Modification of histamine- and methacholine-induced bronchoconstriction by calcium antagonist gallopamil in asthmatics.

We studied the comparative modification of histamine- and methacholine-induced bronchoconstriction by a calcium antagonist, gallopamil, in 8 subjects with bronchial asthma. Dose-response curves to aerosolized methacholine or histamine were performed, without and following pretreatment with inhaled gallopamil (10 mg), on 6 different experiment days to determine the cumulative provocative dose (PD50) of each agonist in breath units which caused a 50% decrease in specific airway conductance (SGaw). Baseline values of SGaw were similar on different experiment days and gallopamil had no significant effect on SGaw. PD50 values for histamine on control and placebo days were 6.8 +/- 2.8 and 5.2 +/- 2.8 breath units (mean +/- SE), respectively. Pretreatment with gallopamil increased histamine PD50 to 19.8 +/- 7.5 breath units, which was significantly greater than on control and placebo days (p < 0.01). PD50 values for methacholine on control and placebo days were 9.5 +/- 5.6 and 8.8 +/- 5.8 breath units, respectively. Gallopamil pretreatment had no significant effect on methacholine-induced bronchoconstriction; methacholine PD50 increased to 13.4 +/- 5.5 breath units (p = NS). The mean dose ratio (ratio of PD50 for the agonist in the presence and absence of gallopamil) for histamine was 6.9, which was 3.7-fold higher than the dose ratio of 1.9 methacholine in the same subjects. These data suggest that gallopamil causes greater inhibition of histamine- versus methacholine-induced bronchoconstriction. This suggests that calcium influx in airway smooth muscle through voltage-dependent channels primarily occurs in response to histamine and not to methacholine.     

Long-term stability of bronchial reactivity in guinea pigs

Measurement of lung function and bronchial reactivity are widely used as outcome parameters to assess the efficacy of therapeutic interventions. In order to interpret the results correctly, it is necessary that the outcome parameters are themselves stable over time so that any significant changes measured may be attributed to the interventions. Specific airway conductance (SGaw) and airway reactivity to histamine are two commonly used parameters in animal models such as guinea pigs. Although short-term variability of these parameters has been investigated, there has been no study of long-term stability. In the present paper, SGaw and bronchial reactivity to histamine were measured in 111 conscious guinea pigs using a non-invasive, whole body plethysmograph. Baseline values of SGaw and ED35 histamine were measured and followed for eight weeks at weekly intervals. At baseline, mean SGaw in guinea pigs was 0.17 +/- 0.055 sec-1 cm H2O-1 and ED35 histamine ranged from 0.064 to more than 10 mg/ml. The distribution of ED35 histamine values was gaussian. We observed that the changes in SGaw and ED35 histamine recorded using this technique are highly reproducible over eight weeks. The reactivity varied by less than a doubling dose of histamine over any two consecutive weeks. Thus, the technique described in this paper is quick, easily learned, reproducible, independent of temperature-humidity artifact and highly suitable for studies of repeated measurements as in the study of dietary interventions and evaluation of effect of drugs.     

Comparative modification of antigen-induced bronchoconstriction by the calcium antagonists, nifedipine and verapamil

We compared the effects of the two calcium antagonists, nifedipine and verapamil, on baseline airway function and antigen-induced bronchoconstriction in asymptomatic subjects with ragweed hypersensitivity and a history of bronchial asthma. Twelve subjects received a single oral dose of 20 mg of nifedipine or 160 mg of verapamil before inhalation with ragweed antigen. Mean specific airway conductance, a measurement of airway obstruction, was not affected by either agent; nifedipine caused bronchodilatation in two subjects, and verapamil was followed by slight bronchoconstriction in another subject. Nifedipine partially or completely blocked the antigen-induced bronchoconstriction in 67 percent (8/12) of the subjects (p less than 0.05). Two of the subjects who were protected by nifedipine were also protected by pretreatment with verapamil, while this drug was without effect in the others. This study demonstrates that both nifedipine and verapamil in a single oral dose may attenuate antigen-induced bronchoconstriction in some subjects with allergic bronchial asthma and that nifedipine may be more effective than verapamil.     

Unchanged bronchial reactivity after killed influenza virus vaccine in adult asthmatics

Polyvalent killed influenza virus vaccine or saline was administered subcutaneously to 27 asthmatics to investigate the effect of influenza vaccine on respiratory function and on airway responsiveness to inhaled histamine. The patients were adults with mild to moderate asthma. Airway resistance (Raw) and intrathoracic gas volume (ITGV) were measured immediately before and 2, 3 and 21 days after vaccine or saline injection. Raw and ITGV values were used to calculate specific airway conductance (SGaw). Bronchial reactivity was expressed as the provocative dose of histamine diphosphate producing a decrease of 40% in SGaw (PD40). Fourteen (87%) of 16 asthmatics who received killed virus vaccine displayed a significant rise in serum antibody level as measured by single radial haemolysis in gel test. No significant alterations in mean Raw, ITGV and SGaw values were observed after viral vaccination. The median PD40 values for histamine also remained unchanged. However, an increased bronchial reactivity was observed in some patients after administration of virus vaccine or saline. Subclinical natural infection or allergen exposure cannot be excluded as possible causes of the increased airway reactivity in these patients. The side-effects of vaccination were minimal and no more harmful than those produced by saline injection. We conclude that the killed influenza virus vaccine used is effective in boosting serum antibody levels and is suitable for adult asthmatics when prophylactic immunisation is indicated.     

Effect of long-term treatment with sodium cromoglycate on nonspecific bronchial hyperresponsiveness in asthma

Several studies in the past have demonstrated a reduction in nonspecific bronchial hyperresponsiveness subjects with seasonal extrinsic asthma after long-term treatment with sodium cromoglycate. Since sodium cromoglycate is an effective drug in the prophylactic treatment of all types of asthma, we assessed the effect of a three-month treatment on nonspecific bronchial hyperresponsiveness in 11 patients with perennial asthma. Bronchial responsiveness was determined by histamine bronchoprovocation test, using SGaw as the index of lung function and expressed as PD35SGaw. During the run-in period of one month when sodium cromoglycate was not used, the histamine PD35SGaw decreased significantly from 0.15 +/- 0.30 to 0.09 +/- 0.29 mg/ml (p less than 0.001). After three months of treatment with the drug, bronchial hyperresponsiveness was reduced significantly; the PD35SGaw was 0.21 +/- 0.29 mg/ml (p less than 0.001). It was concluded that long-term treatment of patients with perennial asthma with sodium cromoglycate results in reduced bronchial hyperresponsiveness.     

Effect of cold air exposure and exercise on nonspecific bronchial reactivity

Exercise and eucapnic hyperventilation with cold air can produce bronchoconstriction in asthmatic subjects, but their enhancement of nonspecific bronchial reactivity remains unclear. We studied the effect of submaximal exercise and cold air exposure on bronchial reactivity to methacholine in a normal control group (n = 10) and in subjects with bronchial asthma (n = 17). Bronchial provocation testing was performed to determine the provoking dose (PD35) of methacholine that caused a 35 percent decrease in specific airway conductance (Gaw/VL) in the two groups. Each subject was studied on three different occasions to determine the PD35 to methacholine on a control day, after ten minutes of submaximal exercise, and after a 30-minute exposure to cold air. Methacholine challenge was performed after the Gaw/VL had returned to the baseline values. In the normal group, neither cold air exposure nor exercise challenge had any significant effect on baseline Gaw/VL, whereas in the asthmatic group, both stimuli caused 20 percent and 15 percent decreases in Gaw/VL, respectively (p less than .05). Mean +/- SD control PD35 was 6.1 +/- 11.6 breath units in the asthmatic group, which decreased to 2.2 +/- 2.8 after exercise and 3.0 +/- 5.0 breath units after cold air exposure (p less than .05). In the normal group, control PD35 was 73 +/- 32 breath units, which was not different from PD35 values of 64 +/- 75 and 52 +/- 64 breath units after exercise and cold air exposure, respectively (p = NS). These data suggest that submaximal exercise and cold air exposure enhance nonspecific bronchial reactivity in asthmatic but not in normal subjects.     

Protective effect of theophylline on bronchial hyperresponsiveness in patients with allergic rhinitis

Disorders of the upper respiratory tract, particularly allergic rhinitis are commonly associated with bronchial hyperresponsiveness. The latter may be responsible for chronic cough, a common symptom in patients with allergic rhinitis, which, as previously shown, can be the sole presenting manifestation of bronchial hyperresponsiveness. Theophylline is widely used in patients with asthma for its bronchodilator effect, whereas its action on bronchial reactivity is controversial. The aim of this study was to determine the effect of theophylline administration on bronchial hyperresponsiveness in patients with allergic rhinitis complaining of chronic cough. Fourteen patients were studied. All of them were judged atopic on the basis of positive skin tests to common allergens. During control, spirometry, flow-volume curves and specific airway conductance (SGaw) were measured. Bronchial challenges were then performed with increasing concentrations of carbachol, and dose-response curves were constructed. The concentration of carbachol, which decreased SGaw by 35% from baseline (PD35) was determined by interpolating from the dose-response curve. After control measurements patients received in a randomized, double-blind crossover fashion either theophylline 10 mg/kg/day orally or placebo for 30 days. Measurements were then redone. After a washout period of 8 days the measurements were repeated, and patients received theophylline or placebo for a second period of 30 days. Measurements were again performed at the end of this last study period. During control all patients had normal baseline lung function data and showed marked bronchial hyperresponsiveness, PD35 amounting to 26 +/- 7 micrograms of carbachol (normal value greater than 160 micrograms). No significant changes in PD35 were noted after placebo and washout when compared with control values.(ABSTRACT TRUNCATED AT 250 WORDS)     

Different effects of nasal and bronchial glucocorticosteroid administration on bronchial hyperresponsiveness in patients with allergic rhinitis.

Disorders of the upper respiratory tract, particularly allergic rhinitis, are commonly associated with bronchial hyperresponsiveness. The latter may be due to postnasal drip or to mediator or chemotactic factors into the lower airways that either directly alter airway reactivity or cause airway inflammation. The aim of this study was to compare the effect of an identical dose of nasal or bronchial corticosteroid administration on bronchial hyperresponsiveness in patients with allergic rhinitis. Eleven patients were studied. All of them were judged atopic on the basis of positive skin tests to common allergens. During control, spirometry, flow-volume curves, and specific airway conductance (SGaw) were measured. Bronchial challenges were then performed with increasing concentrations of carbachol, and dose-response curves were constructed. The concentration of carbachol that decreased SGaw by 35% from baseline (PD35) was determined by interpolating from the dose-response curve. Control measurements were repeated at 1-wk intervals to ensure that PD35 was stable in all the patients. Then the patients received for 2 wk, in a double-blind randomized crossover fashion, a topical administration of either an aerosol of 400 micrograms of beclamethasone dipropionate (B) into the nose (100 micrograms four times per day) or into the bronchi. During each trial period, identical sprays of placebo were used, the latter being administered into the nose when B was administered into the bronchi and vice versa. Measurements were then performed after 2 wk of intranasal administration and after 2 wk of intrabronchial administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adenosine-induced bronchoconstriction in asthma. Role of parasympathetic stimulation and adrenergic inhibition

Adenosine by inhalation causes bronchoconstriction in asthmatic but not in normal subjects by an undefined mechanism. This study investigated the roles of cholinergic reflex stimulation and decreased beta 2-adrenoceptor responsiveness to explain adenosine's bronchoconstrictor action. The protection afforded by the inhaled muscarinic cholinergic antagonist, ipratropium bromide (IB) 1 mg, from bronchoconstriction induced by inhaled adenosine was compared with that of methacholine in 8 allergic asthmatic subjects. After saline placebo, the geometric mean concentrations of adenosine required to produce a 20% fall in FEV1 (PCf20) was 2.20 mg/ml and a 35% fall in SGaw (PCs35) was 1.97 mg/ml, which compared to 0.13 and 0.11 mg/ml, respectively, for methacholine. The IB increased FEV1 by 11 to 15% and SGaw by 69 to 73% and provided a large degree of protection against methacholine, with a geometric mean concentration ratio (CR) of 196 when airway caliber was measured as SGaw (p less than 0.001). In contrast, IB provided little protection against adenosine-induced bronchoconstriction (CR 1.3 for SGaw and 1.51 for FEV1). Beta 2-adrenoceptor responsiveness of the airways after inhaled adenosine and histamine was further studied in 12 asthmatic subjects by observing the antibronchoconstrictor effect of inhaled isoproterenol. After equivalent degrees of bronchoconstriction, 35 to 36% fall in FEV1 and 60 to 62% fall in SGaw cumulative doses of inhaled isoproterenol produced almost identical maximal increases in FEV1 and SGaw after adenosine as achieved after histamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Methacholine inhalation challenge after rapid saline infusion in healthy subjects

Five healthy subjects were challenged with methacholine on 2 different days, 1 week apart, the second day after acute intravenous 30 ml/kg 0.9% saline infusion. After infusion, we observed a significant reduction in vital capacity (VC), maximal expiratory volume in 1 s (FEV1), provocation dose producing a 35% fall in SGaw (PD35SGaw) and in 25% of maximal expiratory flow (MEF25), and an increase in the slopes of log dose-response curves. Our results suggest an increased bronchial reactivity in acute minimal interstitial lung edema.     

Cold air as a bronchial provocation technique. Reproducibility and comparison with histamine and methacholine inhalation

Bronchial provocation testing with cold air was carried out on 36 asthmatic and 13 normal subjects in order to assess the reproducibility and clinical relevance of the technique as a test of airways reactivity. Sixteen subjects underwent repeat testing after an interval of two to three weeks. Using a least squares linear regression analysis, the technique was highly reproducible, with a correlation of r = 0.93 (p less than 0.001). The 21 asthmatic subjects who had exercise-provoked symptoms required a significantly lower level of ventilation of cold air to produce a 35 percent drop in specific airways conductance (PD35) than did those who had no exercise-induced asthma (33.9 L min-1 vs 45.8 L min-1; p less than 0.02). Subjects requiring no regular treatment for their asthma had a geometric mean PD35 of 62.6 L min-1, significantly higher than those requiring inhaled therapy (44.9 L min-1; p less than 0.005). Subjects requiring oral in addition to inhaled treatment had the lowest PD35 (23.6 L min-1; p less than 0.02). Atopic status did not appear to influence the response. There was a strong correlation between the PD35 to cold air and to histamine (r = 0.92; p less than 0.001) and between the PD35 to cold air and to methacholine (r = 0.86; p less than 0.001). The three techniques of assessing bronchial reactivity were equally successful in separating the normal and asthmatic groups. The results indicate that cold air provocation may be reliably and reproducibly used to assess bronchial reactivity. The use of a naturally-occurring stimulus of asthma in all subjects has great potential as an investigational technique.     

Adenosine-induced bronchoconstriction in asthma. Antagonism by inhaled theophylline

Inhaled adenosine causes bronchoconstriction in asthmatic patients. Antagonism of the bronchoconstrictor effect of endogenous adenosine has been proposed as a possible mechanism of action of theophylline in asthma. To directly investigate this, we have compared the airway responses to inhaled adenosine and histamine, with and without the prior administration of inhaled theophylline in 8 allergic asthmatic subjects. Airway response was measured both as forced expiratory volume in one second (FEV1) and as specific airway conductance (SGaw). Inhaled adenosine was less potent than histamine in producing bronchoconstriction, with geometric mean concentrations required to produce a 20% fall of FEV1 (PCf20) and a 40% fall of SGaw (PCs40) being 0.27 and 0.25 mg/ml for adenosine and 0.10 and 0.09 mg/ml for histamine. In a total nebulized dose of 37.5 mg, inhaled theophylline was a weak bronchodilator that caused maximal increases in FEV1 of 2 +/- 2% (mean +/- SE, p less than 0.05) and in SGaw of 8 +/- 4% (p greater than 0.05). However, theophylline significantly inhibited adenosine-induced bronchoconstriction, increasing the PCf20 and PCs40 values for adenosine to 1.66 (p less than 0.001) and 2.34 (p less than 0.005) mg/ml, respectively. Inhibition of histamine-induced bronchoconstriction was less marked, with PCf20 and PCs40 values of 0.19 (p greater than 0.05) and 0.21 (p less than 0.05) mg/ml. Thus, adenosine is a bronchoconstrictor in asthma whose effects are preferentially antagonized by concentrations of theophylline that cause little change in baseline airway caliber.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulation of bronchial reactivity by angiotensin-converting enzyme in unanesthetized guinea pigs.

To investigate the role of angiotensin-converting enzyme (ACE) in the modulation of bronchial reactivity, we tested the effects of a specific ACE inhibitor, captopril (CAP), on the bronchial reactivity to substance P (SP) and methacholine (MCH) in unanesthetized guinea pigs. The relative role of ACE on the vascular endothelium and ACE in the airway tissue was examined by administering CAP as an intravenous infusion and by an inhaled aerosol. Bronchial reactivity was evaluated by a provocative dose of SP or MCH at a concentration that would double the baseline value of the specific airway resistance (PC200 or PD200). Neither pretreatment with infused CAP (10 mg/kg) nor inhaled CAP (5 mg) enhanced bronchial reactivity to inhaled SP, whereas the reactivity to infused SP (7.5 x 10(-3) to 20 nM/kg) was enhanced significantly by pretreatment with infused CAP (10 mg/kg) (p less than 0.05). The infusion of CAP (10 mg/kg) also enhanced the bronchial reactivity to both infused MCH (0.05 to 25 micrograms/kg) and inhaled MCH (0.05 to 25 mg/ml) (both p less than 0.05). However, the inhalation of CAP (5 mg) did not affect the bronchial reactivity to inhaled MCH. These observations suggest that ACE located on the vascular endothelium may modulate bronchial reactivity.     

Dissociation of symptom scores and bronchial hyperreactivity: study in asthmatic children on long-term treatment with inhaled beclomethasone dipropionate.

The aim of the study was to evaluate the effects of inhaled steroids (IS) on the improvement of clinical asthma symptoms and on the decrease in bronchial hyperreactivity (BHR). Twenty-four children with severe asthma were given 1,000 micrograms beclomethasone dipropionate (BDP) daily and compared with ten asthmatic control children. The study included the evaluation of daily clinical score, of exercise induced asthma, of bronchial obstruction (forced expiratory volume in 1 sec, FEV1), and of BHR at months 0, 1, 2-3, and 4-5 (M0, M1, M2-3, and M4-5). BHR was assessed by standardized inhaled carbachol provocation measuring plethysmographic specific airway resistance (SRaw). The carbachol dose causing a 40% decrease in specific conductance (SGaw) was determined (PD40 SGaw). Clinical scores decreased at M1 (P less than 0.01) and throughout the study. FEV1 increased at M1 (P less than 0.05), M2-3 (P less than 0.01), and M4-5 (P less than 0.05) compared to M0. PD40 SGaw only increased significantly at M1 and M2-3. No individual correlation was found between clinical scores and PD40 SGaw at any testing, or between the decrease of clinical scores and the decrease of BHR. We conclude that bronchoconstrictive challenge tests do not adequately assess the clinical efficacy of IS. In clinical practice non-specific BHR should be preferentially measured for diagnosing atypical forms of asthma.     

Effect of diltiazem on histamine- and carbachol-induced bronchospasm in normal and asthmatic subjects

Recently, several transmembrane calcium-channel blockers have been used in experimental models to investigate the mechanisms through which Ca++ ions contribute to the regulation of the contractile response of airway smooth muscle and to determine the therapeutic use of these drugs in bronchial asthma. Since the data from these studies are inconsistent and inconclusive, we studied the effect of diltiazem, a calcium-channel blocker previously not examined to our knowledge, on histamine- and carbachol-induced bronchoconstriction in healthy and in asymptomatic allergic bronchial asthma. The study was performed in a double-blind, randomized, placebo-controlled fashion, using a single oral dose of 60 mg of diltiazem. Airway reactivity to histamine and carbachol expressed by PD35SGaw was significantly but weakly attenuated by diltiazem in the asthmatic, but not in the normal subjects. Baseline lung function was not significantly influenced by diltiazem. We concluded that the effect of diltiazem on unspecific airway hyperresponsiveness in asthmatic subjects is too weak to justify a recommendation as therapy.     

The influence of aerosol retention and pattern of deposition on bronchial responsiveness to atropine and methacholine in humans

We have examined the influence of total intrapulmonary deposition and its pattern on the bronchial response to aerosolized methacholine and atropine in 10 normal and 12 asthmatic subjects. On Day 1 we performed a dose-response challenge to methacholine and defined responsiveness as the provocative dose (PD35) needed to cause a 35% decrease in specific airway conductance (SGaw). On Day 2 we repeated methacholine challenge after premedication with aerosolized atropine, and we defined the response to atropine as dose ratio-1 (DR-1) where DR = PD35 after atropine/PD35 without atropine. On Day 3 we imaged intrapulmonary aerosol deposition by mixing 99mtechnetium with methacholine aerosol and scanning the thorax with a gamma camera during the development of bronchoconstriction. Total pulmonary aerosol deposition varied considerably between individuals (1.2 to 23.6% of nebulized dose) but there was no difference between normal and asthmatic subjects, and no correlation between deposition and baseline SGaw or PD35; there was a significant positive correlation between deposition and DR-1. Deposition of aerosol in central lung zones was inversely related to SGaw and correlated positively with DR-1; there was no significant relationship with PD35. Total intrapulmonary aerosol deposition and its pattern partially determine bronchial responsiveness to atropine, but we have not demonstrated any significant effect on responsiveness to methacholine.     

The effect of inhaled vasoactive intestinal peptide on bronchial reactivity to histamine in humans

Nonadrenergic, noncholinergic nerves are the predominant inhibitory nervous pathway in human airway smooth muscle, and there is evidence in animals that the major neurotransmitter of this system is vasoactive intestinal peptide (VIP). We have investigated the effect of VIP on bronchomotor tone and bronchial responsiveness to inhaled histamine in 6 atopic asthmatic subjects. The VIP was given by inhalation to avoid any indirect effects on the airways that might arise from the potent cardiovascular actions of this peptide when given systemically. The VIP (100 micrograms) was compared with control solution (diluent: 1% human serum albumin in 2 ml 0.9% saline) and with beta 2-agonist (salbutamol, 200 micrograms) given double blind in random order on separate days. Specific airway conductance (SGaw) did not change after control or VIP inhalations, but it significantly increased after salbutamol inhalation. The provocation concentration of histamine causing a 35% fall in SGaw (PC35) did not change after control inhalation, but significantly increased after VIP (from 2.18 +/- 1.04 to 5.00 +/- 2.31 mg/ml histamine, mean +/- SE; p less than 0.05), and after salbutamol (from 1.71 +/- 0.83 to 15.6 +/- 4.2 mg/ml, p less than 0.01), the increase after salbutamol being significantly greater than after VIP. No changes in heart rate or blood pressure were found after any inhalation. We conclude that VIP protects against histamine-induced bronchoconstriction in human airways in vivo, and therefore has the capacity to be the neurotransmitter of nonadrenergic, noncholinergic inhibitory nerves in human airway smooth muscle.     

Effects of inhaled platelet activating factor on bronchial responsiveness in patients with symptomatic and asymptomatic pulmonary embolism.

To determine the possible role of platelet-activating factor (PAF) in pulmonary embolism (PE), the reactivity of the airways to inhaled PAF, using doses ranging from 6.25 to 400 micrograms, was examined in 24 patients with a past episode of PE. Twelve of these patients had experienced acute respiratory insufficiency during the episode (with or without additional symptoms). None of the remaining 12 patients had experienced any respiratory symptoms during the PE episode. Diagnosis was established by means of a ventilation-perfusion lung scan performed when admitted to the hospital because of deep venous thrombosis (DVT) in the lower limbs. Nonspecific bronchial reactivity as measured by the response to bronchoprovocation testing with methacholine showed no significant differences between both groups. PAF caused a dose-dependent bronchoconstriction defined by at least a 35 percent decrease in specific airway conductance (SGaw) in all patients. The average dose of PAF needed to decrease SGaw 35 percent was significantly lower in patients who had had a symptomatic PE than in those with asymptomatic PE (p = 0.011). This finding suggests that patients who suffered from symptomatic PE may present a greater airway reactivity to inhaled PAF. This different behavior might explain the existence of some of the respiratory symptoms of PE, which could be attributed to PAF-related effects. However, additional studies are needed to evaluate the role of PAF in PE.     

Total respiratory resistance and reactance as a measurement of response to bronchial challenge with histamine

The potential of the forced oscillation technique to detect the airway response on histamine bronchial challenge tests was compared with that of FEV1 and plethysmographic SGaw. In 53 subjects with a history of episodic wheezing and a normal baseline airway resistance, we carried out bronchial challenges with successively doubling concentrations of histamine until FEV1 had dropped by 15% or more or a concentration of 16 mg/ml histamine was reached. For the baseline values, a mean within-subject coefficient of variation was found of 2.8% for FEV1, 7.4% for SGaw, 8.7% for the oscillatory respiratory conductance at 6 Hz (1/Rrs6), and 7.7% for the mean oscillatory respiratory conductance (between 2 and 26 Hz) (1/Rrs). The latter coefficients allow the calculation of the following threshold values: PD15FEV1, PD40SGaw, PD47 1/Rrs6, and PD42 1/Rrs. The probability of exceeding these levels by chance is virtually zero. Histamine challenge caused significant absolute changes in Rrs at 6 Hz (Rrs6), in mean level of Rrs and of respiratory reactance (Xrs), in slope of Rrs and Xrs versus frequency, and in mean curvature of Rrs-frequency curve. A multivariate analysis of the differences between prechallenge and postchallenge values showed that the parameters with the best sensitivity to detect the effect of histamine were, in decreasing order: the relative change of SGaw, of 1/Rrs6, of 1/Rrs, of FEV1, of FVC, and of 1/Vtg, followed by the absolute change of Xrs and of the average slope of the Rrs-frequency relationship.(ABSTRACT TRUNCATED AT 250 WORDS)     

Measurement of pharmacological antagonism produced by atropine in bronchi of normal and asthmatic subjects

The bronchial response of six normal and six asthmatic subjects to increasing concentrations of methacholine aerosol was measured by serial measurements of specific airways conductance (sGaw) in a body plethysmograph. On separate days, the subjects were premedicated with 0.9% NaCl, inhaled atropine at four different doses, or intravenous atropine at two different doses. Cumulative log dose-response curves were constructed. The provocative dose of methacholine needed to cause a 35% fall in sGaw was measured from each curve (PD35). The antagonism produced by a given atropine dose was quantified as the dose ratio, which was defined as the ratio of PD35 after atropine to PD35 after saline. In normal subjects, approximately equal amounts of atropine given by the inhaled or intravenous routes produced mean dose ratios of almost identical value. However, in asthmatic subjects inhaled atropine (1.28 mg, 4.4 mumol) produced a mean dose ratio 7.5 times greater than the mean value seen with intravenous atropine (1.0 mg, 3.46 mumol). Intravenous atropine (1.0 mg, 3.46 mumol) produced a mean dose ratio of 18.3 for all subjects, compared to a value of 26 predicted from in vitro experiments. The slope of the regression line for the relationship of log (dose ratio -1) vs -log atropine dose (Schild plot) for all subjects was -0.99. The actions we have observed are compatible with the main actions of atropine being that of a competitive antagonist at the muscarinic receptor. The greater blocking effect of inhaled atropine in some asthmatics suggests that a higher concentration of atropine is achieved at the muscarinic receptor by the inhaled route in these subjects.