Drug treatment for obstructive sleep apnea (OSA) is desirable because at least 30% of patients do not tolerate continuous positive airway pressure (CPAP) treatment. The negative pressure reflex (NPR) ...involving superficially located mechanoreceptors in the upper airway (UA) is an important mechanism for UA patency inhibitable by topical UA anesthesia (lidocaine). The NPR may serve as a target for pharmacological intervention for a topical treatment of OSA. The objective was to determine the effect of pharmacological augmentation of the NPR on UA collapsibility.
We developed a model of UA collapsibility in which application of negative pressures caused UA collapses in spontaneously breathing α-chloralose-urethane anesthetized pigs as indicated by characteristic tracheal pressure and air flow changes.
N/A.
N/A.
N/A.
The potassium channel blocker AVE0118 administered topically to the UA in doses of 1, 3, and 10 mg per nostril sensitized the NPR, shifting the mechanoreceptor response threshold for the genioglossus muscle to more positive pressures (P < 0.001; n = 6 per group) and dose-dependently inhibited UA collapsibility. Ten mg of AVE0118 prevented UA collapses against negative pressures of -150 mbar (P < 0.01) for > 4 h in all pigs, while in control pigs the UA collapsed at -50 mbar or less negative pressures. The effect of AVE0118 was abolished by UA lidocaine anesthesia. Acute intravenous administration of naloxone or acetazolamide was ineffective; paroxetine and mirtazepine were weakly effective and fluoxetine was moderately effective in line with reported clinical efficacy.
Topical administration of AVE0118 to the UA is a promising pharmacologic approach for the treatment of OSA.
Obstructive sleep apnoea syndrome (OSAS) is a breathing disorder with a multifactorial etiology. The respiratory epithelium is lined with a thin layer of airway surface liquid preventing interactions ...between the airflow and epithelium. The effect of the liquid lining in OSAS pathogenesis remains poorly understood despite clinical research. Previous studies have shown that the physical properties of the airway surface liquid or altered stimulation of the airway mechanoreceptors could alleviate or intensify OSAS; however, these studies do not provide a clear physical interpretation. To study the forces transmitted from the airflow to the liquid-lined compliant wall and to discuss the effects of the airway surface liquid properties on the stimulation of the mechanoreceptors, a novel and simplified experimental system mimicking the upper airway fundamental characteristics (i.e., liquid-lined compliant wall and complex unsteady airflow features) was constructed. The fluctuating force on the compliant wall was reduced through a damping mechanism when the liquid film thickness and/or the viscosity were increased. Conversely, the liquid film damping was reduced when the surface tension decreased. Based on the experimental data, empirical correlations were developed to predict the damping potential of the liquid film. In the future, this will enable us to extend the existing computational fluid–structure interaction simulations of airflow in the human upper airway by incorporating the airway surface liquid effect without adopting two-phase flow interface tracking methods. Furthermore, the experimental system developed in this study could be used to investigate the fundamental principles of the complex once/twice-coupled physical phenomena.
Abstract Long-acting muscarinic receptor antagonists (LAMAs) have been reported to attenuate cough in preclinical and clinical studies. The present study was performed on rabbits to compare ...aclidinium and tiotropium efficacy in the downregulation of the cough reflex. This reflex was evoked by citric acid inhalation in unanesthetized animals and by both citric acid inhalation and mechanical stimulation of the tracheobronchial tree in anesthetized animals 90 min following the inhalation of each drug (nebulizer output always at 1 mL/min). Aclidinium 4 mg/mL and tiotropium 200 μg/mL inhaled in 1 min proved to have similar protective effect on methacholine-induced bronchoconstriction in anesthetized animals. The total dosage employed for aclidinium and tiotropium was 4 mg and 200 μg, respectively. In awake animals, similar reductions in the cough number were observed following 10-min inhalation of each drug with a slight, not significant tendency to higher antitussive effects for aclidinium. In anesthetized animals, 1-min inhalation of each drug caused similar depressant effects on cough responses induced by both mechanical and chemical stimulation. A complete suppression of cough responses to mechanical stimuli was seen in some preparations. The results strongly suggest that the LAMA-induced downregulation of cough may be mediated not only by transient receptor potential vanilloid type 1 channels, as already reported, but also by acid-sensing ion channels and mechanoreceptors. The route of administration along with the more rapid hydrolysis of aclidinium into inactive metabolites minimize potential systemic side effects and give to this drug a very favorable safety profile.
R. C. Basner, J. Ringler, E. Garpestad, R. M. Schwartzstein, D. Sparrow, S. E. Weinberger, J. Lilly and J. W. Weiss
Charles A. Dana Research Institute, Boston, Massachusetts.
Six healthy subjects (5 ...males and 1 female, 26-40 yr old) were studied
during non-rapid-eye-movement (NREM) sleep to assess the role of upper
airway (UA) afferents in the arousal response to induced airway occlusion.
Subjects wore an airtight face mask attached to a low-resistance one-way
valve. A valve in the inspiratory circuit allowed instantaneous inspiratory
airway occlusion and release; the expiratory circuit remained unoccluded at
all times. Each subject was studied during two nights. On one night,
occlusions were created during stable stage 2 NREM sleep before and after
application of 4% lidocaine to the oral and nasal mucosa. On the other
night, the protocol was duplicated with saline ("sham anesthesia") rather
than lidocaine. The order of nights was randomized. Occlusions were
sustained until electroencephalographic arousal. Three to 12 occlusions
were performed in each subject for each of the four parts of the protocol
(pre- and post-lidocaine, pre- and post-saline). The auditory threshold for
arousal (1,500-Hz tone beginning at 30 dB) was also tested before and after
UA lidocaine. For the group, arousal time after UA anesthesia was prolonged
compared with preanesthesia arousal time (P less than 0.001); arousal time
after sham anesthesia did not significantly increase from before sham
anesthesia (P = 0.9). The increase in arousal time with UA anesthesia was
greater than the increase with sham anesthesia (P less than 0.001). The
auditory arousal threshold did not increase after UA anesthesia.
Inspiratory mask pressure, arterial O2 saturation of hemoglobin, and
end-tidal PCO2 during occlusions were similar before and after UA
anesthesia.
M. F. Fitzpatrick, T. Zintel, M. Stockwell, J. Mink and C. G. Gallagher
Department of Medicine, Royal University Hospital, University of Saskatchewan, Saskatoon, Canada.
The site for detection of ...added inspiratory resistive loads is unknown, but
recent evidence suggests that the airways may play an important role. The
aim of this study was to discern whether the larynx has an important
independent role in conscious detection of added inspiratory resistive
loads. A randomized double-blind placebo-controlled study of the effect of
superior laryngeal nerve blockade on inspiratory resistive load-detection
threshold was carried out in 12 normal subjects (7 women; mean age 27.5 yr;
range 18-45 yr). Baseline (preinjection) detection thresholds were similar
on the lidocaine 0.58 +/- 0.16 (SE) cmH2O.l-1.s and saline (0.53 +/- 0.12
cmH2O.l-1.s; P = 0.28) days. There was no significant difference in
load-detection thresholds after injection between lidocaine (0.60 +/- 0.15
cmH2O.l-1.s) and saline (0.55 +/- 0.10 cmH2O.l-1.s; P = 0.68). Thus, the
larynx does not appear to be an important independent airway site for
conscious inspiratory resistive load detection.
In these studies we examined the role of excitatory amino acids (EAAs) neurotransmission in communicating sensory inputs to the airway-related vagal preganglionic neurons, by examining the effects of ...either NMDA or AMPA/kainate receptor blockade on reflex and chemical responses of tracheal smooth muscle. Experiments were performed in chloralose anesthetized, paralyzed and mechanically ventilated beagle dogs (
n=18), under hyperoxic, normocapnic, and normohydric conditions. Topical application or microinjection of NMDA receptor blockers, into the region of the ventrolateral medulla where airway-related vagal preganglionic neurons are located, insignificantly decreased the reflex changes in tracheal tone. However, topical application or microinjection of AMPA/kainate subtype of glutamate receptor selective antagonists markedly reduced reflex increase in tracheal tone induced by (1) lung deflation, (2) stimulation of laryngeal cold receptors, and (3) activation of peripheral or central chemoreceptors. These effects were potentiated by prior NMDA receptor blockade. Findings indicate that an increase in central cholinergic outflow to the airways by a variety of excitatory afferent inputs is mediated via activation of EAA receptors, mainly AMPA/kainate subtype of glutamate receptors.
We examined the role of I
1-imidazoline receptors in the control of airway function, by testing the effects of systemic administration of the I
1-imidazoline agonist moxonidine on reflex responses of ...tracheal smooth muscle (TSM) tone to either lung deflation or mechanical stimulation of intrapulmonary rapidly adapting receptors. Experiments were performed in either α-chloralose anaesthetized or decorticate, paralyzed and mechanically ventilated beagle dogs. Moxonidine (10–100 μg/kg) administered via three different routes (the femoral vein, muscular branch of superior thyroid artery, and vertebral artery) attenuated TSM responses to stimulation of airway sensory nerve fibers by two different ways, and caused a decrease in arterial pressure and heart rate. These effects were dose-dependent, and were significantly reversed by efaroxan (an I
1-imidazoline and α
2-adrenergic blocker) administered via the vertebral artery. Intravertebral efaroxan abolished the hemodynamic effects of moxonidine. Intravenous moxonidine (10–100 μg/kg) did not alter airway smooth muscle responses to electrical stimulation of the peripheral vagus nerve. In addition, in vitro moxonidine (1–100 μg/ml) had no effect on contractile responses to increasing doses of acetylcholine. These findings indicate that moxonidine may act at a central site to suppress reflex airway constriction, even when given into the systemic circulation. Given the presence of I
1-imidazoline sites and α
2-adrenergic receptors in brain regions participating in airway reflexes, these receptor classes may be involved in brainstem control of the cholinergic outflow to the airways.
We examined the role of I1-imidazoline receptors in the control of airway function, by testing the effects of systemic administration of the I1-imidazoline agonist moxonidine on reflex responses of ...tracheal smooth muscle (TSM) tone to either lung deflation or mechanical stimulation of intrapulmonary rapidly adapting receptors. Experiments were performed in either alpha-chloralose anaesthetized or decorticate, paralyzed and mechanically ventilated beagle dogs. Moxonidine (10-100 microg/kg) administered via three different routes (the femoral vein, muscular branch of superior thyroid artery, and vertebral artery) attenuated TSM responses to stimulation of airway sensory nerve fibers by two different ways, and caused a decrease in arterial pressure and heart rate. These effects were dose-dependent, and were significantly reversed by efaroxan (an I1-imidazoline and alpha2-adrenergic blocker) administered via the vertebral artery. Intravertebral efaroxan abolished the hemodynamic effects of moxonidine. Intravenous moxonidine (10-100 microg/kg) did not alter airway smooth muscle responses to electrical stimulation of the peripheral vagus nerve. In addition, in vitro moxonidine (1-100 microg/ml) had no effect on contractile responses to increasing doses of acetylcholine. These findings indicate that moxonidine may act at a central site to suppress reflex airway constriction, even when given into the systemic circulation. Given the presence of I1-imidazoline sites and alpha2-adrenergic receptors in brain regions participating in airway reflexes, these receptor classes may be involved in brainstem control of the cholinergic outflow to the airways.
PDF
