Repeated exposure of asthmatic airways to inhaled adenosine 5'-monophosphate attenuates bronchoconstriction provoked by exercise J. P. Finnerty, MRCP, R. Polosa, MD, S. T. Holgate, FRCP Southampton, England

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 FEVI was performed. On the AMP study day, three AMP dose-response bronchial challenges were performed at l-hour intervals. Each AMP challenge was continued until either a provocative concentration causing a 20% fall in FEV~ had been achieved (PC,.o) and the PC2o was calculated, or the maximum concentration of AMP (400 mg/ml) had been administered. After recovery of the FEVI 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 PC2o 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 FEV~ 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. (J ALLERGY CLIN IMMUNOL 1990;86:353-9.)

Adenosine and its nucleotide adenosine monophosphate (AMP), when they are inhaled by atopic subjects with or without asthma cause bronchoconstriction.l' 2 On the basis that the response can be effectively inhibited by a selective H~-receptor antagonist, such as terfenadine, it is likely that a major component of the bronchoconstriction is mediated by histamine released from primed airway mast cells. 3 In support of this finding, adenosine has been demonstrated to augment IgE-dependent histamine release

From the lmmunopharmacologyGroup, SouthamptonGeneral Hospital, Southampton, England. Received for publication Nov. 30, 1989. Revised Feb. 26, 1990. Accepted for publication May 2, 1990. Reprint requests: J. P. Finnerty, MRCP, SouthamptonGeneral Hospital, Med 1, Level D, Center Block, Southampton S09 4XY, England. 1 / 1 / 22268

Abbreviations used

AMP: Adenosine 5'-rnonophosphate PC2o: Provocative concentration causing a 20% fall of all in FEV~ AUC: Area under the curve

from human mast cells in vitro. 4 In addition, bronchoconstriction provoked by adenosine 5 and A M P 6 is effectively antagonized by the mast cell stabilizers, nedocromil sodium and sodium cromoglycate. Finally, increases in plasma histamine concentrations have been demonstrated in association with bronchoconstriction provoked by inhaled AMP. 7 Repreated provocation of the airways with AMP leads to a progressive loss of the bronchoconstrictor response, whereas the airway response to histamine is unaffected. 8' 9 Stimulus-related depletion of bron-

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TABLE I. Subjects' characteristics Subjects 1 2 3 4 5 6 7 8 Mean (SEM)

Age 19 24 23 23 18 35 18 19

Sex M M M F F M M M

22.4 (2.0)

PC~ histamine (rag/mill 1.34 3.36 0.25 0.86 0.03 1.64 0.51 2.30 0.70* (0.41-1.20)

FEV1 (% predicted) 88 113 89 101 96 85 87 80

Therapy S p.r.n. S p.r.n. S, 100 ixg, q.d.s.; B, 50 Ixg q.d.s. S p.r.n. S p.r.n. S, 100 p~g b.d. S, 200 Ixg b.d. S p.r.n.

92.4 (3.7)

S, Salbutamol; B, beclomethasone, both as aerosol inhalers; p.r.n., as needed; q.d.s., four times a day; b.d., twice a day. *Geometric mean and range _+ SE presented for PCzohistamine values. choconstrictor mast cell mediators is one explanation that has been suggested to account for this phenomenon. 8 Similarly, exercise-induced asthma has been attributed, at least in part, to mediator release from activated mast cells, a~ After repeated challenge, refractoriness to exercise can be demonstrated" and appears to be a specific phenomenon, since under these conditions, reactivity to histamine and methacholine is unaffected. ~2' 13 Cross-refractoriness has been demonstrated between exercise and hypertonic airway challenge, 14 which lends support to the concept that these stimuli share a c o m m o n mechanism, possibly via activation o f airway mast cells.15 The present study was undertaken to determine whether a common mechanism underlies loss o f responsiveness to the bronchoconstfictor effects o f inhaled A M P and exercise challenge.

METHOD Subjects Eight subjects with stable mild asthma (six male and two female subjects) took part in the study (Table I). All subjects were atopic, as judged by at least one wheal >3 mm on skin prick testing with Dermatophagoides pteronyssinus, cat dander, and mixed-grass pollens (Bencard Allergy Unit, Brentford, U.K.). Treatment with inhaled 132-agonists was withdrawn at least 6 hours and inhaled steroids at least 12 hours before each study session. Verbal informed consent was obtained from each subject, and the study was approved by the Southampton University and Hospitals Ethical Subcommittee.

Bronchial challenge with AMP AMP (Sigma Chemical Co., St. Louis, Mo.) was made up in 0.9% sodium chloride in a series of doubling concentrations, ranging from 0.78 to 400 mg/ml (2.2 to 1151.6 retool/L). The solutions were administered as aerosols from an Inspiron mininebulizer (C. R. Bard International, Sun-

derland, U.K.) driven by compressed air at 8 L/min. Measurements of FEVz were made with use of a dry wedge spirometer (Vitalograph, Buckinghamshire, U.K.). Before each AMP challenge, three baseline measurements of FEV~ were made, and the highest value was recorded. Subjects then inhaled nebulized 0.9% sodium chloride, taking five slow breaths from functional residual capacity to full inspiration during 30 seconds. After 3 minutes, three additional FEV~ measurements were made, and the highest measurement was recorded. If this value was within 10% of the initial FEV~, then the test proceeded. Five breaths of AMP were taken at the lowest concentration, and paired FEVI measurements were made at 1 and 3 minutes, the higher measurement being used at each time point. If the FEV~ had fallen by >20% from the postsaline value at either time, then the test ended, otherwise AMP was administered in the next doubling concentration. PC2oAMP was calculated from the plot of the percentage fall in FEV~ against the cumulative concentration of AMP expressed logarithmically.

Bronchial challenge with histamine Bronchial challenge was performed with a modified technique according to that of Chai et al? 6 The concentrations of histamine monophosphate used started at 0.03 mg/ml, and doubling concentrations were used up to a maximum of 8 mg/ml. Before challenge, a baseline recording of FEV1 was obtained, being the best of three technically satisfactory attempts. Subjects were than asked to take five breaths from functional residual volume to total lung capacity from an Inspiron nebulizer, from which normal saline was nebulized with compressed air at a flow rate of 8 L/min. Two measurements of FEVI were performed at 3 minutes with the higher value being accepted, ff the postsaline FEV~ was within 10% of the baseline, then the histamine challenge was undertaken. Increasing doubling concentrations of histamine were administered at 3-minute intervals until a 20% fall from the postsaline value in FEV~ had occurred. From the plot of percentage fall in FEV~ against the cumulative

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NUMBER 3, PART 1

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time (minutes) FIG. 1. Mean changes (• SE) in FEV1from baseline (expressed as 100%) against time during 30 minutes after exercise challenge on the control study day (no AMP challenge) (open triangles) and the AMP study day (three AMP challenges) (closed triangles) are illustrated (n = 8).

concentration of histamine administered, the provocative concentration of histamine giving a 20% fall in FEV~ PC20 histamine, was calculated by linear interpolation. Bronchial challenge with exercise Subjects exercised on an electrically driven treadmill (PK Morgan, Ltd., Chatham, Kent, U.K.) while they were inspiring dry air at room temperature and atmospheric pressure from a 200 L Douglas bag via a mouthpiece connected to a two-way valve, and expired into the ambient air. During the exercise test the air inthe Douglas bag (Douglas Products, Walnut Ridge, Ark.) was supplemented from an air cylinder as necessary. The volume of inspired air was measured with a Parkinson Cowan gas meter (PK Morgan, Ltd.), and the volume (expressed as BTPS) was displayed on the monitor of a microcomputer. The highest of three measurements of FEV~ were taken as the baseline value before exercise testing. Each exercise test lasted 6 minutes, and on completion of the exercise task, single measurements of FEV~ were made at 1, 3, 5, 10, 15, and 30 minutes. The gradient and speed of the treadmill were adjusted during practice tests so that the maximum fall in FEV~ from the preexercise level was >20%. During the study, the gradient and speed of the treadmill remained constant for each subject during each exercise test..

Protocol The study was open and randomized. Before enrollment into the study, a histamine bronchial challenge test was performed to establish baseline bronchial reactivity. Preliminary exercise tests were also undertaken to determine an exercise task sufficient to induce a >20% fall in FEVL from baseline. The study was performed on 2 study days, a control day, and an AMP-challenge day. On the control day, the predetermined exercise test was performed. On the AMPchallenge day, three consecutive concentration-response AMP bronchial-challenge tests were performed. After the third AMP challenge, the exercise test was undertaken. The AMP bronchial challenges were separated by at least 1 hour or until the baseline FEV1 had recovered to within 10% of the prechallenge baseline value. On completion of the third AMP challenge, the exercise test was performed after an interval of 30 minutes or until the FEVI had recovered to within 10% of the previous baseline value. The study days were randomized in order, and the exercise test during each study day was performed at the same time of day to within 1 hour. Data a n a l y s i s Baseline FEVL measurements before each challenge were compared with two-way analysis of variance followed by

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TABLE II. PC20AMP values derived from the three consecutive challenges on the AMP study day PCzoAMP (mg/ml)

Subjects 1

2 3 4 5 6 7 8 Geometric mean (+- SEM)

1st challenge

2nd challenge

1.1 304.6 38.0 13.6 23.5 23.7 1.2 24.8

0.4 499.0 130.0 17.9 10.2 89.7 2.2 21.7

15.3 (7.9-29.5)

19.4 (8.7-43.6)

3rd challenge

0.4 800.0* 252.3 19.6 10.6 800.0* 1.6 22.7 28.2 (10.7-77.4)

*Cumulative concentration presented as 20% fall in FEV1 was not achieved. Tukey's test where a significant difference was found. The magnitude of the bronchoconstriction provoked by exercise was compared between the 2 study days as the maximum percentage fall in FEVI from baseline, and the AUC of the percentage fall in FEVI against time during 30 minutes. Repeatability of exercise challenge was assessed by comparison of the total ventilation during exercise on the 2 study days. Statistical comparisons between values were performed with Student's paired t test. Bronchial responsiveness to AMP was assessed with Student's paired t test on the PC2oAMP values after logarithmic transformation. In some of the subjects, repeated AMP challenge of the airways resulted in a reduced bronchoconstrictor effect. To quantify this, an index of refractoriness to AMP challenge was obtained from each subject by dividing the third PC2oAMP by the first PC~cAMP. For each subject, an index of refractoriness to exercise after repeated AMP challenge was also obtained by calculating the ratio of the maximum percentage fall in FEVI after exercise on the AMP-challenge study day to the maximum percentage fail after exercise on the control study day. The relationship between these two indices was assessed by Spearman's rank correlation. RESULTS

All subjects exhibited bronchial hyperreactivity to histamine, the geometric mean PCz0histamine before study entry being 0.70 m g / m l (range _ SE, 0.41 to 1.20 m g / m l ) (Table I). The mean baseline FEV] ( _ SEM) before exercise testing on the control day was 3.70 _ 0.21 L, whereas before exercise testing on the AMP-challenge day, it was 3.49 - 0.21 L (not significant). The mean baseline FEV] values before the second and third A M P challenges on the AMP-challenge day were 3 . 4 1 _ 0.21 L and 3.25 • 0.21 L, respectively~ both significantly lower than before exercise on the control day (p < 0.01). Inhalation of AMP caused bronchoconstriction in all the subjects. There was no significant correlation

between PC2oAMP and PCzohistamine. Repeated challenge of the airways with A M P resulted in a progressive loss of response in five of the eight subjects. For the group as a whole, the geometric mean PC2oAMP increased from 15.3 m g / m l after the first A M P challenge to 19.4 m g / m l after the second challenge and 28.8 m g / m l after the third challenge (Table II), but this did not achieve statistical significance. The geometric mean ratio (__.SEM) of the third to the first PC20AMP was 1.89 (1.11 to 3.21). The mean PC2oAMP after the third challenge is a minimum estimate, since a PCz0 was not achieved in subjects 2 and 6, for whom the PC20 tabulated is the total cumulative concentration administered. Thus, the geometric mean ratio calculated is likely to be an underestimate of the refractoriness induced. Total ventilation (BTPS) during exercise during 6 minutes was almost identical on the 2 study days, being 280.5 _+ 20.9 L on the control day and 276.5 - 21.9 L on the AMP-challenge day (not significant). The response to exercise after the A M P challenges was markedly attenuated in six of eight subjects. The mean maximum percentage fall in FEVi after exercise on the control day was 28.0% _ 2.7% with a mean AUC of 508.5% min • 61.1% min, whereas after repeated A M P challenge on the AMP study day, the mean maximum percentage fall in FEV1 fell to 13.0% • 4.3% (p < 0.01) and the AUC to 134.9% min _ 99.6% min (p < 0.01). The mean minimum postexercise FEV] was 2.68 _ 0.23 L on the control day, representing a mean decrease of 1.02 L from preexercise baseline, whereas the mean minimum postexercise FEV1 was significantly greater at 3.08 - 0.30 L on the AMP-challenge day, representing a mean fall of 0.40 L (p < 0.05). A significant correlation was observed between refractoriness to

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TABLE III. Comparison of exercise tests performed on the control study day and the AMP

study day Control study day

AMP study day

Subjects

Maximum fall (%)*

AUC (% min)l"

Maximum fall (%)

1 2 3 4 5 6 7 8 Mean (SEM)

40.3 16.3 23.5 28.8 27.4 27.0 36.7 23.9 28.0 (2.7)

717.9 288.0 505.1 488.8 309.5 591.5 754.3 413.1 508.5 (61.1)

29.3 2.1 0 4.6 10.9 4.7 23.5 28.6 13.0 (4.3)

AUC (% rain)

626.1 -43.8 -71.0 -26.2 - 98.9 -60.0 326.9 426.4 134.9 (99.6)

*Maximum percentage fall in FEVI from baseline during exercise test. ]'Area under the curve of percentage fail in FEVI against time during 30 minutes.

AMP challenge and refractoriness to exercise challenge (Spearman's correlation coefficient, - 0.74; p < 0.05). DISCUSSION

This study has demonstrated that repeated exposure of asthmatic airways to AMP may lead to a progressive loss of bronchoconstrictor response to this nucleotide, confirming our previous observations. 8' 9 We have extended this observation by demonstrating that repeated bronchial challenge with AMP significantly inhibits the subsequent bronchoconstrictor response to exercise challenge. Although not all subjects exhibited refractoriness to AMP, some degree of protection against exercise-induced bronchoconstriction was observed in most of the subjects studied. Within the group a significant relationship between the degree of AMP refractoriness and the extent of protection against exercise was found. These data suggest that a common mechanism may account for the refractory period observed in asthma with AMP and exercise. Endogenous AMP is largely derived from degradation of adenosine 5'-triphosphate and is metabolized extracellularly to adenosine through the action of membrane-linked, 5'-nucleotidase. 17Adenosine is believed to act as an autacoid, acting on specific cellsurface receptors to either decrease (via A~ receptors) or increase (via A: receptors) intracellular levels of cyclic 3',5'-AMP (cyclic AMP). ~s Inhaled AMP is believed to have its actions after transformation to adenosine,,9. 20 and, in challenge studies, has been used in preferernce to adenosine because of its greater solubility. The action of AMP in inducing broncho-

constriction in subjects with asthma and in atopic subjects is likely to be via the induction of histamine release from airway mast cells 7 by stimulation of specific A2 mast cell receptors. 21 In support of this finding, sodium cromoglycate and nedocromil sodium, both mast cell stabilizing drugs, protect against AMPinduced bronchoconstriction 6 with nedocromil being somewhat more potent. Adenosine may have other relevant effects in the airways; for example, it is likely to have a local vasodilator effect by analogy with its effects in other tissues? 2 We have previously demonstrated that in atopic normal subjects 8 or subjects with asthma, repeated challenge with inhaled AMP leads to a loss of response that appears to be specific to this nucleotide; that is, no cross refractoriness occurs with histamine. The mechanism of tachyphylaxis to inhaled AMP is not known. Although one hypothesis ascribes this phenomenon to mast cell-mediator depletion, a recent study in atopic subjects rendered refractory to AMP has demonstrated the airway response to subsequent allergen to be enhanced rather than suppressed. 9 This provides in vivo evidence for the previous in vitro observation that adenosine augments IgE-mediated mast cell-mediator release. 2' Since the immediate asthmatic reaction to allergen is believed to be mast cell mediated, this finding casts doubt on the hypothesis that tachyphylaxis to adenosine is due to mast cell-mediator depletion. A more plausible explanation is that tachyphylaxis is due to specific down regulation of purinoceptors. This is supported by the finding that mouse mast cells incubated with Nethylcarboxamideadenosine, an Az-receptor agonist,

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are rendered refractory to further challenge by Nethylcarboxamideadenosine and that the effect is reversed by a single cell wash and further cell culture for 4 hours. 23 Another explanation that might explain our findings of diminished responsiveness to exercise and AMP is histamine tachyphylaxis. A recent study reported that after repeated histamine challenge, exerciseinduced bronchospasm was attenuated, 24 and this occurred in parallel with the development of histamine tachyphylaxis. However, other workers have found that refractoriness to bronchoconstriction by exercise can develop while reactivity to histamine is preserved.12.25 It is unlikely that tachyphylaxis to histamine accounts for our findings, since histamine reactivity has been demonstrated to be unchanged once refractoriness to AMP has been induced, s' 9 Indeed, in our experience, significant histamine tachyphylaxis is uncommon in hyperreactive subjects with asthma. Thus, in a recent study, we failed to observe significant loss of histamine responsiveness in a group of 10 subjects with asthma with an initial PC2o to histamine of < 1 mg/ml, and noted repeatable histamine tachyphylaxis in only two subjects of a group of 10 subjects with asthma whose initial PC20 was >2.5 mg/ml. 26 In the present study, only one subject had a PC2ohistamine value greater than this. Although the most likely explanation for loss of the airway response to AMP is tachyphylaxis occurring at or beyond the receptor level, such a mechanism does not easily explain why the airways should also be protected against the bronchoconstrictor effect of exercise. Although some protection against exercise was conferred on those subjects in whom three consecutive AMP challenges failed to induce loss of responsiveness to the nucleotide, on observing the group as a whole, a significant relationship between the level of reduced AMP responsiveness and the extent of protection against exercise-induced asthma implies a common mechanism. O'Byrne and Jones 27 have suggested that refractoriness to the bronchoconstfictor effect of repeated exercise is prostanoid dependent in being prevented by prior administration of the cyclooxygenase inhibitor, indomethacin. We cannot test whether the same mechanism accounts for loss of the airway response to AMP, because cyclooxygenase inhibitors, such as indomethacin and flurbiprofen, inhibit the bronchoconstrictor response to inhaled adenosine and AMP. 28"29 In searching for a shared mechanism accounting for cross-refractoriness between AMP and exercise, it is worth examining the mechanism(s) by which these stimuli are believed to produce airway narrowing. In both cases, augmented preformed mediator release

J. ALLERGY CLIN. IMMUNOL. SEPTEMBER 1990

from airway mast cells is implicated. AMP has been demonstrated to augment antigen-induced mast cell histamine release but has minimal effects on the release of newly generated lipid mediators.3~ It is widely held that the principal mechanism by which exercise induces bronchoconstriction is by inducing hypertonicity of airway lining fluid, 14 and the stimulus of hypertonicity can be demonstrated in vitro to induce the release of histamine but not newly generated mediators from mast cells. 31 Thus, both AMP and hypertonicity operate to degranulate mast cells via a mechanism clearly distinct from the mechanism mediated by allergen in which degranulation is coupled with the generation of prostanoids. It is possible that AMP and hypertonicity stimuli share a biochemical pathway in inducing the degranulation of the "primed" airway mast cells present in asthmatic airways, 32 although no direct evidence exists for this theory. Since lung tissue has the capacity to generate large quantities of adenosine, 33 an additional possibility for an interaction between exercise and AMP bronchial challenge would exist if adenosine were released during exercise and contributed to exercise-induced bronchoconstriction. Adenosine is believed to be generated by, and released from, exercising tissues, exercising a homeostatic role via its vasodilator effect, 34 although its short half-life in whole blood makes it difficult to establish changes in plasma levels during exercise, 35 and lung tissue has been demonstrated to have a facilitated uptake mechanism for circulating adenosine. 36 In theory then, adenosine release during exercise may contribute to exercise-induced bronchoconstriction, and exercise-refractoriness may be due, in part, directly to tachyphylaxis to adenosine. In conclusion, we have demonstrated that repeated exposure of the airways of atopic subjects with asthma to AMP results in the development of refractoriness to exercise. Although release of mediators secondary to bronchoconstriction, for example, of prostaglandin E2, may account for this loss of response, an equally plausible explanation is a shared mechanism for the activation of mediator release from primed mast ceils in the airways. Additional work is required to shed light on the mechanism of this phenomenon. REFERENCES

1. Mann JS, Holgate ST, Renwick AG, Cushley MJ, Airway effects of purine nucleosides and nucleotides and release with bronchial provocationin asthma.J ApplPhysiol 1986;61:166776. 2. OashleyMJ, TattersfieldAE. Holgate ST. Inhaled adenosine and guanosine on airway resistance in normal and asthmatic subjects. Br J Clin Pharmacol 1983;15:161-5. 3. PhillipsGD, RaffertyP, BeasleyCRW,HolgateST. The effect of oral terfenadine on the bronchoconstrictorresponse to in-

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haled histamine and adenosine 5'-monophosphate in non-atopic asthma. Thorax 1987;42:939-45. 4. Church MK, Hughes PJ, Vardey CJ. Studies on the receptor mediating cyclic AMP-independent enhancement by adenosine of IgE-dependent mediator release from rat mast cells. Br J Pharmacol 1986;87:233-42. 5. Crimi N, Palermo F, Oliveri R, et al. Comparative study of the effects of nedocromil sodium (4 mg) and sodium cromoglycate (10 mg) on adenosine-induced brunchoconstriction in asthamtic subjects. Clin Allergy 1988;18:367-74. 6. Phillips GD, Scott VL, Richards R, Holgate ST. Effect of nedocromil sodium and sodium cromoglycate against bronchoconstriction induced by inhaled adenosine 5'monophosphate. Eur Respir J 1989;2:210-7. 7. Phillips GD, Ng WH, Church MK, Holgate ST. The response of plasma histamine to bronchoprovocation with methacholine, adenosine 5'-monophospahte (AMP), and allergen in atopic non-asthmatic subjects. Am Rev Respir Dis 1990;141:9-13. 8. Daxun Z, Rafferty P, Richards R, Summerell S, Holgate ST. Airway refractoriness to adenosine 5'-monophosphate after repeated inhalation. J ALLERGYCLIN IMMUNOL1989;83:152-8. 9. Phillips GD, Bagga PK, Djukanovic R, Holgate ST. The influence of refractoriness to adenosine 5'-monophosphate on allergen-provoked bronchoconstriction in asthma. Am Rev Respir Dis 1989;140:321-6. 10. Lee TH, Brown MJ, Nagy L, Causon R, Walport MJ, Kay AB. Exercise-induced release of histamine and neutrophil chemotactic factor in atopic asthmatics. J ALLERGYCLINIMMUNOL 1982;70:73-81. t 1. Edmunds AT, Tooley M, Godfrey S. The refractor period after exercise-induced asthma: its duration and relation to the severity of exercise. Am Rev Respir Dis 1978;117:247-54. 12. Hahn AG, Nogrady SG, Tumilty DM, Lawrence SR, Morton AR. Histamine reactivity during the refractory period after exercise-induced asthma. Thorax 1984;39:919-23. 13. Zawadski DK, Lenner KA, McFadden ER. Effect of exercise on non-specific airway reactivity in asthmatics. J Appl Physiol 1988;64:812-6. 14. Belcher NG, Rees PJ, Clark TJH, Lee TH. A comparison of the refractory periods induced by hypertonic airway challenge and exercise in bronchial asthma. Am Rev Respir Dis 1987;135:822-5. 15. Finnerty JP, Wilmot C, Holgate ST. Inhibition of hypertonic saline-induced bronchoconstriction by terfenadine and flurbiprofen: evidence for the predominant role of histamine. Am Rev Respir Dis 1989;140:593-7. 16. Chai H, Farr RS, Froehlich LA, et al. Standardization of bronchial inhalation challenge procedures. J ALLERGY CLI~ IMMUNOL 1975;56:323-327. 17. Arch JRS, Newsholm EA. The control of the metabolism and the hormonal role of adenosine. Essays Biochem 1978;14:82123. 18. Londos C, Wolff J. Two distinct adenosine-sensitive sites on adenylate cyclase. Proc Natl Acad Sci USA 1977;74:5482-6.

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19. Christie J, Satchell DG. Purine receptors in the trachea: is there a receptor for ATP? Br J Pharmacol 1980;70:512-4. 20. Burnstock G. Purinergic nerves and receptors. Prog Biochem Pharmacol 1980;16:141-54. 21. Hughes PJ, Holgate ST, Church MK. Adenosine inhibits and potentiates IgE-depednent histamine release from human lung mast cells by an A2 purinoceptor mediator mechanism. Biochem Pharmacol 1984;33:3847-52. 22. Fuller RW, Maxwell DL, Conradson T-BG, Dixon CMS, Barnes PL Circulatory and respiratory effects of infused adenosine in conscious man. Br J Clin Pharmacol 1987;24:309-17. 23. Marquardt DL, Waller LL. Inhibition of mast cell adenosine responsiveness by chronic exposure to adenosine receptor agonists. Biochem Pharmacol 1987;36:4297-302. 24. Hamielec CM, Manning PJ, O'Byrne PM. Exercise refractoriness after histamine inhalation in asthmatic subjects. Am Rev Respir Dis 1988;138:794-8. 25. Boulet L-P, Legris C, Tourcotte H. Bronchial responsiveness to histamine after repeated exercise-induced bronchospasm. Respiration 1987;52:237-45. 26. Finnerty JP, Polosa R, Holgate ST. Assessment of histamine tachyphylaxis in asthma and its relationship to bronchial hyperreactivity (BHR) [Abstract]. Thorax 1989;44:867P. 27. O'Byrne PM, Jones GL. The effect of indomethacin on exercise-induced bronchoconstriction and refractoriness after exercise. Am Rev Respir Dis 1986;134:69-72, 28. Phillips GD, Holgate ST. The effect of oral terfenadine alone and in combination with flurbiprofen on the bronchoconstrictor response to inhaled adenosine 5'-monophosphate in nonatopic asthma. Am Rev Respir Dis 1989;139:463-9. 29. Crimi N, Palermo F, Polosa R, et al. The role of cyclooxygenase-derived mediators on adenosine-induced bronchoconstriction. J ALLERGYCLIN IMMUNOL1989;83:921-5. 30. Marquardt DL, Walker LL, Wasserman SI. Adenosine receptors on mouse bone marrow-derived mast cells: functional significance and regulation by aminophylline. J Immunol 1984; 133:932-7. 31. Eggleston PA, Adkinson NF, Kagey-Sobotka A, Lichtenstein LM. Osmotically activated human lung mast cells (MC) and basophils release histamine but not arachidonic acid metaborites [Abstract]. J ALLERGYCLIN IMMUNOL1985;75:125. 32. Flint KC, Leung KBP, Hudspith BN, Brostoff J, Pearce FL, Johnson NM. Bronchoalveolar mast cells in extrinsic asthma: a mechanism for the initiation of antigen-specific bronehoconstriction. Br Med J 1985;291:923-6. 33. Mentzer RM, Rubio R, Berne RM. Release of adenosine by hypoxic canine lung tissue and its possible role in pulmonary circulation. Am J Physiol 1975;229:1625-31. 34. Watt AH, Roufledge PA. Adenosine: an importance beyond ATP [Editorial]. Br Med J 1986;293:1455-6. 35. Klabunde RE. Dipyridamole inhibition of adenosine metaborism in human blood. Eur J Pharmacol 1983;93:21-6. 36. Das DK, Steinberg H. Adenosine transport by the lung. J Appl Physiol 1988;62:297-305.

Repeated exposure of asthmatic airways to inhaled adenosine 5'-monophosphate attenuates bronchoconstriction provoked by exercise.

Inhaled adenosine 5'-monophosphate (AMP) induces bronchoconstriction in subjects with asthma, probably caused by histamine release from airway mast ce...
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