Thorax 1994;49:1103-1108 1103 Comparison of the effects of salbutamol and adrenaline on airway smooth muscle Thorax: first published as 10.1136/thx.49.11.1103 on 1 November 1994. Downloaded from contractility in vitro and on bronchial reactivity in vivo
David R Baldwin, Ziali Sivardeen, Ian D Pavord, Alan J Knox
Abstract the a adrenergic airway effects of non- Background - The effect of adrenergic selective adrenoreceptor agonists such as agonists in asthma depends on their net adrenaline offer no additional protection effect on microvascular leakage, mucosal against histamine-induced broncho- oedema, vascular clearance of spasmo- constriction in vivo than P2 selective gens, inhibition of cholinergic neuro- drugs such as salbutamol, despite ad- transmission, and airway smooth muscle renaline providing greater protection contractility. It has been postulated that against histamine-induced contraction in adrenaline, by virtue of its alpha effects vitro. The differences between the effects on the vasculature and cholinergic neuro- ofthese agents in vitro and in vivo may be transmission, may have additional useful related to their opposing vascular effects properties in asthma compared with se- in vivo. lective beta agonists such as salbutamol. Methods - The airway effects ofadrenaline (Thorax 1994;49:1 103-1108) (a non-selective adrenoreceptor agonist) were compared with the selective P2 agonist salbutamol. Their airway smooth muscle Beta2 adrenergic agonists are extensively used relaxant potencies and effect on histamine as bronchodilators in the treatment of asthma contraction in human bronchi in vitro were and chronic obstructive airways disease. These compared with their effects on airway cal- drugs were developed to avoid the cardiac tox- ibre and histamine reactivity in asthmatic icity associated with less selective adrenergic subjects in vivo. For the in vitro studies agents whilst retaining a potent relaxant effect changes in tension were measured in re- on airway smooth muscle P2 receptors. Several http://thorax.bmj.com/ sponse to these agents in thoracotomy spe- recent reviews, however, have stressed the po- cimens of human airways. In vivo the tential importance of vascular changes in the effects of adrenaline and salbutamol on airway in altering airway responsiveness.l" Ad- airway calibre and histamine reactivity renergic drugs designed for their effects on were measured in eight subjects with mild airway smooth muscle i receptors may there- to moderate asthma in a randomised fore not be the best adrenergic drugs for the crossover study. treatment of asthma. Experimentally-induced Results - Salbutamol and adrenaline had vascular changes in the airways of animals and on September 25, 2021 by guest. Protected copyright. approximately equivalent airway smooth man have been shown to have significant effects muscle relaxant potencies in vitro and on airway calibre through several interrelated bronchodilator potency in vivo. However, mechanisms.2 Vascular congestion and/or an their effects on histamine induced con- increase in microvascular leakage can alter traction in vitro were significantly differ- mucosal thickness and mathematical modelling ent from their effects on histamine suggests that this can have considerable effects reactivity in vivo. Salbutamol was less po- on bronchial responsiveness.56 Alpha adren- tent in vitro producing a mean (SE) 2*4 ergic agonists confer protection against sev- (0.15) doubling dose increase in the hist- eral thermally-induced bronchial challenges amine EC20 and adrenaline a 5 2 (0.18) such as exercise7 and hyperventilation.8 This doubling dose increase (mean difference protection is thought to be due to the pre- Respiratory Medicine Unit, City Hospital, between salbutamol and adrenaline 2-8 vention of pulmonary vascular engorgement. Nottingham NG5 1PB, doubling doses; 95% CI 1 1 to 4.5). Sal- Vascular changes may also alter bronchial re- UK butamol had no effect on the maximal sponsiveness by altering the vascular clearance D R Baldwin to Z Sivardeen response histamine whereas adrenaline of constrictor mediators from the airway.2 This I D Pavord reduced it by 54%. In contrast, salbutamol has been postulated for changes occurring with A J Knox was more potent in vivo producing a mean antigen inhalation in sheep9 and methacholine Reprint requests to: (SE) increase in PD20 histamine of 1-84 inhalation in dogs'0 and man" following treat- Dr A J Knox. (0.5) doubling doses whereas adrenaline ment with vasodilators or vasoconstriction. Received 29 November 1993 was without effect increasing PD20 by only Differences in the vascular effects of drugs may Returned to authors 4 February 1994 0*06 (0.47) doubling doses (mean differ- thus be very important in determining their Revised version received ence between adrenaline and salbutamol effects on airway function. 12 It has been 25 February 1994 Accepted for publication 1-78, 95% CI 0-26 to 3-29 doubling doses). postulated that the vascular alpha effects of 19 July 1994 Conclusions - These findings suggest that adrenaline could have potential benefits 104 Baldwin, Sivardeen, Pavord, Knox
over salbutamol in the treatment of asthma.'2 over the range 10 --I 0-3mol/l in threefold Non-selective adrenergic agents, through increments. Each concentration was added at
alpha-mediated vasoconstriction, might be ex- the plateau to the previous concentration. We Thorax: first published as 10.1136/thx.49.11.1103 on 1 November 1994. Downloaded from pected to have a different effect on the bronchial have previously shown that the histamine con- and pulmonary vasculature than P agonists. centration-response curve carried out in this For example, in an animal model of asthma way is very repeatable.'4 Rings were excluded microvascular leakage induced by platelet ac- from further study if the initial contraction to tivating factor was inhibited by adrenaline, 10 mol/l histamine was less than 0 2 g. The whilst the selective P2 agonist salbutamol had tissues were then washed repeatedly over the no effect.'2 In acute asthma it has been shown next hour until tension had returned to baseline that, whereas salbutamol produces a small fall values. Adrenaline was then added to half of in Pao2, due to bronchial arteriolar dilatation the rings to achieve a bath concentration of and consequent redistribution of pulmonary 10-8mol/I and the maximum relaxant effect blood to poorly ventilated areas, adrenaline noted. This was followed by serial tenfold in- produced a small but consistent rise in Pao2, creases in cumulative bath concentrations up suggesting an improvement in the ventilation/ to 10-5mol/l, each additional dose being given perfusion relationship due to vasoconstric- after the response had plateaued. Similar re- tion. 3 laxation concentration-response curves for sal- The aim of our study was therefore to com- butamol were measured in parallel rings. pare the relative potencies ofadrenaline (a non- Allocation of paired rings to adrenaline or sal- selective adrenergic agonist) and salbutamol (a butamol was random. The total duration of 02 selective agonist) as bronchodilators and as the concentration-response was similar for sal- protective agents against histamine bronchial butamol and adrenaline. Immediately after the reactivity in vivo. To determine if any difference maximum relaxant effect of the last dose was was due to differences in their effects on airway established (10-5mol/l for both agents, a fur- smooth muscle we performed parallel ex- ther cumulative histamine concentration- periments in vitro where there is little con- response study was performed in an identical tribution from vascular changes. Surprisingly manner. Relaxation and contraction con- there have been no published studies directly centration-response curves were each per- comparing the effects of these agents on hist- formed over 10-15 minutes. amine-induced bronchoconstriction in human airway in vitro or on asthmatic subjects in vivo. The primary hypothesis we were testing was Drugs that adrenaline, by virtue of its alpha effects on Adrenaline and salbutamol were obtained from the airways, might have additional beneficial Sigma Chemicals, Poole, UK. Histamine acid properties compared with salbutamol on airway phosphate was obtained from BDH Chemicals, Poole, UK. All drugs were dissolved in water. calibre and bronchial reactivity in asthma. http://thorax.bmj.com/ Methods Analysis IN VITRO STUDY All contractile responses were expressed as a Macroscopically normal human lung tissue was percentage of the initial maximal response to obtained from thoracotomy specimens of four 10-3mol/l histamine. The contractile effect of patients (all smokers) undergoing lung re- histamine was expressed as the concentration section for carcinoma and placed immediately of drug producing either 20% and 50% of the
in Krebs-Henseleit solution (KHS) of the fol- initial maximal contraction (EC20 and ECso) on September 25, 2021 by guest. Protected copyright. lowing composition (mmol/l) NaCl 118, KC1 and the mean values before and after the drug 4.7, MgSO4 1-2, NaH2PO4 1-2, CaCl 2-5, were compared using analysis of variance. In NaHCO3 25, glucose 11.1, pH 7-4. Tissues addition, the maximum contractile responses were transported immediately on ice to the to 10-'3mol/l histamine after drugs were com- laboratory where they were dissected into bron- pared by analysis of variance. The relaxant chial rings and suspended under 2 g tension, effects of salbutamol and adrenaline on in- in organ baths containing KHS at 37°C con- herent tone were compared at EC20 and EC50 tinuously gassed with 95% 02/5% CO2. No values which were the concentrations of drug attempt was made to remove the epithelium. which produced 20% and 50% of maximal The tensions used had previously been shown relaxation. The change in tension below base- to produce optimal, repeatable responses to line induced by adrenaline or salbutamol in histamine in preparations of a similar size. these studies was expressed as a % ofthe tension Changes in tension were recorded on four force generated by the initial histamine contraction. displacement transducers (FTO3, Grass In- This standardised the response for the amount struments, Quincy, Massachusetts, USA) and of airway smooth muscle present in each bron- displayed on two two-channel flatbed recorders chial ring. The results in this study were ident- (CR600, JJ Instruments, Southampton, UK). ical whether they were expressed in this manner Tissue was allowed to equilibrate under tension or in absolute terms in grams of tension. A p for one hour before each experiment. value of <0 05 was regarded as being stat- Eight bronchial rings from each of the four istically significant. subjects were studied (32 rings in total). A cumulative histamine concentration response study was performed on each ring, increasing IN VIVO STUDY amounts ofhistamine being added to each bath Subjects to produce cumulative bath concentrations Eight men aged between 24 and 51 years with Companison of the effects of salbutamol and adrenaline 1105 mild to moderate asthma and requiring inhaled derland, UK). Each dose was administered in therapy alone were studied. They were other- 1 ml of 0 9% sodium chloride and nebulised
wise healthy and had not had a respiratory tract to dryness. Dilutions were freshly prepared in Thorax: first published as 10.1136/thx.49.11.1103 on 1 November 1994. Downloaded from infection within four weeks of the first study sterile 0-9% sodium chloride each day. Five visit. All subjects had a resting forced expiratory and ten minutes after each dose, pulse rate, volume in one second (FEVI) >60% of their blood pressure, and FEV, were recorded. Ten predicted value and had previously dem- minutes after the final dose of salbutamol or onstrated an improvement in FEV, of greater adrenaline a further histamine challenge test than 15% after 200 Rtg inhaled salbutamol. was performed. The aim of using incremental They also had a provocative dose of histamine doses was to enable us to construct dose- causing a 20% fall in FEV, (PD20 FEV, hist) response curves for the two agents. of <4 jimol. All were taking inhaled ,B agonists either alone or with inhaled corticosteroids. Medications were continued unchanged Analysis throughout the study although P agonists were The PD20FEV, hist values were log transformed withheld six hours before each study visit. Sub- before analysis and expressed as geometric jects gave written consent to participation in mean values. The change in FEV, following the study which was approved by the Not- adrenaline and salbutamol and the differences tingham City Hospital ethics committee. in PD20FEV, hist between adrenaline and sal- butamol were compared using Student's paired t test. Differences in geometric mean values of Measurements PD20FEV, between salbutamol and adrenaline FEV, was measured using a dry bellows spiro- were expressed in doubling doses. A p value meter (Vitalograph, Buckingham, UK) as the <0 05 was regarded as significant. The study higher of the two successive readings within had 80% power to detect a one doubling dose 100 ml. Histamine challenge was performed by change in bronchial responsiveness. the method of Yan et al'5 using DeVilbiss No 40 hand-held nebulisers (DeVilbiss Co, Penn- sylvania, USA). After baseline FEV, had been Results measured, subjects inhaled 0 9% saline fol- IN VITRO STUDY lowed by doubling doses (0-03-8 tmol) ofhist- Thirteen paired bronchial rings gave an initial amine with measurement of FEV, 60 seconds maximal contractile response of greater than after each inhalation. The challenge was dis- 0-2 g. Six rings were rejected because they gave continued when the FEV, had fallen by 20% a response of <0X2 g. or more from post saline values. PD20 FEV, was estimated by linear interpolation on a log a1) dose-response plot. http://thorax.bmj.com/ C.)
CCo 0 Protocol L- The study had a randomised, double blind, E O crossover design. Subjects attended the labora- xC. tory on two non-consecutive days of the same E X week at the same time of day. After resting in 0
the sitting position for 15 minutes, baseline Eo on September 25, 2021 by guest. Protected copyright. measurements of heart rate, blood pressure, EC. and FEV, were made, and a histamine chal- C lenge test performed. One hour later, provided 0~ the FEV, had returned to within 95% of the o -6 baseline level, subjects were asked to inhale 1010-77c10r1 10-o-5 t 10-4o-4 four sequential doses (0 4, 4, 40, and 400 tg) Histamine concentration (molar) of either salbutamol or adrenaline solutions at 10 minute intervals in a cumulative manner via a) 120k B an Inspiron Minineb nebuliser (Bard, Sun- 0 100F- I Concentration of bronchodilator (molar) 0° Figure 1 Relaxant effect 1tcD-9 10-8 0-7 -6 -o-5 E 80 e- of increasing concentrations of salbutamol and I ~~I E adrenaline on inherent c; 0 'A Salbutamol o 60 - tone in human bronchial -20 * Adrenaline E rings in vitro. Values 8 ° 40 H shown are mean (SE) (n= 13). E-40 C. C 0)E) 20 x -60 _~~~~~~~~~ CL p - - - - 4 CE'ID -400 0 a) E'--6A U) -80 10o7 106 10 10-4
0)mm0 -610 Histamine concentration (molar) -100 Ca4) Figurre 2 Histamine concentration response curves before 0) -120 and cafter (A) salbutamol (10-5molll) and (B) adrenaline 0L (10- molll). Values shown are~~~~~~Imean (SE) (n= 13). 106 Baldwin, Sivardeen, Pavord, Knox 4 Figure 3 Effect of * Salbutamol * doses with a 95% CI 1-1 to 4 5; p<0005. At increasing doses of I the mean maximum salbutamol and adrenaline * Adrenaline 1o-3 mol/l histamine (SE) contraction as a percentage of the initial max- Thorax: first published as 10.1136/thx.49.11.1103 on 1 November 1994. Downloaded from on airway calibre in * asthmatic subjects in vivo. A imal response was 100-1 (14-8)% for sal- Values shows are mean ' and 46-2 (9 0)% for adrenaline. The (SE) (n=8). *p<0.001 butamol from baseline values. mean difference in maximum contraction be- a) * tween salbutamol and adrenaline treated tissues L- 3 was 53 9% (95% CI 25-2 to 82-7), p IN VIVO STUDY Bronchodilator potency The mean (SE) FEVy rose from 2-96 (0-26) 1 to 3-41 (0.25)1 after the maximum dose of adrenaline (400 jg) and from 2-95 (0-25)1 to 2 after the maximum dose of sal- Baseline 0-4 4 40 400 3-52 (0-28)1 butamol (400 jig). Figure 3 shows the response DoseDose( (jig)4) of FEV, to adrenaline and salbutamol at the different doses. Both drugs produced sig- Relaxant potency nificant bronchodilatation at 40 jig and 400 jig Figure 1 shows the relaxation curves for both when compared with baseline (p a, none have directly compared the two. Studies cB 0.5 in animal airways in vitro, however, have shown equivalent relaxant potencies of the two 4- 0-W agents. The fact that we found a similar dose equivalence in vitro and in vivo suggests that aN- bronchodilatation as measured acutely in vivo represents airway smooth muscle relaxation. The most surprising finding in our study was that adrenaline had no effect on histamine I I I reactivity in vivo, in contrast to salbutamol 0-1 Before After Before After which produced an approximately two doub- 400 9g 400 gg 400 igg 400 gg ling dilution shift in histamine reactivity in vivo. Companison of the effects of salbutamol and adrenaline 1107 This was the opposite of what we would have we underestimated the effects of adrenaline in expected if the alpha effects of adrenaline are vitro due to its metabolism, but we saw no important. The change we saw with salbutamol diminution of its relaxant effect over the time Thorax: first published as 10.1136/thx.49.11.1103 on 1 November 1994. Downloaded from is in agreement with several other studies in course of our experiment and, in any case, asthma.6"27-30 The only two previous studies to this would serve only to magnify the disparity look at the effect of adrenaline on histamine between its effects in vitro and in vivo. responsiveness in vivo looked at physiological We have considered several explanations for concentrations given intravenously,3"32 rather the lack of effect of adrenaline on histamine than pharmacological concentrations given by responsiveness in vivo despite its marked effect inhalation, and showed small reductions in on airway smooth muscle in vitro. Adrenaline histamine reactivity. In our present study local has several potentially beneficial actions. Its 02 concentrations of adrenaline in the airway were agonist effect on airway smooth muscle would likely to be much higher than in these studies be expected to reduce histamine reactivity as it due to the dosage and route used, and this did in vitro and it would also reduce histamine- might account for the difference by altering induced vasodilatation and capillary leakage the ratio of a to 3 effects. The difference in through its a vasoconstrictor effects. The bal- protective effect of salbutamol and adrenaline ance of its effects on the vasculature would be on histamine responsiveness occurred despite vasoconstrictor as it has much more potent a the drugs producing equivalent broncho- than 1, effects. dilatation. The lack of correlation between There are three mechanisms whereby vaso- bronchodilator properties of drugs and their active substances might alter bronchial re- effects on bronchoconstrictor challenges has sponsiveness, apart from a direct effect on previously been shown in studies comparing airway smooth muscle. Firstly, blood flow may salbutamol and ipratropium.627 affect airway wall thickness through vascular The difference between the relative effects engorgement; secondly, alterations in micro- of adrenaline and salbutamol on histamine re- vascular leakage may alter airway respons- sponses in vivo was not due to differences in iveness; and thirdly, vascular changes may alter their ability to inhibit smooth muscle responses the clearance ofbronchoactive substances from to histamine. Adrenaline had a profound effect the airway. The net effect of these mechanisms on histamine-induced contractions in vitro will determine the effect of the vasoactive sub- whereas salbutamol had little effect at a con- stance on airway reactivity.2 The lack of effect centration producing an identical degree of of adrenaline in vivo would suggest that a smooth muscle relaxation. The histamine re- reduction in the vascular clearance ofhistamine sponse curve after adrenaline was much flatter due to the vasoconstrictor properties of ad- than that after salbutamol. It is difficult to renaline may have negated the other potentially draw conclusions about the significance of this beneficial effects on the vasculature and airway without dose ranging the effect of both drugs. smooth muscle. http://thorax.bmj.com/ Although the second histamine response curve Further evidence to support this hypothesis performed in vitro was from a different baseline is that reduction of tracheobronchial blood from the first, this is analogous to the situation flow in dogs prolongs methacholine-induced in vivo and was the same for both drugs. This bronchial obstruction,'0 and in man metha- cannot, therefore, explain the difference be- choline-induced bronchial obstruction is pre- tween drugs. Interestingly, studies in guinea vented by a potent vasodilator, prosta- pig airways in vitro have also failed to show cyclin."1 Similarly, allergen-induced broncho- large shifts in histamine and muscarinic agonist constriction in sensitised sheep is prolonged on September 25, 2021 by guest. Protected copyright. induced concentration-response curves after by the vasoconstrictor agent vasopressin, and another 32 selective drug, terbutaline.33 The reduced by the vasodilator nitroglycerin.9 authors inferred from their study that P2 agon- The lack of effect of adrenaline on histamine ists may be protecting against histamine-in- responsiveness in our study contrasts with two duced bronchoconstriction in vivo by an effect studies showing that the a agonists meth- other than their smooth muscle effects. Our oxamine and noradrenaline protect against ex- findings would support this. The greater effect ercise and hyperventilation-induced airflow of adrenaline on airway smooth muscle hist- obstruction respectively.78 The apparent dis- amine responses in vitro is most likely to be parity in these results may be due to the mech- due to the fact that it is a full agonist on P2 anisms involved in the different types of receptor whereas salbutamol is only a partial challenge tests. In bronchoconstrictor chal- agonist.34 It is unlikely to represent an a effect lenges with exogenous histamine where smooth as a adrenergic blockade has previously been muscle contraction is the main mechanism of shown to alter histamine-induced contraction bronchoconstriction, the major effect ofa vaso- in human airway smooth muscle,24 and al- constrictor may be to reduce the vascular though airway smooth muscle from several clearance of inhaled histamine. In contrast, animal species contains P, receptors, it has in challenges such as exercise and hyper- been difficult to demonstrate them in auto- ventilation where thermally-induced vaso- radiographic studies of human airway smooth dilatation may be contributing to the airflow muscle.35 It might thus be that the partial agon- narrowing,3 the effect of a vasoconstrictor may ist effect of salbutamol on 12 receptors, whilst be to protect against this. The relation between sufficient to induce relaxation, does not provide bronchial blood flow and thermally-induced the same protection against agonist-induced bronchoconstriction may be complex, however, airway smooth muscle contractility as a full as volume expansion can produce contrasting agonist such as adrenaline. It is possible that effects on hyperventilation-induced broncho- 1108 Baldwin, Sivardeen, Pavord, Knox constriction depending on the timing of in- 9 Csete ME, Chediak AD, Abraham WM, Wanner A. Airway blood flow modifies allergic airway smooth muscle con- fusion.36 traction. Am Rev Respir Dis 1991;144:59-63. An alternative explanation for the lack of 10 Wagner EM, Mitzner WA. Bronchial circulatory reversal of Thorax: first published as 10.1136/thx.49.11.1103 on 1 November 1994. Downloaded from methacholine induced airway constriction. J7 Appl Physiol effect of adrenaline on histamine reactivity in 1990;69: 1220-4. vivo is a pharmacokinetic one, namely 11 Hardy CC, Bradding P, Robinson C, Holgate ST. Bron- that choconstrictor and antibronchoconstrictor properties of adrenaline was metabolised more quickly than inhaled prostacycline in asthma. J Appl Physiol 1988;64: salbutamol. While adrenaline does 1564-7. undergo 12 Boschetto P, Roberts NM, Rogers DF, Barnes PJ. Effect of more rapid metabolism than salbutamol, we anti-asthma drugs on microvascular leakage in guinea-pig feel that this is a less likely explanation for airways. Am Rev Respir Dis 1989;139:416-21. its 13 Coupe MO, Guly U, Brown E, Barnes PJ. Nebulised ad- lack of effect on histamine reactivity for several renaling in acute severe asthma; comparison with sal- reasons. We performed histamine butamol. EurJ RespirDis 1987;71:227-32. challenges 14 Knox AJ, Ajao P, Britton JR, Tattersfield AE. Effect of only 10 minutes after the final dose of ad- sodium transport inhibitors on airway smooth muscle renaline and these were completed in 5-10 contractility in vitro. Clin Sci 1990;79:315-23. 15 Yan K, Salome C, Woolcock AJ. Rapid method for meas- minutes. As bronchodilatation was still max- urement of bronchial responsiveness. Thorax 1983;38: imal at the start of the histamine challenge 760-5. test, 16 Higgins BG, Powell RM, Cooper S, Tattersfield AE. Effect it would seem unlikely that the effect would of salbutamol and ipratropium bromide on airway calibre have worn off in the ensuing 5-10 minutes. and bronchial reactivity in asthma and chronic bronchitis. Eur RespirJf 1991;4:415-20. Furthermore, a study by Kjellman et all'9 found 17 Phillips GD, Finnerty JP, Holgate ST. Comparative pro- no significant difference between salbutamol tective effect of the inhaled J2 agonist salbutamol (al- buterol) on bronchoconstriction provoked by histamine, and adrenaline in bronchodilatation over a methacholine and adenosine 5'-monophosphate in 60 minute period, with maximal asthma. JAUergy Clin Immunol 1990;85:755-62. broncho- 18 Wong CS, Pavord ID, Williams J, Britton JR, Tattersfield dilatation still being apparent 60 minutes after AE. Bronchodilator, cardiovascular, and hypokalaemic adrenaline inhalation. Precise effects of fenoterol, salbutamol, and terbutaline in asthma. pharmacokinetic Lancet 1990;336: 1396-9. data on the half lives of the two agents given 19 Kjellman B, Tolig H, Wettrell G. Inhalation of racemic epinephrine in children with asthma. Allergy 1980;35: by inhalation are, unfortunately, not available. 605-10. Finally, we considered whether the lack of effect 20 Phanichyakern P. Comparison of subcutaneous injections of of adrenaline on histamine responsiveness in terbutaline, salbutamol and adrenaline in acute asthmatic attacks in children.Jf Med Assoc Thai 1989;72:692-6. vivo might be due to its effects on U2 receptors 21 Giner MT, NevotS, Sierra JI, Plaza A, Coma G, Youssef on cholinergic nerve terminals.37 This would W. Treatment of acute crises of bronchial asthma in children using subcutaneous salbutamol as an alternative be unlikely to reduce any protective effect on to adrenaline; comparative study. An Esp Pediatr 1986;25: histamine responsiveness. 165-9. 22 Advenier CE, Naline E, Matran R, Toty L, Bakdach H. In conclusion, salbutamol and adrenaline Interaction between fenoterol, ipratropium, and acetyl- have similar bronchodilator potencies choline on human isolated bronchus. .7 AllergyClin Im- when munol 1988;82:40-6. given by nebulisation in asthmatic subjects in 23 Goldie RG, Paterson JW, Spina D, Wale JL. Classification vivo and when administered directly to of,B-adrenoceptors in human isolated bronchus. Br _7 airway Pharmacol 1984;81:611-5. smooth muscle in vitro. Despite a greater effect 24 Mathe AA, Astrom A, Perssch NA. Some broncho- constricting and bronchodilating responses of human isol- on histamine-induced contractions in vitro, ad- http://thorax.bmj.com/ ated bronchi: evidence for the existence of a- renaline was less effective in protecting hist- adrenoceptors.a Pharn Pharmacol 1971 ;23:905-10. amine-induced bronchoconstriction in vivo. 25 Zaagsma J, Van der Heijden PJCM, Van der Schaar MWG, Bank CMC. Comparison of functional,B-adrenoceptor Our study suggests that the potential beneficial heterogeneity in central and peripheral airway smooth a muscle on guinea pig and man. _7 Receptor Research 1983; adrenergic effects of adrenaline, such as re- 3:89-106. duced microvascular leakage and decrease in 26 Olsson AOT, Swanberg E, Svedinger I, Waldeck B. Effect mucosal blood flow, do not protect of l-adrenoceptor agonists on airway smooth muscle and against on slow-contracting skeletal muscle: in vitro and in vivo histamine-induced constriction in mild asth- results compared. Acta Pharmacol Toxicol 1979;44:272-6. matics when adrenaline is administered acutely 27 Britton J, Hanley SP, Garrett HV, HadfieldJW, Tattersfield AE. Dose related effects of salbutamol and ipratropium on September 25, 2021 by guest. Protected copyright. by nebulisation. Furthermore, the vascular a bromide on airway calibre and reactivity in subjects with effects of adrenaline may be antagonistic to asthma. Thorax 1988;43:300-5. 28 Casterline CL, Evans R, Ward GW. The effect of atropine the beneficial P2 effects, possibly by reducing and albuterol aerosols in the human bronchial response vascular clearance of to histamine. . AllergyClin Immunol 1976;58:607-13. histamine. 29 Chung KF, Morgan B, Keyes SJ, Snashall PD. Histamine The authors thank Mr Morgan, Mr Salama and Professor Jones dose response relationship in normal and asthmatic sub- at Nottingham City Hospital for providing human lung tissue, jects. Am Rev Respir Dis 1982;126:849-54. and Hilary Hughes for secretarial support. 30 Cockcroft DW, Killian N, Mellon JA, Hargreave FE. Pro- tective effect of drugs on histamine induced asthma. Barnes PJ. New concepts in the pathogenesis of bronchial Thorax 1977;32:429-37. hyperresponsiveness and asthma. _7 AlergyClin Immunol 31 Knox AJ, Campos-Gongora H, MacDonald IA, Tattersfield 1989;83:1013-26. AE. Modification of bronchial reactivity by physiological 2 Lockhart A, Dinh-Xuan AT, Regnard J, Cabanes L, Matran concentrations of plasma epinephrine. JApplPhysiol 1992; R. Effect of airway blood flow on airflow. Am Rev Respir 73:1004-7. Dis 1992;146:S19-23. 32 Warren JB, Dalton N, Turner C, Clark TJH. Protective 3 McFadden ER Jr. Hypothesis: exercise-induced asthma as effect of circulating epinephrine within the physiological a vascular phenomenon. Lancet 1990;335:880-3. range on the airway response to inhaled histamine in non- 4 Widdicomb J. Physiologic control. Anatomy and physiology asthmatic subjects. JAlergyClin Immunol 1984;74:683-6. of the airway circulation. Am Rev Respir Dis 1992;146: 33 Gustafsson B, Persson CGA. Effect of different bron- S3-7. chodilators on airway smooth muscle responsiveness to 5 Freedman RJ. Thefunctional geometry of thebronchi. The contractile agents. Thorax 1991;46:360-5. relationship between changes in external diameter and 34 Tattersfield AE, Britton JR.,B-adrenoceptor agonists. In: calibre, and a consideration of the passive role played by Asthma: basic mechanisms and clinical management. 2nd the mucosa in bronchoconstriction. Bull Eur Physiopathol edn. London: Academic Press, 1992:527-54. Respir 1972;8:45-52. 35 Carstairs JR, Nimmo AJ, BarnesPJ. Autoradiographic visu- 6 Moreno R, Hogg JC, Pare PD. Mechanics of airway nar- alisation off-adrenoceptor subtypes in human lung. Am rowing. Am Rev Respir Dis 1986;133:1171-80. Rev Respir Dis 1985;132:541-7. 7 Dinh-Xuan AT, Chaussain M, RegnardJ, Lockhart A. 36 Gilbert IA, WmslowCJ,Lenner KA, Nelson JA, McFadden Pretreatment with an inhaled alpha,-adrenergic agonist ER Jr. Vascular volume expansion and thermally induced methoxamine reduces exercise-induced asthma. EurRespir asthma. EurRespirJ 1993;6:189-97. 1989;2:408-14. 37 Grundstrom N, Andersson RGG, Witberg JES. Pre- 8. Gilbert IA, McFadden ER Jr. Airway cooling and re- junctional alpha2 adrenoreceptors inhibit contraction of warming: the second reaction sequence in exercise-in- tracheal smooth muscle by inhibiting cholinergic neuro- duced asthma. Glin7 Invest 1992;90:699-704. transmission. Life Sci 1981;28:2981-6.