Phasic changes in upper airway impedance

To identify within breath variations in the mechanical properties of the isolated upper airway, we examined changes in impedance spectra over the course of the respiratory cycle. Changes were evaluated with a modified forced oscillation technique applied to the isolated, sealed upper airways of nine anesthetized mongrel dogs. Upper airway impedance spectra were studied during sequential 350 msec epochs. We found spectral changes which were reproducible within the respiratory cycle. Impedance spectra revealed that during mid-inspiration at the point of peak upper airway muscle activity, the low frequency real part decreased and the imaginary part was less negative and less steep. During late inspiration and early expiration the impedance values returned to their end-expiratory values. The only significant change in parameter estimates from a three-parameter model indicated an increase in compliance. Since these changes correlated not only with tidal flow through the lower trachea and lung but also with upper airway muscle activation, we reasoned that changes in impedance could have resulted from an increase in upper airway size. Therefore, we used a sealed speaker system and, while the animal was apnoeic, evaluated impedance at two different airway pressures and the resultant volumes. The changes in impedance spectra with a volume increase were similar to those seen during spontaneous breathing efforts. We conclude that the mechanical properties of the upper airway change during the respiratory cycle and that these changes correlate with the respiratory activation of upper airway muscles. We suspect that these changes in input impedance could reflect a change in the size of the airway rather than a true increase in elasticity.     

Laryngeal receptors responding to transmural pressure, airflow and local muscle activity

The larynx has a rich sensory supply which is the main source of several respiratory reflexes. These reflexes, that influence both the patency of the upper airway and the pattern of breathing, are related to transmural pressure and/or airflow in the upper airway. Yet hardly any information is available on the response of laryngeal mechanoreceptors to transmural pressure and airflow. We recorded action potentials from single fibers separated from the superior laryngeal nerve of anesthetized dogs, breathing spontaneously either through a tracheostomy or the upper airway. The airway could be occluded above or below the larynx. On the basis of their behavior during tracheostomy breathing, upper airway breathing, tracheal occlusion and upper airway occlusion, laryngeal mechanoreceptors were classified as pressure receptors, flow receptors or 'drive' receptors (stimulated by the respiratory activity of upper airway muscles). Pressure receptors were encountered most frequently, representing 63.6% of our sample of 110 receptors, 'drive' receptors constituted 21.8% and flow receptors the remaining 14.6%. Our findings indicate that, even though the three types of receptors differ in sensory modality, they concur in exhibiting a predominant activity during inspiration. In fact, 65% of all receptors are active during eupneic inspiration. Moreover, their activity increases markedly during upper airway obstruction.     

Changes in inspiratory muscle electrical activity and upper airway resistance during periodic breathing induced by hypoxia during sleep

We hypothesized that: the balance of electrical activities between the upper airway and chest wall inspiratory muscles affects upper airway inspiratory caliber, and at low levels of central respiratory neural efferent activity, an imbalance between the electrical activities of these 2 inspiratory muscle groups exists that results in a decreased upper airway caliber. These hypotheses were tested during periodic breathing induced by mild hypoxemia in NREM sleep in 9 healthy male subjects. In 6 subjects during periodic breathing as central respiratory neural activity decreased, the tonic and phasic EMG activity of the upper airway inspiratory muscles decreased at a rate greater than that of the chest wall EMG activity. When the ratio of upper airway to chest wall EMG activity decreased below a critical level, which was reproducible across subjects, upper airway inspiratory resistance increased hyperbolically. Resistance at peak inspiratory flow increased from 4.10 +/- 0.97 (mean +/- SEM) to 48.70 +/- 21.00 cmH2O/L/s as tidal volume decreased from 0.79 +/- 0.12 to 0.20 +/- 0.02 L during periodic breathing in these subjects. In the 3 remaining subjects, the ratio of the upper airway to chest wall EMG activity did not decrease below the critical level as the activity of both muscle groups decreased during periodic breathing, and upper airway resistance did not increase. We conclude that within the confines of this study the nonlinear activation of upper airway and chest wall inspiratory muscles contributed to fluctuations in upper airway resistance observed during periodic breathing in sleep.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of upper airway pressure pulses on breathing pattern

Importance of the time of application of upper airway pressure pulses on breathing pattern was investigated in 19 anesthetized, spontaneously breathing rabbits. The upper airway was functionally isolated into a closed system. A servo-respirator, triggered by the inspiratory activity of the diaphragm, was used to apply pressure pulses to the isolated upper airway. Negative pressure pulses of -5, -10, and -15 cm H2O when applied in early inspiration (within the first half) produced a reversible inhibition of inspiration in most trails (86.2%). This resulted in a prolongation of inspiratory duration (TI) and a decrease in mean inspiratory drive (P.Dia/TI) whereas peak diaphragm (P.Dia) activity and expiratory duration (TE) remained largely unaffected. In the remaining 13.8% of trials, an irreversible inhibition with short TI and reduced P.Dia activity was observed. In contrast, with late application of negative pressure pulses the only significant change was a shortening of TI. When positive pressure pulses were applied during expiration, no significant change in TE occurred with either early or late application. A significant prolongation of subsequent TI was seen irrespective of the time of positive pressure application. These results indicate that time of application during the respiratory cycle is an important variable in determining the response to upper airway pressure pulses.     

Responses of upper airway muscles to gastrocnemius muscle contraction in dogs

We studied electromyographic (EMG) responses of the alae nasi (AN) and the posterior cricoarytenoid (PCA) muscles, which act as upper airway dilators, during contraction of gastrocnemius muscle in six chest-intact anesthetized dogs with spontaneous breathing and in four thoracotomized, phrenicotomized and mechanically ventilated dogs with right thoracic and left cervical vagotomy. Muscle contraction was phasically induced by electrical stimulation of the intact gastrocnemius nerve or the distal cut end of this nerve for 20-30 sec. Stimulation intensity was determined as twice the motor threshold in each dog. In chest-intact animals, phasic contraction induced by intact nerve stimulation produced initial rapid increases in upper airway muscle activity, but stimulation of the distal cut end of the nerve did not show the rapid increase in upper airway muscle activity. Furthermore, stimulation of the proximal cut end did not produce any transient response with the stimulation intensity used in this study. In chest-open and vagotomized animals with artificial ventilation, responses of the upper airway muscles to contraction during the intact nerve stimulation were observed. These results suggest that the contraction of the gastrocnemius muscle activates upper airway dilating muscles via reflex mechanisms.     

Cooling mediates the ventilatory depression associated with airflow through the larynx

Although constant airflow through the upper airway has been shown to induce ventilatory depression in anesthetized newborn animals, the role of laryngeal temperature in this response has not been studied. Experiments were performed in fourteen 1-5 day-old anesthetized puppies breathing through a tracheostomy. Tidal volume and laryngeal temperature were recorded while a constant stream of air (15-25 ml/sec) at room temperature was passed in the expiratory direction for 20 sec through the isolated upper airway. Warm (35-37 degrees C), humidified air at the same flow served as control. When laryngeal temperature was decreased by 7.5 +/- 0.9 degrees C, a marked change in breathing pattern was observed (VT = 54 +/- 5, TI = 187 +/- 33, TE = 636 +/- 179, VT/TI = 45 +/- 10% of control; n = 9). Warm air at the same flow induced no significant changes. Superior laryngeal nerve section abolished the effects of cooling on breathing pattern. In 5 puppies we compared the effect of 'fast' and 'slow' laryngeal cooling. Fast trials altered breathing pattern earlier than slow trials. We conclude that the depressant effect of airflow through the upper airway is entirely due to a decrease in laryngeal temperature and is mediated by superior laryngeal nerve afferents.     

Effect of hypercapnia on upper airway resistance and collapsibility in anesthetized dogs

The upper airway (UAW) is intrinsically unstable and susceptible to collapse when the negative inspiratory intraluminal pressure exceeds the stabilizing forces which prevent obstruction. In the present study we evaluated mechanisms by which UAW patency is maintained in the presence of increased inspiratory flows when respiration is stimulated. In seven anesthetized dogs breathing spontaneously through a low tracheostomy, the UAW was isolated by a second tracheostomy directed rostrally. UAW pressure-flow relationship and stability against collapse were evaluated during steady flow in the inspiratory direction while the animals were breathing 100% O2 or a hypercapnic gas mixture. The pressure-flow curves of the isolated UAW demonstrated the characteristic pattern of collapsible tubes. Steady state hypercapnia resulted in lower UAW resistance during both inspiration and expiration. UAW resistance decreased linearly as PCO2 and ventilation increased over the course of CO2 rebreathing. In addition, during hypercapnia the critical negative intraluminal pressure required to induce UAW collapse and obstruction increased from -4.3 +/- 0.9 to -8.5 +/- 1.5 SE cm H2O (p less than 0.01), indicating increased stability of the UAW. Since hypercapnia is known to stimulate UAW muscles, our findings suggest that increased UAW muscle activity improves UAW patency both by decreasing their resistance to airflow, and by increasing UAW walls rigidity and stability against collapse.     

Effect of cold air on laryngeal mechanoreceptors in the dog

We have previously described laryngeal receptors specifically activated by cooling. The aim of this study is to determine the effect of cold air on laryngeal mechanoreceptors responding primarily to transmural pressure and respiratory movements of the larynx. We have recorded action potentials from 30 single fibers in the peripheral cut end of the internal branch of the superior laryngeal nerve of 11 anesthetized, spontaneously breathing dogs. Of 29 receptors studied with a constant flow of cold air through the isolated upper airway 13 showed a marked reduction in their discharge (0 to 15% of control), 10 showed a moderate decrease (16 to 84% of control) and the remaining 6 were minimally affected. Seven of the 29 receptors showed, prior to the inhibition, a transient initial stimulation. Transient state responses of the most affected receptors lagged behind laryngeal temperature. Three of the most affected endings were also studied during spontaneous breathing of cold air; to a progressive decrease in laryngeal temperature corresponded a progressive decrease in receptor activity. Susceptibility of the receptors to laryngeal cooling and topical anesthesia did not closely correlate. Our results indicate that in evaluating the reflex responses to upper airway cooling both excitation of cold receptors and inhibition of laryngeal mechanoreceptors should be taken into account.     

Respiratory reflexes in the anesthetized miniature swine

To assess the suitability of the miniature swine for studies of the control of breathing we evaluated the response of these animals to commonly used respiratory stimuli. Hanford miniature pigs were anesthetized with alpha chloralose and allowed to breathe spontaneously. Rapid lung inflations induced a prolonged expiratory pause proportional to load. Mechanical stimulation of the upper airways induced coughing. Central venous injections of C-fiber stimulants produced bradycardia, hypotension with apnea and/or rapid shallow breathing. CO2 rebreathing increased ventilation primarily through an increase in tidal volume; inspiratory time was not changed. Bilateral vagotomy caused a slower, deeper pattern of breathing, and significantly attenuated the ventilatory response to CO2; all other reflexes were abolished by vagotomy. Cooling the vagus nerves caused reversible blockade of the cough, inflation and C-fiber mediated reflexes in that order. We conclude that the pig can serve as a useful animal in which to study the control of breathing.     

Local mechanisms drive genioglossus activation in obstructive sleep apnea

Individuals with obstructive sleep apnea (OSA) require increased pharyngeal muscle dilator activation during wakefulness to maintain upper airway patency. Negative pressure is one potential stimulus for this neuromuscular compensation. Individuals with OSA who have previously undergone tracheostomy provide an opportunity to study upper airway physiology in both the presence and absence of upper airway respiratory stimuli. If negative pressure (or another local airway stimulus) were important in driving pharyngeal dilator muscle activation, one would predict that during nasal breathing, the pharynx of a tracheostomized patient would be exposed to negative pressure, and that high levels of muscle activation would therefore be measured. Conversely, during breathing by the patient through the tracheal stoma, one would expect low levels of muscle activation in the absence of local stimuli. We measured a number of respiratory variables, including genioglossus activation under both nasal and tracheal stomal breathing conditions, in five patients. In all five patients there was a significant and substantial decrease in both peak phasic (100 +/- 0 to 53.4 +/- 9.2 arbitrary units [mean +/- SEM], p < 0.01) and tonic genioglossus activation (36.3 +/- 5.3 to 20.7 +/- 3.9 arbitrary units, p < 0.05) during stomal breathing as compared with nasal breathing. We conclude that local upper airway respiratory stimuli, possibly negative pressure, are important in mediating the increased pharyngeal dilator muscle activation seen in sleep apnea patients during wakefulness.     

Effect of neuromuscular blockade and assisted ventilation on breathing pattern, ventilation, and respiratory muscle function of anesthetized dogs

8 healthy dogs were anesthetized with a continuous infusion of pentobarbital (1 mg/kg/h) and were weakened but not paralyzed by intravenous succinylcholine (1 mg/kg/h). They were then studied during alternating periods of spontaneous breathing and assisted ventilation (IPPB). After succinylcholine, there was a significant increase in PaCO2, no significant change in respiratory frequency, a significant decrease in tidal volume, no significant change in P100 and a significant decrease in peak diaphragm EMG. Comparing periods of IPPB with periods of spontaneous breathing, there was a decrease in PaCO2 to a mean approximating that before succinylcholine, an increase in tidal volume, no change in frequency, and significant decreases in P100 and diaphragm EMG. In three experiments in which PaCO2 was maintained constant during IPPB, IPPB again resulted in a decrease in EMG and P100. Assisted mechanical ventilation of partially paralyzed dogs resulted in a fall in PaCO2 and a decrease in respiratory center output as measured by diaphragm EMG and P100. The fall in PaCO2 could be ascribed to decreasing the limited muscular work of breathing even in the presence of normal mechanics. A major part of the changes in EMG and P100 could be ascribed to chages in chemoreceptor drive but alteration of other inputs which were not specifically indentified, such as lung reflexes and/or chest wall reflexes, must also have had an effect.     

Effect of laryngeal anesthesia on pulmonary function testing in normal subjects

Pulmonary function tests (PFT) were performed on 11 normal subjects before and after topical anesthesia of the larynx. The PFT consisted of flow volume loops and body box determinations of functional residual capacity and airway resistance, each performed in triplicate. After the first set of tests, cotton pledgets soaked in 4% lidocaine were held in the pyriform sinuses for 2 min to block the superior laryngeal nerves. In addition, 1.5 ml of 10% cocaine was dropped on the vocal cords via indirect laryngoscopy. PFT were repeated 5 min after anesthesia. Besides routine analysis of the flow volume loops, areas under the inspiratory (Area I) and expiratory (Area E) portions of the loops were calculated by planimetry. Area I, peak inspiratory flow (PIF), as well as forced inspiratory flow at 25, 50, and 75% forced vital capacity (FVC), decreased after anesthesia. Peak expiratory flow decreased after anesthesia, but Area E and forced expiratory flow at 25, 50, and 75% FVC were unchanged. This protocol also was performed in 12 normal subjects with isotonic saline being substituted for the lidocaine and cocaine. In this group, no significant differences were observed when flow volume loop parameters were compared before and after topical application of saline. In 5 spontaneously breathing anesthetized dogs, posterior cricoarytenoid muscle and afferent superior laryngeal nerve activity were recorded before and after laryngeal anesthesia performed with the same procedure used in the human subjects. Laryngeal anesthesia resulted in a substantial decrease or a complete disappearance of afferent SLN activity recorded during unobstructed and obstructed respiration. The data suggest that laryngeal receptors help modulate upper airway patency in man.     

Effects of electrical stimulation of the genioglossus on upper airway resistance in anesthetized dogs

We examined the relationship between the frequency of stimulation of the genioglossus and upper airway resistance in six anesthetized dogs in the supine position. The upper airway was isolated from the lower airway by transecting the cervical trachea, and the pressure flow relationship of the upper airway was obtained by applying constant negative pressure (5, 10, and 20 cm H2O) to the proximal cut end of the trachea. Electrical stimulation of the genioglossus was performed at a constant voltage (10 to 20 V) and at various frequencies (as high as 100 Hz). Upper airway resistance (Rua) during both inspiration and expiration increased with an increase in tracheal negative pressure, and at each tracheal negative pressure Rua was significantly reduced by stimulation of the genioglossus. The effects of genioglossal muscle stimulation were nonlinearly dependent on the stimulating frequency. Below 50 Hz, Rua decreased markedly as the stimulating frequency was increased, but above 50 Hz, Rua plateaued at a minimum value. These findings suggest that at a stimulating frequency of more than 50 Hz, upper airway patency is stably maintained in anesthetized dogs.     

Effects of oral narcotics on sleep-disordered breathing in healthy adults

Alcohol and benzodiazepines may increase sleep-disordered breathing by decreasing activity of pharyngeal dilating muscles, favoring the development of obstructive apneas and hypopneas. Narcotics cause greater depression of wakeful respiration than the previously mentioned drugs; however, the influence of narcotics on the upper airway and breathing during sleep has not been studied. We, therefore, examined, in 12 healthy adults, the effects of oral hydromorphone hydrochloride (2 and 4 mg) on breathing during sleep and on a variety of awake respiratory variables (minute ventilation, gas exchange, and chemoresponsiveness). In addition, awake pharyngeal inspiratory airflow resistance was determined before and after narcotic administration to assess the drug's influence on patency of the upper airway. Following both doses, minute ventilation decreased, and carbon dioxide pressure increased. The 4-mg dose of hydromorphone hydrochloride also produced a significant decrement in the hypoxic ventilatory response, whereas hypercapnic responsiveness and pharyngeal resistance did not change following either dose of the drug. Despite the respiratory depression during wakefulness described previously, no significant change was observed in any measure of sleep-disordered breathing after either dose of narcotic. We conclude that in healthy individuals without suspected sleep apnea, oral hydromorphone in standard dosages does not significantly increase sleep-disordered breathing. This result may be due to a lack of selective depression of upper-airway muscular function by the doses of narcotic used.     

Determinants of rib motion in flail chest

We have previously developed a canine model of isolated flail chest to assess the effects of this condition on the mechanics of breathing, and these studies have led to the conclusion that the respiratory displacement of the fractured ribs is primarily determined by the fall in pleural pressure (Delta Ppl) and the action of the parasternal intercostal muscles. The present studies were designed to test the validity of this conclusion. A flail was induced in six supine anesthetized animals by fracturing both dorsally and ventrally the second to fifth ribs on the right side of the chest, after which the phrenic nerve roots were bilaterally sectioned in the neck. Sectioning the phrenic nerves caused a 34% decrease in Delta Ppl, associated with a 39% increase in parasternal intercostal inspiratory EMG activity (p < 0.05), and resulted in a marked reduction in the inspiratory inward displacement of the ribs. In three animals, the inward rib displacement was even reversed into a small outward displacement. When the airway was then occluded at end-expiration to increase Delta Ppl during the subsequent inspiration, all animals again showed a clear-cut inward rib displacement. These observations therefore confirm that in dogs with flail chest, the inspiratory displacement of the fractured ribs is set by the balance between the force related to pleural pressure and that generated by the parasternal intercostals. These observations also point to the critical importance of the pattern of inspiratory muscle activation in determining the magnitude of rib cage paradox in such patients.     

Effects of cooling on laryngeal reflexes in the dog

We investigated the reflex effects of laryngeal cooling on posterior cricoarytenoid (PCA) muscle activity, breathing pattern, arterial blood pressure and heart rate. We performed experiments on 9 anesthetized, spontaneously breathing dogs. Laryngeal temperature was decreased by passing cold air through the functionally isolated larynx while the dog was breathing through a tracheostomy. Inspiratory and expiratory durations, esophageal pressure, peak PCA activity, heart rate and blood pressure did not change significantly during laryngeal cooling. Upon interruption of cold airflow, while the laryngeal temperature was returning to control values, we assessed PCA response to upper airway occlusion. At laryngeal temperatures of 20-25 degrees C the peak PCA activity during upper airway occlusion was approximately 2/3 of that observed at control temperature (approximately equal to 33 degrees C). This difference was abolished by topically applied anesthetics or by superior laryngeal nerve section. In addition, we recorded from 4 laryngeal mechanoreceptors stimulated by negative pressure; their response to upper airway occlusion was reduced to 1/2 by laryngeal cooling. These results indicate that laryngeal cooling has a marked depressive effect on the PCA response to collapsing pressure in the larynx, thereby compromising the mechanism subserving upper airway patency.     

Respiratory afferent activity in the superior laryngeal nerves

This study evaluates the afferent activity in the superior laryngeal nerve (SLN) during breathing as well as during occluded inspiratory efforts. Experiments were performed in 11 anesthetized and spontaneously breathing dogs. Electroneurographic activity was recorded from the peripheral cut end of the SLN and, in 3 dogs, also from the contralateral vagus nerve. A tracheal cannula with a side arm allowed the bypass of the larynx during breathing and occluded efforts. A clear inspiratory modulation was present in all experimental conditions. Both peak and duration of the SLN activity decreased (87% and 89%) when breathing was diverted from the upper airway to the tracheostomy. Peak and duration of the SLN activity (as % of upper airway breathing) increased during occluded efforts; however, the increase was greater when the larynx was not by-passed (peak = 118% vs 208%, duration = 143% vs 178%). Section of the ipsilateral recurrent laryngeal nerve reduced the inspiratory modulation. Vagal afferent activity increased equally during tracheostomy and upper airway breathing and decreased markedly during tracheal and upper airway occlusions. Our results indicate that collapsing pressure in the larynx is the major stimulus in activating laryngeal afferents.     

Comparison of the responses of the diaphragm and upper airway muscles to central stimulation of the sciatic nerve

Electrical stimulation of the central end of the sciatic nerve was used to assess the effect of increased somatic sensory input on respiratory muscle electrical activity in anesthetized, spontaneously breathing dogs. Graded electrical stimulation of the sciatic nerve was associated with progressively greater activity of the upper airway dilating muscles (alae nasi, genioglossus, and posterior cricoarytenoid) as well as the diaphragm. Breathing frequency also increased because of a reduction in inspiratory and expiratory time. After cessation of stimulation of the sciatic nerve, increased activity of all the muscles studied persisted and only gradually returned to control levels. The responses to sciatic nerve stimulation were independent of the CO2 concentration of the inspired gas mixture. At any level of chemical drive electrical stimulation caused greater increases in the electrical activity of upper airway dilating muscles than that of diaphragm. Based on these results, it is concluded that stimulation of sciatic nerve activates upper airway muscles as well as the diaphragm, and the upper airway muscle activity is augmented to a greater degree than diaphragm activity. It seems possible that somatosensory afferent input produces unequal effects on different respiratory motoneurons.     

Genioglossal inspiratory activation: central respiratory vs mechanoreceptive influences.

Upper airway dilator muscles are phasically activated during respiration. We assessed the interaction between central respiratory drive and local (mechanoreceptive) influences upon genioglossal (GG) activity throughout inspiration. GG(EMG) and airway mechanics were measured in 16 awake subjects during baseline spontaneous breathing, increased central respiratory drive (inspiratory resistive loading; IRL), and decreased respiratory drive (hypocapnic negative pressure ventilation), both prior to and following dense upper airway topical anesthesia. Negative epiglottic pressure (P(epi)) was significantly correlated with GG(EMG) across inspiration (i.e. within breaths). Both passive ventilation and IRL led to significant decreases in the sensitivity of the relationship between GG(EMG) and P(epi) (slope GG(EMG) vs P(epi)), but yielded no change in the relationship (correlation) between GG(EMG) and P(epi). During negative pressure ventilation, pharyngeal resistance increased modestly, but significantly. Anesthesia in all conditions led to decrements in phasic GG(EMG), increases in pharyngeal resistance, and decrease in the relationship between P(epi) and GG(EMG). We conclude that both central output to the GG and local reflex mediated activation are important in maintaining upper airway patency.     

Leukotriene D4 (LTD4) induces mucus secretion from goblet cells in the guinea pig respiratory epithelium

To study the potential role of leukotriene (LTD4) as a mucus secretagogue, anesthetized and spontaneously breathing guinea pigs were intubated and challenged with various concentrations of an LTD4 aerosol. The resulting changes in airway resistance and compliance were then observed for 20 min, after which the animals were euthanized and the lower respiratory tract airways fixed for morphometric evaluation. Sections for these airways were stained with alcian blue-periodic acid Schiff (AB-PAS), photographed, and the content of AB-PAS positive granules in the epithelium of the extrapulmonary bronchi quantified. The fractional volume of mucus granules in the respiratory epithelial volume. Aerosol LTD4 produced a dose-dependent decrease in the granule fractional volume (GFV) over the range of 0.1 to 1 microgram/ml when compared with epithelia challenged with saline aerosols. Increasing the concentration of administered LTD4 from 1 microgram to 3 micrograms/ml produced further bronchoconstriction but had no further effect on the GFV. Decreases in GFV did not appear to be secondary to smooth muscle contraction since aerosols of other agonists (0.05% histamine and 1% acetylcholine), which yielded resistance changes similar to those of LTD4, did not effect the GFV. Pretreatment with an aerosol of the specific LTD4 receptor antagonist SK&F 104353-Z2 produced a dose-dependent inhibition of the changes in both the airway resistance and GFV. The data suggest that LTD4 mediates epithelial mucus secretion as well as bronchoconstriction in the guinea pig airway and may provide an additional therapeutic use for specific LTD4 receptor antagonists in the treatment of obstructive pulmonary disease.