bronchodilator, and airway calibre

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1 Thorx 1982;37: Bronchil responsiveness to histmine: reltionship to diurnl vrition of pek flow rte, improvement fter bronchodiltor, nd irwy clibre G RYAN, KM LATIMER, J DOLOVICH, FE HARGREAVE From the Firestone Regionl Chest nd Allergy Unit, Deprtment of Medicine, St Joseph's Hospitl nd McMster University, Hmilton, Ontrio, Cnd ABSTRACT Fetures of sthm include increses in both bronchil responsiveness nd vribility of irflow rtes. We exmined the reltionship between bronchil responsiveness to histmine nd the vrition of pek expirtory flow rte (PFR) during the dy nd in response to slbutmol (2,ug), nd the initil FEV1 t the time of the histmine test nd FEVy response to slbutmol. Bronchil responsiveness to histmine ws expressed s the provoction concentrtion cusing fll in FEV1 of 2% (PC2). PC2 rnged between 13-9 nd 13 mg/ml in nonsthmtic subjects, between 1*5 nd 59-9 mg/ml in five symptomtic sthmtics, nd between -3 nd 2-8 mg/ml in 27 sthmtics with symptoms controlled by mediction. The lower the PC2 (the greter the bronchil responsiveness) the lower the morning PFR (r =.79), the greter the increse in PFR fter slbutmol (morning r = --75, evening r = --8), nd the greter the difference between the highest nd lowest PFR ech dy (r = -.81). Mesurements of PFR were bnorml, compred with those in nonsthmtic subjects, in ll subjects with PC2 less thn 2 mg/ml-tht is, moderte or severe increse in nonspecific bronchil responsiveness-nd in none with PC2 greter thn 21 mg/ml-tht is, norml responsiveness; five of nine sthmtics with controlled symptoms hd bnorml PFR mesurements when PC2 ws between 2 nd 21 mg/ml-tht is, mild hyperresponsiveness. In contrst, FEV1 t the time of the histmine test ws greter thn 8% predicted in ll subjects with PC2 greter thn 2 mg/ml nd ws not less thn this in 1 of 18 subjects with PC2 less thn 2 mg/ml. When improvement in FEV, ws 2% or more fter slbutmol, the PC2 ws usully modertely or severely incresed (less thn -4 mg/ml). The results identify close reltionship between nonspecific bronchil responsiveness to histmine nd the vribility in flow rtes which occurs spontneously nd fter bronchodiltor. In ddition, they rise the possibility tht incresed irflow obstruction in sthm my be consequence of incresed responsiveness. Scdding' hs simplified the definitions of sthm proposed by the Cib Foundtion Guest Symposium2 nd the Committee on Dignostic Stndrds of the Americn Thorcic Society3 to " disese chrcterised by wide vrition over short periods of time in resistnce to flow in the irwys of the lungs." Increses in resistnce to irflow my occur spontneously s in diurnl vrition, my be induced by vrious nonspecific stimuli which ffect sthmtics nd by llergens, some industril chemi- Address for reprint requests: Dr FE Hrgreve, Firestone Regionl Chest nd Allergy Unit, St Joseph's Hospitl, 5 Chrlton Avenue Est, Hmilton, Ontrio, Cnd L8N 1Y4. cls such s isocyntes, nd non-steroid ntiinflmmtory gents which only ffect some sthmtics. Airwy resistnce my be reduced by tretment with drugs such s bronchodiltors or corticosteroids. Confirmtion of the presence of sthm is usully mde by improvement in FEVI fter bronchodiltor,4 by mesurements of diurnl vrition of pek expirtory flow rte (PFR),56 nd by demonstrtion of n increse in bronchil responsiveness to nonspecific or llergic or other specific stimuli.7 Nonspecific bronchil responsiveness is often mesured by inhltion tests with histmine or methcholine,8 nd this correltes closely with 423 Thorx: first published s /thx on 1 June Downloded from on 3 December 218 by guest. Protected by copyright.

2 4244Ryn, Ltimer, Dolovich, Hrgreve responsiveness to other nonspecific stimuli such s exercise9 nd cold ir.' In this study we hve exmined, in nine nonsthmtic nd 32 sthmtic subjects, the reltionship between nonspecific bronchil responsiveness to histmine nd the diuml vrition of PFR nd the response to bronchodiltor, the FEVI mesured t the time of the histmine test, nd the improvement in FEV produced by bronchodiltor. Methods Nine dults regrded s nonsthmtic were recruited from hospitl stff (tble). None hd current or previous episodic dyspnoe, chest tightness, wheezing, or chronic cough. Two were current cigrette smokers nd two others were topic s indicted by one or more whel nd flre responses to prick skin tests with 16 common llergen extrcts. Thirty-two subjects considered to hve sthm nd no other chest disese were selected from ptients ttending the Chest nd Allergy Clinic (tble). All hd history of episodic dyspnoe nd wheeze nd relief of symptoms by tretment with bronchodiltor. Five hd not hd symptoms or required mediction for six months to 1 yers. The remining 27 sthmtic subjects hd current symptoms or were symptom-free on regulr mediction. Three were current smokers nd 21 were topic. All 41 subjects were free of respirtory infection or exposure to llergen to which they were sensitised (except for house dust in 16) for four weeks before the study nd during the study. Mediction used by the 27 sthmtics ws inhled slbutmol less thn once dily in nine nd dily slbutmol in 18 with dditionl beclomethsone in 12 nd dditionl prednisone in one. Slbutmol ws withheld for t lest six hours before mesurement of pek expirtory flow rte (PFR) nd bronchil responsiveness to histmine or slbutmol. At the time of the study, the initil FEV1 ws greter thn 86% predicted in the nonsthmtics nd greter thn 91% predicted in the sthmtics without symptoms; in the sthmtics with current symptoms it ws greter thn 8% in 19 nd 43-78% in other eight (tble). MEASUREMENT OF BRONCHIAL RESPONSIVENESS TO HISTAMINE An inhltion test with histmine ws crried out in ech subject between 12 nd 17h using the method described by Cockcroft et l. " First the subjects rested in the lbortory for 3 min nd then their FEV1 ws mesured. Then ech inhled n erosol of sline followed by two-fold incresing concentrtions of histmine cid phosphte (-3-64 mg/ml). Aerosols were generted by Wright nebuliser (irflow rte 7-5 1/min, pressure 5 lb/in2 (344 kp), output -145 ml/min) nd inhled by tidl brething for 2 min. The response ws mesured by FEV1 3 s nd 9 s fter ech inhltion. Inhltions were discontinued when there ws fll in FEV, of 2% or more from the lowest post-sline vlue. The results were expressed s the concentrtion of histmine which cused fll in FEV, of 2% (PC2) nd this ws obtined from the log concentrtion-percent fll in FEV, curve by liner interpoltion of the lst two points. Concentrtions of greter thn 64 mg/ml were not used becuse of systemic side effects. If this concentrtion cused fll in FEV, of 15-19% the PC2 ws estimted by extrpoltion of the concentrtion-response curve. Four nonsthmtic subjects were excluded becuse the fll in FEV1 fter this concentrtion ws less thn 15%. MEASUREMENT OF PFR AND RESPONSE TO SALBUTAMOL The subjects mesured their PFR with mini Wright pek flow meter twice dily (6-8h nd 16-18h) for seven dys fter the histmine inhltion test. On ech occsion the best of three blows ws recorded before nd 15 min fter inhltion of slbutmol (2 ug) from pressurised cnnister. Subjects kept diry of their symptoms nd tretment over this period. On the dy fter completion of PFR mesurements, t the sme time of dy s their PC2 ws determined, the subjects returned to the lbortory nd, fter rest of 3 min, their FEV, ws mesured before nd 15 min fter inhltion of slbutmol (2,ug). ANALYSIS Logrithmic trnsformtion of PC2 ws used for ll clcultions. From the four PFR results ech dy the percentge increse fter bronchodiltor morning nd evening nd diurnl vrition of PFR ws clculted. Diurnl vrition ws estimted from both the difference between the two pre-slbutmol results nd the difference between the mximum nd minimum PFR, nd expressed s percentge of the mximum vlue. The verge of seven dys' results ws used for nlysis. Predicted vlues for PFR were tken from Chernick'2 nd for FEV1 from Morris et l. '3 Liner regression nlysis ws used to exmine the reltionship between PC2 nd PFR or FEV,. If the reltionship ppered non-liner, s for the increse in PFR fter slbutmol, logrithmic trnsformtion of both PC2 nd PFR ws used. A norml rnge for increse in PFR nd FEV, fter slbutmol nd for diurnl vrition in PFR ws tken Thorx: first published s /thx on 1 June Downloded from on 3 December 218 by guest. Protected by copyright.

3 Bronchil responsiveness to histmine Tble Summry ofdetils nd results of test mesurements in study subjects Nonsthmtic Asthmtic Pst History Current Number Mle Age (yr) 32 (25-36)* 39 (35-52) 44 (21-67) PC (mg/ml) 45 ( ) 25-6 (14-6) -87 (-3-2.8) FEV, initil (% mximum) 94.2 (4.5)t 96-7 (3.4) 8765 (11.7 mximum (% predicted) 15-3 (8-5) (9-9) 96-6 (17-5 PFR mximum (% predicted) 16-9 (1-1) 15-2 (1-8) 94-5 (13-7 diurnl vrition (% mximum) without slbutmol 2-7 (1-7) 5- (3-9) 7-5 (5.9) with slbutmol 6-7 (2-) 8- (4-) 21-9 (9-9) Response to slbutmol (% increse) PFR (2-4) ) 22.6 (14.9 PFR (1-5) (18.1 FEV 31 (2.7) 2-4 ( (18-8 *men (rnge) tmen (SD) s the 95% confidence intervl for single sevendy estimte bout the men of the nine nonsthmtic subjects. Results Bronchil responsiveness to histmine, expressed s PC2 (mg/ml), rnged between 13-9 nd 13 in nonsthmtics, 1-5 nd 59 9 in symptomtic sthmtics, nd *3 nd 25 in sthmtics with current symptoms (tble). Bronchil responsiveness in ech subject ws relted to the men morning nd evening PFR (expressed s peicent of mximum), the men increse in morning nd evening PFR fter slbutmol, nd the diurnl vrition in PFR (figs 1-3). Strong correltions were observed between PC2 nd PFR, increse in PFR fter slbutmol, nd diurnl vrition using minimum pre-slbutmol nd mximum post-slbutmol vlues. The lower the PC2 (the more incresed the bronchil responsiveness) the lower the PFR in the morning (r =.82, p < -1) nd evening (r = -68, p <.1) (fig 1), the greter the increse in PFR fter slbutmol (morning r = --75, p < -1; evening r = --8, p <.1) (fig 2), nd the greter the vribility in PFR during the dy (r = --81, p <.1) (fig 3B). A weker correltion ws observed between PC2 nd diurnl vrition of PFR using only the pre-slbutmol vlues (r = --41, p <.1) (fig 3A). Pek flow rte mesurements were interpreted s bnorml if they were bove the 95% confidence intervl determined from the nonsthmtic subjects (figs 2, 3). When PC2 ws less thn 2 mg/ml ll subjects (sthmtics with current symptoms) hd bnorml vlues, when it ws greter thn 2-8 mg/ml the three symptom-free sthmtics hd norml vlues, nd when it ws between 2 nd 28 mg/ml six out of 12 subjects (five of nine sthmtics nd one of two symptom-free sthmtics) hd bnorml vlues. Bronchil responsiveness in ech subject ws lso relted to the increse in FEV, fter slbutmol mesured one week fter but t the sme time of dy s the histmine test (fig 4). The bseline FEVI ws within 15% of FEVI on the dy of the histmine test except in four subjects, higher in two, nd lower in two (fig 4). When FEVI t the time of the histmine test ws expressed s percent of mximum, it ws not bnorml until the PC2 ws less thn.4 mg/ ml-tht is, it could be norml when bronchil responsiveness ws modertely to severely incresed (fig 5). When the FEV1 incresed by 2% or more fter slbutmol the PC2 ws lwys less thn.4 mg/ml-tht is, bronchil responsiveness ws modertely or severely incresed. Discussion 425 The results of this study demonstrte. strong ssocition between the level of bronchil responsiveness to histmine nd the degree of reduction in the morning PFR, the degree of improvement in morning PFR fter slbutmol, nd the diurnl vrition of PFR s mesured by the lowest preslbutmol vlue (usully on wking) nd the highest post-slbutmol vlue (usully in the fternoon). The greter the bronchil responsiveness (the lower the PC2) the lower the PFR, the greter the response to slbutmol, nd the greter diurnl vrition of flow rtes. The study covered wide rnge of PC2nd included sthmtic subjects with current symptoms, subjects with pst history of sthm, nd norml subjects. All subjects with PC2 less thn 2 mg/ml hd greter thn norml vribility of irflow obstruc- Thorx: first published s /thx on 1 June Downloded from on 3 December 218 by guest. Protected by copyright.

4 426 Ryn, Ltimer, Dolovich, Hrgreve 1 C 9 ~~~~~~~~~~~ 9_.* _ o 8 me 7 E 6 E x 5 ( E If E =1F U. mm So Lu B 5 4,I I PC2 HISTAMINE (mg/ml) Fig 1 Reltionship between PC2histmine (mglml) nd pek expirtory flow rte (PFR) mesured t 6-8h (A) (r =.82) nd 16-18h (B) (r =.68). PFR is the men ofmesurements on seven dys nd is expressed s percentge of the mximum PFR ech dy. Forty-one subjects-nine nonsthmtic (), fve previous sthmtic (), nd 27 current sthmtics (U). 6-71% A cr.1 _J2 u * cc 6_9% B U. ż 5 _ 4 Z \ 3 z 2 E 13t l PC2 HISTAMINE (m/ml) Fig 2 Reltonship between PC2 histmine (mglml) nd response to slbutmol (2 pg), expressed s percentge increse in PFR. Response to slbutmol ws mesured t 6-8h (A) (r = -.78) nd 16-18h (B) (r = -.8) for seven dys. The horizontl line represents the upper bound ofthe 95% confidence intervl bout the men ofthe nonsthmtc subjects; A, 9.9% nd B, 6-6%o. The curviliner reltionship ws obtined by liner regression nlysis using logrithmic trnsformtion of both PC2 nd chnge in PFR. Symbols s in fig 1. A Thorx: first published s /thx on 1 June Downloded from on 3 December 218 by guest. Protected by copyright.

5 Bronchil responsiveness to histmine 31 2 _ E 8 E *1 *. *. _8 IL. CL * * - e os. *l 41 :5 B F? c 2 IL 1C ~ ~~~~~~~~~~~~~ 2..! / PC2 HISTAMINE (mg/ml) Fig 3 Reltionship between PC2 histmine (mglml) nd vribility ofpfr during the dy. PFR ws mesured before nd fter slbutmol t 6-8h nd 16-18h. Vribility ws clculted by two methods: (A) the difference between the two PFRs before slbutmol nd expressed s percentge ofthe higher (r = -.41) nd (B) the difference between the mximum nd minimum of the four PFR results ech dy nd expressed s percentge of the mximum (r = -.81). The horizontl line represents the upper boundry ofthe 95% confidence intervl bout the men of the nonsthmtc subjects; A 6-7% nd B 11-8%. Symbols s in fig 1. tion, s indicted by mesurements of diurnl fluctution of PFR nd response to bronchodiltor, nd were regrded s hving sthm with current symptoms. When PC2 ws greter thn 2 mg/ml no subject hd current symptoms of sthm or ny increse in vribility of PFR. Three subjects with previous symptoms of sthm hd PC2 bove 2 mg/ml; this is to be expected since bronchoconstriction my be incited by vigorous enough specific rection stimulted by llergen'4 or chemicl,'5 nd nonspecific responsiveness my be incresed so tht the PC2 flls below 2 mg/ml by these'6 1' nd other stimuli such s infection.'8 In subjects with PC2 from 2 to 2 mg/ml only bout hlf of those with current symptoms showed incresed vribility of PFR. Subjects with this mild degree of responsiveness might hve greter perception of sthm'7 or hve symptoms induced by 427 vrious potent nonspecific stimuli. For exmple, exercise in wrm ir my induce bronchoconstriction in subjects with PC2 histmine of up to 4 mg/ml9 nd isocpnic hyperventiltion of cold dry ir my induce bronchoconstriction in subjects with PC2 of up to 16 mg/ml.' The observtions in the present study re consistent with the findings of Juniper et l,'7 who reported tht subjects with PC2 of more thn 2 mg/ml required either no tretment or bronchodiltor tken only s required but not dily, indicting tht they were not hving reductions in flow rte of sufficient severity to cuse troublesome symptoms. It is possible for pprently nonsthmtic people to hve PC2 in this rnge with n increse in vribility of flow rtes which they hve not detected or regrded s bnorml. The results of our study show tht diurnl fluctution of PFR of more thn 12%, response to bronchodiltor in the morning of more thn 1%, nd improvement in FEV1 fter bronchodiltor of more thn 1% is greter thn norml vrition in flow rte nd is suggestive of sthm. These results for PFR differ from those recorded by Hetzel nd Clrke, who suggested tht diurnl vrition of 2% ws useful screening test for sthm.5 However, they studied sthmtics during or shortly fter dmission to hospitl becuse of severe sthm nd milder or more stble sthmtics my not demonstrte this degree of vribility. Mesurement of FEV, before nd fter bronchodiltor t clinic visit or estimtion of diurnl vrition without use of bronchodiltor ppered less sensitive thn mesurement of diurnl vrition recorded before nd fter bronchodiltor. Obviously the usefulness of mesurements of vribility of flow rtes for the dignosis of sthm needs to be exmined formlly nd compred with the usefulness of mesurement of bronchil responsiveness to histmine or methcholine in lrger number of subjects who re crefully chrcterised by clinicl fetures.2' The results lso rise the question of the role of bronchil responsiveness in the pthogenesis of sthm; is hyperresponsiveness the primry bnormlity in sthm nd prerequisite for the occurrence of irflow obstruction or is it consequence of reduced irwy clibre?2223 Our results show tht sthmtics my hve moderte or severe increse in responsiveness (PC2 < 2- mg/ml) t time when their FEV, is within 1% of mximum. Furthermore chnges in irwy resistnce hve been observed without chnges in responsiveness,24 nd chnges in responsiveness hve been observed without chnges in resistnce.'6 These observtions suggest tht other fctors re involved in incresed responsiveness-for exmple, there my be n intrinsic bnormlity in smooth muscle. In bronchil smooth muscle removed from sensitised nd unsensitised dogs bseline tone ws the sme but the Thorx: first published s /thx on 1 June Downloded from on 3 December 218 by guest. Protected by copyright.

6 428 -i 4 12 (A _1 zro w *, - u O 6 I U. T 7 p ~~~t! Ryn, Ltimer, Dolovich, Hrgreve * r 7 TP.. * 1T 1- X PC2 HISTAMINE (mg/ml) Fig 4 Reltionship between PC2 histmine (mglml) nd FEV,, s % predicted, - mesured before ( ) nd 15 minutes fter inhled slbutmol (2 jg). ( nonsthmtics, previous sthmtics, U current sthmtics). Ifthe FEV, before slbutmol ws more thn 1% different from the FEV, before the histmine inhltion test the ltter is lso shown (v). When the difference ws <2 % only one symbol is shown. * EU zs* OUV n i - 1 1,/2 A. I Fig 5 I - m 4. I 2-4, l1r- > E u E 8 j _ E E 7~ 7 I - 7 l4/, i.: : U U n U n EU". U* * * ** * 1 1 o * PC2 HISTAMINE (mg/ml) Reltionship between PC2histmine (mglml) nd initl FEV, t the time ofthe histmine inhltion test. FEV, is expressed s percentge ofmximum FEV, fter inhled slbutmol (2 Mg) mesured seven dys lter. Symbols s in fig 1. smooth muscle of the sensitised dogs ws more hyperresponsive to crbchol.25 It is therefore possible tht bronchil responsiveness is the primry bnormlity in sthm, which leds to the chnges in smooth muscle tone nd irwy clibre. Agreement hs not been reched on the definition of sthm. Until there is more understnding of the cuses nd mechnisms of sthm definition in terms of disorder of function, such s tht proposed by Scdding,' is most stisfctory. However, s illustrted in the present study, n increse in the vribility in irflow rtes my be difficult to confirm in mild sthm without provoction chllenge procedures. Fortuntely incresed nonspecific bronchil responsiveness is present in virtully ll subjects with current symptoms of sthm nd the responses to different nonspecific stimuli seem to correlte quite closely.9 Nonspecific responsiveness to histmine or methcholine cn be esily mesured1' 1 nd norml responses to these gents nd bnorml response to others such s exercise nd cold ir hve not been observed. The study ws supported by grnts from the Medicl Thorx: first published s /thx on 1 June Downloded from on 3 December 218 by guest. Protected by copyright.

7 Bronchil responsiveness to histmine Reserch Council of Cnd nd from Schering Corportion Limited. We thnk Robin Roberts for sttisticl dvice nd Dr NL Jones for reviewing the mnuscript. References ' Scdding JG. Definition nd clinicl ctegoristion. In: Weiss EB, Segl MS, eds. Bronchil sthm: mechnisms nd therpeutics. Boston: Little, Brown nd Compny, 1976: Cib Foundtion. Terminology, definitions nd clssifiction of chronic pulmonry emphysem nd relted conditions. Thorx 1959;14: Americn Thorcic Society. Definitions nd clssifiction of chronic bronchitis, 3thm, nd pulmonry emphysem. Am Rev Respir Dis 1962;85: Pride NB. Prcticl use of pulmonry function tests. In: Clrk TJH, Godfrey S, eds. Asthm. Phildelphi: Sunders, 1977: Hetzel MR, Clrk TJH. Comprison of norml nd sthmtic circdin rhythms in pek expirtory flow rte. Thorx 198;35: Prior JG, Cochrne GM. Home monitoring of pek expirtory flow rte using mini-wright pek flow meter in dignosis of sthm. J R Soc Med 198;73: Pepys J, Hutchcroft B. Bronchil provoction tests in etiologicl dignosis nd nlysis of sthm. Am Rev Respir Dis 1975;112: 'Hrgreve FE, Juniper EF, Ryn G et l. Clinicl significnce of nonspecific irwy hyperrectivity. In: Hrgreve FE, ed. Airwy rectivity. Mississug: Astr Phrmceuticls Cnd, 198: Anderton RC, Cuff MT, Frith PA et l. Bronchil responsiveness to inhled histmine nd exercise. J Allergy Clin Immunol 1979;63: ' O'Byrne PM, Ryn G, Morris M et l. Asthm induced by cold ir nd its reltion to nonspecific bronchil responsiveness to methcholine. Am Rev Respir Dis 1982;125: "Cockcroft DW, Killin DN, Mellon JJA, Hrgreve FE. Bronchil rectivity to inhled histmine: method nd clinicl survey. Clin Allergy 1977;7: Chernick RM. Pulmonry function testing. Phildelphi: Sunders, '3 Morris JF, Koski A, Johnson LC. Spirometric stndrds for helthy nonsmoking dults. Am Rev Respir Dis 1971;13: Cockcroft DW, Ruffin RE, Frith PA et l. Determinnts of llergen-induced sthm: dose of llergen, circulting IgE ntibody concentrtion nd bronchil responsiveness to inhled histmine. Am Rev Respir Dis 1979;12: O'Brien IM, Newmn-Tylor AJ, Burge PS, Hrries MG, Fwcett IW, Pepys J. Toluene di-isocynte-induced sthm. II Inhltion chllenge tests nd bronchil rectivity studies. Clin Allergy 1979;9: Crtier A, Frith PA, Roberts R, Thomson N, Hrgreve FE. Allergen-induced increse in bronchil responsiveness to histmine: reltionship to the lte sthmtic response nd chnge in irwy cliber. J Allergy Clin Immunol (in press). 7 Lm S, Wong R, Yeung M. Nonspecific bronchil rectivity in occuptionl sthm. J Allergy Clin Immunol 1979;63: Empey DW, Litinen LA, Jcobs L, Gold WM, Ndel JA. Mechnisms of bronchil hyperrectivity in norml subjects fter upper respirtory trct infection. Am Rev Respir Dis 1976;113: '9 Rubinfeld AR, Pin MCF. Perception of sthm. Lncet 1976;1: Juniper EF, Frith PA, Hrgreve FE. Airwy responsiveness to histmine nd methcholine: reltionship to minimum tretment to control symptoms of sthm. Thorx 1981;36: Deprtment of Clinicl Epidemiology nd Biosttistics, McMster University Helth Sciences Centre. How to red clinicl journls: II. To lern bout dignostic test. Cn Med Assoc J 1981;124: De Vries K, Goei JT, Booy-Noord H, Orie NGM. Chnges during 24 hours in the lung function nd histmine hyperrectivity of the bronchil tree in sthmtic nd bronchitic ptients. Int Arch Allergy 1962;2: Benson MK. Bronchil hyperrectivity. Br J Dis Chest 1975;69: Rubinfield AR, Pin MCF. Reltionship between bronchil rectivity, irwy clibre nd severity of sthm. Am Rev Respir Dis 1977;115: Stephens NL, Mitchell RW, Antonissen LA et l. Airwy smooth muscle: physicl properties nd metbolism. In: Hrgreve FE, ed. Airwy rectivity. Mississug: Astr Phrmceuticls Cnd, 198; Thorx: first published s /thx on 1 June Downloded from on 3 December 218 by guest. Protected by copyright.