The renin-angiotensin system is activated in acute severe asthma, although not in all asthmatics [1,2]. The mechanism of this activation is unclear, but recent evidence has shown elevation of renin and angiotensin II in response to nebulized and intravenous salbutamol [3,4]. A wide variation in plasma β 2 -agonist levels has been found in acute asthmatics in previous studies [5], and could, therefore, account for the variation in renin and angiotensin II levels.However, the degree of activation of the renin-angiotensin system following administration of β 2 -agonists is less than that seen in acute asthma, suggesting an additional mechanism. The generation of angiotensin II via an "alternative" pathway, through the action of inflammatory proteases [6] either circulating or locally within the airways, could occur in addition to the "classical" activation of the renin-angiotensin system. Endogenous catecholamines released during an acute attack of asthma [7] could stimulate adrenoceptors on juxtaglomerular cells in the kidney [8] resulting in renin release, and may act synergistically with systemically absorbed albuterol.Serum angiotensin-converting enzyme (ACE) levels vary between individuals and correlate with a genetic polymorphism of the ACE gene [9]. Homozygotes for the deletion polymorphism have a higher ACE activity [10], and, therefore, the capacity to produce greater levels of angiotensin II in response to activation of the renin-angiotensin system. Thus, serum ACE activity could contribute to the variation seen in angiotensin II levels in acute asth-ma.We hypothesize that activation of the renin-angiotensin system in acute severe asthma is partly due to high levels of circulating β 2 -agonists in some asthmatics, and that other factors, as suggested above, may also contribute, possibly with a synergistic effect. Thus, we have examined the associations between renin, angiotensin II and multiple factors during acute attacks of asthma, with particular emphasis on the mechanisms outlined above. Materials and methods PatientsForty adult asthmatic patients (26 females and 14 males; mean (SD) age 45 (17) yrs) were recruited into the study. All presented nonconsecutively at the accident and emergency department, with acute exacerbations of asthma unresponsive to their regular medication and requiring hospital admission for treatment. Admission parameters were measured with peak expiratory flow rate (PEFR) 35 (18) % predicted, oxygen saturation 94 (4) %, cardiac frequency 108 (16) beats·min -1 , systolic blood pressure 139.5Investigations on the renin-angiotensin system in acute severe asthma. S.G. Ramsay, K.D. Dagg, I.C. McKay, B.J. Lipworth, C. McSharry, N.C. Thomson. ERS Journals Ltd 1997. ABSTRACT: The renin-angiotensin system is activated in acute severe asthma. The precise mechanism of activation is at present unknown, but may involve, β 2 -agonists, catecholamines or proteases released in airway inflammation.This study aims to identify potential factors involved in the activation of the reninangiotensin ...

Abstractmild to moderate patients with stable asthma. Background -Recent in vitro and in vivo studies in animals have suggested that am- (Thorax 1997;52:453-457) bient oxygen tension may influence airway Keywords: hyperoxia, hypoxia, bronchoconstriction, responsiveness to bronchoconstrictor methacholine, asthma. stimuli. These observations may have relevance to the management of acute exacerbations of asthma. The present studiesLittle is known about the effect of acute alterwere designed to examine the influence ations in oxygen tension on the responsiveness of inspired oxygen tension (Fi 2 1.0, 0.21, of the airways to bronchoconstrictor stimuli. 0.15) on methacholine induced broncho-Recent in vitro and in vivo studies in animals constriction in patients with asthma.suggest that hypoxia potentiates and hyperoxia Methods -In a dual study two groups of attenuates the airway constrictor response to asthmatic patients performed methacertain stimuli. 1 2 Similar in vivo studies in man, choline inhalation challenges breathing however, have produced conflicting findings. The present studies were designed to in-(dose of methacholine causing a 20% fall vestigate the effect of acute hypoxia and in forced expiratory volume in one second hyperoxia on methacholine induced broncho-(FEV 1 )) were calculated after each methaconstriction in patients with asthma. choline challenge by linear interpolation from the logarithmic dose response curve. Plasma catecholamine levels were measured before and after methacholine chal-Methods lenges as well as heart rate, oxygen  saturation, and percentage end tidal car-Study 1 Department of bon dioxide levels.Eleven mild asthmatic patients (five men) of Respiratory Medicine, West GlasgowResults -The geometric mean PC 20 value mean (SD) age 42 (12) years were recruited Hospitals University for methacholine was significantly lower into the study (table 1). All were receiving NHS Trust, Glasgow on the hypoxic study day than on the nor-inhaled 2 agonists as required, 10 were re- Fourteen adult mild asthmatic patients (five Returned to authors ml (95% CI 0.83 to 2.51)). men) of mean (SD) age 36 (9.2) years were 16 September 1996 Conclusions -Acute hypoxia potentiatesRevised version received recruited into the study (table 1). All were 7 January 1997 methacholine induced bronchoconstric-taking inhaled 2 agonists on an as required Accepted for publication tion and acute hyperoxia has no effect in 9 January 1997 basis, 10 were receiving regular inhaled corticosteroids, two were taking regular oral theophyllines, and one inhaled salmeterol. In both studies on each study day inhaled 2 as usual. They were asked to refrain from caffeine containing products for eight hours FEV 1 =forced expiratory volume in one second; PC 20 methacholine=concentration of methacholine provoking a fall in FEV

The renin-angiotensin system is activated in acute severe asthma. Angiotensin II causes bronchoconstriction in mild asthmatics and potentiates methacholine-evoked bronchoconstriction both in vitro and in vivo. To evaluate the effect of angiotensin II on histamine-induced bronchoconstriction, human bronchial rings (n = 6) were obtained from lung tissue at thoracotomy and were prepared in organ baths. Contractions were measured isometrically and cumulative concentration-response curves obtained to angiotensin II alone and to histamine in the presence and absence of threshold concentrations of angiotensin II. Eight asthmatic patients with bronchial hyper-reactivity to histamine were challenged with histamine during intravenous infusion of placebo, angiotensin II 1 ng kg-1 min-1 and angiotensin 2 ng kg-1 min-1 administered in a randomized, double-blind fashion, FEV1 was measured prior to, during the infusion and during the histamine challenge. Angiotensin II (3 x 10(-7)M and 10(-6)M) alone evoked small contractions (< 0.25 g) of human bronchi in vitro, but pre-incubation with threshold concentrations of angiotensin II (10(-7)M, 3 x 10(-7)M and 10(-6)M) had no effect on histamine-evoked contractions. In asthmatic patients, angiotensin II alone had no effect on baseline FEV1 at the low levels infused and did not affect the response to nebulized histamine as measured by the PC20 histamine: Geometric mean (range) PC20 histamine (mg ml-1) screening day 3.58 (1.26-7.75), placebo infusion 2.67 (0.89-9.57), angiotensin II 1 ng kg-1 min-1 2.45 (0.42-6.97) and angiotensin II 2 ng kg-1 3.09 (0.8-10.78). It is concluded that, in contrast to its potentiating effect on methacholine-induced bronchoconstriction, angiotensin II has no effect on histamine-evoked bronchoconstriction in human bronchi in vitro or in vivo.

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Background -Recent animal studies have suggested that changes in oxygen tension may alter airway responses to bronchoconstrictor and bronchodilator stimuli. These effects may have relevance to the management of acute exacerbations of asthma but have not been well studied in man. This study was designed therefore to examine the effect of acute hyperoxia (Fio2 1.0) on the bronchodilator response to salbutamol in stable asthmatic patients. Methods -Twelve stable adult asthmatic patients (three women) were studied using a randomised double blind placebo controlled crossover design. On two study days following baseline measurements patients breathed either air (Fio2 0.21) or oxygen (Fio2 1.0) for 10 minutes alone and then in combination with three incremental doses ofnebulised salbutamol administered at 15 minute intervals. The same protocol was employed on two further study days using nebulised saline instead of salbutamol. Results -The mean absolute change in forced expiratory volume in one second (FEV1) from baseline after salbutamol was similar on the normoxic and hyperoxic study days but significantly greater than the study days on which nebulised saline was administered. Conclusion -Acute hyperoxia does not potentiate the immediate bronchodilator response to salbutamol in stable asthmatic patients. (Thorax 1996;51:853-854) Keywords: hyperoxia, salbutamol, asthma.tions of asthma may not only improve gas exchange, but could also enhance the effect of bronchodilators. The present study was designed to examine the effect of acute hyperoxia on the bronchodilator response to salbutamol in patients with asthma. MethodsTwelve adult asthmatic patients (three women) with a mean (SD) age of 47 (14) years and forced expiratory volume in one second (FEVI) of 2.05 (0.6) litres (79 (17)% predicted) were recruited into the study. On four study days after 30 minutes of supine rest patients were commenced on a closed breathing circuit. Following a 10 minute run-in period during which patients breathed air (Fio2 0.21), baseline measurements of FEV1, oxygen saturation (Sao2%), respiratory rate, heart rate, and inspired and expired oxygen and carbon dioxide levels (%) were made. Venous blood was also taken for assay of plasma catecholamines. Patients were then randomised to receive either air (Fio2 0.21) on two study days or oxygen (Fio2 1.0) on the remaining two study days. The gases were administered in a randomised double blind fashion. Following a further 10 minutes breathing the study gas through the closed breathing circuit, the patients received either three incremental concentrations of nebulised salbutamol (0.05 mg/ml, 0.17 mg/ml, 5 mg/ml) or placebo (normal saline) at 15 minute intervals, again in a double blind fashion. Baseline measurements were repeated 13 minutes after each nebulisation until completion of the study day. All patients gave written informed consent to the study and the protocol was approved by the West ethics committee.