The Effects of Vadocaine, Dextromethorphan, Diphenhydramine and Hydroxyzine on the Ciliary Beat Frequency in Rats in Vitro (original) (raw)
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Influence of substance P on ciliary beat frequency in airway isolated preparations
European Journal of Pharmacology, 1986
The neuropeptide substance P (SP), which is released from sensory C-fibres after stimulation by chemical irritants, accelerates mucociliary activity in rabbit maxillary sinus in vivo. In order to investigate the mechanism behind this finding, we recorded ciliary beat frequency (CBF) in vitro from various respiratory explants by a photoelectric technique. It was noticed that ciliated cells from the maxillary sinus displayed a higher beating frequency than cells from the trachea and the bronchus, in that order. SP 10-1°-10-4 M did not influence the CBF in explants from rabbit maxillary sinus, rabbit trachea and main bronchi, guinea-pig trachea and human adenoids. Neurokinin A (NKA) 10-6-10-5 M, which is also thought to be released from sensory C-fibres, did not influence the CBF in guinea-pig trachea. Neither did the C-fibre stimulant capsaicin 10-8-10-4 M increase CBF in explants from human adenoids. The present findings indicate that the mucociliary effect of SP in vivo is not mediated by an effect on the cilia themselves.
Clinical and Experimental Pharmacology and Physiology, 1994
1. The ciliary beat frequency (CBF) of six animal species from six regions of the respiratory tract were measured: inferior turbinate, nasopharynx, the upper part of trachea from first to second cartilage, the lower part of trachea, main bronchus and subsegmental bronchi. Cow, pig, dog, rabbit, guinea-pig and rat were studied.
The effect of nasal drug formulations on ciliary beating in vitro
International Journal of Pharmaceutics, 1996
In order to estimate the potential of nasal drug formulations to influence ciliary beating, ciliary beat frequency (CBF) measurements were performed in vitro, using chicken embryo trachea and a photo-electric registration device. The effects of nasal prescription and non-prescription drug formulations were studied and compared with a number of investigational nasal drug formulations containing estradiol, dihydroergotamine mesylate and salmon calcitonin. The influence of all formulations on CBF was related to the effects of formulation additives such as preservatives and nasal absorption enhancers on the ciliated tissue. For almost all nasal drug formulations, the preservatives used in the formulations (e.g. benzalkonium chloride, chlorobutanol) play a decisive role in the observed ciliostatic effects. Methylated fl-cyclodextrins, used as nasal absorption enhancers/solubilizers in the investigational formulations, appeared to be relatively non-toxic for the ciliated tissue, having similar effects on CBF as physiological saline. After dilution five times, most drug formulations studied showed a moderate ciliostatic effect, but marked differences could still be detected. The present study demonstrates that CBF measurements in vitro are a valuable tool in the design of safe nasal drug formulations.
Toxicology in Vitro, 2020
Nasal drug formulations can be effective for local delivery of therapeutic drugs to the sinonasal mucosa or for systemic drug delivery by absorption directly into the bloodstream. The growing field of potential nasal therapies includes nasal vaccination and even treatment of neurodegenerative diseases. However, it is important that nasal drug formulations don't have a disruptive effect on the cilia and mucosa of nasal epithelium. Mucociliary clearance represents the first host defence of the respiratory tract that requires the coordinated beating of cilia. A key parameter to determine mucociliary clearance is ciliary beat frequency (CBF). The objective of this study was to validate the high-speed digital imaging for CBF measurements in nasal MucilAir™ in vitro model and to test its potential for ciliotoxicity studies to evaluate the safety of investigational nasal drug formulations. Our CBF measuring setup was first validated by benzalkonium chloride, a common-practice preservative with cilio-inhibiting effect. Next, MucilAir™ model was treated with mometasone nasal spray (Mommox®/Mometasone Sandoz®). Short term cilio-stimulatory effect and dose dependent effect of mometasone nasal spray were demonstrated. Post-treatment analysis showed unaltered ultrastructure of MucilAir™ model. In conclusion, characterization of the ciliary activity of nasal MucilAir™ in vitro model and its response to relevant agents with herein developed efficient and reproducible set up for CBF analysis show great potential of this model for airway ciliotoxicity studies.
European Journal of Pharmacology, 1990
Guinea-pig tracheas were perfused with recirculating modified Krebs-Wenseleit solution while monitoring changes in ~flow-o~t~ow pressure difference, which is an index of trachealis muscle tone. The reactivities of the trachealis muscle to methacholine, histamine and isoproterenol applied separately to the mucosal (intraluminal, IL) or serosal (extralvminal, EL) compartments were compared, and evidence for the agonist-induced release of epithelium-derived &axing factor (EpDRF) was sought. All agents were more potent when added to the EL compartment, but the IL/EL EC, ratios were different: 100 for methacho~ne, 41 for ~sta~ne and 25 for isoproterenol. Methacho~ne or histamine added to the IL compartment, after the preparations were pre-contracted with the same concentration of the agonist or 30 mM KC1 added EL, did not result in relaxation. Likewise, IL isoproterenol did not evoke contraction. IL KC1 evoked relaxation. The results indicate that the epithelium reduces access of bronchoactive agents to the muscle, while an i~ediate relaxant effect of EpDRF released by agonists couid not be demonstrated. Trachea; Epithelium; EpDRF (epithelium-delved relaxing factor); Smooth muscle (airway); (Reactivity) 0014-2999/90/$03.50 (23 1990 Elsevier Science Publishers B.V. (Biomedical Division)
The effects of temperature and anesthetic agents on ciliary function in murine respiratory epithelia
Frontiers in pediatrics, 2014
Mucus transport mediated by motile cilia in the airway is an important defense mechanism for prevention of respiratory infections. As cilia motility can be depressed by hypothermia or exposure to anesthetics, in this study, we investigated the individual and combined effects of dexmedetomidine (dex), fentanyl (fen), and/or isoflurane (iso) at physiologic and low temperatures on cilia motility in mouse tracheal airway epithelia. These anesthetic combinations and low temperature conditions are often used in the setting of cardiopulmonary bypass surgery, surgical repair of congenital heart disease, and cardiac intensive care. C57BL/6J mouse tracheal epithelia were excised and cilia dynamics were captured by videomicroscopy following incubation at 15, 22-24, and 37°C with different combinations of therapeutic concentrations of dex (10 nM), fen (10 nM), and iso (0.01%). Airway ciliary motion was assessed and compared across conditions by measuring ciliary beat frequency and ciliary flow ...
Dexmedetomidine and fentanyl exhibit temperature dependent effects on human respiratory cilia
Frontiers in pediatrics, 2015
Dexmedetomidine (dex) is commonly used in intensive care due to its effective sedation and analgesia with few adverse effects and minimal respiratory depression. However, we recently observed that exposing mouse epithelial respiratory cells to dex decreased ciliary beat frequency (CBF), suggesting dex may pose pulmonary risk. The purpose of this study is to determine the effects of dex at clinically relevant doses on CBF in human respiratory epithelia. Human nasal epithelial cilia were obtained from the inferior nasal turbinate with a rhinoprobe and placed in culture medium at 15°C and 37°C. At 5 and 30 min, video-microscopy was used to assess CBF, either without (control) or with different concentrations (1, 5, and 10 nM) of dex, fentanyl (fen), and dex + fen combination. At 15°C, CBF was lower in the dex group compared to controls at 5 and 30 min. At 37°C, there was a significant increase in CBF with dex at 5 and 30 min, except for dex at 5 nM after 5 min, which showed a significa...
British Journal of Pharmacology, 1990
A method has been used in guinea-pig isolated tracheal rings to achieve selective drug entry from the adventitial or mucosal surface. A study has been made of the effects of epithelium removal on responses to spasmogens entering the tissue solely from the adventitial or the mucosal surface. 2 Cumulative concentration-response curves for KCl (1 to 100mM), acetylcholine (0.1 uM to 10mM) and histamine (1 UM to mM) were constructed in intact and epithelium-denuded tracheal rings in circumstances where drug entry was unrestricted or restricted to the adventitial or mucosal surface. 3 Epithelium removal did not alter the responsiveness or sensitivity of tracheal rings to KCl either when drug entry was unrestricted or when drug entry was restricted to the adventitial or mucosal surface. 4 When acetylcholine entered from the mucosal or adventitial surfaces of intact tracheal rings its concentration-response curve was displaced to the right with respect to that obtained for unrestricted drug entry. A greater rightward shift was observed for mucosal drug entry than for adventitial drug entry. Epithelium removal potentiated acetylcholine entering from the mucosal surface to a greater extent (27.5 fold) than it potentiated acetylcholine entering from both surfaces (4 fold). Epithelium removal did not potentiate effects of acetylcholine entering from the adventitial surface alone. 5 In intact tracheal segments, concentration-response curves for histamine entering from the mucosal surface were displaced to the right compared with those for histamine entering in an unrestricted fashion or from the adventitial surface alone. This displacement was absent in epithelium-denuded preparations. Epithelium removal potentiated (2-3 fold) histamine entering from the mucosal surface or entering in an unrestricted way. It did not potentiate histamine entering from the adventitial surface alone. 6 Our findings suggest that the epithelium does not modulate tracheal responses to KC1. Its ability to modulate responses to acetylcholine and histamine is observed when these spasmogens enter the tissue from the mucosal surface but not when they enter from the adventitial surface. The mechanism by which epithelium removal preferentially potentiates acetylcholine and histamine entering from the mucosal rather than the adventitial surface remains to be determined.
Effects of dantrolene on the responses to methylxanthines in the isolated guinea-pig trachea
European Journal of Pharmacology, 1991
The effect of dantrolene on the responses to methylxanthines (caffeine and theophyiline) and a fl-adrenoceptor agonist (salbutamol) was studied in isolated guinea-pig trachea. Caffeine and theophylline (1 #M-10 mM) and salbutamol (1 nM-10 #M) produced concentration-dependent relaxation of spontaneous and stimulated (acetylcholine 1 mM) tone. Responses to high concentrations (10 raM) of caffeine and theophylline added to tracheal strips either unstimulated (spontaneous tone) or indomethacin (2.8 laM)-treated were reversed to contractions in the presence of dantrolene (3 #M-0.3 mM). This effect was not observed for salbatamol or when relaxant responses to the agonists were generated in pre-contracted (acetylcholine 1 mM) strips. Dantrolene inhibited concentration dependently the contraction evoked by caffeine (1 raM) in indomethacin (2.8 ~tM)-treated strips at 20°C. This effect of dantrolene was attenuated in a low Ca 2+ (0.8 mM) medium or when the bath temperature was lowered to 10 ° C. Although an intracellular site of action cannot be excluded these results suggest that dantrolene mainly interferes with transmembrane Ca 2+ movements in the guinea-pig trachea.