the HMN, but responses to non-N-methyl-D-aspartate receptor activation remained. These effects of IBMX were mimicked by 8-Br-cGMP. CONCLUSIONS: Genioglossus responses to manipulation of cAMP at the HMN are differentially modulated by sleep-wake state. Selective abolition of serotonin and phenylephrine responses after IBMX suggests that under conditions of nonspecific phosphodiesterase inhibition the HMN is unresponsive to certain, otherwise potent, excitatory inputs. Similar responses with 8-Br-cGMP suggest this effect is likely mediated by cGMP pathways.
Animals↗
Role of endogenous serotonin in modulating genioglossus muscle activity in awake and sleeping rats.
RATIONALE: Exogenous serotonin at the hypoglossal motor nucleus (HMN) stimulates genioglossus (GG) muscle activity. However, whether endogenous serotonin contributes to GG activation across natural sleep-wake states has not been determined, but is relevant given that serotonergic neurons have decreased activity in sleep and project to pharyngeal motoneurons. OBJECTIVES: To determine the role of endogenous serotonin at the HMN in modulating GG activity across natural sleep-wake states. METHODS: Ten rats were implanted with electroencephalogram and neck muscle electrodes to record sleep-wake states, and GG and diaphragm wires for respiratory muscle recordings. Microdialysis probes were implanted into the HMN for perfusion of artificial cerebrospinal fluid and the serotonin receptor antagonist mianserin (100 microM). MEASUREMENTS AND MAIN RESULTS: In room air, there was no effect of mianserin on respiratory-related or tonic GG activities across sleep-wake states (p > 0.300). In hypercapnia, however, the normal declines in GG activity from non-REM to REM sleep, and wakefulness to REM sleep, were reduced with mianserin (p < 0.005). These data demonstrate a normally low endogenous serotonergic drive modulating GG activity unless augmented by reflex inputs. We also demonstrated a significant serotonergic drive modulating GG activity in vagotomized rats, but not in vagi-intact rats, under anesthesia, suggesting that previous results in reduced preparations may have been influenced by vagotomy. CONCLUSIONS: The results show a minimal endogenous serotonergic drive at the HMN modulating GG activity across sleep-wake states, unless augmented by reflex inputs. This result has implications for pharmacologic strategies aiming to increase GG activity by manipulating endogenous serotonin in patients with obstructive sleep apnea.
Animals↗
Opposing muscarinic and nicotinic modulation of hypoglossal motor output to genioglossus muscle in rats in vivo.
The genioglossus (GG) muscle of the tongue, innervated by the hypoglossal motor nucleus (HMN), helps maintain an open airway for effective breathing. In vitro studies in neonatal rodents have separately characterized muscarinic and nicotinic receptor influences at the HMN but the net effects of combined nicotinic and muscarinic receptor activation and increased endogenous acetylcholine have not been determined in adult animals in vivo. Urethane-anaesthetized, tracheotomized and vagotomised rats were studied. Microdialysis perfusion of acetylcholine into the HMN significantly decreased respiratory-related GG activity (28.5 +/- 11.0% at a threshold dose of 0.1 mm). Application of the cholinergic agonists carbachol and muscarine have similar suppression effects (GG activity was decreased 11.8 +/- 4.3 and 20.5 +/- 5.8%, respectively, at 0.01 microm). Eserine, an acetylcholinesterase inhibitor, also decreased the amplitude of respiratory-related GG activity (36.4 +/- 11.3% at 1.0 microm) indicating that endogenous acetylcholine modulates GG activity. Although these results showed that suppression of GG activity predominates during cholinergic stimulation at the HMN, application of the nicotinic receptor agonist dimethyl-4-phenylpiperazinium iodide significantly increased tonic and respiratory-related GG activity (156 +/- 33% for respiratory activity at 1.0 mm) showing that excitatory responses are also present. Consistent with this, 100 microm carbachol decreased GG activity by 44.2 +/- 7.5% of control, with atropine (10 microm) reducing this suppression to 13.8 +/- 4.0% (P < 0.001). However, the nicotinic receptor antagonist dihydro-beta-erythroidine (100 microm) increased the carbachol-mediated suppression to 69.5 +/- 5.9% (P = 0.011), consistent with a role for nicotinic receptors in limiting the overall suppression of GG activity during cholinergic stimulation. Application of eserine to increase endogenous acetylcholine also showed that inhibitory muscarinic and excitatory nicotinic receptors together determine the net level of GG activity during cholinergic stimulation at the HMN. The results suggest that acetylcholine has mixed effects at the HMN with muscarinic-mediated GG suppression masking nicotinic excitation.
Animals↗
A serotonergic (5-HT2) receptor mechanism in the laterodorsal tegmental nucleus participates in regulating the pattern of rapid-eye-movement sleep occurrence in the rat.
Serotonin [5-hydroxytryptamine (5-HT)] plays an inhibitory role in rapid-eye-movement (REM) sleep although the exact mechanism(s) and site(s) of action are not known. It is commonly assumed that 5-HT exerts its influence on REM sleep via input from the dorsal raphe nucleus (DRN) directly onto cholinergic neurons involved in the generation of REM sleep. 5-HT(2) receptor sites have been found on cholinergic neurons in the laterodorsal tegmental nucleus (LDT) and pedunculopontine tegmental nucleus (PPT). We locally microinjected the 5-HT(2) agonist DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl) and the 5-HT(2) antagonist, ketanserin, in LDT in rats to determine whether these receptor sites are involved in the regulation of behavioral states. DOI and ketanserin primarily affected REM sleep, by significantly decreasing or increasing, respectively, the number, but not the duration, of REM sleep episodes. DOI specifically decreased the occurrence of clusters of REM sleep episodes appearing at intervals less than or equal to 3 min (sequential episodes) without affecting single episodes separated by more than 3 min. An opposite effect of ketanserin on REM sleep clusters, although not statistically significant, was observed.
Animals↗
5-HT at hypoglossal motor nucleus and respiratory control of genioglossus muscle in anesthetized rats.
Serotonin (5-HT) from medullary raphe neurons excites hypoglossal motoneurons innervating genioglossus (GG) muscle. Since some raphe neurons also show increased activity in hypercapnia, we tested the hypothesis that serotonergic mechanisms at the hypoglossal motor nucleus (HMN) modulate GG activity and responses to CO2. Seventeen urethane-anesthetized, tracheotomized and vagotomized rats were studied. Microdialysis probes were used to deliver mianserin (5-HT receptor antagonist, 0 and 0.1 mM) or 5-HT (eight doses, 0-50 mM) to the HMN during room air or CO2-stimulated breathing. Mianserin decreased respiratory-related GG activity during room air and CO2-stimulated breathing (P<0.001), and also suppressed GG responses to CO2 (P=0.05). In contrast, GG activity was increased by 5-HT at the HMN, and was further increased in hypercapnia (P<0.02). However, 5-HT increased respiratory-related GG activity at levels lower (1 mM) than those eliciting tonic GG activity (10-30 mM 5-HT). The results show that 5-HT at the HMN contributes to the respiratory control of GG muscle.
Analysis of Variance↗
Role of inhibitory amino acids in control of hypoglossal motor outflow to genioglossus muscle in naturally sleeping rats.
The hypoglossal motor nucleus innervates the genioglossus (GG) muscle of the tongue, a muscle that helps maintain an open airway for effective breathing. Rapid-eye-movement (REM) sleep, however, recruits powerful neural mechanisms that can abolish GG activity even during strong reflex stimulation such as by hypercapnia, effects that can predispose to sleep-related breathing problems in humans. We have developed an animal model to chronically manipulate neurotransmission at the hypoglossal motor nucleus using in vivo microdialysis in freely behaving rats. This study tests the hypothesis that glycine receptor antagonism at the hypoglossal motor nucleus, either alone or in combination with GABAA receptor antagonism, will prevent suppression of GG activity in natural REM sleep during room air and CO2-stimulated breathing. Rats were implanted with electroencephalogram and neck muscle electrodes to record sleep-wake states, and GG and diaphragm electrodes for respiratory muscle recording. Microdialysis probes were implanted into the hypoglossal motor nucleus for perfusion of artificial cerebrospinal fluid (ACSF) and strychnine (glycine receptor antagonist, 0.1 mM) either alone or combined with bicuculline (GABAA antagonist, 0.1 mM) during room air and CO2-stimulated breathing. Compared to ACSF controls, glycine receptor antagonism at the hypoglossal motor nucleus increased respiratory-related GG activity in room air (P = 0.010) but not hypercapnia (P = 0.221). This stimulating effect of strychnine in room air did not depend on the prevailing sleep-wake state (P = 0.625) indicating removal of a non-specific background inhibitory glycinergic tone. Nevertheless, GG activity remained minimal in those REM sleep periods without phasic twitches in GG muscle, with GG suppression from non-REM (NREM) sleep being > 85 % whether ACSF or strychnine was at the hypoglossal motor nucleus or the inspired gas was room air or 7 % CO2. While GG activity was minimal in these REM sleep periods, there was a small but measurable increase in GG activity after strychnine (P < 0.05). GG activity was also minimal, and effectively abolished, in the REM sleep periods without GG twitches with combined glycine and GABAA receptor antagonism at the hypoglossal motor nucleus. We conclude that these data in freely behaving rats confirm that inhibitory glycine and GABAA receptor mechanisms are present at the hypoglossal motor nucleus and are tonically active, but that such inhibitory mechanisms make only a small contribution to the marked suppression of GG activity and reflex responses observed in periods of natural REM sleep.
Amino Acids↗
GABAA receptor antagonism at the hypoglossal motor nucleus increases genioglossus muscle activity in NREM but not REM sleep.
The pharyngeal muscles, such as the genioglossus (GG) muscle of the tongue, are important for effective lung ventilation since they maintain an open airspace. Rapid-eye-movement (REM) sleep, however, recruits powerful neural mechanisms that can abolish GG activity, even during strong reflex respiratory stimulation by elevated CO2. In vitro studies have demonstrated the presence of GABAA receptors on hypoglossal motoneurons, and these and other data have led to the speculation that GABAA mechanisms may contribute to the suppression of hypoglossal motor outflow to the GG muscle in REM sleep. We have developed an animal model that allows us to chronically manipulate neurotransmission at the hypoglossal motor nucleus using microdialysis across natural sleep-wake states in rats. The present study tests the hypothesis that microdialysis perfusion of the GABAA receptor antagonist bicuculline into the hypoglossal motor nucleus will prevent the suppression of GG muscle activity in REM sleep during both room-air and CO2-stimulated breathing. Ten rats were implanted with electroencephalogram and neck muscle electrodes to record sleep-wake states, and GG and diaphragm electrodes for respiratory muscle recording. Microdialysis probes were implanted into the hypoglossal motor nucleus for perfusion of artificial cerebrospinal fluid (ACSF) or 100 microM bicuculline during room-air and CO2-stimulated breathing (7 % inspired CO2). GABAA receptor antagonism at the hypoglossal motor nucleus increased respiratory-related GG activity during both room-air (P = 0.01) and CO2-stimulated breathing (P = 0.007), indicating a background inhibitory GABA tone. However, the effects of bicuculline on GG activity depended on the prevailing sleep-wake state (P < 0.005), with bicuculline increasing GG activity in non-REM (NREM) sleep and wakefulness both in room air and hypercapnia (P < 0.01), but GG activity was effectively abolished in those REM periods without phasic twitches in the GG muscle. This abolition of GG activity in REM sleep occurred regardless of ACSF or bicuculline at the hypoglossal motor nucleus, or room-air or CO2-stimulated breathing (P > 0.63). We conclude that these data in freely behaving rats confirm previous in vitro studies that GABAA receptor mechanisms are present at the hypoglossal motor nucleus and are tonically active, but the data also show that GABAA receptor antagonism at the hypoglossal motor nucleus does not increase GG muscle activity in natural REM sleep.
Animals↗
Arousal from sleep--perspectives relating to autonomic function.
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Arousal↗
Glycine at hypoglossal motor nucleus: genioglossus activity, CO(2) responses, and the additive effects of GABA.
There is evidence for glycine and 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. This study tests the hypotheses that glycine at the hypoglossal motor nucleus (HMN) will suppress genioglossus (GG) muscle activity, even in the presence of hypercapnic respiratory stimulation, and the effects of glycine will be blocked by strychnine. We also determined whether coapplication of glycine and muscimol (GABA(A)- receptor agonist) to the HMN is additive in suppressing GG activity. Twenty-four urethane-anesthetized, tracheotomized, and vagotomized rats were studied. Diaphragm and GG activities, the electroencephalogram, and blood pressure were recorded. Microdialysis probes were implanted into the HMN for delivery of artificial cerebrospinal fluid (control), glycine (0.0001-10 mM), or muscimol (0.1 microM). Increasing glycine at the HMN produced graded suppression of GG activity (P < 0.001), although the GG still responded to stimulation with 7% inspired CO(2) (P = 0.002). Strychnine (0.1 mM) reversed the glycine-mediated suppression of GG activity, whereas combined glycine and muscimol were additive in GG muscle suppression. It remains to be determined whether the recruitment of such glycine and GABA mechanisms explains the periods of major GG suppression in behaviors such as rapid eye movement sleep.
Animals↗
Effects of sleep-wake state on the genioglossus vs.diaphragm muscle response to CO(2) in rats.
The effects of sleep on the ventilatory responses to hypercapnia have been well described in animals and in humans. In contrast, there is little information for genioglossus (GG) responses to a range of CO(2) stimuli across all sleep-wake states. Given the notion that sleep, especially rapid eye movement (REM) sleep, may cause greater suppression of muscles with both respiratory and nonrespiratory functions, this study tests the hypothesis that GG activity will be differentially affected by sleep-wake states with major suppression in REM sleep despite excitation by CO(2). Seven rats were chronically implanted with electroencephalogram, neck, GG, and diaphragm electrodes, and responses to 0, 1, 3, 5, 7, and 9% CO(2) were recorded. Diaphragm activity and respiratory rate increased with CO(2) (P < 0.001) across sleep-wake states with significant increases at 3-5% CO(2) compared with 0% CO(2) controls (P < 0.05). Phasic GG activity also increased in hypercapnia but required higher CO(2) (7-9%) for significant activation (P < 0.05). Further studies in 15 urethane-anesthetized rats with the vagi intact (n = 6) and cut (n = 9) showed that intact vagi delayed GG recruitment with hypercapnia but did not affect diaphragm responses. In the naturally sleeping rats, we also showed that GG activity was significantly reduced in non-REM and REM sleep (P < 0.04) and was almost abolished in REM even with stimulation by 9% CO(2) (decrease = 80.4% vs. wakefulness). Such major suppression of GG activity in REM, even with significant respiratory stimulation, may explain why obstructive apneas are more common in REM sleep.
Animals↗