Reversibility of induced bronchoconstriction by deep inspiration in asthmatic and normal subjects

Five normal and five asthmatic subjects underwent a progressive methacholine provocation study. At each concentration inspiratory pulmonary resistance (RL) was measured, as well as isovolumic maximal flow and residual volume from both partial and complete forced expirations. Results were compared over the RL range of 6-11 cmH2O.1-1.S-1. The reversibility of bronchoconstriction by deep inspiration was quantified as the ratio of the flow increase to potential maximal increase; the reversibility of gas trapping was the ratio of decrease in residual volume to potential maximal decrease. The reversibility of bronchoconstriction did not differ between the groups. In contrast, the reversibility of gas trapping was smaller in asthmatic subjects (21 +/- 17%) than in normals (84 +/- 6%). As gas trapping reflects airway closure, our findings suggest that during induced bronchoconstriction airway closure is more resistant to the effects of deep inspiration in asthmatic than in normal subjects but the reversibility of bronchoconstriction by deep inspiration is not different.     

Protective effects of inhaled ipratropium bromide on bronchoconstriction induced by adenosine and methacholine in asthma.

Although adenosine-induced bronchoconstriction is mainly due to mast cell mediator release, vagal reflexes have also been implicated in this response. We have investigated the effect of a specific muscarinic-receptor antagonist, ipratropium bromide, on methacholine- and adenosine-induced bronchoconstriction in a randomized, placebo-controlled, double-blind study of 12 asthmatic subjects. Airway response was evaluated as forced expiratory volume in one second (FEV1). Inhaled ipratropium bromide (40 micrograms), administered 20 min prior to bronchoprovocation, increased the provocation dose of inhaled methacholine and adenosine required to reduce FEV1 by 20% from baseline (PD20) from 0.11 to 0.79 mg (p less than 0.01) and from 0.57 to 1.27 mg (p less than 0.01), respectively. The mean baseline FEV1 values after administration of ipratropium bromide were significantly higher than after placebo administration (p less than 0.05). However, there was no correlation between the degree of bronchodilatation and dose-ratios for methacholine and adenosine. The findings of the present study implicate vagal reflexes in the bronchospastic response induced by inhaled adenosine in asthma.     

Theophylline minimally inhibits bronchoconstriction induced by dry cold air inhalation in asthmatic subjects

The aim of this study was to evaluate the effect of a sustained-release theophylline preparation on bronchial responsiveness to cold dry air inhalation in asthmatic subjects. Sixteen adult subjects with asthma in a clinical steady state underwent 3 isocapnic cold air challenges on 3 consecutive days at a time when they had not received oral theophylline medication over the past 3 days. The dose of cold air causing a 20% (PD20) fall in FEV1 was obtained from each subject's dose-response curve. Subjects were then administered active or placebo sustained-release theophylline preparations according to a double-blind, randomized, two-treatment crossover design. Medication was given for a minimum of 3 consecutive days. PD20 was reassessed on 4 different days, 3 to 4 h after receiving active or placebo medication (two visits for each medication). We found a significant bronchodilator effect of theophylline as compared to the placebo (mean +/- SD differences in changes of FEV1 of 8.8 +/- 1.9%). We also documented a significant blocking effect of the active medication as opposed to the placebo on PD20 (p = 0.01). This difference (mean = 0.18 on the loge scale) was statistically beyond the intraindividual between-day variability observed on the 3 control days (p less than 0.001) but was physiologically minimal. This blocking effect was also partially related to changes in airway caliber. We conclude that theophylline showed a blocking effect on bronchial responsiveness to dry cold air, which was physiologically minimal and was partially related to changes in airway caliber.     

Effects of breathing warm humidified air on bronchoconstriction induced by body cooling and by inhalation of methacholine.

The effect of breathing warm humidified air upon bronchoconstriction induced with body cooling or inhalation of methacholine was studied in two groups of eight asthmatic subjects. One group had the body cooled using one-minute exposures, first to a cold shower at 15 degrees C and then to a current of wind. The other group received methacholine by inhalation until a decrease of 20 percent or more occurred in the forced expiratory volume in one second. Both groups of asthmatic subjects were tested when breathing room air and warm humidified air. Pulmonary functions were assessed before and after cooling of the body and during inhalation of methacholine. Breathing warm humidified air substantially reduced bronchoconstriction induced by body cooling, but not that induced by inhalation of methacholine. Thus, bronchoconstriction induced by cooling of the body appears to be related to cooling of the airways, which may be compensated by breathing warm humidified air.     

Time course and calcium dependence of transmitter release at a single ribbon synapse

At the first synapse in the auditory pathway, the receptor potential of mechanosensory hair cells is converted into a firing pattern in auditory nerve fibers. For the accurate coding of timing and intensity of sound signals, transmitter release at this synapse must occur with the highest precision. To measure directly the transfer characteristics of the hair cell afferent synapse, we implemented simultaneous whole-cell recordings from mammalian inner hair cells (IHCs) and auditory nerve fiber terminals that typically receive input from a single ribbon synapse. During a 1-s IHC depolarization, the synaptic response depressed >90%, representing the main source for adaptation in the auditory nerve. Synaptic depression was slightly affected by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor desensitization; however, it was mostly caused by reduced vesicular release. When the transfer function between transmitter release and Ca(2+) influx was tested at constant open probability for Ca(2+) channels (potentials >0 mV), a super linear relation was found. This relation is presumed to result from the cooperative binding of three to four Ca(2+) ions at the Ca(2+) sensor. However, in the physiological range for receptor potentials (-50 to -30 mV), the relation between Ca(2+) influx and afferent activity was linear, assuring minimal distortion in the coding of sound intensity. Changes in Ca(2+) influx caused an increase in release probability, but not in the average size of multivesicular synaptic events. By varying Ca(2+) buffering in the IHC, we further investigate how Ca(2+) channel and Ca(2+) sensor at this synapse might relate.     

Respiratory conductance response to a deep inhalation in children with exercise-induced bronchoconstriction

Airway response to deep inhalation (DI) may provide information relevant to the mechanisms of airway obstruction (AO). The hypothesis examined here is that DI provokes bronchodilation in children during exercise-induced bronchoconstriction (EIB). EIB was attested in 15 children aged 10+/-3 year (mean+/-SD) by a decrease in forced expiratory volume in 1 s (FEV1) > or = 15% from baseline after a free running test. The respiratory resistance was measured by the forced oscillation technique at 12 Hz using a head generator to vary transrespiratory pressure around the head. The airway response to DI was estimated by the effect on respiratory conductance (Grs), calculated as the reciprocal of respiratory resistance in inspiration. During EIB, DI induced a variable but significant increase in Grs, from 0.085+/-0.023 to 0.101+/-0.029 l hPa(-1) s(-1) (P = 0.0003). The post- to pre-DI Grs ratio (1.19+/-0.14) was found to correlate negatively with EIB-induced reduction in FEV1 (P = 0.02), forced vital capacity (FVC) (P = 0.01) but not FEV1/FVC, i.e., DI induced more bronchodilation in those children with small EIB associated reduction in FVC. It is concluded that the bronchodilator effect of DI may be demonstrated in children with EIB. It is suggested that the associated small airway closure and lung hyperinflation may contribute to limit this response to DI.     

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)     

Perception of bronchoconstriction in chronic asthma.

Twenty-nine asthmatic children were studied to assess their ability to detect the severity of their bronchoconstriction. First (STEP 0): each child was asked if he "felt asthma," inviting him to give a self-estimated obstruction score (SEOS) from 0 (no asthma) to 3 (severe asthma) and a baseline FEV1 was recorded. Then (STEP 1): methacholine was administered to all except 9 children with an FEV1 less than 80% of predicted who received saline nebulization and a second SEOS was recorded. Finally: salbutamol aerosol was administered and a third SEOS and FEV1 were obtained (STEP 2). Spearman's correlation coefficients r between SEOS and FEV1 were for the overall population -0.602, -0.517, and -0.104 at STEP 0, STEP 1, and STEP 2, respectively. The r values reduction during the trial can be due either to a decrease of children's concentration during the study or to a real difficulty in recognizing repeated changes in airway status. Some children tend to underestimate their bronchospasm. For these patients an accurate assessment of the severity of the bronchoconstriction requires an objective measurement during acute changes in asthmatic children.     

Excessive bronchoconstriction induced by histamine and effects of volume history in patients with bronchial asthma

Abstract The aim of this study was to examine the inter-relationships between the different effects of deep breaths and histamine provocation on airway function in patients with bronchial asthma. Group 1 consisted of 38 consecutive out-patients with newly diagnosed mild asthma, group 2 consisted of 20 patients with bronchial asthma of varying severity who were studied during clinical remission. We measured bronchial responsiveness (BR) to histamine inhalation as the dose of histamine which provoked a 20% fall in FEV₁ (PD₂₀). The fall in forced vital capacity (FVC) after inhaling the highest dose of histamine during each BR test was calculated and expressed as percentage of the value measured at baseline (δFVC in percentage). We studied the effects of deep breaths on airway caliber in group 2 patients by comparing isovolumic flow rates on partial (P) and maximal (M) forced expiratory flow volumes curves expressed as the M/P ratio. The changes in residual volume (RV) after deep breaths (δRV) were expressed as a percentage of the largest VC measured on the composite M and P curves. The patients in group 1 had significantly higher PD₂₀ and lower δFVC than patients in group 2. There was, however, no significant correlation between PD₂₀ and δFVC measurements in individual patients (r<0.1, P>0.05). The M/P ratio was significantly related to δFVC (r=?0.6, P<0.006). There was also a significant positive relation between the magnitude of increase in residual volume following deep breaths (δRV) and the degree of fall in FVC following histamine inhalation (δFVC) (r= 0.65, P= 0.001). This significant relationship between the degree of airway closure after a deep breath and airway closure after histamine challenge is a new finding. In patients with bronchial asthma, the effects of a deep breath on airway function may be indicative of the tendency for airway closure during BR testing.     

Time course of histamine-induced bronchoconstriction and its adrenergic and H2 modulation

We characterized the complete time course of histamine-induced bronchoconstriction and its modulation via the release of endogenous catecholamines and by its actions on H₂-receptors in anesthetized, tracheostomized, paralyzed, and artificially ventilated mongrel dogs. Respiratory resistance (R) and elastance (E) were estimated continuously with a recursive least squares estimator. Three protocols were followed in which multiple histamine bolus injections were given 1 h apart. We found that the time courses of E and R had consistent patterns (transient peak that returned to baseline within 1000 sec) even in cases of low mean arterial pressure (MAP). Indomethacin pre-treatments prevented tachyphylaxis to repeated i.v. challenges. β-blockade produced a mild increase in baseline and a potentiation of the histamine-induced response in E and these effects were not altered with further α-or H₂-blockade. Blockade of α-receptors increased the time to recovery in both E and MAP presumably by decreasing blood flow. Finally, we suggest that preventing the H₂-receptor induced increase in bronchial blood flow may have increased the time to maximal E without affecting the recovery time.     

Repeated inhalation of bradykinin attenuates adenosine 5'-monophosphate (AMP) induced bronchoconstriction in asthmatic airways.

Repeated bronchial challenges with inhaled bradykinin lead to a rapid loss of the bronchoconstrictor response and this has been suggested to be due to depletion of contractile neuropeptides from sensory nerve endings. If adenosine 5'-monophosphate (AMP), another potent bronchoprovocant in asthma, and bradykinin share a common pathway in inducing bronchoconstriction in asthmatic subjects, then repeated bradykinin bronchoprovocation tests should reduce the response to subsequent inhalation of AMP. We examined this hypothesis in eight asthmatic subjects in a double-blind, randomized study. On the histamine study day, two consecutive concentration-response studies with inhaled histamine were followed by a third consecutive challenge with AMP and the provocation concentration producing a 20% fall in forced expiratory volume in one second from the post-diluent baseline value (PC20 FEV1) for this agonist was calculated. On the bradykinin study day, two consecutive bronchoprovocation tests with bradykinin were followed by a third inhalation challenge to obtain the PC20AMP value. On a further occasion, the asthmatic subjects underwent two consecutive concentration-response studies with inhaled bradykinin followed by a third consecutive challenge with histamine. On the histamine study day, the geometric mean PC20AMP value was 28.1 mg.ml-1, whilst on the bradykinin study day, the fifteenfold reduction in bradykinin responsiveness after the second bradykinin challenge was accompanied by a significant reduction of the airway responsiveness to AMP, the PC20AMP being 59.8 mg.ml-1. A similar reduction in bradykinin responsiveness failed to alter the airway response to a subsequent inhalation with histamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of helium on maximal expiratory flow in patients with asthma before and during induced bronchoconstriction.

The effect of breathing helium on maximal expiratory flow at 50 per cent of vital capacity (V50) was studied in 27 patients with asthma during remission and during induced bronchoconstriction. Nine patients gave a history of asthma induced by exercise; two had asthma due to timothy pollen allergy, and the remaining 16 had asthma due to exposure to western red cedar. Bronchoconstriction was induced by exercise in 10 patients, timothy pollen in 4 patients, methacholine in 4 patients, and red cedar in 16 patients. During remission, the increase in V50 with helium (deltaV50He) was greater than 20 per cent in 22 patients who were classified as responders; deltaV50He was less than 20 per cent in the remaining 5 patients, who were classified as nonresponders. There was a significant correlation between the severity of airway obstruction as measured by V50 and the response to helium, both during remission and during induced bronchoconstriction; however, there was no correlation between helium response and specific airway conductance. In general, patients who were responders during remission remained responders during induced bronchoconstriction, and nonresponders remained nonresponders, regardless of the method of challenge or the type of reaction (immediate verus late). There were a few exceptions in which a responder became a nonresponder during severe bronchoconstriction. The results of this study suggest that in most patients with asthma, the site of airway obstruction is likely to be in the large airways and, in most cases, remains constant in an individual asthmatic; however, an asthmatic who is a helium responder may become a nonresponder during severe bronchoconstriction.     

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.     

Chest wall hyperinflation during acute bronchoconstriction in asthma.

The mechanics of the chest wall was studied in seven asthmatic patients before and during histamine-induced bronchoconstriction (B). The volume of the chest wall (VCW) was calculated by three-dimensional tracking of 89 chest wall markers. Pleural (Ppl) and gastric (Pga) pressures were simultaneously recorded. VCW was modeled as the sum of the volumes of the pulmonary-apposed rib cage (VRC,p), diaphragm-apposed rib cage (VRC,a), and abdomen (VAB). During B, hyperinflation was due to the increase in end-expiratory volume of the rib cage (0.63 +/- 0.09 L, p < 0.01), whereas change in VAB was inconsistent (0.09 +/- 0.07 L, NS) because of phasic recruitment of abdominal muscles during expiration. Changes in end-expiratory VRC,p and VRC,a were along the rib cage relaxation configuration, indicating that both compartments shared proportionally the hyperinflation. VRC,p-Ppl plot during B was displaced leftward of the relaxation curve, suggesting persistent activity of rib cage inspiratory muscles throughout expiration. Changes in end-expiratory VCW during B did not relate to changes in FEV(1) or time and volume components of the breathing cycle. We concluded that during B in asthmatic patients: (1) rib cage accounts largely for the volume of hyperinflation, whereas abdominal muscle recruitment during expiration limits the increase in VAB; (2) hyperinflation is influenced by sustained postinspiratory activity of the inspiratory muscles; (3) this pattern of respiratory muscle recruitment seems to minimize volume distortion of the rib cage at end-expiration and to preserve diaphragm length despite hyperinflation.     

Airway inflammation and occurrence of delayed bronchoconstriction in exercise-induced asthma.

We studied nine asthmatic patients with a history of exercise-induced asthma (EIA) in order to investigate whether inflammatory changes in the airways occur after exercise and are eventually associated with the development of a late-phase asthmatic response. On two separate study days, bronchoalveolar lavage (BAL), bronchial lavage (BL), and bronchial biopsy (BB) were performed 3 h after an exercise or a methacholine (MCh) challenge. On two other separate occasions, FEV1 was monitored for 12 h after identical exercise and MCh challenges not followed by BAL, BL, and BB. We found a greater percentage of eosinophils in BAL after exercise versus MCh challenge (p < 0.05). In five patients, BAL eosinophils after exercise were > or = 2% of total inflammatory and immunoeffector cells. In three of these patients an FEV1 fall > 20% of control was recorded 5 to 12 h after exercise. However, two of these patients had 2% or more eosinophils in BAL and similar late falls of FEV1 after MCh challenge. The percentage of degranulating mast cells in BB was higher (p < 0.05) after EIA than after MCh, but no significant differences were found in BL histamine and leukotrienes. We conclude that (1) exercise may enhance mast cell degranulation and eosinophilic inflammation of the airways, and (2) a delayed bronchoconstriction after exercise is not specific to EIA but is more likely the result of fluctuations in lung function associated with airway inflammation.     

Attenuation of platelet-activating factor induced bronchoconstriction by nedocromil sodium.

We assessed the effect of nedocromil sodium on bronchoconstriction and airway responsiveness induced by platelet-activating factor (PAF) in eight normal subjects, in a double-blind, placebo-controlled cross-over study. Subjects inhaled PAF by a dosimeter method in 5 doses of 18 micrograms each, separated by an interval of 15 min, (total dose of 90 micrograms). Airway calibre was measured by partial expiratory flow at 30% of vital capacity (Vp30) before and at 1, 3, 5, 10 and 15 min after each dose of PAF. The bronchoconstrictor response was assessed by measuring the area under the curve of the percentage fall in Vp30 over time. There was a significant reduction in PAF-induced bronchoconstriction after nedocromil sodium (1,225 +/- 392 arbitrary units; mean +/- SEM) compared to placebo (2,395 +/- 598; p < 0.01). There was no significant difference in the fall in peripheral neutrophil count measured at 5 min after PAF with nedocromil sodium (48.5 +/- 9.5%) compared to placebo (43.3 +/- 6.8%). In conclusion, nedocromil sodium significantly attenuates PAF-induced bronchoconstriction but not the peripheral neutropenia in normal subjects. Since PAF is not a direct constrictor of human airway smooth muscle, this effect of nedocromil sodium may indicate inhibition of release of bronchoconstrictor mediators.