Mild isocapnic hypoxia enhances the bronchial response to methacholine in asthmatic subjects

We studied the effect of mild isocapnic hypoxia (FIO2 = 15.5%) on lung mechanics, heart rate, circulating plasma catecholamines, and bronchial responsiveness to methacholine in ten asthmatic adults. Hypoxia did not alter lung mechanics (i.e., dynamic pulmonary compliance [CLdyn], pulmonary resistance [RL]) nor did it increase plasma catecholamines, but it significantly increased bronchial responsiveness to aerosolized methacholine, as assessed by the fall in forced expiratory volume in one second (FEV1: 1.2 +/- 0.18 versus 0.9 +/- 0.14 L/s, p less than 0.05), the rise in RL (RL: 19.1 +/- 1.4 versus 8.4 +/- 1 cm H2O/L/s, p less than 0.05), and the steeper slope of the dose-response curve to methacholine. We concluded that the hypoxic characteristic of asthmatic attacks may aggravate airflow obstruction.     

Effect of eucapnic hypoxia on bronchomotor tone and on the bronchomotor response to dry air in asthmatic subjects

Because hypoxia has been shown to cause bronchoconstriction and to potentiate bronchomotor responsiveness in animals, we investigated whether hypoxia has similar effects in subjects with asthma. We measured specific airway resistance (SRaw; the mean of 5 sequential readings taken 30 s apart) before and immediately after each of 15 asthmatic subjects breathed a mixture of 8% O2 in N2 until hemoglobin saturation (SaO2; by ear oximetry) fell to 80% or less for at least 2 min. We maintained end-tidal CO2 at resting levels, the temperature of the inspirate at 22.0 +/- 1.1 degrees C, and the dew point at 18.5 +/- 1.6 degrees C (mean +/- SD). The SaO2 fell to 70 +/- 8%; minute ventilation rose to 28.4 +/- 8.5 L/min, and heart rate rose by 27 +/- 6 beats/min. The SRaw did not increase significantly in the group (baseline SRaw, 6.61 +/- 2.36; posthypoxia SRaw, 6.69 +/- 2.21 L X cm H2O/L/s) or in any subject. To determine if hypoxia increases bronchomotor responsiveness, we also compared the responses to eucapnic hyperpnea with dry air and with dry gas mixtures of 7 to 10% O2 in N2 in a randomized, double-blind sequence in 9 of the subjects. We measured SRaw in each subject before and after stepwise increases in minute ventilation, for 3 min at each level, until SRaw doubled or until the subject's maximal voluntary ventilation was achieved. The SaO2 fell to 82% or less at each level of ventilation with the hypoxic gas mixture. The 2 stimulus-response curves thus obtained did not differ in any subject.(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparison between the airway response to isocapnic hyperventilation and hypertonic saline in subjects with asthma

We compared the response to isocapnic hyperventilation (ISH), where both cooling and drying of the mucosa occur, with the response to inhaling aerosols of hypertonic saline (HS), where airway osmolarity increases without airway cooling. We studied nine subjects on two days. For ISH, subjects ventilated at 70% of their estimated maximum voluntary ventilation (MVV). For HS, they inhaled aerosols of 2.7, 3.6, or 4.5% saline. The concentration that was used depended on the rate of ventilation during ISH. For both challenges the stimulus was given for one minute. Forced expiratory volume in one second (FEV1) was measured once between each minute, and the challenge ceased when the FEV1 did not change for two successive minutes. A plateau in FEV1 occurred after 8.1 +/- 2.4 (mean +/- 1 SD) min of ISH, and 8.3 +/- 2.4 min of HS. The lowest FEV1 (% predicted) after ISH was 45 +/- 16% and after HS was 51 +/- 18% (r = 0.93). However, the maximum responses occurred after the final challenge and were not the same as the plateau. For HS, the plateau represented 89 +/- 11% of the maximum response which developed within one minute of the final challenge. For ISH, the plateau was only 56 +/- 26% of the maximum response, which developed within 5.2 +/- 2.9 min after challenge. The similarities in the response to these challenges are consistent with the hypothesis that ISH induces asthma via hyperosmolarity. The delayed response to ISH suggests that cooling may delay the response to hyperosmolarity.     

Comparative effects of volume history on bronchoconstriction induced by hyperventilation and methacholine in asthmatic subjects

The aim of this study was to find out if bronchodilatation following deep inspiration can be induced by the inhalation of a "natural" stimulus (hyperventilation of cold dry air), and if the effect is similar to that induced by methacholine. After baseline assessment of lung resistance (RL), 10 asthmatic subjects were asked to inhale cold dry air for 3 min. RL was monitored continuously for 3-4 min, at which time subjects were asked to take a fast deep inspiration. After recovery, the manoeuvre was repeated and RL was reassessed. The manoeuvre was then repeated a third time. After functional recovery, progressive doses of methacholine were inhaled until the increase in RL was comparable to that obtained after hyperventilation (56 +/- 16% and 65 +/- 24%, respectively, mean +/- SD, NS). The same deep inspiration manoeuvre was repeated three times with recovery as after hyperventilation of cold dry air. Maximum changes in RL were not significantly different after each of the three manoeuvres for either type of bronchoconstriction. The mean fall in RL was 14.2 +/- 9.9% after hyperventilation and 16.4 +/- 10.5% after methacholine. There was a satisfactory correlation (r = 0.80, p less than 0.01) between the bronchodilatation after deep inspiration for both types of stimuli. We conclude that the bronchodilator effect of deep inspiration is no different using either a pharmacological stimulus (methacholine) or a "natural" stimulus (hyperventilation of unconditioned air). These results show that assessing the response to hyperventilation with manoeuvres requiring deep inspiration, forced expiratory volume in one second (FEV1) may alter airway tone in a way similar to pharmacological stimuli.     

Bronchial response to methacholine in parents of asthmatic children

Cumulative dose response curves to inhaled methacholine were established in 28 parents of asthmatic children, seven parents of healthy children, and four asthmatic patients. Bronchial sensitivity was defined as the dose of methacholine causing a 25 percent decrease in specific airway conductance while bronchial reactivity was determined by the slope of the cumulative dose response curve. Results indicated that parents with allergic rhinitis or airflow limitation in small airways may represent a high risk group, while parents with no atopy and normal pulmonary functions may reflect only the inherited characteristics of bronchial response.     

Different response to doubling and fourfold dose increases in methacholine provocation tests in healthy subjects

RATIONALE: In a modified methacholine provocation test that was used to study changes in airway responsiveness to occupational irritants or sensitizers in healthy subjects, two protocols were used: a long protocol (doubling methacholine concentrations between dose steps) or a short protocol (fourfold increases in concentration). This modified methacholine provocation allows measurements of the provocative dose causing 20% decrease in FEV(1) (PD(20)) in a high proportion of a normal population. METHODS: The distribution of PD(20) was investigated in healthy nonatopic men without history of allergy or asthma symptoms using the long protocol (n = 101) or the short protocol (n = 309). In addition, 30 healthy subjects underwent methacholine provocation tests using both protocols. RESULTS: PD(20) was defined in 79% of subjects with the long protocol and in 48% of subjects with the short protocol. The provocative concentration of methacholine causing a 20% decline in FEV(1) (PC(20)) and PD(20) were significantly lower using the long protocol: long-protocol PC(20) (median [25th to 75th percentile]), 19.9 mg/mL (3.9 to > 32 mg/mL) compared with short-protocol PC(20), > 32 mg/mL (8.7 to >32 mg/mL; p < 0.0001); long-protocol PD(20), 4.2 mg (1.6 to 20 mg) compared with short-protocol PD(20), > 13.7 (2.6 to > 13.7 mg; p = 0. 006). The differences in PD(20) using short and long protocols were confirmed in a randomized trial of 30 healthy subjects tested with both protocols. CONCLUSION: Using doubling concentrations, PC(20) and PD(20) could be defined in a higher proportion of healthy subjects than a protocol using fourfold dose increases. Furthermore, the doubling protocol results in a PD(20) estimate that is less than half the value obtained when using a protocol with fourfold concentrations between dose steps. The difference remains, whether the methacholine effect is regarded as cumulative or noncumulative. The explanation for the difference between the protocols is unclear.     

Bronchial reactivity increases soon after the immediate response in dual-responding asthmatic subjects

To determine whether bronchial reactivity is augmented soon after an allergen-induced immediate asthmatic response, we compared reactivity to histamine before and immediately upon resolution of the immediate asthmatic response in seven subjects with mild asthma who were known to develop dual asthmatic responses after inhalation of Kentucky bluegrass allergen. Using a body plethysmograph and quiet breathing technique, specific airway resistance (SRaw) and reactivity to aerosol histamine were assessed on two days prior to allergenic challenge. The dose of histamine that doubled SRaw (PC200His) was determined by interpolation from histamine dose-response curves. On the day of allergenic challenge, each subject inhaled a concentration that was sufficient to induce a dual asthmatic response. Upon resolution of the immediate asthmatic response (45 to 105 minutes) after allergen, the PC200His in all cases had decreased more than 50 percent of its original value (PC200His for the group was 0.29 +/- 1.42 mg/ml [mean +/- SE], compared to 0.84 +/- 1.23 mg/ml initially). Seven or more days after the allergen, each subject had a PC200His comparable to original values. Our data indicate that airway reactivity in dual-responding asthmatic subjects markedly increases soon after the immediate asthmatic response and much before the late asthmatic response manifests clinically. Whether this early increase in bronchial reactivity is a putative requirement for, or shares common characteristics with the late asthmatic response requires further study.     

CO2 response and pattern of breathing in patients with symptomatic hyperventilation, compared to asthmatic and normal subjects

We studied six patients with symptomatic hyperventilation, using new techniques to quantify baseline variability of respiratory variables, and to assess CO2 sensitivity around the control point using a stimulus not detectable by the subject. We compared them with six normal subjects and six patients with mild asthma. Symptomatic hyperventilators had normal mean ventilation and end-tidal carbon dioxide tension (PETCO2) at rest. Asthmatic subjects had higher ventilation and lower PETCO2. Symptomatic hyperventilators had a larger number of sighs and abnormally wide fluctuations in baseline for inspiratory time, expiratory time, and PETCO2. These could not be explained by an abnormal ventilatory response to a transient CO2 input; the transient response near the control point was undoubtedly normal.     

Intraesophageal acid perfusion sensitizes the esophagus to mechanical distension: a Barostat study

OBJECTIVE: The pathogenesis of noncardiac chest pain is unclear. Increased gastroesophageal reflux and decreased pain thresholds to intraesophageal balloon distension have been demonstrated in a proportion of such patients. We aimed to investigate whether acid exposure sensitizes esophageal mechanoreceptors in healthy volunteers. METHODS: After an overnight fast, an infinitely compliant balloon, 4.5 cm in length and mounted on a multilumen transnasal manometry catheter, was placed 8.5 cm above the lower esophageal sphincter in 12 healthy male volunteers aged 18-39 yr. After determination of the minimal distending pressure, the balloon was inflated up to 48 mm Hg by means of a computer-controlled barostat (G & J Electronics, Canada). Graded stepwise distensions were interspersed with random decreases in pressure to two-thirds of the previous value. At each pressure level, the subjects were asked to report on sensation and the presence of pain. Baseline distension was repeated to determine reproducibility of the pressure/volume relationship and also the perception and pain thresholds. After the baseline distension sequence, the esophagus was perfused for 20 min (at 7 ml/min) with either normal saline (control) or 0.1 N hydrochloric acid at 37 degrees C on a random basis. RESULTS: Basal sensory thresholds varied widely (first perception 5-36 mm Hg, pain 8 > or = 43 mm Hg). Two subjects did not experience pain up to the maximum distending pressure (42 and 43 mm Hg, respectively, after correction for the minimal distending pressure). Esophageal body compliance was similar on repeat distension. Sensory thresholds were reproducible with different distensions (perception r = 0.99, pain r = 0.95). Saline resulted in no significant changes in perception or pain thresholds. Acid perfusion reduced first perception (median before and after acid, 15 mm Hg and 8 mm Hg, respectively, p = 0.05) and pain threshold (median before and after acid, 32.5 mm Hg and 26.5 mm Hg, respectively, p = 0.05). When compared to changes after saline perfusion, acid perfusion reduced the perception threshold (median change, -3.8 mm Hg vs 0 mm Hg, p = 0.04) and tended to reduce the pain threshold (median change, -3.75 mm Hg vs +0.75 mm Hg, p = 0.09). CONCLUSIONS: Intraesophageal balloon distension using a barostat is a reproducible method of measuring esophageal body compliance and sensory thresholds. Acute exposure to acid seems to sensitize the esophagus to perception from intraluminal balloon distension.     

Airway cough sensitivity to inhaled capsaicin and bronchial responsiveness to methacholine in asthmatic and bronchitic subjects

The objective of this study was to evaluate the effect of chronic airway inflammation on airway cough sensitivity and non-specific bronchial responsiveness, and the relationship between them. The capsaicin cough threshold, defined as the lowest concentration of capsaicin causing five or more coughs, and non-specific bronchial responsiveness, defined as the methacholine concentration causing a 20% fall in forced expiratory volume in 1 s (FEV1) (PC20-FEV1), were measured in 18 asthmatic, 13 bronchitic (sinobronchial syndrome) and 28 healthy non-atopic subjects. All subjects were non-smoking men. The geometric mean values (mumol) of the cough threshold were 18.9 (GSEM 1.29), 8.69 (GSEM 1.29) and 27.6 (GSEM 1.31) in asthmatic, bronchitic and normal subjects, respectively. The value in bronchitic subjects was significantly lower (P < 0.02) than that in normal subjects. The geometric mean value of PC20-FEV1 in asthmatic subjects (0.48 mg/ml (GSEM 1.38)) was significantly lower than that in bronchitic subjects (18.5 mg/ml (GSEM 1.75)) (P < 0.001). There was no correlation between cough threshold and PC20-FEV1 values (correlation coefficient (r) = 0.155). These results indicate that cough sensitivity is potentiated by chronic airway inflammation in bronchitis but not in asthma, and suggest that cough sensitivity and bronchial responsiveness may be independently potentiated by different mechanisms resulting from chronic airway inflammation.     

Modulation of the bronchomotor effects of chemical mediators by prostaglandin F2 alpha in asthmatic subjects

Prostaglandin F2 alpha (PGF2 alpha) is generated by human lung tissue in response to a number of stimuli and is widely viewed as a bronchoconstrictor mediator. We have shown that aerosolized PGF2 alpha in concentrations between 1 and 100 micrograms/ml caused dose-related bronchoconstriction, but that continued stimulation at higher concentrations resulted in a partial return of pulmonary function toward control, suggesting that airways were refractory to further stimulation. To explore the mechanism and specificity of airway refractoriness induced by PGF2 alpha, we examined bronchomotor responses evoked by repeated PGF2 alpha stimulation, repeated histamine stimulation, and PGF2 alpha stimulation followed by histamine. Studies were carried out on 3 separate days in 7 subjects with allergic asthma. For each subject the aerosol concentration of each agonist remained constant throughout the study. Responses were measured as the percent change in FEV1 versus time, and comparisons were made between the first and second agonist challenge of each study day. We found that prior stimulation with PGF2 alpha resulted in diminished airway responsiveness, not only to PGF2 alpha but to histamine as well. In contrast, similar refractoriness could not be induced by repeated histamine stimulation, indicating that the PGF2 alpha-induced decrease in responsiveness was not a nonspecific effect of bronchoconstriction per se. Further, the finding that PGF2 alpha caused a decrease in the response to histamine suggests that diminished airway responsiveness was not due to down-regulation of specific PGF2 alpha receptors. Our findings suggest that in addition to its bronchoconstrictor properties, PGF2 alpha may play a role in the modulation of acute airway responses.     

Duration of tachyphylaxis in response to methacholine in healthy non-asthmatic subjects

It is well recognized that bronchial responsiveness to methacholine is reduced after methacholine-induced bronchoconstriction in non-asthmatic subjects, but not in asthmatic subjects. However, it is unknown how long the methacholine tachyphylaxis lasts. The present study was conducted to elucidate duration of the methacholine tachyphylaxis in healthy non-asthmatic subjects. Measurements of methacholine responsiveness were repeated six times at intervals of 1 h and 1, 2, 3 and 7 days in eight healthy non-asthmatic young female subjects in whom methacholine concentrations causing a 20% fall in forced expiratory volume in 1 sec (FEV1; PC20-Meth) were 40 mg/mL or less. Geometric mean value (GSEM) of PC20-Meth was 10.6 (1.44) mg/mL at the first challenge, 63.4 (1.85) at the 1-h interval, 50.2 (1.67) at the 1-day interval, 49.7 (1.68) at the 2-day interval, 17.3 (1.51) at the 3-day interval and 13.1 (1.44) mg/mL at the 7-day interval. The values at intervals of 1 h to 3 days were significantly greater than the initial value. These results indicate that measurements of methacholine responsiveness should be separated by at least 7 days to avoid the tachyphylaxis when the tests are repeated in non-asthmatic subjects.     

Effect of circadian rhythm on bronchomotor tone after deep inspiration in normal and in asthmatic subjects

Bronchomotor tone after deep inspiration and bronchial responsiveness to methacholine were studied at 4:00 A.M. and 4:00 P.M. in 14 normal and 13 asthmatic subjects. Bronchomotor tone was assessed with respiratory resistance (Rrs) measured by the forced oscillation method. Bronchial responsiveness to methacholine and baseline Rrs were higher at 4:00 A.M. than at 4:00 P.M. in both normal and asthmatic subjects (p less than 0.01). The difference in methacholine threshold between 4:00 P.M. and 4:00 A.M. In asthmatics was similar to that in normal subjects. Immediately after deep inspiration, Rrs decreased more at 4:00 A.M. than at 4:00 P.M. In normal subjects. In contrast, asthmatic subjects showed a significantly greater immediate increase in Rrs after deep inspiration at 4:00 A.M. than at 4:00 P.M. It is suggested that the bronchoconstrictive effect after deep inspiration is a distinguishing characteristic of asthmatics.     

Kinetics of the recovery from bronchial obstruction due to hyperventilation of cold air in asthmatic subjects

The timecourse of recovery from bronchial obstruction due to inhaled cold air was studied in eight adult asthmatic subjects. On the first visit, bronchial responsiveness to inhaled histamine was assessed. On the other two visits, after assessment of baseline lung resistance (RL) and spirometry, dry cold (-20 degrees C) air was inhaled for three minutes. RL was monitored continuously until its return to baseline +/- 20%. The baseline concentration of histamine causing a 20% fall in FEV1 (PC20) varied from 0.03 to 5.9 mg.ml-1. The mean maximum increase in RL was 2-fold (2.03 +/- 0.41) and was reached 2-11 min after the challenge. RL values were linearly correlated to time (r2 values greater than 0.80 in 14/16 instances). The two slopes of recovery were not significantly different. Slopes of recovery and total time of recovery (14-55 min) varied greatly between subjects. No relationship was found between baseline airway calibre, bronchial hyperresponsiveness and maximal increase in baseline RL on the one hand and the slopes of recovery on the other.     

Thromboxane A2 could be involved in bronchial hyperresponsiveness to methacholine in asthmatic subjects but not in bronchitic subjects

To determine whether the involvement of thromboxane A2 in bronchial hyperresponsiveness is specific to asthma, we examined the effects of a selective thromboxane synthetase inhibitor (OKY-046) and a cyclooxygenase inhibitor (indomethacin) on bronchial responsiveness to methacholine in patients with bronchial asthma and chronic bronchitis. The provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20-FEV1) was measured before and after oral administration of OKY-046 and indomethacin in eight asthmatic and 10 bronchitic subjects. Baseline FEV1 value was not altered by OKY-046 or indomethacin. The geometric mean value of PC20-FEV1 increased significantly (p less than 0.005) from 1.78 to 4.27 mg/ml after OKY-046 in asthmatic subjects, but not in bronchitic subjects. On the other hand, PC20-FEV1 was not altered by indomethacin in all subjects. It was concluded that the involvement of thromboxane A2 in bronchial hyperresponsiveness may be specific to asthma.     

Dose-response effects of methacholine in normal and in asthmatic subjects. Relationship between the site of airway response and overall airway hyperresponsiveness

We examined the dose-response curves to methacholine in 6 normal subjects and 13 asthmatics by simultaneous assessment of respiratory resistance (Rrs) and anatomic dead space (VDan). Methacholine was continuously inhaled in stepwise incremented concentrations during tidal breathing until a nearly twofold increase in respiratory resistance (Rrs) was observed. Large airway response was determined by VDan, and overall airway response was determined by Rrs. Small airways response was inferred from Rrs when the decrease in VDan was slight. Respiratory resistance was measured with the 5-Hz oscillation technique, and the VDan was measured by Langley's method (14) with CO2 as the test gas, and both were recorded simultaneously breath by breath. In the normal subject, VDan decreased by 28 +/- 7% (mean +/- SD) and Rrs increased simultaneously by 100%, suggesting a large airways responder. Five asthmatics were large airway responders in a manner similar to that of the normal subjects, but in 8 asthmatics, VDan decreased by 10% or less, whereas Rrs increased by 100%, suggesting that the increase in Rrs was due to an increase in small airways resistance (small airways responder). In the asthmatic subjects, small airways responders showed more hypersensitivity than did large airways responders (p less than 0.01). These results suggest that the site of airway response is one of the determining factors in bronchial hypersensitivity.     

The effect of inhaled corticosteroids on the maximal degree of airway narrowing to methacholine in asthmatic subjects

Airway hyperresponsiveness in asthma is characterized by an increase in sensitivity and in maximal response to airway-narrowing stimuli. Long-term therapy with inhaled corticosteroids is known to reduce airway hypersensitivity in asthmatic patients. To investigate whether these drugs also reduce the maximal degree of airway narrowing we studied the effects of inhaled budesonide on the maximal response plateau of the dose-response curve to inhaled methacholine in mildly asthmatic patients in whom a raised plateau could be measured. Sixteen atopic patients with mild asthma were placed randomly into two parallel treatment groups to receive double-blindly either budesonide (400 micrograms twice daily) or placebo, inhaled via a Turbuhaler, for 4 wk. Before treatment, after 2 and 4 wk of treatment, and after 2 and 4 wk of wash-out, complete dose-response curves to methacholine were obtained using a standardized 2-min tidal breathing method. The response was measured by FEV1, expressed in % fall from baseline. A plateau on the log dose-response curve was considered if three or more data points fell within a 5% response range. The maximal response was obtained by averaging the values on the plateau (MFEV1), and the sensitivity was calculated from the provocative concentration of methacholine, causing a 20% fall in FEV1 (PC20). After 4 wk of budesonide treatment, mean MFEV1 decreased from 41.6 to 33.7% fall (p = 0.0004). The changes in MFEV1 were significantly different between placebo and budesonide (p = 0.03). The geometric mean PC20 increased from 3.4 to 6.3 mg/ml (p = 0.02), but the changes in PC20 were not different between the two groups (p = 0.23).(ABSTRACT TRUNCATED AT 250 WORDS)     

Omeprazole reduces the response to capsaicin but not to methacholine in asthmatic patients with proximal reflux

OBJECTIVE: To study the relationships between airway responsiveness to methacholine and capsaicin, proximal or distal reflux and the effects of short-term acid inhibition. MATERIAL AND METHODS: Twenty-nine asthmatics, not taking steroids regularly, underwent respiratory symptom measurements, 24-h dual-probe pH monitoring, and challenges with methacholine and capsaicin. Challenges and symptom measurements were repeated after 12 days' omeprazole treatment (20 mg b.i.d.). The results (median and range) were expressed as PD20 methacholine (mg) and PD5 capsaicin (dose causing five coughs, nmol). RESULTS: Seventeen patients presented pathological reflux in the distal esophagus, and 17 in the proximal esophagus. At baseline no correlation was found between PD20 or PD5 and reflux. Treatment with omeprazole did not change bronchial responsiveness to methacholine (basal: 0.16 mg, 0.02-1.27; omeprazole: 0.15 mg, 0.02-1.60); omeprazole decreased the tussive response to capsaicin (basal: 0.08 nmol, 0.08-2.46; omeprazole: 0.61 nmol, 0.08-9.84, p<0.001) only in patients with pathological reflux. The decrease was positively correlated with proximal acid exposure (r2=0.70, p<0.001). Omeprazole reduced asthma symptoms in patients with proximal reflux, cough in those with proximal or distal reflux. CONCLUSIONS: In asthmatics, inhibition of gastric acid secretion does not influence bronchial hyperresponsiveness but decreases tussive sensitivity and this effect is related to proximal reflux.     

The relative responsiveness to inhaled leukotriene E4, methacholine and histamine in normal and asthmatic subjects

The relative bronchoconstricting potencies of leukotriene E4 (LTE4) methacholine and histamine have been compared in asthmatic and normal subjects. LTE4 responsiveness in asthmatic subjects, as measured by the dose which produced a 35% fall in specific airways conductance (PD35), ranged from 0.06-24.4 nmol (geom mean 4.1 nmol, n = 20). This was significantly less than the PD35 in normal subjects (range 39.0-370 nmol, geom mean 105 nmol, n= 6; p less than 0.001). There was a correlation between LTE4 and methacholine responsiveness (r = 0.84, p less than 0.001) and between LTE4 and histamine responsiveness (r = 0.79, p less than 0.001). LTE4 was 73 times more potent than methacholine and 112 times more potent than histamine in asthmatic subjects. LTE4 was 20 times more potent than methacholine and 58 times more potent than histamine in normal subjects. LTE4 is a potent bronchoconstrictor agent, and LTE4 responsiveness correlates with both histamine and methacholine responsiveness.