R. HAASIS* AND H. BETHGEf * Medizinische Universitatsklinik Tubingen and fstddtische Kliniken, Medizinische Klinik, Darmstadt F.R.G.

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1 European Heart Journal (1987) 8, {Supplement M), Exercse blood pressure and heart rate reducton 24 and 3 hours after drug ntake n hypertensve patents followng 4 weeks of treatment wth bsoprolol and metoprolol: A randomzed multcentre double-blnd study (BISOMET) R. HAASIS* AND H. BETHGEf * Medznsche Unverstatsklnk Tubngen and fstddtsche Klnken, Medznsche Klnk, Darmstadt F.R.G. KEY WORDS: Hypertenson, beta-adrenoceptor antagonsts, metoprolol, bsoprolol, exercse test, duraton of acton, 24-h resdual effects, beta,selectvty In a 4-week randomzed, double-blnd study, 87 patents wth essental hypertenson receved ether 10mg bsoprolol (B) or loomg metoprolol (M) once daly (o.d.). The effects of the beta blockers on systolc blood pressure, heart rate and rate-pressure product durng exercse, 24 h (E2) and 3h (E3) after admnstraton (p.a.) were compared wth the values obtaned n the baselne exercse test (El). 24 hours p.a. the effects of B were sgnfcantly stronger than of M (E1-E2: B vs M; P <0-01) whereas 3hp.a. no sgnfcant dfferences were detectable between B and M. The resdual effects 24 h p.a. n relaton to the effects 3hp.a. (E1-E2/E1-E3) were sgnfcantly greater wth B (86-93%) than wth M (53-66%). In contrast to the fndngs wth loomg M o.d., Wmg bsoprolol o.d. guarantees a persstent reducton n exercse blood pressure and heart rate throughout the entre dosage nterval of 24 h. Introducton Exercse heart rate s a generally acknowledged parameter for the assessment of the potency of beta blockers. To assess the extent of the beta receptor blockade and the blood pressure reducton at the end of a dosage nterval of, for example 24 hours, t s necessary to know the effects that the beta blockers have n the perod between the 1st and 4th hour followng admnstraton (p.a.). In ths perod the beta blockers reach ther maxmum concentraton n the blood and also ther maxmum effect on exercse heart rate. In only a few studes blood pressure and heart rate have been measured n patents wth hypertenson after several weeks' admnstraton of beta blockers n the perod between the 1st and 4th hour p.a. as well as 24 h p.a. at rest and also durng exercse 1 '" 8 '. The am of the present study was to compare the beta blockers bsoprolol (B) and metoprolol (M) wth regard to the extent and duraton of beta receptor blockade and blood pressure reducton after 4 weeks of treatment. Address for correspondence: Prof. Dr. R. Haass, Medznsche Unverstatsklnk, Innere Medzn II, D-7400 Tubngen, F.R.G. From the relaton between the fndngs 24 and 3hp.a. at 100 W durng exercse the resdual effects at the end of the dosage nterval were to be derved and evaluated n relaton to the plasma elmnaton half-lves of the beta blockers. Bsoprolol has a plasma elmnaton half-lfe of h and a boavalablty of 90% 9 - n. The plasma elmnaton half-lfe of metoprolol s 3-4 h and ts boavalablty s 50% lz. Nether of the beta blockers shows an ntrnsc sympathommetc actvty 1 ' 2 " 141 and both are consdered beta,se!ectve l2 ~ 171. The beta,selectvty of a beta blocker, however, s not an absolute property but rather a relatve one that s dependent on the dose or respectvely on the concentraton n the blood" Patents A multcentre randomzed double-blnd study wth verfcaton of complance (BISOMET study) was performed. Fve centres for hypertensve dseases and 15 general practtoners took part. The study was approved by an ethcal commttee. 113 outpatents between 18 and 70 years of age X/87/08M $02.00/ The European Socety of Cardology

2 104 R. Haass and H. Bethge wth mld to moderate essental hypertenson (WHO stages I and II) and a sttng dastolc blood pressure (at the end of a 2-4-week placebo phase) of >95 to = 115 mmhg took part n the study. The followng patents were excluded from the study: patents wth typcal beta-blocker contrandcatons (congestve heart falure, bronchal asthma, bradycarda at rest (<50 beats mn" 1 ), ECG conducton dsturbances, refractory dabetes melltus), patents wth essental hypertenson of stage HI, patents who had had a myocardal nfarcton wthn the last 12 months, patents wth secondary hypertenson, ntermttent claudcaton or angna pectors (e.g. termnaton crteron n ergometry), alcoholsm, drug abuse, concurrent mpared renal functon (creatnne >l-7mgdl~'), bone marrow, lver, gastrontestnal tract or central nervous system dseases, and women of chldbearng age. Concomtant ntake of ovulaton nhbtors, cmetdne, thyreostatcs, antarrhythmcs and psychotropcs (phenothazne, MAO nhbtors, trcyclc antdepressants) was not allowed. 26 of the 113 patents could not be evaluated for effcacy: 6 patents dropped out n the placebo prelmnary phase (5 of these on account of sde-effects); 2 patents ended the beta-blocker therapy prematurely (see below); 8 patents (3B, Table I Patent characterstcs Number Men Women Age (years) Weght (kg.) Heght (cm) Smokers (no.) Coronary heart dsease (no.) Concomtant therapy (no.) for Heart falure Hyperurcaema Hyperlpdaema Prevous treatment wth beta blockers (no.) Outcome: Very good Good Moderate Poor Mean ± SD Bsoprolol ±9-7* 80-2 ±12-5* 174 ±9* M) showed nadequate complance; and n the case of the 10 remanng patents (6B, 4M), the physcans had not compled properly wth the protocol. The characterstcs of the 87 evaluable patents (44 B, 43 M) are summarzed n Table 1. There are no apprecable dfferences between the two treatment groups. Study schedule (Fg. 1) The randomzed double-blnd study was preceeded by a 2-4 week ntal phase n whch all patents receved a placebo under sngle-blnd condtons. Pror to the ntal phase a clncal hstory was taken and a thorough medcal examnaton was performed to check the ncluson and excluson crtera. In addton, blood pressure, heart rate (sttng) and body weght were measured, an ECG was recorded and blood and urne samples were taken for laboratory tests. At least 2 weeks and at most 4 weeks after the start of the placebo treatment the randomzed double-blnd study began as soon as the 3rd dastolc pressure readng wth the patent sttng quetly (three readngs at 1-mnute ntervals) was n the range >95 and = 115 mmhg. At ths pont, 24 h after the last placebo tablet, the followng tests were Metoprolol ±70' 77-3 ± 12-9* 173 ±7*

3 Exercse blood pressure and heart rate reducton 105 ^ rrg r: soprc o Placebo 00 mg metoorolol week BP; HR at rest: \ n BP; HR at rest and durng exercse: \7 24 h p.a; C = complance check 4 h and 3 h p.a. Fgure 1 Study schedule (BP = blood pressure, HR= heart rate). performed: blood pressure and pulse after 5 mnutes sttng and durng exercse (El), ECG at rest, laboratory analyses, count of returned capsules, recordng of spontaneously reported symptoms. The measurements of blood pressure and heart rate at rest and durng exercse were repeated 3 h later. Snce some of the patents had already taken the frst actve-substance capsule by ths tme, the relevant fndngs are not reported. The patents were randomzed nto two treatment groups: one group receved capsules contanng 10 mg bsoprolol; the other receved capsules of dentcal shape and color contanng 100 mg metoprolol. Suffcent capsules for a 2-week perod were ssued. One capsule was swallowed wth breakfast every mornng. After 2 weeks of treatment the followng readngs were taken: blood pressure and pulse when seated, body weght, any adverse reactons, complance check by countng the returned capsules and qualtatve determnaton of the beta blocker n a urne sample. The patents were then gven the capsules for the remanng 2 weeks. At the end of the 4-week treatment perod the followng tests were performed n the mornng, 24 h after the last beta blocker capsule had been taken: blood pressure and pulse when seated and durng exercse (E2), restng ECG, laboratory analyses, recordng of any adverse reactons and complance check. A further capsule was then swallowed n the presence of the doctor. Three hours later the cardovascular measurements were repeated wth the patent seated and durng exercse (E3). Methods of nvestgaton The blood pressure measurements were always made by the same doctor at the same tme of day usng a conventonal sphygmomanometer. The systolc and dastolc blood pressure readngs (SBP and DBP) concded wth the frst fant Korotkoff sounds (phase I) and the dsappearance of Korotkoff sounds (phase V), respectvely. The cuff pressure was reduced by no more than 2-3 mm s" 1 n the measurement range. In accordance wth the recommendatons of Franz' 19 ' the exercse test was performed on an electrcally or mechancally braked, regularly calbrated bcycle ergometer operatng at a speed of 50 rpm. The exercse began wth 2 mn at 50 W followed by 2 mn at 75 W and 2 mn at 100 W. Systolc blood pressure was measured durng the last 20 s of each workload and heart rate was determned by means of a ECG recorded durng the last 10 s. After the exercse test blood pressure and pulse were measured at 1 mn ntervals up to the 5th mn of recovery, wth the patent stll seated on the ergometer. The ECGs were evaluated centrally. Adverse reactons and symptoms reported spontaneously by the patents were recorded by the doctor, assessed accordng to severty, duraton and frequency and evaluated for any possble connecton wth the beta blockers. The beta blockers n a 2 ml urne sample were assayed by an HPLC method' 20 '. The urne samples were stored deep frozen at 20 C untl processed for analyss. Evaluaton The man am of the study was to compare the effects of the beta blockers on systolc blood pressure (SBP), heart rate (HR) and rate-pressure product (RPP) followng a 4-week treatment perod 24 h (E2) and 3h (E3) p.a. durng bcycle ergometry at the end of a 2-mnute 100 W workload (confrmatve statstcs for the SBP dfferences E1-E2 and E2-E3).

4 106 R. Haass and H. Bethge In addton, the followng fndngs were consdered and checked for drug related dfferences n terms of descrptve statstcs: HR- and RPPdfferences E1-E2 and E2-E3, dfferences n SBP, HR and RPP at 100 W, dfferences n the areas (El to E2 and El to E3) between the ascendng curves of SBP, HR and RPP durng the entre 6-mnute exercse, 24-hour resdual effects durng ergometry (at 100 W and durng the entre exercse perod): calculaton of the ratos E1-E2/E1-E3 n percentages (the resdual actvty ratos gven n the results were calculated from the dfferences n mean values and are thus only approxmate values: ths method of calculaton was selected n order to facltate comparsons wth references n the dscusson), blood pressure and heart rate at rest followng 2 and 4 weeks treatment 24 h and 3hp.a., and responder rates after 4 weeks treatment (responders were consdered those patents whose restng dastolc blood pressure after sttng for 5 mnutes was below 95 mmhg; the value that was taken for evaluaton was n each case the 3rd of 3 readngs taken at 1-mnute ntervals.) The planned sze of the random sample was 2 x 45 patents. The dfference between the treatments was consdered to be at least 10 mmhg (SBP) after 2 mnutes exercse at 100 W 24hp.a. The standard devaton (SD) was estmated to be between 5 and 10 mmhg (SD of the dfferences E2-E3). The Wlcoxon rank sum test was used for testng the dfferences. The type 1 error was set at a = 5%. Snce two tests (SBP dfferences E1-E2 and E2-E3 at 100 W) were to be performed for the confrmatve statstcs at least one of the two tests had to reject the null hypothess at the a- = 2-5% level to acheve the am of the study. If the other test led to a P-value less than a = 5%, both null hypotheses could be rejected at a type 1 error of <x = 5%. Ths s true n accordance wth the Holm-Bonferron sequentally rejectve multple test procedure. Results SYSTOLIC BLOOD PRESSURE. HEART RATE AND RATE-PRESSURE PRODUCT DURING EXERCISE Durng exercse 24hp.a., lower values of SBP, HR and RPP were attaned wth B than wth M at all measurement tmes (Fg. 2). Comparson of the results wth B and M showed that the SBPdfferences E1-E2 and E2-E3 at 100 W were sgnfcantly dfferent (/><0-01 and P<005, respectvely) (Table 2). Sgnfcant dfferences were also found between B and M for the respectve HR- and RPP-dfferences at 100 W, the recorded values at 100 W (Table 2), and for the dfferences n area (Fg. 3; shaded areas). Three hours p.a. there were no sgnfcant dfferences n the effects of B and M on SBP, HR and RPP durng exercse at 100 W (Table 2). Ths s also vald for the dfferences n area (not shown separately). Whereas the 3-hour-effects of the two beta blockers on SBP, HR and RPP were comparable at 100 W and durng the entre 6-mn exercse perod, the 24hp.a. resdual effects were sgnfcantly greater wth B than wth M (86-93% and 53-66% respectvely) (Table 3; Fg. 3). BLOOD PRESSURE AND HEART RATE AT REST Whereas the SBP, DBP and HR values at the begnnng and end of the 2-4-week ntal placebo phase were comparable, a sgnfcantly greater reducton was observed n restng SBP (P<0-05), DBP (F<0-01) and HR (P<0-05) wth B than wth M, 24hp.a., after only 2 weeks of treatment (Fg. 4). After 4 weeks the sgnfcantly stronger effect of B on DBP and on HR was stll present, whereas the dfference n SBP was no longer sgnfcant at ths pont. Three hours p.a. the restng values (x ± SD) were as follows n the patents treated wth B or M: SBP 137 ± 19 and 141 ±18 mmhg, respectvely (P<005), DBP 82 ±9 and 86 ±8 mmhg, respectvely (P<005), HR 63 ±8 and 67 ± 10 beats mn ~ ', respectvely (). After 4 weeks of treatment the restng dastolc blood pressure 24 h p.a. was less than 95 mmhg n 86-4% of the bsoprolol patents and 69-8% of the metoprolol patents. Ths dfference n responder rate was not sgnfcant (P = ). TOLERANCE 13 patents n each treatment group reported at least one adverse reacton durng the beta blocker therapy. Symptoms reported by at least 3 patents n one or n both of the treatment groups are lsted n Table 4. In the prelmnary placebo phase headache and vertgo were reported by 7 and 3 patents, respectvely. Durng the beta-blocker treatment the predomnant symptoms were headache on metoprolol and nausea on bsoprolol. The symptoms were mostly assessed as mld/moderate and short/transent. One bsoprolol patent dropped out on account of nausea and vomtng after 1 week of treatment. One metoprolol patent

5 Exercse blood pressure and heart rate reducton 107 2IOr en x EE bsoprolol (B) metoprolol (M) baselne curves mean SEM " HR E 100- n S 80 CD 60 < Watt 0 50 W I Mn I 100. T ^ I 8 I 9 l 10 b^ O O 5-B x l E II E W II Mn Fgure 2 Comparson of the effects of bsoprolol (B) and metoprolol (M) on systolc blood pressure (SBP), heart rate (HR) and rate-pressure product (RPP) durng and after ergometry before (b) and after 4 weeks of beta-blocker therapy 24hp.a. Whereas before treatment the fndngs are smlar n both groups, durng exercse the curves are lower wth B than wth M ndcatng stronger effects of B. experenced angnal symptoms durng therapy; the fnal tests were not carred out. Apart from those that could be attrbuted to other dseases, no clncally sgnfcant laboratory changes occurred before or durng the 4 weeks of beta-blocker therapy. Thus both beta blockers showed overall good tolerance. Dscusson The present study showed that, measured n terms of the results of an exercse test up to 100 W wth determnaton of SBP, HR and RPP n patents wth hypertenson, the acton of 10 mg bsoprolol perssts throughout the dosage nterval of 24 h. The resdual effects 24 h p.a. were 86-93% of the acute effects 3 h p.a. Whereas bsoprolol and metoprolol showed comparable 3-hour effects on SBP, HR and RPP durng exercse, the effects observed 24 h p.a. were sgnfcantly less wth 100 mg metoprolol than wth 10 mg bsoprolol. For metoprolol the resdual effects 24hp.a. were 53-66% of the acute effects 3hp.a. In contrast to the fndngs wth 10 mg bsoprolol, 100 mg metoprolol does not guarantee a persstant reducton n exercse blood pressure and heart rate throughout the entre 24-h dosage nterval. Our fndngs wth metoprolol confrm the results of prevous nvestgatons n patents wth hypertenson n whch exercse tests after several weeks of treatment wth once-daly admnstraton of mg metoprolol revealed that the effects on blood pressure and heart rate were consderably less 24hp.a. than 1-4 hours after admnstraton' 1 " 3 ' 5 " 71. The reference data regardng perods of treatment of 3-4 weeks are gven n Fgs 5 and 6. The values 1-4 h p.a. are dstnctly lower than those 24hp.a. and thus ndcate ncomplete beta receptor blockade and exercse blood pressure control at the end of the dosage nterval.

6 108 R. Haass and H. Bethge Table 2 Systolc blood pressure (SBP), heart rate (HR) and rate-pressure product (RPP) at 100 W and dfferences between values at the three ponts of tme SBP (mmhg) HR (beats mn" 1 ) RPP (mmhg x beats mn" 1 ) B M B M B M Before therapy El: mean P value E3(3hp.a.) mean P value El E2: mean P value E2 E3: mean P value <005 B bsoprolol, M- metoprolol After 4 weeks of treatment E2(24hp.a.) mean P value < The nformaton from the lterature on (50-) 100 mg atenolol once-a-day over a perod of 3-4 weeks' 1 3 ~ 7 ' s also shown n Fgs 5 and 6. Infveout of sx studes n whch 100 mg atenolol was compared wth mg metoprolol n conventonal formulaton, beta-receptor blockade was dstnctly more persstent on atenolol than on metoprolol. Even wth atenolol, however, lower values of SBP and HR durng physcal exercse were observed 1-4 h p.a. than 24hp.a., ndcatng that once-daly 100 mg atenolol does not provde beta-receptor blockade that perssts for the entre 24-h dosage nterval ether. Even after once-a-day 200 mg metoprolol n slow or delayed release formulatons for 2-4 weeks, the dfferences were usually relatvely small between 0 and 24 h p.a. and dstnct between 24 and 2-4 h p.a. (Fgs 5 and 6) 4fr ~ 8 '. Thus even n sustaned release formulatons metoprolol does not nduce a beta-receptor blockade and exercse blood pressure control that last convncngly throughout the 24-h dosage nterval. For the publshed studes n whch the exercse heart rate was measured both 24hp.a. and 1-4 h p.a., t s possble to calculate from the means of the respectve maxmum exercse heart rates quoted n the publcatons' 1 ' 3 " 5 ' 7 ' the resdual < effect 24hp.a. (see 'Evaluaton'). The resdual effect on exercse heart rate can be consdered a measure of the degree of the beta-receptor blockng acton 24 h p.a. The doses requred are defned by the affnty of the beta blockers to the beta receptor, by the plasma elmnaton half-lfe upon whch the beta-blocker concentratons at the ste of acton depend and also by the respectve degree of sympathetc actvty' 2 ' 18 '. There seems to be a relatonshp between the resdual effects of mg metoprolol, (50-) 100 mg atenolol and 10 mg bsoprolol and the respectve plasma elmnaton half-lves (Fg. 7). Bsoprolol has the longest plasma elmnaton half-lfe (10-12 h) of the three beta blockers under dscusson and the strongest resdual effect (about 90%) on exercse heart rate. In the steady state after several days of treatment, plasma concentratons of between 8 and longml" 1 were recorded 24 h after the admnstraton of 10 mg bsoprolol 110 ' 211. At ths pont n tme after the maxmum bsoprolol plasma concentratons of ng ml" h p.a.' 21 ' about 21 hours and thus about two plasma elmnaton half-lves have elapsed. Whle the plasma concentraton of bsoprolol have thus decreased to 20-25% of ts maxmum, the

7 SBP Metoprolol T Mn HR " Metoprolol Mn _ W RPP 250r Metoprolol A Bsoprolol /\ Mn W Fgure 3 Effects of bsoprolol (B) and metoprolol (M) on systolc blood pressure (SBP), heart rate (HR) and rate-pressure product (RPP) durng and after ergometry 24 and 3 h p.a., before (b) and after 4 weeks of beta-blocker therapy (x ± SEM). For all three parameters the shaded areas between the baselne curves (b) and the 24hp.a. curves are sgnfcantly (P) larger wth B than wth M, ndcatng stronger effects of B. The dark areas between the 24 h pa. and 3 h p.a. curves provde a measure of the resdual effects 24 h p.a.: the smaller these areas, the greater the resdual effects. The resdual effects are clearly larger wth B than wth M.

8 110 R. Haass and H. Bethge Table 3 24 h resdual effects (as percentage of acute effect 3h p.a.) at 100W and calculated from area dfferences SBP: HR: RPP: 100 W Area 100 W Area 100 W Area B M B bsoprolol; M metoprolol BusM. P value* 002 < <0-001 pharmacodynamc effect on exercse heart rate at 100 W was stll 90% of the 3-hour value. The pharmacodynamc half-lfe of 10 mg bsoprolol under these condtons s thus obvously consderably longer than the knetc half-lfe. The more persstent pharmacodynamc effects of beta receptor blockers when compared to the 180 Slsoprolol (B) O mean Metoprolol IM) SO *- 2-4 wttks -» * * p<o-oi 1 * /a<005j + 2»eek + 4 Fgure 4 Systolc and dastolc blood pressure (SBP, DBP) and heart rate (HR) at rest, before and after a 2- to 4-week prelmnary placebo phase and after 2 and 4 weeks of treatment wth bsoprolol and metoprolol, 24hp.a. Table 4 Adverse reactons: symptoms reported by at least three patents (number of reports) Headache Dzzness Nausea Placebo Bsoprolol Metoprolol half-lfe of the elmnaton from the plasma has frequently been attrbuted to deep compartments, actve metaboltes or to the persstent receptor bndng due to a hgh affnty. In contrast to these auxllary hypotheses, the concentraton-effect relaton analog to the law of mass acton enables an explanaton that s plausble because of ts smplcty' 221. The relatonshp between the temporal course of the beta blocker concentratons n the blood on one hand and the duraton of effect of beta blockers on the other as derved from the above explanaton by Palm et al. [22 ], however, s completely vald from a quanttatve pont of vew only after a sngle dose and n the case of the maxmum possble competton of antagonst and agonst at the beta receptor,.e. only n the case of maxmum physcal exerton wth maxmum sympathetc actvty. In the case of the exercse load of 100 W (whch corresponds to the daly physcal exercse load) selected n the present study, the beta-receptor blockade stll present 24 h after admnstraton of 10 mg bsoprolol s n hypertensve patents treated for 4 weeks suffcent to guarantee 90% of the 3-hour effect. The respectve value for 100 mg metoprolol was 53%. In comparson wth the clearly dfferent effects of the two beta blockers on SBP, HR and RPP durng exercse there were only relatvely slght and nconsstent dfferences wth regard to SBP and DBP at rest. Ths observaton ndcates that durng treatment wth beta blockers, blood pressure homeostass under restng condtons,.e. at a low sympathetc actvty and after chronc treatment n hypertensve patents, dsplays lttle or no dependence on the prevalng agonst/antagonst stuaton at the beta receptors, but rathermore s regulated by other factors that are only ndrectly connected wth the more persstent blockade of the beta receptors. In other words: the plasma elmnaton half-lfe of a beta blocker seems to be of relatvely lttle mportance regardng the reducton of restng

9 Exercse blood pressure and heart rate reducton 111 Mel c Tme!h, p.a.) L Fgure 5 Exercse heart rate (HR) at the respectve maxmum workload before (0) and 24 and 1-4 h after admnstraton of metoprolol (M), atenolol (A) and metoprolol n two sustaned release formulatons (SR, SA) (means of lterature values). The symbols represent the followng studes: ref. [5]: 100 mgm, 100 mg A; V ref. [6]: 100 mgm, 50 and 100 mg A, 200mgSR; ref. [7J: 200 mgm, 100 mg A, 200mgSA; D ref. [7]: 200mgSR; ref. [1]: 100 mgm 100 mg A, ref. [3]: 200 mgm, 100 mg A, O ref. [4], 100 mg A, 200 ng SA; A ref. [8]: 200mgSA. The results of the present study (BISOMET) are gven for comparson purposes: mg M, 10 mg bsoprolol. o- 220 J Metopr o 10' 24 ; Atenolol ' Meloprolol SR(SA Fgure 6 Systolc blood pressure (SBP) durng exercse at the respectve maxmum workload, before (0) and 24 and1 4 h after admnstraton of metoprolol, atenolol and metoprolol n two sustaned release formulatons (means of lterature values). See legend to Fg. 5 for further explanaton. v 2-4» blood pressure n long-term therapy of hypertensve patents. However, ths concluson should be qualfed n the context of therapeutc recommendatons, for the followng reasons: 1. Patents wth essental hypertenson should lead a largely normal lfe. They are therefore exposed to numerous, often unforeseeable, physcal and psychologcal stuatons that ncrease the release of endogenous catecholamnes. The exercse level of 100 W chosen for ths study corresponds to everyday physcal exerton. Under these condtons the therapy of patents wth hypertenson should take nto account the followng three objectves: (a) Increase n heart rate and blood pressure caused by exercse should be reduced as relably and as evenly as possble throughout the entre dosage nterval, (b) On account of the generally

10 112 R. Haass and H. Bethge O t z> "5 (/ </» u»< jr j <r C\J loor Meoprolol Atenolol Bsoprolol I Plasma elmnaton half-lfe (h) Fgure 7 24 h resdual effect of metoprolol, atenolol and bsoprolol on heart rate at the respectve maxmum workload versus the plasma elmnaton half-lves of the three beta blockers. See legend to Fg. 5 for explanaton of symbols. non-optmal complance on the part of the hypertensve patent, whch decreases further stll as the number of tablets to be taken daly ncreases, the dosage nterval should be 24 hours, (c) If a beta,selectve beta blocker s selected, ts beta,selectvty n the therapeutc dose range should be guaranteed also at the begnnng of the dosage nterval at relatvely hgh plasma concentratons. By analogy to the hypothess that the duraton of effects of beta blockers s denned by the concentraton-(dose)-effect rato, whch n turn s based on the law of mass acton, the frst two therapeutc objectves should theoretcally be achevable wth any beta blocker, ndependent of ts plasma elmnaton half-lfe, provded the dose s adequately hgh. However, dose ncreases n the once-daly admnstraton of beta,selectve beta blockers wth a short plasma elmnaton half-lfe wth the am of guaranteeng a constant betareceptor blockade for 24 hours ental apart from economc aspects very hgh concentratons at the begnnng of the dosage nterval wth the ensuant possblty of dose-dependent sde-effects and, partcularly, of a decrease of the concentratondependent beta,selectvty When admnstered n sngle daly doses, the plasma concentratons of bsoprolol fluctuate by a factor of durng the dosage nterval, whereas those of metoprolol fluctuate by a factor of 30-40' 2-7 '. The only beta blocker that s sutable for sngle daly admnstraton wth the objectve of a beta-receptor blockade that perssts to as great an extent as possble for 24 hours s one wth a long 12 plasma elmnaton half-lfe. Moreover, the only beta blocker that s able to guarantee plasma concentratons at whch only the beta,-receptors are blocked also at the start of such a dosage nterval of 24 hours s one wth a hgh beta,selectvty. Bsoprolol combnes a long plasma elmnaton half-lfe wth a partcularly dstnct beta^electvty' 13 " 17 ' and therefore appears to be partcularly well suted for a once-daly betablocker therapy of essental hypertenson. 2. Unformly strong beta-receptor blockade s partcularly desrable and necessary when coronary heart dsease s present. Many hypertensve patents undoubtedly suffer addtonally from symptomatc or asymptomatc coronary heart dsease. In these patents the persstent reducton n rate-pressure product under exercse condtons s helpful n reducng angna pectors attacks because such attacks nvarably occur on reachng the same rate-pressure product, regardless of the type of exercse nvolved. 3. The blood pressure reducton to be produced by beta-blocker treatment s ultmately (rrespectve of the mechansm) the drect or ndrect consequence of the blockade of beta,-receptors n varous tssues. A beta,-receptor blockade persstng throughout the dosage nterval therefore probably guarantees more constant drect and ndrect favourable effects on blood pressure than a beta-receptor blockade that vares consderably durng the dosage nterval. The sgnfcantly stronger effect on restng dastolc blood pressure wth bsoprolol than wth metoprolol that was observed n the present study can be nterpreted n ths sense. Not only the quantty but also the qualty or constancy of the blood pressure control over the dosage nterval mght be of mportance for regresson of left-ventrcular hypertrophy due to hypertenson. The bometrc evaluaton of ths study was performed by the Department of Bometry of the Arznemttelforschung Berln GmbH (AFB). The excellent help of our Medcal Records Offcer Ms. P. Pollert s gratefully acknowledged as are the contrbutons of the followng nvestgators: G. G. Belz, R. G. Englert, H.-J. Gesecke, MD; S. Gorltz, MD; M. Helmann, MD; B. Krong, MD; H. Plum, R. Rost, G. V. Sabn, W. Walldorf, Ch. Watz, G. Wess. References [1] Comerford MB, Besterman E. Dosng ntervals n beta-blocker therapy. Lancet 1980; 4: 1196.

11 Exercse blood pressure and heart rate reducton 113 [2] Danelson M, Kjellberg J, Kuylensterna J, Lundkvst L, Svensson O. Influence of tme and physcal actvty on blood pressure and heart rate durng treatment wth /3-blockng agents once daly. Acta Med Scand 1983; 214: [3] Franz IW. Ergometre be Hochdruckkranken. Sprnger: Berln, [4] Morley CA, Cavalcant C, Perrns EJ, Sutton R. A comparson of once daly atenolol and metoprolol SA n mld to moderate hypertenson. Br J Cln Pharmacol 1983; 15: [5] Nlsson OR, Atterhog JH, Castenfors J et at. A comparson of 100 mg atenolol and 100 mg metoprolol once a day at rest and durng exercse n hypertensves. Acta Med Scand 1984; 215: [6] Scott AK, Rgby JW, Webster J, Hawksworth GM, Petre JC, Lovell HG. Atenolol and metoprolol once daly n hypertenson. Br Med J 1982; 284: [7] Slas JH, Freestone S, Lennard MS, Ramsay LE. Comparson of two slow-release formulatons of metoprolol wth conventonal metoprolol and atenolol n hypertensve patents. Br J Cln Pharmacol 1985; 20: [8] Wtchtz S, Mosson P, Kolsky H. A comparatve tral of ordnary metoprolol tablets and metoprolol sustaned release tablets n hypertensve patents at rest and on exercse. Pharmatherapeutca 1984; 3: [9] Leopold G, Pabst J, Ungethm W, Bhrng KU. Basc pharmacoknetcs of bsoprolol, a new hghly beta,-selectve adrenoceptor antagonst. J Cln Pharmacol 1986; 26: [10] Leopold G. Balanced pharmacoknetcs and metabolsm of bsoprolol. J Cardovasc Pharmacol 1986; 8 (Suppl 11): S [11] Wellsten A, Palm D, Belz GG, Leopold G, Buhrng KU, Pabst J. Concentraton knetcs of propranolol, bsoprolol and atenolol n humans assessed wth chemcal detecton and a subtype-selectve f}- adrenoceptor assay. J Cardovasc Pharmacol 1986; 8 (Suppl 11): S41-5. [12] Benfeld P, Clssold SP, Brogden RN. Metoprolol: an updated revew of ts pharmacodynamc and pharmacoknetc propertes, and therapeutc effcacy, n hypertenson, schaemc heart dsease and related cardovascular dsorders. Drugs 1986; 31: [13] Brodde OE. Bsoprolol (EMD ), a hghly selectve 0,-adrenoceptor antagonst: In vtro and n vvo studes. J Cardovasc Pharmacol 1986: 8 (Suppl 11): S [14] Haeusler G, Schlep HJ, Schellng P et at. Hgh ^,-selectvty and favourable pharmacoknetcs as the outstandng propertes of bsoprolol. J Cardovasc Pharmacol 1986; 8 (Suppl 11): S2-15. [15] Kramer B, Balser J, Stubbg K, Kramer G, Kubler W. Comparson of bsoprolol wth other /3- adrenoceptor blockng drugs. J Cardovasc Pharmacol 1986; 8 (Suppl 11): S [16] Wang XL, Brnkmann M, Brodde OE. Selectve labellng of /5,-adrenoceptors n rabbt lung membranes by ( - yh bsoprolol. Eur J Pharmacol 1985; 114: [17] Wellsten A, Palm D, Belz GG. Affnty and selectvty of /3-adrenoceptor antagonsts n vtro. J Cardovasc Pharmacol 1986; 8 (Suppl 11): S [18] Borchard U. Pharmakologe der Beta- Rezeptorenblocker. Basel: Aesopus, [19] Franz IW. Ergometre zur Dagnostk be der arterellen Hypertone. Therapewoche 1984; 34: [20] Buhrng KU, Garbe A. Determnaton of the new /3-blocker bsoprolol and of metoprolol, atenolol and propranolol n plasma and urne by hgh performance lqud chromatography. J Chromatogr 1986; 382: [21] Krsten R, Neff J, Hentz B, Nemeth N, Rahlfs VW, Nelson K. Influence of dfferent bsoprolol doses on haemodynamcs, plasma catecholamnes, platelet aggregaton and a 2 and /3-receptors n hypertensve patents. J Cardovasc Pharmacol 1986; 8 (Suppl 11): S [22] Palm D, Wellsten A, Jablonka B, Wemer G. Rezeptor-Affntat, Knetk der Plasmakonzentraton und Doss als bestmmende GroBen fur das Zet-Wrkungsprofl von Beta-Rezeptorenblockern. Verglechende Untersuchungen mt Propranolol und Carteolol. In: Palm D, ed. Therape der koronaren Herzkrankhet mt Beta-Rezeptorenblockern. Pharmakodynamsche und pharmakoknetsche Aspekte. Erlangen: Permed, 1984;