Beta-Adrenoceptor Blockers and T erbutaline in Patients with Chronic Obstructive Lung Disease*

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1 Beta-Adrenoceptor Blockers and T erbutalne n Patents wth Chronc Obstructve Lung Dsease* Effects and nteracton After Oral Admnstraton ]. Wunderlch, M.D.; H. N. Macha, M.D.; H. Wudcke, M.D.; a.ndh. Huckauf, M.D. We studed the efteccs of a combned treatment wth p:a4muladng and p-blocldng drugs n 35 patents nller ng from chronc obstructve hmg dsease (COLD) and llchemlc heart dsease, and or arteral hypertenson. The drup used were equpotent repeated oral doses of metoprolol (100 mg twce daly [bfdd, propranolol (80 mg bd), and a matchng placebo for p-adrenoceptor block ade gven n a double-blnd and crot1110ver fashon. The lnfake perod of each p-blocker was two days wth consecutve two-day-washout perod; 2.5 mg terbotalne and p-stlmulator placebo, respectvely, were gven tbroolhout the whole tral three tmes daly (tld). Pro- pranolol alone caused severe deteroraton of fudc. tlon. After 18 patents had been studed, ths drug had to be excluded from the tral. When compared wth placebo, metoprolol provoked ncreasng obstructon, too, but to a sgnfcantly lesser degree than propranolol These negatve effects on FEV 1 and FRC were completely equalzed by terbufalne. Predctve facton for the tolerablty of p-blocken n patents wth COLD could not be found. Therefore, careful observatons n the ntal phase of the treatment wth p-selectlve blocken are necessary. The pharmacologc acton of p-blockng agents, e ncreasng bronchal resstance, lmts ther use n patents wth chronc obstructve lung dsease (COLD). Accordng to the classfcaton of P For edtoral comment, see page 675 adrenoceptors by Lands et al, 1 selectve blockers have been developed whch mght also provoke ncreasng obstructon, but n most cases, to a far lesser degree than nonselectve blockers. M On the bass of ths theoretcal model, p-stmulators were gven concomtantly wth,8-blockers n order to mnmze the bronchal response to the blockng therapy. 5 But all the studes performed to test the clncal relevance of ths dealt wth a small number of patents, or modes of drug admnstraton whch are not used clncally, and the desgns of these studes were not completely double-blnd. w One am of our study was to compare the effects of two p-blockers, metoprolol and propranolol, and a placebo blocker, on lung functon and cardovascular factors gven wth and wthout an underlyng treatment of a,8-stmulator, terbutalne. Another objectve was to use repeated clncal oral doses of the blockers snce selectvty of a p-receptor blocker From Medznsche Klnk und Polldnk, Abtelung Cardo- Pneumonologe, Klnkum Stegltz der Freen Unverstt, Berln, Germany. Manuscrpt receved June 12; revson acrepted January 29..Reprnf request8: Dr. Wunderlch, Helgolatder ufer 6, 1000 Berln.21, West Germany 714 WUNDERLCH ET AL seems to be dose-dependent, 9 and some effects of a,8-blockng agent are not seen after sngle doses.8 10 Desgn of Study (Fg 1) MATERALS AND METHODS Ths study was double-blnd, and wth regard to the fjblockng agents, crossed-over. After baselne measurements and before enterng the study, the patents were randontly allocated to two groups, one group havng a contnuous 14- day terbutalne basal treatment, the other group havng a terbutalne-matchng placebo treatment. The {J-blocker treatment admnstraton was randomzed too, and was used n a cross-over fashon n both groups. The dosages used were 2.5 mg terbutalne three tmes daly ( td) or a placebo td for the {J-stmulaton and for {J-blockade equpotent dosages7 of metoprolol ( 100 mg twce a day [bd] ), propranolol ( 80 mg bd). or a placebo bd. Patents were fully nformed about the am, rsks, and procedure of the study and ther rght to wthdraw from the tral. The consent to partcpate was provded by each patent before enterng the tral. Patents Ths study was comprsed of 36 patents wth COLD, 11 women and 25 men. None of them had asthma. One patent had to nterrupt the study after the ntal phase of terbutalne-placebo because of an acute nfectve exacerbaton of hs COLD. Hs data was not used n the statstcal analyss. None of the patents had an acute exacerbaton at the begnnng of ths study. Besdes ther COLD, 28 patents suffered from angna pectors based on coronary artery dsease ( 6 of them had myocardal nfarcton n ther hstory), and 17 patents suffered from essental hypertenson (WHO,

2 -..., <... f T...,.,. 11 T""oalnl R. R CM CM }...,... _ -ll-... ~ "_,,_ porod lofl7pollllllllll_...,... 1ao111, D Doy...,._ jl-lllocbr,,_ zllll... - jl-11 r......,,_ - CM CM CM CM B.M. = baselne-measurements CM = control-measurements R = Randomzaton F.GtJBE 1. Desgn of study. group l-111. WHO 1962) for more than three years. Eleven patents suffered from coronary heart dsease and essental hypertenson. One patent had recurrent chest pan and tachycardas based on hypertrophc obstructve cardomyopathy ( HOCM). n all patents, treatment wth drugs such as sterods, dgtals, duretcs, anthypertensves, and organc ntrates was not changed durng the tral Treatment wth bronchodlators (j-stmulators and am!nophyllne) was wthdrawn before the tral was started. Patents were thus advsed to use them n case of emergency after contactng the nvestgators. Metl81Jrements and Ratngs All the measurements were performed two to three hours after ntake of regular medcaton and test medcaton. Conventonal lung functon tests were performed n the sttng poston. sprometry frst (wet sprometer, Pulmotest [Godard] lnear dsplacement recorded wth an accuracy of 1 percent full-scale deflecton. tme as 2 percent) and thereafter, body plethysmography (volume constant body plethysmograph, spontaneous breathng Uaeger] ). Predcted normal values were taken from Goldmann and Becklake.11 Best values of three lung-functonal maneuvers performed were taken, and statstcal analyses were performed. Thereafter, the ECG was regstered and blood pressure measurements were performed by the same observer wth the subject n the horzontal poston. After ths procedure, patents were ntervewed by another observer as to nterm hstory and drugs taken wthn the past 48 hours. Subjectve declaratons of breathlessness were classbed as mld (no therapeutc nterventons needed), moderate (njecton of 0.24 g amnophyllne and j-stmulator nhalaton), and severe (njecton of 0.24 g amnophyllne, 50 mg cortsone and nhalaton of j-stmulators). Complance control was performed by pllcount. Statstcs (a) Lung functonal data of functonal resdual capacty (FRC) were calculated n percentage of predcted normal. Forced expratory volume n one second ( FEV 1 ), systolc arteral blood pressure (BP 8 ), dastolc arteral blood pressure (BP 4 ), heart rate (HR), and arway resstance (Raw) were calculated as absolute values. We calculated mean values and the standard devatons ( SD). ( b) The Wlcoxon-Mann-Whtney test for two ndependent samples, two-taled, was used for statstcal evaluaton between the groups wth and wthout j-stmulator. ( c) The Wlcoxon test for pared dfferences, two-taled. was used for statstcal evaluaton between the effects of jbloclc:er placebo and metoprolol. TERBUTALNE GROUPln 101 TERBUTALNE PLACEBO GROUP(nal) A'!. sot.39.d, :1:49.6 "'" _.,,. "' 50:1: ==-~-~--~~ ~~ - 10 su ". 5-:o.o ,.,.,. ~---~~-:11.a 0 -t-",., 50:1:65.7 SD :1:29.6 SD :: 16.3 '--~'"' '"" =-~..,,...-=-- { SD:tU J!... 50:1:7.1 :::: FRC SD:!: l.o! SD:US.G 50:1:75.G 50:1:21. - :1: Raw., so~., SD:l:ll.5. '.,..._ SD:ttU FEVt, SD:l:20.3., SD:tl3.6 t t l l days FlcVBE 2. Effect of propranolol and metoprolol n patents on and off terbutalne therapy; mean values (.,..) and standard devatons (SD) of postve and negatve dfferences (6S) of FRC-, Raw and FEV 1 -values measured before and after a two-day-treatment perod wth terbutalneterbutalne placebo and propranolol, metoprolol, p-bloclc:er placebo, respectvely. Astersks ( 0 ) = Between groups wth and wthout terbutalne astersks-marked values are sgnfcantly dfferent (p~0.05); postve sgn of 6S = ncrease n FEV 1 ; Raw, FRC; negatve sgn of 6S =decrease of FEV 1, Raw, FRC; = terbutalneterbutalne placebo; = propranolol; -- = j-blocker placebo; = metoprolol. BETA BLOCKERS AND TERBUTAUNE N COLD 715

3 Terbutalne (n-18) Placebo (n-17) ±SD ±SD p Age (years) D8 Heght (cm) D8 Weght (kg) D8 Functonal resdual capacty (% pred) D8 Resdual volume (% pred) D8 Forced expratory volume n L sec D8 Arway resstance (cm H10Lsec) D8 Heart rate (mn 1) D8 Systolc blood pressure (mm Hg) D8 Dastolc blood pressure (mm Hg) 95 Number Number 9 D8 Women 5 6 Men Smokng hstory ( d) The Fredman test for several related samples was used to test the dfferences between three drugs: placebo, metoprolol and propranolol. ( e) Postve and negatve dfferences were calculated and expressed as percentage of the value measured before a new perod of drug nterventon (baselne value E = 0 percent). Comparson was unformly performed at a level whch was prevously fxed at 5 percent. General fu:sults After 18 patents had been studed ( 10 wth terbutalne, 8 wthout), the decson was taken to exclude propranolol from the tral because 12 of these patents had developed moderate to severe bronchospasm wth subsequent nterrupton of the propranolol ntake (Fg.2). Sx of these patents had terbutalne, and sx had terbutalne placebo treatment. n fve patents, a bronchospastc attack occurred after ntake of one tablet of propranolol. Four patents developed bronchospasm after takng two tablets of propranolol Three patents reported breathlessness after the whole propranolol ntake perod. n all these patents, objectve evaluaton usng lung functon tests confrmed these subjectve declaratons. Because of ths break n the study, when 18 patents had been nvestgated, two groups were formed for comparson: group 1 (n = 35) whch had placebo p-blocker and metoprolol wth ( n = 8) and wthoutterbutalne ( n = 17); and group 2 ( n = 18) whch had placebo p-blocker, metoprolol and pro- 718 WUNDERLCH ET AL pranolol wth ( n = 10) and wthout ( n = 8) terbutalne. Patent Characterlstca As can be seen from Table 1 (patents wthout propranolol treatment) and Table 2 (patents wth propranolol treatment), respratory and cardovascular measurements n both groups ( terbutalne and placebo) yelded no sgnfcant dfferences when tested wth Wlcoxon-Mann-Whtney, at a 5 percent level. Group.2 has been proven a representatve sample of group 1. The dstrbuton of hstory data (angna pectors, myocardal nfarcton), drugs, fndngs of chest roentgenograms and ECG at rest were smlar n both groups. The patents' complance was nearly 100 percent n both groups. Subfectve State1118nts There were no dfferences n respect to reported attacks of angna pectors, subjectve feelng of tachycarda, and use of ntrates n both groups (wth or wthout terbutalne). Comparson of Two Groups (n=lo wth, and n=b wthout Terbutal.ne) n Respect to Effects of P- Blocker Pl.acebo, Metoprolol, and Propranolol Fgure.2 presents means and standard devatons of postve or negatve dfferences n percentage of baselne values measured after a two-day treatment wth terbutalne, and thereafter a two-day treatment wth ether p-blocker placebo, metoprolol, or pro-

4 Terbutalne (n-10) Placebo (n-8). ±SD ±SD p Age (years) ns Heght (cm) ns Weght (kg) ns Functonal resdual capacty(% pred) ns Resdual volume(% pred) ns Forced expratory volume n L sec ns Arway resstance (cm H10Lsec) ns Heart rate (mn ) ns Systolc blood pressure (mm Hg) ns Dastolc blood pressure (mm Hg) 93 Numbers Numbers 9 ns Women 5 4 Men 5 4 Smokng hstory 7 6 pranolol. The FRC s not decreased sgnfcantly by terbutalne ( ± 8.1 percent) as compared to placebo terbutalne ( +0.4 ± 4.9 percent). Terbutalne ncreased FEV1 ( ± 29.6 percent, P < 0.05) and decreased Raw ( ± 23.6 percent, p < 0.05) sgnfcantly when compared to,8-stmulator placebo ( FEV ± 13.5 percent, Raw + 8. ± 28.1 percent). When,8-blocker placebo was gven, there was nearly no nfluence on FEV1, FRC, and Raw. These effects were nearly dentcal n both groups. Metoprolol treatment wth terbutalne smultaneously caused an ncrease of FRC ( percent) and of Raw ( percent), and a decrease of FEV1 ( percent). These deteroratons of lung functon were not sgnfcantly dfferent when metoprolol was gven wthout terbutalne: FRC ( ± 7.8 percent), Raw ( percent), and FEV1 ( ± 20.3 percent). Propranolol caused severe deteroratons of FRC ( percent), FEV1 ( ± 11.5 percent), and Raw ( percent) n the terbutalne group as well as n the,8-stmulator placebo group: FRC ( percent), FEV 1 ( ± 13.6 percent), and Raw ( ± 65.0 percent). As Fgure 2 ponts out, the negatve effects of propranolol on FEV1, Raw, and FRC are not essentally dfferent n both groups, whereas terbutalne reduced the negatve effects of metoprolol n a remarkable degree, the mpresson s warranted that both drugs produced nearly a 0 result. n respect to the varables FEV1, Raw, and FRC n the groups wth and wthout terbutalne, separate statstcal analyss was performed by use of the formula accordng to Fredman (see "statstcs") n order to dfferentate between three drugs:,8- blocker placebo, metoprolol, and propranolol. Wth or wthout terbutalne, placebo caused the lowest and propranolol the hghest deteroraton of FEV 1, Raw, and FRC. The dfferences between these three drugs were statstcally sgnfcant. Comparson of Two Groups, Terbutalne (n = 18) and P'lacebo (n = 17) n Respect to Effects of,8- blocker P'lacebo and Metoprolol Treatment Effects of FEV1 FRC, Raw: As presented n Fgure 3, the effects of terbutalne on FRC ( ± 9.9 percent) and Raw ( percent) are not sgnfcantly dfferent from those of,8-stmu- ator placebo: FRC ( percent) and Raw ( ± 59.8 percent), whereas FEV 1 s ncreased by terbutalne to a remarkable degree when compared to placebo ( ± 25.8 percent) vs ( percent, P :S;; 0.05). n both groups, placebo,8-blocker dd not nfluence FRC, Raw, or FEV 1 n a dfferent degree. As expected, FRC ncreased durng the metoprolol treatment perod, but dfferences between the two groups are not seen ( ± 10.9 percent wth terbutalne vs ± 28.0 percent wthout terbutalne, ns. Nether the reductons of FEV1 ( ± 14.6 percent wth terbutalne vs - 16.l BETA BLOCKERS AND TERBUTALNE N COLD 717

5 TERBUTALNE GROUP(n=18) TERBUTALNE PLACEBO Ahl 40 ~U GROUP(n=17) SD±l , SD:t9.9 SD±l0.1 SD±28.0 SD± :::::::: S0± ~ F RC SD± SD± ± SD± SD±25.8,,.,~~--- SD±14.5 F1GUBE 3. Effect of metoprolol n pa- + 1 O.... tents on and off terbutalfne therapy; SD±20. SD±24.6 mean values ( ) and standard dev- O -+< ,,,-=----..,,.-t "5>- FE V 1 atons (SD) of postve and negatve -lo SD±l4.6 ~ dfferences (~S) of FRC-, Raw, and -30 t t t percent wthout terbutalne ), nor the ncrease of Raw ( ± 45.4 percent wth terbutalne vs ± 66.2 percent wthout terbutalne) caused by metoprolol are statstcally sgnfcant as far as the dfferences are consdered. Snce FEV 1 was ncreased sgnfcantly by terbutalne when compared wth placebo (Fg 3) and the decrease of FEV 1 by metoprolol was of the same degree n both groups consstently, the fnal absolute values between both groups are statstcally dfferent as well. When comparson was made between mprovements caused by terbutalne on FEV 1 ( ± 25.8 percent) and on FRC ( percent), and deteroraton caused by metoprolol on FEV 1 ( ± 14.5 percent) and on FRC ( ), we acheved a "so-called" 0 result, e, the effects of,8-blockade are neutralzed. Such a result s not to be seen when Raw s chosen for comparson. These values are over the preterbutalne values, but the dfferences are not sgnfcantly dfferent due to wde standard devatons.... FEV 1 -values measured before and af- ter a two-day-treatment perod wth terbutalneterbutalfne placebo and metoprolol, p-blocker placebo, respectvely. Defntons of abbrevatons ex- 2 da vs planed under Fgure 2. SD±19.7 t Wth or wthout terbutalne smultaneously, metoprolol caused a dstnct reducton of FEV 1 and an ncrease of Raw when compared to the effects of,8- blocker placebo. These results were sgnfcant on a level of 5 percent. Effects on Heart Rate and B'lood Pressure. As presented n Fgure 4, terbutalne nduced an ncrease of heart rate ( percent vs percent, P ~ 0.05) and a decrease of dastolc blood pressure ( ± 11.2 percent vs, percent, P~0.05), when compared wth terbutalne placebo, whereas the effects of both drugs on systolc blood pressure were not sgnfcantly dfferent. n respect to heart rate, systolc and dastolc blood pressure, placebo,8-blocker had no effects on these varables, nether wth nor wthout terbutalne. When metoprolol was gven, the reducton of heart rate n the terbutalne-treated group was sgnfcantly dfferent when compared wth,8-stmulator placebo ( percent vs WUNDERLCH ET Al

6 TERBUTALNE GROUP(n=181 A% +10 SD:l:U.3 SD:tlU... TERBUTALNE PLACEBO GROUP(n SD:tl "' ~w~sd-:1:~""" =.. =...-- HR ~ SD:tl9.4 SD:l:l& O -! ~ ~~ ~ s SD:U SD:l: SD:tt0.9 SD:ll ~; SD:l: SD:l:t3.2 SD:l:l k c== ::::::."::.- BPd..._..._ -10 ~D~ SD:ll2.7 SD:tl0.9 t t t t days F'ctJRE 4. Effect of metoprolol n patents on and off terbutalne therapy; mean values ( ) and standard devatons (SD) of postve and negatve dfferences ( Al) of heart rate (HR), systolc blood pressure (BP 8 ) and dastolc blood pressure (BP d) measured before and after a two-day treatment perod wth terbutalneterbutalne placebo and metoprolol, f-blocker placebo respectvely. Postve sgn of Al = ncrease of HR, BP 8, BP d; negatve sgn of Al = decrease of HR, BP 8, BP d; = terbutalneterbutalne placebo respectvely; --= p-blocker placebo; = metoprolol 19.4 percent, P~ 0.05); metoprolol wth and wthout terbutalne caused a reducton of heart rate of smlar magntude. n both treatment groups, metoprolol caused nearly dentcal reductons of systolc blood pressure ( ± 9.1 percent wth terbutalne vs percent wthout terbutalne). Metoprolol caused slght reducton of dastolc blood pressure wth no dfferences between the two groups ( percent and percent). Data suggest that terbutalne and metoprolol together caused more pronounced decrease of dastolc blood pressure than metoprolol alone (P~ 0.05). DlscuSSON The present study demonstrated that oral admnstraton of,82-stmulator ( terbutalne, 7.5 mg daly) mproved ventlatory functon n patents wth COLD n comparson to placebo. The cardovascular result of the effects of terbutalne n our study s an ncreased ampltude of arteral blood pressure (BP. unchanged, HR ncreased, and BP d de- BPS creased). The ncrease of the heart rate and of the ampltude of arteral blood pressure may be due to stmulaton of cardac and vascular,82-receptors. Therefore, accordng to Ablad et al,2 and Carlsson et al, 12 cardac output mght be ncreased and vascular resstance reduced. n our study, propranolol caused severe deteroratons of ventlatory functon (Fg 2). Lke Johnsson et al, 7 and Tvenus, 13 we found that these effects were not nhbted sgnfcantly by oral admnstraton of terbutalne. Therefore, propranolol was omtted, and the effects of ths,b-blocker on heart rate and blood pressure are not gven and dscussed because the comparson between metoprolol and propranolol s reported by several other authors..,15 Our data suggest that the admnstraton of propranolol cannot at all be recommended n COLD. Nevertheless, we found n two cases no subjectve complants wth respect to breathlessness durng the propranolol treatment perod. Both patents suffered from rreversble COLD. Ther values of lung functon were lttle nfluenced when propranolol was compared to placebo. Because fve of 17 patents (wthout terbutalne ) tolerated metoprolol wthout subjectve breathlessness and objectve deteroratons of ventlatory functon, and n 11 of 18 patents wth terbutalne, metoprolol dd not change the mprovements of terbutalne, we looked for ndvdual prestudy characterstcs, hstory of chronc bronchts, and dfferental hemograms wth respect to eosnophla n all these cases. No predctve factor could be found ndcatng why these patents tolerated,8-blockade better than the others. n our study, we found that the mprovement of ventlatory functon caused by terbutalne s prevented by the applcaton of metoprolol. These observatons are n accordance wth Formgren,6 but not wth other authors.b.13 Some of them13 used 100 mg metoprolol daly and performed measurements before and after nhalaton of soprenalne, whle others8 had used sngle doses of metoprolol, 100 mg, and soprenalne nfusons. They found that the soprenalne-medated ncrease n FEV 1 and FVC was not sgnfcantly altered after metoprolol compared wth placebo. Ths shows that metoprolol had not mnmzed the pharmacologc effects of soprenalne on the bronchal system. The dfferent results of our study mght be explaned by the greater,81-effects of soprenalne n comparson wth terbutalne because there are,81-adrenoceptors n the bronch too, and or a dose-dependent deteroraton6 9 of lung functon values-we used 100 mg metoprolol twce a day. Wth regard to the ncreased heart rate caused by terbutalne, the reducton of ths measurement after BETA BLOCKERS AND TERBUTALNE N COLD 719

7 metoprolol s of a greater magntude than that whch has been regstered by metoprolol alone. The comparson of the effects of metoprolol wth and wthout terbutalne s quanttatvely of the same degree. The reducton of systolc and dastolc blood pressure s nearly dentcal n both groups. The mpresson s warranted that the reducton of dastolc blood pressure caused by terbutalne s renforced by metoprolol. Our observatons corresponded wth the fndngs of Formgren. 6 From our results, we came to the followng conclusons: accordng to the supposton that terbutalne s a relatvely selectve,ba-stmulatng drug, and that metoprolol s a relatvely selectve,81-adrenoceptor blocker, the effects of 200 mg metoprolol and 7.5 mg terbutalne daly on the bronchal system may be explaned by blockade of,81-receptors equpotent to the,82-stmulaton. Because these dosages of terbutalne and metoprolol produced, n combnaton, a decrease of heart rate, the dstrbuton pattern of,81:,82-adrenoceptors n the heart must not only be nverse to that n the bronch, but also be more greatly n favor to,81- adrenoceptors. Therefore, t s nearly mpossble that any drug would have absolute selectvty wth respect to organ systems, nether,8-stmulators nor,8- adrenoceptor blockers at the present state of knowledge of,8-receptor mechansms. Because a total of 15 ( 5 of 17 wthout and 11 of 18 wth terbutalne) out of 35 patents tolerated ( e, nether subjectve declaratons of breathlessness nor deteroratons' of ventlatory functon) metoprolol, ths blocker may be gven n ndvdual dosage n patents who suher from coronary artery dsease and or hypertenson n combnaton wth COLD. Careful observatons n the ntal phase of the treatment are necessary, because selectvty depends on ndvdual response of the bronchal system and or dosage. We do not agree wth other authors who recommended an a pror regular basal,82- adrenoceptor stmulaton n optmal dosage (oral and nhalaton) when,81-receptor blockers were gven to patents wth COLD. However, n ndvdual cases, dependng on symptoms and or effects, terbutalne mght be added, and n some patents, even larger doses than we used n ths study mght be necessary. 1 Lands AM, Arnold A, Mc Aulff JP, Lunduena FP, Brown TG: Dfferentaton of receptor systems actvated by sympathommemc amnes. Nature 1967; 214: Ablad B, Carlsson E, DahlOf C, Ek L: Some aspecb of the pharmacology of,6-adrenoceptor blockers. Drugs 1976; ll(suppl 1): Astrom H, Valln H: Effect of a new beta-adrenergc blockng agent C 66082, on exercse hemodynamcs and arway resstance n angna pectors. Br Heart J 1974; 36: Sngh BN, Whtlock RML, Comler RH, Wllams FH, Harrs EA: Effects of cardoselectve adrenoceptor blockade on spec6c arways resstance n normal subjects and n patents wth bronchal asthma. Cln Pharmacol Ther 1976; 19: Johnsson G: Use of,6-adrenoceptor blockers n combnaton wth,6-stmulators n patents wth obstructve lung dsease. Drugs 1976; ll(suppl 1): Formgren H: The effect of metoprolol and practolol on lung functon and blood pressure n hypertensve asthmatcs. Br J Cln Pharmacol 1976; 3: Johnsson G, Svedmyr N, Thrnger G: Effects of ntravenous propranolol and metoprolol and ther nteracton wth soprenalne on pulmonary functon, heart rate and blood pressure n asthmatcs. Europ J Cln Pharmacol 1975; 8: Thrnger G, Svedmyr N: nteracton of orally admnstered metoprolol, practolol and propranolol wth soprenalne n asthmatcs. Europ J Cln Pharmacol 1976; 10: Flemng GM, Chester EH, Schwartz HJ, Jones PK: Beta adrenergc blockade of the lung: dose-dependent cardoselectvty of tolamol n asthma. Chest 1978; 73:8C Johnsson G, Nyberg G, Solvell L: nfluence of metoprolol and propranolol on hemodynamc effects nduced by physcal work and soprenalne. Acta Pharmacol 1975; 36(suppl 4) : Goldmann HJ, Beclclake MR: Respratory functon tests. Am Rev Respr Ds 1959; 79: Carlsson E, Ablad B, BranstrOm A, Carlsson B: Dfferentated blockade of the chronotropc effects of varous adrenergc stmul n the cat heart. Lfe Sc 1972; 2: Tvenus L: Effects of multple doses of metoprolol and propranolol on ventlatory functon n patents wth chronc obstructve lung dsease. Scand J Respr Ds 1976; 57: Bengtsson C: Comparson between metoprolol and propranolol as anthypertensve agents: a double-blnd crossover study. Acta Med Scand 1976; 199: Johnsson G: nfluence of metoprolol and propranolol on hemodynamc effects nduced by adrenalne and physcal work. ActaPharmacol 1975; 36(suppl5): WUNDERUCH ET Al