Eur Respir J 1989, 2, 409-414

Pretreatment with an inhaled a 1-adrenergic agonist, methoxamine, reduces exercise-induced asthma

A.T. Dinh Xuan, M. Chaussain, J. Regnard, A. Lockhart

PretreatmenJ with an inhaled a,-adrenergic agonist. methoxamine, reduces Laboratoire de Physiologie, Faculte de Medecine eurcise-induced asthma. A.T. Dinh Xuan, M. Chaussain, J. Regnard, A. Cochin Port-Royal et Laboratoires d'Exploration Lockhart. Fonctionnelle Respiratoire, Hopitaux Cochin et ABSTRACT: In order to assess the role of the bronchial circulation in the Saint Vincent de Paul, 75014 Paris, France. pathogenes.ls of exercise-.induced asthma (EIA), we conducted a double­ Correspondence: Dr A.T. Dinh Xuan, Laboratoire blind, randomlzed study of the effects of pretreatment with an inhaled a - 1 d 'Explorations Fonctionnelles, Pavilion Potain, adrenergic agonist, methoxamine (Mx), l.n nine asthmatic teenagers with Hopital Cochin, 27 Rue du Faubourg Saint known r..:rA. Exercise consisted of S min cycle ergometry at a submaximal, Jacques, 75014 Paris, France. constant work-load, while the subjecfs breathed dry air at ambient tem­ ) Keywords: Airway oedema; a.,-adrenoceptors; perature. Forced expiratory volume in one second (FEV1 was measured at ba...eJine, JS min after pretreatment of either Mx or saline, and ser ially bronchial circulation; exercise-induced asthma; methoxamine. after exercise. Mx significantly reduced the exercise-induced fa ll of FEV 1 without modifying baseline FEV1 In five of the eight subJec t~ , had li ttle or no effect In three and caused an acute asthmatic attack in the remaining Received: June, 1988; accepted after revision December 29, 1988. subject. Mx has p<>tent constrictor effects on both bronchial and vascular smooth muscles through stimulation of postjunctlonal a 1-nd renoceptors. 1'his study was supported by grant No. 7.87 R Therefore, the protective effect of Mx on EIA may be attributed to vaso­ from the Scientific Council of the Faculte de constriction of tracheobronchial vessels opposing the hyperaemla and Medccine Cochin-Port Royal. mucosal airway oedema that may cause, at least in part, the exercise­ induced acute bronchial obstruction in EIA. Alternatively, Mx stimulates mucus, water and electrolyte secretion by airway epithelium and may, therefore, oppose the dehydration of airway surface that could be a causa­ tive factor of EIA. Eur Respir J., 1989, 2, 409-414.

The mechanisms that cause airway narrowing in smooth muscle and stimulates submucosal glands, both exercise-induced asthma (EIA) are still debated. During effects that should, if anything, aggravate airways nar­ physical exercise, bolh heat [1] and water [2) losses rowing. We wondered, therefore, if a potent vasocon­ increase over resting values but !he intermediate mecha­ strictor agent such as methoxamine might prevent EIA, nisms linking the ensuing increase in energy losses by which would indirecll.y confinn Lhe role of vasodilatation the airways to post-exertional asthma are poorly under­ of the tracheobronchial circulation [4, 5) in !his condi­ stood, allhough cooling and dehydration of the airway tion. surface may be the primary events [3}. There is circum­ stantial evidence in favour of a role for the tracheal and bronchial circulation in production of exercise-induced Subjects aslhma [4, 5). Rewanning of the tracheobronchial tree during the recovery period !hat follows exercise is more Nine asthmatic teenagers with sporadic and moderate rapid in subjects suffering from post-exertional asthma asthma responding to the defmition of !he American than in control subjects. This may sti mulate mediator Thoracic Society [81 were studied (table 1). All subjectS release by mast cells and is suggestive of an exaggerated had a history of EIA which was documented by a fall in ) reactive hyperaemia r4, 5] which may, in turn, result in forced expiratory volume in one second (FEY 1 ~20% of luminal narrowing due to vascular engorgement and oe­ baseline FEY, after 5 rnin of outdoor free running. All of dema in !he airway mucosa and submucosa. them were in a stable phase of their disease; only three

Alpha1-ad.renergic agonists are potent vasoconstrictor of the nine patients made regular use of bronchodilators agents of the bronchial circulat ion in experimental to control their symptoms and none had been Lreatcd animals l6). We have previously shown that inhaled with corticosteroids for a month before the study. All methoxamine, an a. 1-adrenergic agonist, prevented other medications were withheld according to standard melhacholine-induced bronchial obstruction in patients recommendations [9). After approval by the Elhical wilh impaired left ventricular function r?J. an effect which Committee of our Medical School, the design of the study we explained by constriction of bronchial vesseLs, was thoroughly explained to the subjects and their parents since methoxamine is a contractile agent for bronchial before obtaining their informed consent 410 A.T. DINH XUAN ET AL.

Methods Methoxamine was diluted in saline at a concentration 1 (w/v) of 40 mg·ml· • Osmolarity and pH of the solution Outline of the study were 300 mosm·l·1 and 7, respectively. Aerosols were generated by a DcVilbiss model 646 nebulizer operated Eight subjects carried out two standardized exercise by compressed air at 1.50 kPa and an inhalation trig­ tests after inhalation of either methoxamine or saline gered dosimeter (FDC 87. Mediprom S.A., Paris), set to solution according to a double-blind, randomlzcd design. deliver an aerosol of 1 s duration, that provided 0.8 mg Fifteen min after pretreatment, lhe subject carried out a of methoxamine for each inspiration. Volume history was submaximal exercise for 5 min on a cycle ergometer. standardized by having each participant inhale from functional residual capacity to total lung capacity. The FEV1 was meas ured at baseline, 15 min after dosing, every m in for the ftrst 5 min following the end of e xer­ total number of inhalations was predetermined as a cise, and then every 10 min until return to baseline. Blood function of body weight to achieve a target dose of inhaled 1 pressure and heart rate were measured at baseline and 15 methoxamine of about 0.15 mg·kg- of body weight (table m in after inhalation of methoxamine or placebo. The study 1). FEV 1 was measured in triplicate a t each time point was discontinued in the remaining subject (No. 9) who and the highest value was retained for analysis. had an acute aslhmalic auack following pretreatment of methoxamine and recovered after administration of sal­ butamol (2x 100 J.Lg) from a metered dose inhaler. Statistical analysis

The entire set of values of FEV I' blood pressure and Technical details heart rate was submitted to a two way analysis of vari­ ance (treatment, time) for repeated measurements (sub­ The two exercise tests were performed on the same jects). Intra-individual comparisons of the effects of day. There was at least a 6 h interval between the first methoxamine and placebo on FEV1 were made by a paired and the second challenges which took place, respectively, Wilcoxon signed rank test. before 9 am and after 3 pm. This interval was chosen in order to avoid the confounding effect of the refractory period that may occur after a first attack of EIA [10). Results The exercise consisted of S min of pedalling on a cycle ergometer (Gauthier MSR, France) while the subject, The eight subjects, whose airways patency was not wearing a nose-clip, breathed compressed dry air (0% affected after pre treatment of methoxamine as shown by , humidity) at room temperature through a mouthpiece. an unchanged FEV1 carried out lhc two exercise chal­ The work-load used for each subject was chosen to obtain lenges and results from lhesc subjects form lhe basis of 90% of predicted maximal heart rate (HRmax) deter­ this report mined from the usual formula: HRmax=220-age (yrs). Individual time-response curves for FEV 1 are presented Heart rate was monitored (Gould IM 1000, USA) and in figure 1. As a result of the randomized design of the recorded every 30 s. Individual tailoring of lhe work­ study, pretreatment before the 9 am exercise was load was chosen to account for differences in height and methoxamine in four subjects and placebo in the remain­ weight between subjects (table 1). Immediately after the ing four subjects and pretreatments were crossed-over exerdsc, the subjects began to respire room air and for the afternoon exercise. Since there was no order effect, continued to do so throughout the entire recovery period, results of both subgroups were analysed together. as recommended by GILBERT et al. [5]. Group-average (±so) values for pre- and post-exercise

Table1. - Anthropometric, baseline lung function and exercise data

Subjects Sex Age Height Weight FEY, HR (mean±so) Inhaled Mx cm kg %pred p Mx mg

1 M 13 166 58 3.0 101 171±6 174±6 8.8 2 F 12 146 38 1.8 94 163±8 163±9 5.6 3 M 13 161 51 2.8 101 176±4 177±6 7.2 4 F 10 149 39 2.3 114 178±3 179±4 5.6 5 M 16 163 47 2.8 100 176±6 174±6 7.2 6 M 12 142 36 2.2 114 174±6 174±8 5.6 7 F 16 154 65 2.2 99 177±4 177±4 9.6 8 F 17 160 46 2.4 97 176±5 177±7 7.2 9 M 18 177 63 3.2 90 9.6

) Predicted values of forced expiratory volume in one second (FEY1 are those of Bounuvs [40]. Heart rate (HR) was recorded every 30 s during the two exercises that followed pretreaiJnent of placebo (P) or methoxamine (Mx) and the maximal HR on exercise is listed in the table. Doses of inhaled Mx are given as a function of corporeal weight (0.15 1 mg·kg· ). METHOXAMINE REDUCES EXERCISE-INDUCED ASTHMA 411

6 0

B Mx/ P 5 1 5 2 5 3 5 8 Mx/ P 5 1 5 2 5 3 5 8 Mx/ P 5 1 5 2 5 3 5 8 Mx / P 5 1 5 2 5 3 5 time mln time mln

) Fig. 1. - Changes in forced expiratory volume in one second (FEV 1 caused by exercise after pretreatment of methoxamine and placebo. FEV was recorded at baseline (B), after pretreatment of methoxamine (Mx: closed circles) or placebo (P: open circles) and serially after the exercisd challenge (column).

FEV, FEV1 I % pred 3 120

100

2 80

60 n = 8

1 40

ll Mx / P 5 1 5 25 35 1 5 25 35 time min time min

Fig. 2. - Group-average values of forced expiratory volume in one second (FEV 1) (mean±so). Difference between pretreatment of methoxamine (Mx: closed circles) and placebo (P: open circles) are signficant at the p

FEY, and changes of FEY, from baseline on pretreat­ p

FEY1=2.3±0.5 l and 2.3±0.5 1 at baseline and after pre­ and a partial protective effect in two (Nos 3 and 4). Con­ treatment with methoxamine). Methoxamine reduced the versely, in the remaining subjects (Nos 2, 7 and 8) FEY, , exercise-induced fall in FEY1 an effect which was fell to similar values on both placebo and methoxamine, maximal and significant at 5 min (LWEV1=0.9±0.3 I and the latter having had no protective effect Inspection of 0.4±0.4 I on placebo and methoxamine, respectively individual dose response curves in figure 1 conveyed the 412 A.T. DINH XUAN ET AL.

impression that methoxamine had a full protective effect Methoxamine is a selective a 1-adrenoceptor agonist only in subjects having a mild degree of exercise­ [13] that has various effects on different effector struc­ - induced bronchial obstruction. Indeed, by use of a tures of the airways. Stimulation of postjunctional a 1 Spearman rank correlation test, we found that patients adrenoceptor of airway smooth muscle and submucosal with the largest bronchial responses to exercise placebo glands induces in vitro contraction of the former [14, 15J also had the largest responses on methoxamine, whereas and secretion of mucus by the latter [16]. These effects subjects with the lesser falls on placebo were also the account for the aggravation of the bronchial obstruction most likely to be partially or fully protected by methoxam­ by alpha-adrenergic agonists observed in a majority ine (r,=0.83, p<0.05). of asthmatic subjects [17, 18]. Consistent with the dele­ time min terious effects of alpha-agonist agents in asthma is the B Mx/P 5 I S 25 35 observation that EIA may be prevented by alpha-adrener­ 0.2 gic antagonists [19- 22]. The direct effects of alpha­ 0 adrenergic agonists on bronchial smooth muscle and -0.2 glands warrant the contention that such compounds are - 0.4 contra-indicated in asthmatic patients. However, benefi­ -0.6 cial effects on airways patency of a 1-adrenergic agonists -0.8 have already been reported in animals [23] and humans - I [7] and we report in this study that inhaled methoxamine

6FEV1 is capable of preventing EIA in patients with mild asthma. *.. .* Firstly, the protective effect may be explained by Methoxamine 0 PlacebO"] - I • stimulation of bronchial vascular post-junctional a 1 Fig. 3.-Group-average values (±so) of fall in forced expiratory volume adrenoceptors. Stimulation of a 1-adrenoceptors of vas­ in one second (FEV ) from baseline. Post-exercise fall in FEV, on cular smooth muscle causes vasoconstriction [6, 13, 24] methoxamine (Mx: closed areas) is significanlly le.~s than on placebo and therefore reduces vasodilatation and vascular engor­ (P: open areas). •• pcatecholamines upon cessation of exercise. a systematic bias related to diurnal variation of the rest­ Tracheobronchial vasoconstriction during exercise may ing bronchial tone. We believe, however, that such a bias be facilitated by the increase of alpha-adrenoceptor is unlikely. Firstly, previous studies have shown absence sensitivity of vascular smooth muscle upon cooling [25], of diurnal variation in EIA [11, 12]. Secondly, randomi­ although airway temperature does not fall on exercise to zation achieved an identical distribution of pretreatments the low 20-24oc at which this effect was found in vitro of methoxamine and placebo in the morning and the (26]. A rapid rise in bronchial blood flow may lead to afternoon without discernable effects of the order of increased thickness of the airways wall due to vascular administration of the pretreatments on the bronchial re­ engorgement, plasma exudation, submucosal and mucosal sponse to exercise of our subjects. Exercise challenge oedema facilitated by the presence of chronic inflamma­ was only performed once on placebo in this study since tory changes in the airways of asthmatic subjects. a preliminary study of six other comparable asthmatic Additional evidence for deleterious effects of local subjects demonstrated that duplicate exercise challenges vasodilatation in asthmatic subjects has been provided without active pretreatment and similar to that used in by a recent study in which it was shown that inhaled the present study caused almost identical maximal falls prostacyclin may cause airway narrowing which was best explained by mucosal engorgement [27]. from baseline FEV1 of 31±7% and 30±7% of predicted FEVI. It is not possible to explain the protection offered by We used a 15 min interval between pretreatment of both alpha-adrenergic agonists and antagonists against inhaled methoxamine and the exercise test since we have EIA by only taking into account their effects on airway shown in a previous work that methoxamine fully pre­ smooth muscle. Methoxamine is a potent vasoconstrictor vented the bronchial obstruction caused by a methacho­ agent [6, 13, 24] and may therefore protect against EIA line challenge commencing 15 min after dosing in cardiac by preventing the rebound hyperaemia at recovery. In patients with impaired left-ventricular function [7]. addition, methoxamine may also reduce, through its METHOXAMINE REDUCES EXERCISE-INDUCED ASTHMA 413 vasoconstrictor effect, the rate of water delivery to the Acknowledgements: We express our gratitude to Professors c_ Advenier, S.D. Anderson and 1-L Gu~nard airways after exercise [28] that is supposed to modify the for many helpful suggc.~tions whilst !his work was in airway surface osmolarity which is a possible trigger­ progress. We also tbank Dr M. Islassc for preparing ing factor of EIA [2, 29]. Alpha-adrenergic antagonists the solution of methoxamine. The powder of melhoxam­ [19-22] and calcium channel blockers [30) are bronchodi­ ine was a gift from Dr M. Renaudie, Wellcome S.A-, lator as well as vasodilator agents and have a protective France_ effect against EIA. In addition to their relaxant effect on bronchial smooth muscle, these drugs may, therefore, References limit hyperpnoea-induced vasoconstriction, thus minimiz­ ing the post-challenge rebound hyperaemia. 1. Deal EC Jr. McFadden ER Jr, Ingram RH Jr, Jaeger JJ.­ In addition it is possible that the respective role of Hyperpnea and heat flux: initial reaction sequence in exercise­ contraction of airway smooth muscle and reactive hy­ induced asthma. 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Lockhart. Clin Invest, 1985, 76, 1007-1010. RESUME: Pour determiner le rOle de la circulation bronchique 27. Hardy CC, Bradding P, Robinson C, Holgate ST. - dans l'asthme post-exercice (APE), nous avons etudie en double­ Bronchoconstrictor and antibronchoconstrictor properties of insu l'effet d'un pretraitement par un alpha-1 agoniste inhale, inhaled prostacyclin in asthma. J Appl Physiol, 1988, 64, la methoxamine (Mx), chez 9 adolescents asthmatiques ayant 1567- 1574. un APE connu. L'exercice rectangulaire est effectue sur bicy­ 28. Smith CM, Anderson SD, Mihalyka M, Walsh S. - Water clette ergometrique pendant 5 min a puissance submaximale, delivery during recovery rather than rapid rewarrn.ing may le sujet respirant par la bouche de !'air sec a temperature enhance the airway response to exercise in patients with asthma. ambiante. Le volume expiratoire maximal seconde (VEMS) Am Rev Respir Dis, 1988, 137, 340 (abstract). est mesure al' etat de base, 15 m in apres inhalation du produit, 29. Anderson S, Schoeffel R, Follet R, Perry C, Daviskas E, et regulierement apres l'exercice. La Mx reduit significative­ Kendall M. - Sensitivity to heat and water loss at rest and ment la chute du VEMS induite par l'exercice sans modifier during exercise in asthmatic patients. Eur J Respir Dis, 1982, le VEMS de base chez 5 des 8 sujets, a peu d'effet chez 3 63, 459-471. autres sujeL~ mais entralne une crise d'asthme ehez le sujet 30. Cerrina J, Denjean A, Alexandre G, Lockhart A, Duroux restant. En stimulant Jes recepteurs alpha-1 adn!nergiques P. - Inhibition of exercise-induced asthma by a calcium post-jonctionnels, la Mx exerce un effet constricteur sur le antagonist, nifedipine. Am Rev Respir Dis, 1981, 123, muscle lisse, aussi bien bronchique que vasculaire. 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