Methacholine Inhalation Research Articles

アレルギー性鼻炎とその類似疾患の下気道過敏性

Perennial rhinitis was classified as allergic rhinitis, probable allergic rhinitis, vasomotor rhinitis or eosinophilic nonallergic rhinitis. Then these various types were classified according to whether there was any difference with respect to lower respiratory tract hypersensitivity for methacholine.The various types of perennial rhinitis were identified through eosinophilic cell number in nasal smears, allergen skin testing, and IgE RIST and IgE RAST determination. In addition, we carried out a methacholine nasal provocation test using an Astograph and an allergen nasal provocative test.Lower respiratory tract hypersensitivity was determined based on respiratory resistance, spirometry and a flow-volume curve before and after methacholine inhalation through the nose.The lower respiratory tract of the subjects with perennial rhinitis showed differences in terms of methacholine hypersensitivity. Allergic rhinitis showed methacholine hypersensitivity in the entire lower respiratory tract. Probable allergic rhinitis showed hypersensitivity in the large airway. Vasomotor rhinitis showed hypersensitivity in the relative large airway. Eosinophilic nonallergic rhinitis did not show hypersensitivity in the lower respiratory tract.

Relationship between bronchial hyperreactivity and symptoms of cardiac asthma in patients with non-valvular left ventricular failure.

To determine whether a relationship exists between bronchial hyperreactivity and cardiac asthma, which is commonly observed in patients with left heart failure, a methacholine inhalation test was performed in 15 patients with stable left ventricular failure (LVF) and 10 normal subjects. The subjects were divided into 3 groups based on symptoms of nocturnal coughing and/or wheezing in acute exacerbation of LVF. Group A consisted of 8 patients with nocturnal coughing and/or wheezing. Group B consisted of 7 patients without such symptoms, and Group C consisted of the 10 age-matched normal controls. Eleven of the 15 patients with LVF showed a significant increase in respiratory resistance in the methacholine inhalation test, as opposed to none of the normal subjects. The median cumulative dose which produced a 35% decrease in respiratory conductance (PD35Grs) was significantly lower in Group A than in Group B (1.45 log units and 1.90 log units, respectively, p < 0.05). The results of pulmonary function tests were not significantly different between Groups A and B. The minimum cumulative dose required to initiate a decrease in respiratory conductance from the baseline, as an index of bronchial sensitivity to methacholine, was significantly correlated with DLCO/VA (r = 0.710, p < 0.01). We conclude that bronchial hyperreactivity is responsible for cardiac asthma and that it might be related to pulmonary interstitial changes in stable patients with non-valvular LVF.

Maximal airway narrowing on the dose-response curve to methacholine is increased after exercise-induced bronchoconstriction.

The changes in airway responsiveness between before and after exercise in asthma are not well defined. We investigated the effect of exercise on PC20 (bronchial sensitivity) and maximal airway narrowing (MAN) on the dose-response curve to methacholine in 56 mildly asthmatic children. High-dose methacholine inhalation tests were performed before and 7 hr after exercise challenge. Methacholine PC20 was not changed by exercise, irrespective of exercise-induced bronchoconstriction (EIB). However, the subjects with (+)EIB displayed increased MAN after exercise, whereas those with (+/-)EIB or (-)EIB did not. The results showed that EIB may be followed by increased MAN but not by the change of bronchial sensitivity.

Magnitude and determinants of short-term tachyphylaxis to methacholine in subjects with symptomatic or asymptomatic airway hyperresponsiveness and in normal controls.

Tachyphylaxis to methacholine has been reported in nonasthmatic subjects. In a recent study on the prevalence of airway hyperresponsiveness (AHR) and atopy, we performed duplicate methacholine inhalation tests at a 60-min interval, in subjects with symptomatic asthma (n = 33), asymptomatic AHR (AAHR) (n = 72) and in a group of normal subjects (n = 130); 135/235 subjects were atopic. All subjects had a respiratory questionnaire, allergy skin prick tests, blood eosinophil counts and determination of total serum IgE level. In asthmatic subjects, PC20 just failed to be significantly higher on a second methacholine challenge (p = 0.09); when they were stratified according to severity of AHR and use of inhaled corticosteroids, we observed a significant increase in PC20 on the second test in asthmatic subjects with mild AHR not using corticosteroids (p < 0.01). In normal controls, PC20 methacholine was slightly increased on rechallenge (p < 0.01) as it was in those with AAHR (p < 0.01). There was no relationship between the magnitude of the change in PC20 and age, sex, baseline airway responsiveness, percent fall in FEV1 on the first challenge, atopic score, blood eosinophil counts and serum IgE levels. In conclusion, tachyphylaxis to methacholine is observed in normal or mild asthmatic subjects not using inhaled corticosteroids and in subjects with AAHR; however, in most subjects this change is of a small magnitude.

Methacholine-induced pulmonary gas trapping in guinea pigs, hamsters, mice, and rats.

Postmortem pulmonary gas trapping was investigated as an index of in vivo airway obstruction following methacholine inhalation in four different rodent species. Male guinea pigs (Hartley), hamsters (golden Syrian), mice (A/J, BALB/c, and ICR), and rats (Brown-Norway, Fischer 344, Lewis, and Sprague-Dawley) were exposed to aerosols of methacholine or sodium chloride. Maximum excised lung gas volumes (ELGV) of methacholine-exposed guinea pigs, hamsters, mice, and rats were 2.3-8.7 times those of sodium chloride-treated animals. Mean ELGV values of sodium chloride-exposed animals ranged from 1.50 +/- 0.20 ml/kg for guinea pigs to 2.75 +/- 0.20 ml/kg for Brown-Norway rats. Although all species responded to methacholine, guinea pigs were the most responsive, with approximately 1.6 microgram/kg of inhaled methacholine needed to increase ELGV to 200% of control. Compared with guinea pigs, hamsters, mice, and rats were 11- to 1,395-fold less responsive. Although hamsters, mice, and rats are less sensitive than guinea pigs to the airway-obstructive effects of methacholine, pulmonary gas trapping appears useful as a measure of airway responses in these species.

Effect of ozone exposure on maximal airway narrowing in non-asthmatic and asthmatic subjects.

1. Ozone is a major constituent of air pollution in the summer. Epidemiological studies have demonstrated that there is an increase in hospital admissions for respiratory diseases 1 day after peak levels of ambient ozone. This may be due to an increase in the responsiveness of the airways to bronchoconstrictor stimuli. 2. In the present study we therefore studied the effect of a controlled exposure to ozone on the maximal degree of airway narrowing to a non-specific bronchoconstrictor, methacholine, 12 h after exposure. Both non-asthmatic and mild-asthmatic volunteers were exposed to ozone. 3. The study had a single blind design. Experimental exposures were to filtered air, 0.40 ppm ozone and filtered air respectively, at 1-week intervals. The duration of each exposure was 2 h with alternating periods of 15 min rest and exercise. At 12 h after exposure, methacholine inhalation challenge tests and sputum induction were performed. 4. Twelve hours after exposure to ozone there was a significant increase in the maximal degree of airway narrowing to methacholine (P < 0.02) compared with exposure to air, in non-asthmatic as well as asthmatic subjects. These physiological changes were accompanied by a significant rise in the percentage of neutrophils in induced sputum (P < 0.02). All changes had returned to baseline values 1 week after exposure to ozone. 5. Exposure to ozone causes a transient increase in the maximal degree of airway narrowing to methacholine in both non-asthmatic and asthmatic subjects. These laboratory results, obtained using relatively high ozone exposure in carefully selected subjects, might provide an explanation for the temporal relationship between ambient ozone levels and hospital admissions for asthma.

Repeated measurement of respiratory function and bronchoconstriction in unanesthetized mice.

A noninvasive forced oscillation technique was used to determine respiratory function in unanesthetized and spontaneously breathing mice. Pseudorandom noise pressure variations in a frequency range of 16-208 Hz were applied to the body surface, and the flow response was measured at the nose. From the pressure-flow relationship, respiratory transfer impedance was calculated. Study of intra-animal variability on a short- and a long-term basis revealed that the real part of respiratory transfer impedance was reproducible within 9%. The imaginary part appeared less reproducible (within 22%). Furthermore, bronchoconstrictive responses were investigated and analyzed by evaluation of respiratory resistance as measured at 16 Hz (Rrs16). During the first 15 min after ovalbumin challenge in ovalbumin-sensitized mice, Rrs16 was significantly increased [49 +/- 7% (SE)]. Inhalation of methacholine in untreated mice induced an increase in Rrs16 of 75 +/- 16% (SE). In saline-challenged animals, no significant changes were observed. This method enables evaluation of long-term respiratory function in mice and appeared to be a sensitive measure for bronchoconstriction.

Rapid Onset of Tolerance to the Bronchoprotective Effect of Salmeterol

Twice-daily inhaled salmeterol for 4 weeks produces marked reduction in its acute bronchoprotective effect against methacholine. This investigation examined the onset of this effect over 5 days, and also assessed cross-tolerance with salbutamol. Ten asthmatic volunteers who were able to withhold beta 2-agonist therapy for 4 weeks before and during the study participated in a double-blind, crossover, placebo-controlled study with two random-order treatment periods: inhaled salmeterol, 50 micrograms twice a day for seven doses, and placebo in similar fashion. Methacholine inhalation tests were done 1 h after doses 1, 3, 5, and 7, and then 24 h after the last dose of the study inhaler 10 minutes after 200 micrograms of salbutamol. Baseline FEV1 value before doses 3, 5, and 7 of salmeterol (ie, 12 h after salmeterol) was significantly higher than all other (n = 7) values. Twenty-four hours after the last dose of salmeterol, the FEV1 was no different from that during the placebo period. The geometric mean methacholine concentration causing a 20% fall in FEV1 (PC20) after the first dose of salmeterol (6.1 mg/mL) was statistically similar to the value achieved 10 min after salbutamol after the placebo period (8.3 mg/mL), and these were significantly (analysis of variance, p < 0.00005) larger than the second, third, and fourth salmeterol days (3.4 mg/mL, 2.6 mg/mL, 1.9 mg/mL, respectively). The methacholine PC20 10 min after salbutamol measured after the salmeterol period was significantly lower than after placebo (2.3 mg/mL vs 8.3 mg/mL; p < 0.001). Tolerance to the acute bronchoprotective effect of salmeterol was significant after the first two doses and progressively increased to the seventh dose. Tolerance to the acute bronchoprotective effect of salbutamol was significant after regular use of salmeterol for seven doses.

Chronic Cough with a History of Excessive Sputum Production: The Spectrum and Frequency of Causes, Key Components of the Diagnostic Evaluation, and Outcome of Specific Therapy

To determine (1) the spectrum and frequency of causes of chronic cough with a history of excessive sputum production (CCS) and (2) the response of these causes to specific therapy.Prospective study utilizing the anatomic diagnostic protocol originally developed to diagnose chronic cough.Seventy-one immunocompetent adults who complained of expectoration of greater than 30 mL of sputum per day.University hospital pulmonary outpatient clinic.Patients were seen an average of 4.2 times over 4.6 months before a specific diagnosis was made. The cause of CCS was determined in 97%. It was due to one cause in 38%, 2 in 36%, and three in 26%. Postnasal drip syndrome (PNDS) was a cause 40% of the time, asthma 24%, gastroesophageal reflux disease (GERD) 15%, bronchitis 11%, bronchiectasis 4%, left ventricular failure 3%, and miscellaneous causes 3%. Among patients with a normal chest radiograph who were nonsmokers and not taking an angiotensin converting enzyme inhibitor; CCS was due to PNDS, or asthma, or GERD, or all three in 100% of cases. Chest radiograph, methacholine inhalation challenge, 24-h esophageal pH monitoring, bronchoscopy, and spirometry with bronchodilator each had a sensitivity and negative predictive value of 100%. Chest radiograph and barium swallow had positive predictive values of only 38% and 30%, respectively.(1) The anatomic diagnostic protocol for cough is also valid for CCS; (2) the major causes of chronic excessive sputum production and chronic cough are so similar that CCS should be considered a form of chronic cough; (3) the evaluation of CCS is more complicated and takes longer than the evaluation of chronic cough; (4) the major strength of the laboratory diagnostic protocol is that it reliably rules out conditions; (5) the outcome of specific therapy is almost always successful; and (6) the term "bronchorrhea" can be misleading if it is applied to excessive sputum production before a specific diagnosis of its source is made since the most common cause of excessive sputum that is expectorated (PNDS) is a disorder of the upper respiratory tract. Therefore, nonspecific therapies theoretically aimed at reducing mucus production in the lower respiratory tract are not likely to be helpful.

Age-related changes in bronchial hyperreactivity to methacholine in asthmatic children.

To evaluate the influence of aging on bronchial hyperreactivity (BHR) during the childhood period, age-related changes in bronchial reactivity to methacholine (BRm) in children from 2 to 13 yr of age were studied using the same method, employing a methacholine inhalation challenge with transcutaneous oxygen pressure (tcPO2) monitoring. Three hundred and thirty-nine asthmatic subjects (male:female = 200:139, aged [mean +/- SEM] 7.2 +/- 0.2 yr) and 107 age-matched controls (male:female = 55:52, aged 5.3 +/- 0.3 yr) were enrolled in this study. TcPO2 was measured by a tcPO2 monitor, and subsequent doses of methacholine were then doubled until a 10% decrease in tcPO2 from its baseline value was reached. The cumulative dose of methacholine at the inflection point of tcPO2 (Dmin-PO2) was considered to represent the BRm. For the sake of comparison, respiratory resistance (Rr) in subjects more than 6 yr old was measured by the oscillation technique during methacholine inhalation challenge, and the threshold point of Rr (Dmin-Rr) was also considered to represent the BRm. In the asthmatic children aged 2 to 7 yr, Dmin-PO2 decreased significantly from 12.2 +/- 2.1 to 3.1 +/- 0.8 units, but after age 8 yr the values gradually increased from 3.1 +/- 0.7 to 6.4 +/- 1.6 units. In children aged 6 to 13 yr, Dmin-Rr showed the same increase as Dmin-PO2, from 2.0 +/- 0.5 to 5.8 +/- 1.4 units. These age-related changes in BRm reflected in both Dmin-PO2 and Dmin-Rr were also seen in the age-matched controls.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of size and age of subject on airway responsiveness in children.

Methodologies used to assess airway responsiveness (AR) in children administer the same dosage schedule to all children despite the great range in the size of subjects. The aim of this study was to examine the hypothesis that the level of AR is size dependent within same-age cohorts and between different ages. Among a birth cohort of 1,037 New Zealand children participating in a longitudinal study, 818 had at least two measurements of airway responsiveness between ages 9 and 15 yr. Each child performed spirometry and a four-dose methacholine inhalation test. A continuous slope index of methacholine responsiveness was computed. AR slope indexes were analyzed using longitudinal methods, which included an indicator variable for subjects who reported having any wheeze. AR was lowest in both males and females in the upper quartile for height than those in the lower quartile, independently of age. AR tended to be higher (responded to lower concentrations of methacholine) in boys than girls and to decline with age among wheezers. The greater level of responsiveness in smaller or younger children could be explained by these individuals having received a dose of methacholine that was relatively large for their size.

High resolution computed tomography of the lung in lifelong non-smoking patients with rheumatoid arthritis.

To define pulmonary involvement on high resolution computed tomography (HRCT) of the thorax in lifelong non-smoking rheumatoid arthritis patients and to relate the results to pulmonary function, bronchial reactivity, and a variety of clinical and serological factors. Twenty lifelong non-smoking RA patients (mean age 59 years (range 44-72; 18 females) were studied. Detailed medical and drug histories were taken. Protease inhibitor phenotype (Pi) and HLA-DR4 status were assessed. Schirmer's tear tests were performed to detect keratoconjunctivitis sicca (KCS). Spirometry, flow volume loops, and gas transfer factor measurement were recorded. The degree of bronchial reactivity (PC20 FEV1) was measured by a methacholine inhalation test. Chest and hand radiographs and HRCT of the lung were performed in all patients. Thirteen patients were HLA-DR4 positive. Eighteen had the Pi MM and two the Pi MS phenotype. Eight patients had evidence of KCS on Schirmer's tear testing. Ten patients achieved PC20 FEV1 in the methacholine inhalation test. All the patients had normal chest radiographs and all showed evidence of erosive arthropathy on hand radiographs. Five patients (25%) showed basal bronchiectasis and one mild interstitial lung disease on HRCT. All five patients with bronchiectasis had the Pi MM phenotype, four had HLA-DR4, four had KCS and three achieved PC20 FEV1; these values were not significantly different (p > 0.05) from those in patients without bronchiectasis. Using the highly sensitive technique of HRCT, we found evidence to suggest that the incidence of bronchiectasis in lifelong non-smoking RA patients may be much higher than previously reported.

Asthma symptoms and airway hyperresponsiveness are lower during treatment with nedocromil sodium than during treatment with regular inhaled albuterol

In a double-blind, double-dummy, multicenter study, 212 patients with asthma whose symptoms were not controlled by as-needed use of inhaled bronchodilators were randomized to receive either 4 mg of nedocromil sodium or 180 μg of albuterol four times daily for 12 weeks. Asthma symptom scores (daytime asthma, nighttime asthma, morning chest tightness, and cough) and peak expiratory flow rate were recorded daily on diary cards. Bronchial hyperresponsiveness was assessed by changes in diurnal variation in peak expiratory flow rate and by methacholine inhalation challenge. Statistically significant differences were found between groups favoring nedocromil sodium for relief of day and nighttime asthma and morning chest tightness. Patients treated with nedocromil sodium also had significantly lower diurnal variation in peak expiratory flow rate compared with patients treated with albuterol. Compared with patients treated with albuterol, patients treated with nedocromil sodium showed a greater improvement in cough and a decreased sensitivity to methacholine challenge. Patients in both groups reduced their as-needed albuterol use. Regular treatment with nedocromil sodium therefore led to greater asthma symptom control and reduced bronchial responsiveness compared with regular treatment with albuterol. The study also showed that more frequent use of a β2-agonist (for symptom relief or not) did not improve asthma control. Both drugs were well tolerated. (J A LLERGY CLIN I MMUNOL 1995;95:541-7.)

Chronic cough with eosinophilic bronchitis: examination for variable airflow obstruction and response to corticosteroid

The purpose of this study was to examine airway responsiveness, sputum cells and the effects of inhaled corticosteroid in the chronic cough syndrome associated with eosinophilic bronchitis. We studied nine consecutive referrals with chronic cough, sputum with > 10% eosinophils, normal spirometry, and normal methacholine airway responsiveness. Clinical assessment, sputum analysis, allergy skin tests and a methacholine inhalation test were performed at the first visit. Peak expiratory flow (PEF) was measured twice daily for 1 week followed by an adenosine monophosphate (AMP) inhalation test. Subjects were then treated with inhaled beclomethasone 0.4 mg twice daily for 7 days. Sputum analysis and measurement of methacholine responsiveness were then repeated. Excessive airway narrowing to methacholine was not present in any of the subjects. A methacholine plateau response was present in five subjects. Hyperresponsiveness to AMP was absent in six of the nine subjects, and PEF variability was not increased for eight subjects. Corticosteroid therapy led to a reduction in sputum eosinophil counts from 40.1 (SD 21.4)% to 4.0 (4.5)% but there was no significant change in metachromatic cell counts (0.8 SD 0.5% vs 0.6 SD 0.6%) or total cell counts. Methacholine responsiveness improved within the normal range in the three subjects in whom it could be determined. Chronic cough associated with eosinophilic airway inflammation can occur in the absence of variable airflow obstruction (asthma) and can improve after treatment with inhaled corticosteroid. This treatment can reduce the level of methacholine responsiveness within the normal range and reduces sputum eosinophils but not mast cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory Effects of Occupational Exposure to Aerosolized Pentamidine

To determine the respiratory effects on health care workers of occupational exposure to aerosolized pentamidine (AP) used for the prophylaxis of Pneumocystis carinii pneumonia, we designed a clinical prospective study using subjects as their own controls. Sixteen health care workers whose job duties included administration of AP at one or more of nine San Francisco Bay Area medical centers participated in the study. Pentamidine concentrations ranged in breathing zone samples from < 0.03 to 62.2 micrograms/m3. Pentamidine was not detected in the urine of any of the subjects. There were no significant increases in symptoms on days when AP was administered. Cross-workshift spirometry on days when AP was administered showed a statistically significant mean decrease (0.14 liter) in forced expiratory volume in 1 second. There was no statistically significant difference in mean diurnal variation of peak expiratory flow rate on days when AP was administered. Methacholine inhalation challenge testing did not show a statistically significant mean change in airway responsiveness across the workweek. The ambient concentrations of pentamidine that we measured document that detectable occupational exposure to AP can occur in poorly ventilated treatment rooms. The cross-workshift decrement in forced expiratory volume in 1 second that we observed in association with AP administration supports the respiratory tract irritant potential of inhaled pentamidine. We recommend that steps be taken to minimize health care worker exposure to AP.

Airway Responses to Bronchoprovocation Using High-Resolution Computed Tomography in Patients with Bronchial Asthma

Background: Bronchial hyperresponsiveness and abnormal response such as a loss of distensibility are pathophysiologic characteristics if bronchial asthma. The only means of direct in vivo measurement of airway size had been a tantalium bronchography, until high-resolution computed tomography(HRCT) enabled to measure noninvasively two dimensional airway area more accurately and reliably. Method: To investigate airway area responses to bronchial provocation with methacholine and evaluate the major sites of bronchial constriction in patients with bronchial asthma. We examined HRCT scans in five patients with bronchial asthma who had significant bronchoconstriction(20% or more decrease in ) using CT scanner(5,000T CT, Shimadzu Co, Japan) before and in 3~5 min. after methacholine inhalation. Airways which were matched by parenchymal anatomic landmarks in each patient before and after methacholine inhalation were measured using film scanner(TZ-3X scanner; Truvel Co. Chatsworth CA, USA) and a semiautomated region growing method. Results: 1) We identified 9 to 12 airways in each patient which were matched by parenchymal anatomic landmarks before and after methacholine inhalation. 2) Airway responses to methacholine are quite different even in a patient. 3) The constriction of small airways(average diameter ) was 48.7%(8.3; SEM, n=43), being more prominant than that of large airways(average diameter >2 mm; area > ), 53.8% (4.4;SEM, n=10), but not significantly different(p>0.05). 4) There was no significant difference in the degree of constriction between upper(44.3% +5.8; mean + SEM, n=30) and lower lung regions(56.7% +4.5, n=23). Conclusions: Thus airway responses to methacholine bronchoprovocation is quite variable in a patient with bronchial asthma and has no typical pattern in patients with bronchial asthma.

Importance of impairment of the airway epithelium for ozone-induced airway hyperresponsiveness in guinea pigs.

We examined the relationship between ozone (O3)-induced airway hyperresponsiveness (AHR) and inflammation in guinea pigs. Inhalation of methacholine (MCh) was adopted in the time course study of AHR that was assessed by measuring pulmonary inflation pressure after O3 exposure (3 ppm, for 2 hr) because the degree of AHR detected by inhalation of MCh was greater than that detected by i.v. administration. AHR was detected up to 5 hr after O3 exposure and was not observed at 24 and 48 hr. In the bronchoalveolar lavage (BAL) study, the numbers of neutrophils, eosinophils, lymphocytes and macrophages in BAL fluid (BALF) reached maximum at 24 hr or later. On the other hand, the number of airway epithelial cells in the BALF significantly increased at 2 and 5 hr. In the histological study, disorder and impairment of the airway epithelium in the trachea and lung were observed at 2 and 5 hr. Changes in the airway epithelium were recovered at 48 hr, although an increase in leukocytes was observed in the lung. These results indicate that O3-induced AHR in guinea pigs is most probably associated with impairment of the epithelium rather than with infiltration of inflammatory cells in the airway.

Implantación, metodología y valoración de las pruebas de provocación bronquial inespecíficas en nuestro país

With the aim of determining the current use of non-specific bronchial inhalation challenge (BIC) testing in Spain, 147 questionnaires were sent to hospitals with pneumology departments or units. The questionnaire covered general, technical and methodological aspects of this diagnostic procedure, as well as its assessment and interpretation. Of the 42 informants who returned questionnaires, mainly from large urban hospitals, 34 reported using BIC. The most widespread criterion applied in deciding to use BIC was the presence of atypical asthma symptoms (33/34). The stimulus most often used was methacholine inhalation (33/34). We found that technical preparation of the drug was highly standardized, but that administration and follow-up protocols differed greatly. There was also great variety in the PC20/PD20 value assigned to indicate bronchial hyperresponsiveness. This study contributes to our better understanding of the current use of BIC in Spain and highlights the need to work toward greater standardization for this diagnostic procedure, to enable us to assess and interpret the results more consistently.

Methacholine-induced histamine liberation during airway challenge tests in Ascaris skin-sensitive sheep.

The interaction of vagal neuronal and pharmacological mediator mechanisms on the airway-constrictory responses obtained from challenges with aerosolized methacholine (MCH) before and after bilateral vagotomy and in combination with electrical stimulation of the peripheral ends of the cut vagal nerves was investigated in anesthetized Ascaris allergen skin-sensitive sheep. Inhalation of aerosols of 2 and 5% MCH for 2 min in a control group of 10 sheep resulted in airway muscle constriction indicated by an increase in dynamic elastance (Edyn) (+70 and +256% of the basic value) or inspiratory airway resistance (RI) (+45 and +155%) and was associated with a significant rise in plasma histamine concentration (HiPl) from 0.2 +/- 0.2 to 0.9 +/- 1.1 and 1.5 +/- 1.2 ng/ml, respectively. Respiratory and cardiovascular responses to MCH were reproducible after 90 min of recovery. A second group of another 6 intact sheep showed similar alterations of respiratory mechanical parameters and HiPl after MCH challenges. After bilateral vagotomy, Edyn and RI increased after 2 and 5% MCH inhalation only by 15-30% of the control responses with intact vagi. The diminished airway constriction was associated with similar changes in HiP1 as observed with intact vagi. Inspite of severe cardiovascular responses, the most effective electrical stimulation of the peripheral ends of the vagal nerves resulted in an increase in Edyn or RI by only 40-50% of the basic value. In a tracheal segment beneath the cuff of the endotracheal tube isometric pressure effectively increased by almost 500% of the basic value. Vagus nerve stimulation was found without detectable changes in HiPl. Stimulation of the central ends of the vagal nerves did not induce airway constriction or alterations in HiPl. The combination of electrical vagus nerve stimulation and MCH inhalation resulted in a more than additive increase in Edyn and RI, but the airway responses did not reach the same level of obstruction after challenge with 5% MCH as observed with intact vagi. Electrical stimulation of the efferent vagi failed to stimulate spontaneous vagal nerve activity at higher levels of airway muscle responses. The results demonstrate that vagal neuronal mechanisms interact with local mediator liberation in acute airway obstruction. Airway challenge tests using cholinergic substances liberate histamine from inflammatory cells in the lungs of Ascaris skin-sensitive sheep.

Correlation of Exercise-Induced Bronchoconstriction to PC20 and Maximal AirwayNarrowing on the Dose-Response Curve to Methacholine

Background: Exercise is one of the most common precipitants of acute asthma encountered in clinical practice. The development of airflow limitation that occurs several minutes after vigorous exercise, i. g. exercise-induced bronchoconstriction(EIB), has been shown to be closely correlated with the nonspecific bronchial hyperresponsiveness, which is the hallmark of bronchial asthma. All previous reports that assessed the correlation of EIB to nonspecific bronchial hyperresponsiveness have focused on airway sensitivity() to inhaled bronchoconstrictor such as methacholine or histamine. However, maximal airway narrowing(MAN), reflecting the extent to which the airways can narrow, when being exposed to high dose of inhaled stimuli, has not been studied in relation to the degree of EIB. Methods: Fifty-six children with mild asthma(41 boys and 15 girls), aged 6 to 15 years(meanSD, years) completed this study. Subjects attended the laboratory on two consecutive days. Each subject performed the high-dose methacholine inhalation test at 4 p.m. on the first day. The dose-response curves were characterized by their position() and MAN, which was defined as maximal response plateau(MRP: when two or three data points of the highest concentrations fell within a 5% response range) or the last of the data points(when a plateau could not be measured). On the next day, exercise challenge, free running outdoors for ten minutes, was performed at 9 a.m.. was measured at graduated intervals, 3 to 10 minutes apart, until 60 minutes after exercise. Response(the maximal from the pre-exercise value) was classified arbitrarily into three groups; no response((-) EIB: EIB:10%EIB:>20%). Results: 1) When geometric mean of the three groups were compared, of (+) EIB group was significantly lower than that of (-)EIB group. 2) There was a close correlation between and the severity of EIB in the whole group(r=-0.568, p) to methacholine is correlated well with the severity of EIB. The results suggest that the two main components of airway hyperresponsiveness may be equally important determinants of exercise reactivity, although the mechanism may be different from each other. The present study also provides further evidence that EIB is a manifestation of the increased airway reactivity characteristic of bronchial asthma.