Inhibition of PAF-induced Gas Exchange Defects by Beta-adrenergic Agonists in Mild Asthma Is Not Due to Bronchodilation ORLANDO DÍAZ, JOAN A. BARBERÀ, RAMÓN MARRADES, K. FAN CHUNG, JOSEP ROCA, and ROBERT RODRIGUEZ-ROISIN Serveis de Pneumologia i Al.lèrgia Respiratòria, Departament de Medicina, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain; and National Heart and Lung Institute, Imperial College, School of Medicine, London, United Kingdom Salbutamol inhibits neutropenia, increased airway resistance, and gas exchange abnormalities pro- voked by platelet-activating factor (PAF) challenge in normal persons. To further explore the intrigu- ing dissociation between spirometric abnormalities and gas exchange defects shown in patients with asthma, we investigated whether the salbutamol-induced improvement in gas exchange distur- bances after PAF is the result of bronchodilation by comparing this effect with that of ipratropium bromide. We hypothesized that ipratropium bromide, an anticholinergic agent without vascular ef- fects, should block PAF-induced bronchoconstriction but not interfere with its systemic, neutropenic, and gas exchange effects. We studied eight nonsmokers with mild asthma (26 2.0 SE yr of age) who, prior to PAF challenge (18 g), inhaled either ipratropium bromide (80 g) or salbutamol (300 g) in a randomized, double-blind, crossover fashion 1 wk apart. Peripheral blood neutrophils, · · respiratory system resistance (Rrs), arterial blood gases and ventilation-perfusion (VA/Q ) inequalities were measured 5, 15, and 45 min after PAF. Compared with pretreatment with salbutamol, ipratro- pium bromide also blocked the increase of respiratory system resistance (Rrs) but did not prevent fa- cial flushing and neutropenia (p 0.03) at 5 min nor the decrease of PaO2 (p 0.08 and 0.05), the in- · · crease of AaPO2 (p 0.02 each), and the deterioration of VA/Q relationships (p 0.05 each) at 5 and 15 min, respectively. This functional pattern was similar to that observed previously in normal sub- jects and in nonpremedicated asthmatic patients after PAF, with return to baseline values at 45 min. By contrast, salbutamol blocked PAF-induced increased Rrs, in addition to all the other PAF-induced abnormalities. These findings indicate that, in patients with mild asthma, salbutamol inhibits PAF- induced neutropenia and gas exchange abnormalities by mechanisms involving other than airway smooth muscle narrowing, possibly by acting on both the bronchial and pulmonary circulations. Díaz O, Barberà JA, Marrades R, Chung KF, Roca J, Rodriguez-Roisin R. Inhibition of PAF-induced gas exchange defects by beta-adrenergic agonists in mild asthma is not due to bronchodila- tion. AM J RESPIR CRIT CARE MED 1997;156:17–22. Platelet-activating factor (PAF) is a potent ether-linked phos- characterized by an increased dispersion of pulmonary blood pholipid mediator of inflammation that is considered to have flow, including the development of low ventilation-perfusion · · · · a role in the pathogenesis of bronchial asthma and other pul- (VA/Q) areas, identical to the entire spectrum of VA/Q inequal- · · monary disorders (1, 2). We have shown that PAF induced or ities seen in patients with bronchial asthma (5). Although VA/Q worsened gas exchange abnormalities in normal subjects (3) mismatching in patients with asthma is akin to airway narrow- and in patients with mild asthma (4). These disturbances were ing by both inflammation and bronchoconstriction, the precise · · mechanism by which VA/Q inequalities may occur still remains · · elusive. We suggested that the VA/Q defects could be related (Received in original form October 28, 1996 and in revised form March 7, 1997) to an increased tracheobronchial vascular permeability induced Supported by Projects 94/0986 from the Fondo de Investigación Sanitaria (FIS) by PAF, therefore supporting the notion that PAF may play a and 1995 SGR 00446 from the Comissionat per a Universitats i Recerca de la Generalitat de Catalunya, and a Training Grant (Formación de Investigadores, key role as a putative mediator of inflammation in airways (3, 4). Programa de Cooperación Científica con Iberoamérica) from the Ministerio de Previous studies in asthmatic patients have consistently Educación y Ciencia, Spain. shown a poor correlation between the behavior of reduced Dr. Díaz is Associate Professor of Universidad Pontificia de Santiago de Chile, Chile. maximal expiratory airflow rates and abnormal pulmonary gas Correspondence and requests for reprints should be addressed to J. Roca, M.D., exchange, namely, arterial blood gases and their major intra- · · Servei de Pneumologia i Al.lèrgia Respiratòria, Hospital Clínic, Villarroel, 170, pulmonary determinant, VA/Q imbalance, in individual pa- 08036-Barcelona, Spain. tients and also within clinically similar asthma patients’ cate- Am J Respir Crit Care Med Vol. 156. pp. 17–22, 1997 gory, such that it can be extended across the full constellation 18 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 156 1997 of asthma severity (5, 6). Conceivably, these intriguing find- TABLE 1 ings reflect two different pathophysiologic phenomena and ANTHROPOMETRIC AND BASELINE FUNCTION DATA ON concur with the hypothesis that decreased spirometric indices IPRATROPIUM BROMIDE AND SALBUTAMOL STUDIES* reflect reduction of airway caliber in larger and middle-size Age, yr 26 2 bronchi, whereas pulmonary gas exchange disturbances pre- Sex, F/M 5/3 dominantly refer to structural changes in distal small airways Height, cm 165 3 (6). Thus, the latter changes could be more preferentially re- Weight, kg 63 3 lated to airway inflammation rather than to airflow obstruction FEV1, L 3.4 0.3 (93 3% pred) by itself. Notwithstanding, cause and effect relationship will be FEV1/FVC, % 80 1.5 PD20, mol 0.39 0.12 very difficult to establish in humans. Salbutamol, a short-acting beta-adrenergic agonist, inhibits Ipratropium Bromide Salbutamol PAF-induced increased airway resistance and the systemic Rrs, cm H2O/L/s 3.36 0.31 3.12 0.28 · (cough, facial flushing, and feeling of warmth), cellular (pe- VE, L/min 7.5 0.8 7.0 0.4 ripheral blood neutropenia), and gas exchange (impaired arte- RR, /min 15 1.6 15 0.9 · · Ps, mm Hg 83 5 86 3 rial oxygenation and VA/Q imbalance) effects in normal sub- · QT, L/min 5.6 0.2 6.2 0.4 jects (7, 8). We postulate that these effects of salbutamol could HR, /min 77 5 81 6 be related preferentially to an inhibition of PAF-induced pre- Neutrophils, 109/L 3.56 0.35 3.67 0.46 capillary and postcapillary endothelial constriction in the bron- PaO2, mm Hg 101 3 101 2 chial microcirculation (9, 10), although its potent relaxant effect PaCO2, mm Hg 35 1 36 1 on airway smooth muscle cannot be overlooked. If so, an anti- pH 7.44 0.01 7.44 0.01 AaPO2, mm Hg 13 2 9 1 cholinergic agent devoid of vascular effects such as ipratro- · Shunt, % of QT 0.0 0.1 0.3 0.4 pium bromide should prevent PAF-induced bronchoconstric- · · Low VA/Q, % of QT · 1.0 0.4 0.3 0.2 tion but not interfere with its systemic, cellular, and gas exchange Log SDQ 0.59 0.07 0.46 0.05 effects. The present study was undertaken to test this hypothe- Log SDV 0.49 0.05 0.43 0.05 · sis by assessing the cellular, lung mechanical, and gas exchange Dead space, % of VA 27 2.8 29 3.9 responses to PAF after ipratropium bromide (80 g) and sal- DISP R-E* 3.79 0.67 2.80 0.61 butamol (300 g) given by inhalation in patients with mild Definition of abbreviations: PD20 provocative dose of methacoline producing a 20% · asthma. fall in FEV1; Rrs total respiratory system resistance; V E minute ventilation; RR re- · spiratory rate; Ps mean systemic arterial pressure; QT cardiac output; HR heart · rate; AaPO2 alveolar-arterial PO2 difference; Shunt % of QT to lung units with V A/Q · · · · · · · T to lung units with V A/Q ratios 0.1; Log SDQ METHODS ratios 0.005; Low V A/Q % of Q dispersion of the perfusion distribution; Log SDV dispersion of the ventilation distri- Patients · · · bution; Dead space % V A to lung units with V A/Q ratios 100; DISP R-E* overall · · index of V A/Q inequality. Eight nonsmokers with mild asthma were recruited for the study (Table * Values are mean SE. Predicted values for forced spirometry were taken from Ref- 1), which was approved by the Ethical Committee of Hospital Clínic. erence 11. All subjects gave informed written consent after the purpose, risks, and potential benefits of the study were explained to them. Inclusion crite- ria were: no respiratory infection or exacerbation of asthma within the preceding 6 wk; FEV1 70% predicted and positive methacholine steady-state conditions after PAF challenge was demonstrated by sta- bronchial challenge (PD20 4.0 mol); maintenance therapy with aero- bility ( 5%) of both ventilatory and hemodynamic variables, and by sol short-acting beta-adrenergics and/or inhaled corticosteroids, but no the close agreement between duplicate measurements of mixed ex- previous treatment with oral steroids; absence of any systemic or car- pired and arterial O2 and CO2 (within 5%). These conditions were diopulmonary disease other than asthma. met in all patients throughout the whole period of study. Total resistance of the respiratory system (Rrs) was measured by Measurements the forced oscillation technique and its analysis restricted to 8 Hz Blood samples were collected anaerobically through a catheter in- (3, 4). A three-lead electrocardiogram, heart rate (HR), and systemic serted into the radial artery. Total white cell counts in arterial blood pressure (Ps) were continuously recorded throughout the whole study were measured with a Technicon H.1™ System (Technicon, Tarry- (HP 7830A Monitor and HP 7754B Recorder; Hewlett-Packard, town, NY). Arterial PO2, PCO2, and pH were analyzed in duplicate us- Waltham, MA). ing standard electrodes (IL 1302; Instrumentation Laboratories, Mil- ano, Italy). Hemoglobin concentration was measured by a Co-oximeter Study Design · (IL 482; Instrumentation Laboratories). Oxygen uptake (VO2) and CO2 A randomized double-blind crossover design was used to compare the · production (VCO2) were calculated from mixed expired O2 and CO2 effect of salbutamol with that of ipratropium bromide on PAF- concentrations measured by mass spectrometry (Multigas Monitor induced effects, with subjects breathing room air and seated in an · MS2; BOC-Medishield, London, UK). Minute ventilation (VE) and armchair. Medication was withheld for 12 h before arrival to the labo- respiratory rate (RR) were measured using a calibrated Wright spirom- ratory. Once the inert gas solution had been infused for at least 45 min eter (Respirometer MK8; BOC-Medical, Essex, UK). The AaPO2 was to allow for the establishment of adequate steady-state conditions, calculated according to the alveolar gas equation using the measured baseline measurements were performed. All subjects were challenged respiratory exchange ratio (R). The multiple inert gas elimination tech- on two occasions 1 wk apart with inhaled PAF 30 min after the admin- · · istration of either ipratropium bromide (two puffs 80 g) or sal- nique (MIGET) estimated the distributions of VA/Q ratios without sampling mixed venous inert gases in the customary manner, a modality butamol (three puffs 300 g), using a regular metered-dose inhaler that can be used with similar accuracy (12) in all but one patient. With with an approximately 1-L holding chamber, one puff at a time, and a this approach cardiac output needs to be directly measured by dye dilu- set of measurements was taken 15 min later. It has been shown that tion technique (DC-410; Waters Instruments Inc., Rochester, MN) us- 80% of the maximal bronchodilation produced by ipratropium bro- ing a 5-mg bolus of indocyanine green injected through a catheter mide can be achieved with a cumulative dose of 72 g (13). Patients placed percutaneously in a vein of the arm while mixed venous inert were challenged with PAF (C16) (1-0-Hexadecyl-2-acetyl-sn-glycero- gas concentrations are computed from mass balance equations (12). 3-phosphocholine) (18 g) (Novabiochem AG, Lucerne, Switzerland). The duplicate samples of each set of measurements were treated sepa- Duplicate measurements were taken at 5, 15, and 45 min after PAF in- rately, the final data resulting in the average of variables determined halation, as described previously (6). All sets of measurements consisted · · of the following steps in sequence: inert gas sampling and ventilatory from both VA/Q distributions at each point in time. Maintenance of Díaz, Barberà, Marrades, et al.: PAF, Bronchodilators, and Gas Exchange in Asthma 19 TABLE 2 LUNG FUNCTION DATA ON IPRATROPIUM BROMIDE AND SALBUTAMOL STUDIES BEFORE AND 5 MIN AFTER PAF CHALLENGE* Ipratropium Bromide Salbutamol (before PAF ) (after PAF ) (before PAF ) (after PAF ) Rrs, cm H2O/L/s 2.76 0.3 3.27 0.3 2.63 0.2 2.74 0.2 · VE, L/min 7.6 0.9 8.2 1.0 7.3 0.4 7.3 0.7 RR, /min 15 1.6 16 1.6 15 0.9 15 1.0 Ps, mm Hg 83 5 82 4 87 3 86 3 · QT, L/min 5.3 0.3 5.5 0.4 6.9 0.4 6.5 0.5 HR, /min 77 5 76 5 81 6 84 7 Neutrophils, 109/L 3.74 0.35 1.67 0.39† 3.62 0.44 3.03 0.58† PaO2, mm Hg 101 4 87 5 101 3 97 5 PaCO2, mm Hg 36 1 35 1 37 1 36 1 pH 7.44 0.01 7.43 0.03 7.44 0.01 7.44 0.04 AaPO2, mm Hg 13 3 30 5† 11 2 16 4† · Shunt, % of QT 0.0 0.1 0.0 0.1 0.3 0.4 0.2 0.1 · · · Low VA/Q, % of QT 1.6 1.0 4.6 2.0 0.5 0.5 1.9 1.8 Log SDQ 0.57 0.09 0.87 0.11† 0.51 0.07 0.57 1.0† Log SDV 0.47 0.04 0.57 0.05 0.56 0.07 0.50 0.04 · Dead space, % of VA 29 2.5 26 3.8 27 4.0 30 3.1 DISP R-E* 3.46 0.80 6.35 1.36† 3.69 0.75 3.77 0.95† For definition of abbreviations, see Table 1. * Values are mean SE. For p values, see RESULTS. † Significant changes between ipratropium bromide and salbutamol after PAF inhalation. recordings; respiratory gas sampling; hemodynamic measurements; 5 min; in addition, PaO2 showed a trend to decrease (from 101 sampling for circulating white blood cells; measurements of Rrs. 4 to 87 5 mm Hg) (p 0.08) at 5 min, which persisted at 15 min (to 93 5 mm Hg) (p 0.05), whereas AaPO2 increased Statistics markedly (from 13 3 to 30 5 mm Hg and to 24 3 mm Hg) Results are expressed as mean SE. Changes in neutrophils, Rrs, ar- at 5 and 15 min, respectively (p 0.02 each), returning to base- · · terial blood gases, and VA/Q inequalities were assessed by an analysis line values at 45 min. These findings were paralleled by a con- of variance (ANOVA) model appropriate to the two-period two-treat- · · siderable VA/Q deterioration, essentially illustrated by a ment crossover design, to determine the effect of ipratropium bro- marked increase of the dispersion of pulmonary blood flow mide compared with that of salbutamol, hence allowing for intraindi- (log SDQ) (from 0.57 0.09 to 0.87 0.11 and 0.73 0.10) at vidual comparisons at each time point. Homoscedasticity was obtained 5 and 15 min, respectively (p 0.04 each) along with an in- by logarithmic transformation. This statistical approach was identical · · to that used in our previous studies (7, 8). Significance was set at p crease of an overall index of VA/Q inequality (DISP R-E*) 0.05 in all instances. (the combined dispersion of both blood flow and ventilation distributions corrected for dead space ) (from 3.46 0.80 to 6.35 1.36 and 4.91 1.09) at 5 and 15 min, respectively RESULTS (p 0.05 each), to return to baseline values at 45 min. Individ- Baseline Data and Effects of Inhaled Ipratropium and ually, all patients pretreated with ipratropium bromide had a Salbutamol before PAF deterioration in pulmonary gas exchange after PAF, whereas Baseline measurements for all patients were similar to those re- in all but one patient, PAF-induced gas exchange defects were ported in our previous investigation (7), without differences be- prevented after salbutamol (Figure 2). Similarly, the first mo- · · · · tween ipratropium bromide and salbutamol studies (Tables 1 ment of the VA/Q distributions (the mean VA/Q ratio of the and 2 and Figure 1). Compared with ipratropium bromide, how- ventilation distribution, V) increased (from 1.28 0.12 to · 1.42 0.08) at 15 min (p 0.02) after ipratropium bromide. ever, salbutamol produced an increase of QT (from 6.2 0.4 to 6.9 0.4 L/min) (p 0.02) before PAF inhalation, whereas the Overall, the changes observed in neutrophils and both res- · · · · piratory and inert gas exchange descriptors after ipratropium first moment of the VA/Q distribution (the mean VA/Q ratio of the perfusion distribution, Q) decreased (from 0.78 0.06 to bromide were similar to those previously detected in unpre- 0.70 0.05) (p 0.03), an effect also shown previously in nor- medicated patients with asthma (4), or in normal subjects mal subjects after they had received salbutamol (7). unpretreated (3) or pretreated with saline (vehicle) (7, 8), in- dicating that ipratropium bromide had no effect on the PAF- Effects of Ipratropium Bromide and Salbutamol after PAF induced abnormalities. By contrast, salbutamol prevented all PAF-induced functional defects, including systemic and neu- Compared with pretreatment with salbutamol, after ipratro- trophil changes. Ventilatory and hemodynamic variables and pium bromide there were no significant differences in Rrs after all the other gas exchange indices remained unchanged be- PAF challenge, indicating that both agents were efficacious in tween studies after PAF challenge. blocking the expected PAF-induced increase of Rrs (Table 2 and Figures 1 and 2). However, after pretreatment with ipra- DISCUSSION tropium bromide six subjects noticed facial flushing, and five coughed immediately; by contrast, after salbutamol only one The unique finding of this study is that, in patients with mild patient had facial flushing. On the other hand, after pretreat- asthma, ipratropium bromide administered at a maximal bron- ment with ipratropium bromide there was significant neutrope- chodilating dosage had a protective effect on bronchoconstric- nia (from 3.74 0.35 to 1.67 0.39 109/L) (p 0.03) at tion but not on the systemic, neutropenic, and pulmonary gas 20 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 156 1997 Figure 1. Mean SE values showing peripheral neutrophils, resistance of the respiratory system, alveolar- arterial PO2 difference, and ventilation-perfusion mismatching (expressed as DISP R-E*, dimensionless ) after PAF challenge in the two groups. Closed symbols pretreated with ipratropium bromide (IB); open symbols pretreated with salbutamol (s) at baseline (BL), at 15 min after bronchodilators, and at 5, 15, and 45 min. Asterisks denote significance (see RESULTS for p values). Figure 2. Individual time courses of alveolar-arterial P O2 and ventilation-perfusion inequalities (expressed as DISP R-E*, dimensionless ) (n 7) after inhaled PAF with pretreatment with inhaled ipratropium bromide or with salbutamol at baseline (BL), at 15 min after bronchodilators, and at 5, 15, and 45 min (see Table 1 and Figure 1 for other abbreviations). Díaz, Barberà, Marrades, et al.: PAF, Bronchodilators, and Gas Exchange in Asthma 21 exchange responses provoked by PAF challenge. By contrast, bronchial tree (18). PAF may also act directly on postcapillary salbutamol prevented all PAF-induced lung function distur- venular endothelial cells in the bronchial microcirculation (9, bances, including facial flushing and peripheral neutropenia. 10). Salbutamol could also prevent the ensuing release of other Our findings complement and extend our previous investiga- mediators into the pulmonary circulation with potential re- tions in normal subjects that pretreatment with inhaled sal- gional vasodilator effects that can disturb the matching of ven- butamol suppressed all PAF-induced effects (3, 7, 8). It is of tilation and perfusion at the alveolar level, hence antagonizing · · note that a lower dose of salbutamol (200 g) had no effect on further VA/Q disturbances. It is of note that these potential the flushing, neutropenia, and bronchoconstriction observed vasodilator effects of salbutamol on the bronchial and pulmo- · · after a higher dosage of inhaled PAF in normal subjects (15). nary circulations, precluding the VA/Q deterioration by PAF · · · · The VA/Q mismatching, expressed as an increase of the dis- as alluded to above, do not contend with their impact on VA/Q persion of pulmonary blood flow (log SDQ), observed in the worsening in patients with asthma. We have previously shown current study in the asthmatic patients premedicated with ip- that inhaled salbutamol (total doses, 600 and 300 g) does not · · ratropium bromide was quantitatively similar to that shown in alter the underlying VA/Q status in patients with either severe healthy subjects (3, 7) in whom a higher dose (24 g) of in- acute (19) or persistent (20) asthma, respectively. haled PAF was used and to that in patients with mild asthma Likewise, the beneficial role of salbutamol in preventing inhaling a lower dose (12 g) of PAF (4); likewise, the falls in PAF-induced neutrophil sequestration in the lungs may indi- peripheral blood neutrophil counts were of a similar order of cate an antiedema property that may result from inhibition of magnitude to those of normal subjects (3, 8) or even greater PAF-induced inflammation in airway wall, possibly amplified than in asthmatics (4). In the current study and in the previous by its potent relaxant effect on conducting airways. This inter- one (4), in patients with asthma, however, inhaled PAF was pretation is consistent with the inhibition by 2-adrenergic ag- qualitatively detrimental to pulmonary gas exchange, provok- onists of the increased tracheobronchial microvasculature per- · · ing VA/Q defects in a pattern similar to that commonly ob- meability provoked by PAF (21, 22) and also by histamine served in patients with moderate to severe asthma (5). In the (23). Indirect evidence (22) suggests, however, that the protec- · · present study, the deterioration of VA/Q relationships resulted tive role of salbutamol on gas exchange may be more related mainly from an increase in the dispersion of pulmonary blood to an inhibition of a PAF-induced venoconstrictor effect on · · flow caused by the development of poorly ventilated VA/Q units, the airway microcirculation (23–27). Moreover, salbutamol akin to the underlying pathophysiology of bronchial asthma (5). causes vasodilatation that can increase the postmicrovascular Our data are, however, at variance with those obtained by Smith to premicrovascular resistance ratio of the bronchial circula- and coworkers (16) in normal subjects and in asthmatics, in tion, thereby decreasing the hydrostatic pressure and subse- whom pretreatment with atropine paradoxically enhanced PAF- quent plasma exudation (28). The reduction of hydrostatic · · induced bronchoconstriction. Collectively, these VA/Q findings pressure in the airway capillary network could decrease the after salbutamol and ipratropium bromide strengthen the view degree of airway submucosal and adventitial swelling, thereby that bronchoconstriction and gas exchange disturbances in pa- preventing the narrowing of the caliber in distal airways, re- tients with asthma are related to two different pathophysiologic sulting in pulmonary gas exchange abnormalities. Salbutamol components. Thus, a bronchodilator acting predominantly on would have thus enhanced the ability of endothelial cells to ei- larger airways and devoid of other effects such as ipratropium ther minimize and/or close PAF-induced interendothelial gap bromide prevented PAF-induced increased resistance of the junctions by facilitating their relaxation. · · respiratory system only without influencing VA/Q deteriora- If pretreatment with salbutamol has a protective effect on tion or the neutropenic and systemic responses. By contrast, the transient sequestration of neutrophils in the pulmonary cir- salbutamol, a bronchodilator with potent vasodilator effects, culation produced by PAF, it may reduce the activation of these blocked all PAF-induced effects, possibly by modulating ab- cells in the lungs and the subsequent cascade of other released normal vascular permeability-increasing mediators that oper- mediators that may also play a role in the PAF-induced pulmo- ate directly on the venular endothelium. In this respect, gas nary function abnormalities. Both facial flushing and cough in- exchange measurements can emerge as a better tool than any duced by PAF have been attributed to the release of by-prod- other lung function test to more accurately identify the patho- ucts, possibly derived from neutrophils, acting systemically (23). biologic events that involve more peripheral quiet regions of Taken in sum, the inhibition of PAF-induced bronchocon- the lungs. striction but not of neutropenia, systemic effects, and gas ex- In our previous work, in both healthy subjects (3, 7, 8) and change disturbances by ipratropium bromide, but the inhibition in patients with mild asthma (4), we suggested that pulmonary of all these PAF-induced changes by salbutamol in this subset gas exchange abnormalities and the simultaneous modest in- of asthmatic patients reinforces the view that beta-adrenergic crease of Rrs caused by inhaled PAF were more related to agonists may block the postcapillary venoconstriction of the narrowing of airway caliber secondary to increased microvas- bronchial circulation provoked by PAF. 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