Airway refractoriness to adenosine 5′-monophosphate after repeated inhalation

doi:10.1016/0091-6749(89)90490-9

Journal of Allergy and Clinical Immunology

Volume 83, Issue 1, January 1989, Pages 152-158

https://doi.org/10.1016/0091-6749(89)90490-9 Get rights and content

Abstract

Adenosine-5′-monophosphate (AMP) is a bronchoconstrictor agonist in subjects with atopic and nonatopic asthma. In this study we have investigated the effect of repeated airway challenge with AMP in 10 atopic, subjects without asthma. At the first visit, subjects had repeated inhalation challenges with increasing doubling concentrations of AMP, and the provocation concentration required to reduce FEV₁ by 20% of baseline was determined (PC₂₀ AMP). When the FEV₁ had returned to within 5% of the baseline, the AMP challenge test was repeated on a further one or two occasions. When the maximum concentration of AMP (400 mg/ml) failed to produce a PC₂₀, a bronchial provocation test with histamine was performed and the PC₂₀ was determined. On the second visit, the effect of three consecutive inhalation challenge tests with histamine on the airway response to this agonist was determined. On the third visit, the duration of induced refractoriness to AMP was assessed. With the first AMP challenge, all subjects demonstrated bronchoconstriction with a geometric mean (GM) PC₂₀ of 332 mg/ml. With a second AMP challenge, five of the 10 subjects became refractory and failed to achieve a PC₂₀. In the remaining five subjects, the GM PC₂₀ increased from 110 to 583 mg/ml. With a third AMP challenge, these subjects also failed to achieve a PC₂₀. The initial GM PC₂₀ histamine for the group was 22.9 mg/ml, which did not change significantly with two further histamine challenges or when the airways were refractory to AMP, suggesting that loss of AMP effect was not related to loss of contractility of airway smooth muscle or down regulation of H₁-histamine receptors. Once it was induced, refractoriness to AMP lasted approximately 4 hours. We conclude that with repeated challenge the airways became refractory to AMP compatible with depletion of mast cell mediators or tachyphylaxis at the level of cell-surface adenosine receptors.

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Refractoriness to inhaled mannitol 3 hours after allergen challenge
2013, Annals of Allergy, Asthma and Immunology
Citation Excerpt :
The number of patients was too small to attempt to stratify the population, and we did not capture the LAR; in fact, we inhibited any potential LAR with a single dose of fluticasone. Refractoriness, even cross-refractoriness, is well recognized after indirect challenges.2–6 Early studies documented that airway responsiveness to methacholine5 and histamine20 were preserved at a time when airways were refractory to a repeat indirect challenge.
A positive response to indirect airway challenges (eg, mannitol) that cause release of mast cell mediators causes refractoriness to a repeat exposure to the same or different indirect stimulus that lasts for at least several hours. Allergen challenge causes increased response to methacholine measured at 3 hours.
To compare allergen-induced changes in airway response to methacholine and mannitol 3 hours after completion of an allergen challenge.
Ten atopic patients with asthma completed a randomized clinical trial. The provocation concentration of methacholine causing a 20% decrease in forced expiratory volume in 1 second (FEV₁) was measured 24 hours before and 3 hours after a standard allergen challenge. The provocation dose of mannitol causing a 15% decrease in FEV₁ was also measured 24 hours before and 3 hours after allergen challenge. The allergen challenges were separated by 7 to 14 days.
The allergen-induced early responses, expressed as the maximum (SD) percent decrease in FEV₁, were 29.7% (11.1%) and 27.8% (7.6%) on the methacholine and mannitol days, respectively. Airway response to methacholine increased significantly after allergen challenge (P = .02). By contrast, the airway response to mannitol was reduced by almost a doubling dose (P = .02) after allergen.
Three hours after allergen challenge at a time when the airways are more responsive to methacholine, there is a significant refractoriness to the indirect stimulus mannitol.
clinicaltrials.gov Identifier: NCT01699594
Refractoriness to Exercise Challenge. A Review of the Mechanisms Old and New.
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Citation Excerpt :
The more intense the exercise during the first challenge, the more refractory the patients were to the second challenge. A refractory period occurs not only after exercise challenge but also after other indirect challenges, such as EVH,30,31 hypertonic saline,32 adenosine,33 ultrasonically nebulized distilled water,34 and mannitol.35,36 All these indirect challenges are associated with the release of mediators, all are inhibited by premedication with sodium cromoglycate, and all are thought to induce refractoriness via a similar pathway.37
Application of a shortened inhaled adenosine-5′-monophosphate challenge in young children using the forced oscillation technique
2009, Chest
Citation Excerpt :
We found the log10 PC values increased significantly with the second AMP challenge compared to the initial challenge, although without altering the categorical designation of responsive or nonresponsive. Refractoriness following AMP challenge testing has been demonstrated18 to last up to 6 h; therefore, it is unlikely to have caused the small increase in PC values seen in the present study in which tests were at least 6 days apart. The increase in PC values did not alter the only clinically significant result, which is the categorical designation of responsive or nonresponsive.
Adenosine-5′-monophosphate (AMP) is an indirect challenge agent thought to reflect allergic airway inflammation. The forced oscillation technique (FOT) is ideal for use in young children and is suitable for inhaled challenge studies in patients who are in this age group. We assessed the agreement between a shortened and a standard AMP challenge and the repeatability of the shortened AMP challenge using FOT as a primary outcome variable.
Eighteen children completed a shortened and a standard AMP challenge, and 20 children completed repeated shortened AMP challenges. The children inhaled nebulized AMP tidally for 2 min, following which the presence of wheeze and pulse oximetric saturation (Spo₂) was recorded prior to FOT measurement. Testing continued until the maximum dose was reached or until wheeze, a decrease in Spo₂ to < 90%, or an increase in respiratory resistance at 8 Hz of 2.0 hPa/s/L or 30% was noted. Concordance was assessed as a binary response, and agreement in provocation concentrations (PCs) causing a response was assessed with intraclass correlations.
There was a high degree of concordance between the shortened and standard AMP protocols (94%) and repeated shortened AMP protocols (100%). The mean log₁₀ PCs displayed a high degree of agreement for both AMP protocols, with intraclass correlation coefficients of 0.94 (95% confidence interval, 0.85 to 0.98) and 0.94 (95% confidence interval, 0.82 to 0.98), respectively.
We demonstrated that a shortened AMP challenge that can be applied to young children is comparable to the standard AMP challenge and is highly repeatable. Further studies in young children to assess the clinical role of a shortened AMP challenge using FOT are required.
The effect of challenge method on sensitivity and reactivity to adenosine 5′-monophosphate in subjects with suspected asthma
2006, Chest
Citation Excerpt :
Finally, inhalation challenges were performed randomly and were separated by 1 to 5 days. This is relevant to the evaluation of AMP responsiveness because it has been demonstrated that, at least in atopic nonasthmatic subjects, repeated inhalation challenge with AMP induces a loss of response or refractoriness to the nucleotide.31 However, the time taken for the AMP PC20 values to return to the starting baseline value ranged from 2 to 6 h, and, to our knowledge, tachyphylaxis to AMP has not been seen after 24 h.
The following two methods of inhalation challenge have been used to determine the airway responsiveness: the tidal-breathing method; and the dosimeter method. The objective of the study was to determine the influence of the challenge method on the response to adenosine 5′-monophosphate (AMP).
This study measured airway responsiveness to AMP by dosimeter and tidal-breathing methods in 25 subjects with suspected asthma. The two AMP challenges were conducted in random order, on separate days, at the same time of day, at intervals of 1 to 5 days. Concentration-response curves were characterized by the provocative concentration of a substance causing a 20% fall in FEV₁ (PC₂₀) and slope.
The dosimeter PC₂₀ values were significantly higher than the tidal-breathing PC₂₀ values, with geometric mean (95% confidence interval [CI]) values of 50.35 mg/mL (95% CI, 19.50 to 129.72 mg/mL) and 28.97 mg/mL (95% CI, 11.99 to 69.98 mg/mL; p = 0.02), respectively. The mean difference in the PC₂₀ values obtained with each method was 0.80 doubling concentrations (95% CI, 0.16 to 1.44 doubling concentrations). The mean values for the slope were 17.0%/log mg/mL (95% CI, 12.5 to 21.5 mg/mL) with the tidal breathing method and 13.8%/log mg/mL (95% CI, 9.0 to 18.7 mg/mL; p = 0.03) with the dosimeter.
The tidal-breathing method produces AMP PC₂₀ values that are significantly lower than the dosimeter method and slope values that are significantly higher than the dosimeter method. These data suggest that the results obtained with each method of testing may not be comparable.
Adenosine-induced bronchoconstriction and its inhibition by nedocromil sodium
1993, The Journal of Allergy and Clinical Immunology
The inhalation of adenosine or adenosine-5′-monophosphate (AMP) causes a reproducible and transient bronchoconstriction in both atopic and nonatopic asthmatic subjects that is not followed by a late-phase response. The response may be prevented by prophylactic treatment with histamine H₁-receptor antagonists, local anesthetics, and atropine, which suggests that both mast cell mediator release and neuronal reflexes are involved. Adenosine- and AMP-induced bronchoconstriction are both blocked by cromolyn sodium and nedocromil sodium, with the PD₂₀FEV₁ for the latter approximately four times lower than that of cromolyn sodium in atopic asthmatic patients and approximately 2.3 times lower than that of cromolyn sodium in nonatopic asthmatic patients. We suggest that AMP-induced bronchoconstriction, in combination with other indirect-acting provicants, may be used to determine the effectiveness and mechanism of action of antiasthmatic drugs.
Repeated exposure of asthmatic airways to inhaled adenosine 5′-monophosphate attenuates bronchoconstriction provoked by exercise
1990, The Journal of Allergy and Clinical Immunology
Inhaled adenosine 5′-monophosphate (AMP) induces bronchoconstriction in subjects with asthma, probably caused by histamine release from airway mast cells, and repeated AMP bronchial challenge leads to attentuation of the bronchoconstrictor response. Since exercise-induced bronchoconstriction may be mediated by hypertonic mast cell degranulation, we postulated that repeated AMP bronchial challenge should reduce the response to subsequent exercise challenge. Eight atopic subjects with asthma took part in an unblinded, randomized trial. On the control study day, a treadmill exercise test previously demonstrated to induce a >20% fall in FEV₁ was performed. On the AMP study day, three AMP dose-response bronchial challenges were performed at 1-hour intervals. Each AMP challenge was continued until either a provocative concentration causing a 20% fall in FEV₁ had been achieved (PC₂₀) and the PC₂₀ was calculated, or the maximum concentration of AMP (400 mg/ml) had been administered. After recovery of the FEV₁ from AMP challenge, a treadmill exercise test identical to the test on the control study day was performed. On the AMP study day, the geometric mean PC₂₀ was 15.3 (7.9 to 29.5) mg/ml for the first test, and 28.2 (10.7 to 77.4) mg/ml for the third test (not significant). On the control study day, the mean maximum percentage fall in FEV₁ after exercise was 28.0%±2.7%, whereas on the AMP study day, it was reduced to 13.0%±4.3% (p<0.01). A significant correlation was found between the change in responsiveness to AMP induced by repeated challenge and the attenuation of the subsequent exercise response (p<0.05). We conclude that repeated challenge with AMP attenuates subsequent responsiveness to exercise, suggesting a shared mechanism of refractoriness.

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Original articleAirway refractoriness to adenosine 5′-monophosphate after repeated inhalation

Abstract

Biochem Pharmacol

J Allergy Clin Immunol

J Allergy Clin Immunol

Adenosine-induced bronchoconstriction in asthma: specificity and relationship to airway reactivity

Thorax

Antigen bronchial provocation causes an increase in plasma adenosine levels in asthma

Clin Sci

Adenosine release from stimulated mast cells

Release of adenosine and its metabolites from human leukocytes

Clin Sci

Adenosine-induced bronchoconstriction in asthma: antagonism by inhaled theophylline

Am Rev Respir Dis

Effect of vagal blockade on adenosine-induced bronchoconstriction in asthma

Thorax

Potentiation of mast cell mediator release by adenosine

J Immunol

Adenosine inhibits and potentiates IgE-dependent histamine release from human basophils by an A2 receptor-mediated mechanism

Br J Pharmacol

Adenosine receptors on mouse bone marrow-derived mast cells—functional significance and regulation by aminophylline

J Immunol

The bronchial effects of adenosine in the rat

Arch Int Pharmacodyn Ther

Original article
Airway refractoriness to adenosine 5′-monophosphate after repeated inhalation

Adenosine inhibits and potentiates IgE-dependent histamine release from human basophils by an A₂ receptor-mediated mechanism