,3-adrenoceptor blockade in normotensive and hypertensive

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1 Br. J. clin. Phrmc. (1988), 25, Exercise hemodynmics nd mximl exercise cpcity during,3-drenoceptor lockde in normotensive nd hypertensive sujects M. A. VAN BAAK' 3, F. M. M. KOENE2 & F. T. J. VERSTAPPEN2 Deprtments of Phrmcology' nd Movement Sciences2, University of Limurg, nd Institute of Sports Medicine Limurg3, Mstricht, The Netherlnds 1 The effects of tenolol dministrtion on mximl exercise cpcity nd exercise hemodynmics hve een compred in eight normotensive nd eight mildly hypertensive sujects, mtched for sex, ge, ody weight, nd mximl oxygen uptke, nd fmilir with mximl exercise testing. 2 Supine nd exercise lood pressure, nd exercise totl peripherl resistnce were significntly higher, nd exercise crdic output ws significntly lower in the hypertensive thn in the normotensive sujects. 3 Administrtion of tenolol (1 x 100 mg dy-') for 3 dys reduced supine nd exercise systolic lood pressure, hert rte, nd crdic output, nd incresed exercise stroke volume. Supine nd exercise distolic lood pressure nd exercise totl peripherl resistnce were unffected y tenolol. The effects of tenolol did not differ in the normotensive nd the hypertensive sujects. 4 Mximl work lod, mximl oxygen uptke, nd mximl hert rte were reduced to similr extent in normotensive nd hypertensive sujects during tenolol tretment. 5 It is concluded tht there is no difference in the effects of short-term tenolol dministrtion on exercise hemodynmics nd mximl exercise cpcity in normotensive nd mildly hypertensive sujects. Keywords 3-drenoceptor lockde exercise hemodynmics hypertension Introduction In mny studies, cute s well s chronic dministrtion of nonselective nd p1-selective,bdrenoceptor locking gents hs een shown to reduce mximl exercise cpcity in normotensive sujects (Anderson et l., 1979; Folgering & Vn Bussel, 1980; Hughson & McFrlne, 1981; Tesch & Kiser, 1983; Smyth et l., 1984; Vn Bk et l., 1985, 1986). On the other hnd, the mjority of studies in hypertensive sujects suggests tht mximl exercise cpcity is not ffected during,-drenoceptor lockde (Hnsson et l., 1977; Reyrouck et l., 1977; Frnz et l., 1979, 1982, 1985; Lijnen et l., 1979; Leenen et l., 1980; Losment et l., 1986). It is likely tht the reduction of mximl exercise crdic output during,-drenoceptor lockde (Epstein et l., 1965; Eklom et l., 1972) is involved in the reduction of mximl exercise cpcity in normotensive sujects. Therefore, we investigted the hypothesis tht the effect of,b-drenoceptor lockde on exercise hemodynmics differs in normotensive nd hyperten- Correspondence: Dr M. A. vn Bk, Deprtment of Phrmcology, University of Limurg, P.O. Box 616, 6200 MD Mstricht, The Netherlnds 169

2 170 M. A. vn Bk, F. M. M. Koene & F. T. J. Verstppen sive sujects. In order to minimize is due to differences in trining sttus nd fmilirity with exercise testing, we selected normotensive nd hypertensive sujects who hd experience with mximl exercise testing nd mtched them for mximl oxygen uptke, ody weight, ge nd sex. The,-drenoceptor locker studied ws tenolol, predominntly P1-drenoceptor selective locker. Methods Sujects Sujects were recruited from group of recretionl cyclists, whose physicl condition hd een tested regulrly y mens of mximl icycle ergometer testing, nd from sujects who hd prticipted in previous exercise studies in our deprtment. Sixteen sujects (14 mle, two femle) etween 23 nd 53 yers of ge were included in the study. Hlf of the sujects hd history of hypertension with sitting lood pressures > 140/90 mm Hg for t lest 1 yer prior to the study. Only two of the hypertensive sujects used ntihypertensive mediction, which ws withdrwn 2 weeks efore the strt of the study. Normotensive nd hypertensive sujects were mtched for ge, sex, ody weight nd mximl oxygen uptke. The protocol of the study ws pproved y the Ethics Committee of the University of Limurg nd ll sujects gve their written informed consent. Study protocol The study ws performed ccording to doulelind rndomized crossover design. Ech suject ws tested fter 3 dys of orl tretment with plceo nd tenolol (1 x 100 mg dy-'). Tretment periods were seprted y wsh-out period of 1 week. The exercise test ws performed pproximtely 2 h fter the lst dose hd een tken. After 10 min supine rest, lood pressure ws mesured y sphygmomnometry (Korotkoff V for distolic lood pressure). Therefter, the sujects were seted on chir nd performed three CO2 rerething mnoeuvres in order to fmilirize with the equipment nd rething technique. Susequently, the exercise test on the electromgneticlly rked icycle ergometer (Lode, Groningen, The Netherlnds) ws strted. Sujects exercised 6 min t 100 W, 6 min t 130 W nd 6 min t 160 W. At ech work lod, lood pressure ws mesured y sphygmomnometry (Korotkoff IV for distolic lood pressure) nd two estimtions of crdic output (Q) were mde using the CO2 rerething technique (Collier, 1956; Defres, 1958; Jones et l., 1967) in conjunction with the MMC Horizon system (Sensormedics). The men of the two determintions ws used for sttisticl nlysis. After completion of the rerething mnoeuvres t 160 W, the rerething pprtus ws removed. The exercise test ws continued, incresing the work lod y 30 W/3 min until exhustion of the suject. During this prt of the test, sujects rethed through low-resistnce vlve (Hns Rudolph, Inc.) nd minute ventiltion nd gs exchnge vriles were determined with the MMC Horizon system nd registered per 15 s. Gs exchnge dt nd hert rte (HR) (electrocrdiogrm) during the lst 30 s of ech work lod were used for sttisticl nlysis. Between 2 nd 5 min fter the end of the exercise test, lood ws otined y venepuncture for determintion of plsm lctte concentrtion (Roche lctte nlyzer 640). Dt nlysis Results re presented s mens ± s.d. The following clcultions were mde: stroke volume (SV) = Q/HR; men rteril pressure (MAP) = distolic lood pressure (DBP) + 1/3 (systolic lood pressure (SBP)-DB.P); totl peripherl resistnce (TPR) = MAP/Q. Sttisticl nlysis of the vriles t rest nd during mximl exercise ws performed y two-wy nilysis of vrince with repeted mesures (BMDP2V). The dt during sumximl exercise t 100, 130 nd 160 W were lso nlyzed y two-wy nlysis of vrince with repeted mesures, using two tretment fctors (drug nd work lod). The significnce level of the nlysis of vrince ws set t Results Chrcteristics of the normotensive nd hypertensive sujects prticipting in the study re shown in Tle 1. Except for systolic nd distolic lood pressure, there were no sttisticlly significnt differences etween the two groups. Rest Supine systolic nd distolic lood pressure ws significntly higher in hypertensive thn in normotensive sujects (Tle 2). Systolic lood pressure ws significntly reduced during tenolol tretment. No sttisticlly significnt interction etween tretment nd suject group ws found,

3 Tle 1,8-drenoceptor lockde nd exercise Chrcteristics (men ± s.d.) of the normotensive (NT) nd hypertensive (HT) sujects Normotensive Hypertensive (n =8) (n =8) NTvsHT Age (yers) 37.0 ± ± 11.5 NS Sex 7M,1F 7M,1F Body weight (kg) 71.7 ± ± 12.0 NS Height (cm) ± ± 5.7 NS VO2mx (ml min-1 kg-') 52.1 ± ± 10.4 NS Sitting systolic lood pressure (mm Hg) ± ± 8.0 P < Sitting distolic lood pressure (mm Hg) 78.1 ± ± 4.4 P < Tle 2 Supine lood pressure (BP) nd hert rte (men ± s.d.) of normotensive (NT) nd hypertensive (HT) sujects during plceo (P) nd tenolol (A) tretment Normotensives (n = 8) Hypertensives (n = 8) P A P A PvsA NTvsHT Systolic BP (mm Hg) ± ± ± ± 11.6 < 0.01 < Distolic BP (mm Hg) 71.2 ± ± ± ± 2.2 NS < Hert rte (ets min-1) 66.1 ± ± ± ± 8.4 < NS indicting tht the systolic lood pressure reduction did not differ in normotensive nd hypertensive sujects. Supine distolic lood pressure ws not ffected during tenolol tretment (Tle 2). Resting hert rte ws similr in normotensive nd hypertensive sujects nd the hert rte reduction during tenolol tretment ws lso similr in the two groups (Tle 2). Sumximl exercise Although exercise hert rte ppered to e somewht lower in hypertensive sujects, the difference with the normotensive sujects ws not sttisticlly significnt. The reduction of exercise hert rte during tenolol tretment ws similr in oth groups (Figure 1). Exercise systolic nd distolic lood pressure were significntly higher in hypertensive thn in normotensive sujects. Atenolol reduced exercise systolic lood pressure nd the effect ws similr in normotensive nd hypertensive sujects. P-drenoceptor lockde did not influence exercise distolic lood pressure significntly (Figure 2). Men rteril pressure ws significntly reduced during tenolol tretment. Crdic output during exercise, estimted y the CO2 rerething technique, ws significntly higher in normotensive thn in hypertensive sujects. Atenolol cused reduction of Q tht did not differ sttisticlly significntly etween normotensive nd hypertensive sujects (Figure 3). Stroke volume, which did not differ sttisticlly significntly etween the two groups of sujects, incresed during tenolol tretment (Figure 4). Clculted totl peripherl resistnce ws significntly higher in hypertensive thn in normotensive sujects, ut there ws no effect of tenolol on totl peripherl resistnce (Figure 5). Oxygen consumption during the three sumximl work lods tended to e lower (P = 0.08) nd respirtory exchnge rtio ws significntly higher during tenolol tretment thn during plceo. There ws no sttisticlly significnt difference etween normotensive nd hypertensive sujects (Tle 3). Mximl exercise Mximl work lod (Wmx) (i.e. the highest work lod tht could e mintined t lest 1 min), mximl oxygen uptke (V02 mx), mximl hert rte (HRmx), nd plsm lctte concentrtion fter mximl exercise (lcttem.) did not differ etween normotensive nd hypertensive sujects (Tle 4), nor did the chnges in these vriles during tenolol differ etween the two groups. Atenolol reduced mximl work lod, mximl oxygen uptke nd mximl hert

4 172 M. A. vn Bk, F. M. M. Koene & F. T. J. Verstppen 160 I E Cu 00) 120 F drug P< ptient NS 0) IW I Work lod (wtt) 1 1 Figure 1 Hert rte (HR) (men ± s.d.) during sumximl exercise in () normotensive nd () hypertensive sujects during plceo (0) nd tenolol (v) tretment. rte significntly. Respirtory exchnge rtio during mximl exercise ws unffected. Plsm lctte concentrtion fter mximl exercise ws significntly reduced during tenolol tretment (Tle 4). Discussion In this study, we confirmed the finding of previous studies (Anderson etl., 1979; Folgering & Vn Bussel, 1980; Hughson & McFrlne, 1981; Tesch & Kiser, 1983; Smyth et l., 1984; Vn Bk et l., 1985, 1986) tht dministrtion of 3-drenoceptor lockers reduces mximl exercise cpcity in normotensive sujects. In ddition, we showed tht similr reductions of mximl work lod nd mximl oxygen uptke re found in hypertensive ptients mtched for ge, sex, ody weight nd mximl oxygen uptke. This ppers to e in contrst with numer of other studies in hypertensive ptients showing no significnt reduction of mximl exercise cpcity fter 1-drenoceptor lockde (Hnsson et l., 1977; Reyrouck et l., 1977; Frnz et l., 1979, 1982, 1985; Lijnen etl., 1979; Leenen et l., 1980; Losment et l., 1986). One possile explntion for the discrepnt findings is tht most of the studies mentioned ove my hve suffered from methodologicl is. In the mjority of studies, plceo nd,-drenoceptor locker tretment periods were not rndomized (Hnsson et l., 1977; Reyrouck et l., 1977; Frnz et l., 1979, 1982, 1985; Lijnen et l., 1979; Losment et l., 1986) with the risk of is due to hitution effects which is especilly lrge in sujects unfmilir with mximl exercise testing. In our study, we crefully selected normotensive nd hypertensive sujects who exercised regulrly nd were fmilir with mximl exercise testing in order to minimize hitution effects. In ddition, tretment periods were rndomized. Plsm lctte concentrtion fter mximl exercise ws 10.1 ± 3.6 mmol I1 during plceo tretment. Only two sujects (one normotensive nd one hypertensive) did not rech the 8 mmol 1-1 level which is generlly ccepted s the minimum lctte level fter mximl effort in progressive exercise testing (Lollgen & Ulmer, 1985). In one of these sujects, oth hert rte

5 ,B-drenoceptor lockde nd exercise I SBP drug P<0.001 ptient P< ) I EE 160 F L- en ) 0 to F T DBP drug NS ptient P< Work lod (wtt) 1 Figure 2 Blood pressure (BP) (men ± s.d.) during sumximl exercise in () normotensive nd () hypertensive sujects during plceo (0) nd tenolol () tretment. nd respirtory exchnge rtio, however, were within the rnge expected during mximl exercise. These dt suggest tht the gret mjority of our sujects exercised mximlly. In the other studies this is often not cler, either ecuse plsm lctte concentrtions were low (Frnz et l., 1979; Losment et l., 1986) or improly high (Leenen et l., 1980) or dt on lctte concentrtions nd/or respirtory exchnge rtio re lcking (Hnsson et l., 1977; Frnz et l., 1979, 1982; Lijnen et l., 1979). During tenolol tretment plsm lctte concentrtions were reduced, which is in greement with findings in severl other studies (Kindermnn et l., 1983; Kiser et l., 1986; Verstppen & Vn Bk, 1987). Becuse muscle lctte concentrtions fter mximl exercise hve een shown to e unffected y,-drenoceptor locker dministrtion (Kiser et l., 1986), the lower plsm concentrtions my e due to decresed wshout from the ctive muscle, or n incresed utiliztion of lctte in ctive or non-ctive tissues (Frisk-Holmerg et l., 1981, 1985; Stnley et l., 1986). Other possile explntions for the fct tht we found similr reduction in mximl exercise cpcity in normotensive nd hypertensive sujects while other studies did not find n effect of,-drenoceptor locker tretment in hypertensive ptients, could e difference in popultion studied or difference in the durtion of tretment. The sujects in our study were mildly hypertensive similr to those in the study y Leenen et l. (1980). However, especilly the studies y Reyrouck et l. (1977) nd Lijnen et l. (1979) include sujects with more severe hypertension. We cnnot e sure tht our results re lso vlid for ptients with higher levels of lood pressure. Although in most studies, tretment periods were longer thn in our study, we do not consider this very likely explntion for the discrepncies, since in normotensive sujects it hs een shown tht there is no difference in effect etween single dose nd chronic

6 174 M. A. vn Bk, F. M. M. Koene & F. T. J. Verstppen 20 L1 1. E drug P<0.001 ptient P< I 100 t l 100 Work lod (wtt) 'k Figure 3 Crdic output (Q) (men ± s.d.) during sumximl exercise in () normotensive nd () hypertensive sujects during plceo (0) nd tenolol (O) tretment. 180 E cn drug P<0.001 ptient NS 100l I I 100 1,I 100 Work lod (wtt) 1 Figure 4 Stroke volume (SV) (men ± s.d.) during sumximl exercise in () normotensive nd () hypertensive sujects during plceo (0) nd tenolol (O) tretment.

7 P-drenoceptor lockde nd exercise E 10 cm I EE..6 drug NS ptient P< j 100 Work lod (wtt) Figure 5 Totl peripherl resistnce (TPR) (men ± s.d.) during sumximl exercise in () normotensive nd () hypertensive sujects during plceo (0) nd tenolol (U) tretment. Tle 3 Oxygen uptke (V02) nd respirtory exchnge rtio (R) during sumximl exercise in normotensive (NT) nd hypertensive (HT) sujects during plceo (P) nd tenolol (A) tretment (men ± s.d.) Work lod V02 (1 min-) R (wtt) NT HT NT HT 100 P ± ± ± ± A ± ± ± ± P ± ± ± ± A ± ± ± ± P ± ± ± ± A ± ± ± ± Two-wy nlysis drug: P = 0.08 drug: P < 0.01 of vrince ptient: NS ptient: NS - 1 tretment of 4 weeks with 13-drenoceptor locker (Smyth et l., 1984; Vn Bk et l., 1985). Bsed on the results otined we hve to reject the hypothesis tht the effect of 1- drenoceptor locker dministrtion on exercise hemodynmics differs etween normotensive nd hypertensive sujects. However, normotensive nd hypertensive sujects hd different hemodynmic profiles during exercise: higher lood pressure, lower crdic output nd higher totl peripherl resistnce in the hypertensives, pttern which is similr to tht descried y Lund-Johnsen (1967). In our study, the lower

8 176 M. A. vn Bk, F. M. M. Koene & F. T. J. Verstppen Tle 4 Vriles t mximl exercise (men ± s.d.) in normotensive (NT) nd hypertensive (HT) sujects during plceo (P) nd tenolol (A) tretment Normotensives (n = 8) Hypertensives (n = 8) P A P A PvsA NTvsHT Wmx (wtt) 291 ± ± ± ± 48 < NS VO2mx (1 min-') 3.71 ± ± ± ± 0.56 <0.001 NS HRmx (ets min-1) ± ± ± ± 16.4 <0.001 NS Lcttemx (mmol 1-1) 10.7 ± ± ± ± 2.2 < 0.05 NS Rmx 1.00 ± ± ± ± 0.06 NS NS crdic output ppered to e due to comintion of lower hert rte nd lower stroke volume in the hypertensives thn in the normotensives, lthough oth differences s such were not sttisticlly significnt. Since the oxygen uptke during sumximl exercise did not differ etween the normotensive nd the hypertensive group, the lower crdic output in the hypertensives suggests either lower lood flow to the ctive muscle in comintion with n incresed cpility for oxygen extrction or different regionl distriution of the lower crdic output, so tht lood flow to the ctive muscles is similr to tht in normotensive sujects t the cost of lood flow to inctive tissues. Atenolol tended to decrese the oxygen uptke during sumximl exercise, which is in greement with numer of other studies (Person et l., 1979; Tesch & Kiser, 1983; Wilmore et l., 1985; Vn Bk etl., 1987). This my e due to shift from ft to crohydrte metolism, since P-drenoceptor lockers hve een shown to limit the supply of plsm free ftty cids to exercising muscle (Frisk-Holmerg et l., 1985). The explntion is supported y the increse in respirtory exchnge rtio during sumximl exercise found in this nd other studies (Tesch & Kiser, 1983; Wilmore et l., 1985; Vn Bk et l., 1987). References Anderson, S. D., Bye, P. T. P., Perry, C. P., Hmor, G. P., Theold, G. & Nyerg, G. (1979). Limittion of work performnce in norml dult mles in the presence of et-drenergic lockde. Austr. N.Z. J. Med., 9, Collier, C. R. (1956). Determintion of mixed venous CO2 tensions y rerething. J. ppl. Physiol., 9, Defres, I. G. (1958). Determintion of PVCO2 from the exponentil CO2 rise during rerething. J. ppl. Physiol., 13, Eklom, B., Goldrg, A. N., Kilom, A. & Astrnd, P.-O. (1972). Effects of tropine nd proprnolol on the oxygen trnsport system during exercise in mn. Scnd. J. clin. l. Invest., 30, Epstein, S. E., Roinson, B. F., Khler, R. L. & Brunwld, E. (1965). Effects of et-drenergic lockde in the crdic response to mximl nd sumximl exercise in mn. J. clin. Invest., 44, Folgering, H. & Bussel vn, M. (1980). Mximl exercise power fter single dose of metoprolol nd of slow-relese metoprolol. Eur. J. clin. Phrmc., 18, Frnz, I.-W. & Lohmnn, F. W. (1979). Der Einfluss einer chronischen sog. krdioselektiven und nichtkrdioselektiven Bet-Rezeptoren-Blockde uf den Blutdruck, die 02-Aufnhme und den Kohlenhydrt-stoffwechsel. Z. Krdiol., 68, Frnz, I.-W., Lohmnn, F. W. & Koch, G. (1982). Effects of chronic ntihypertensive tretment with ceutolol nd pindolol on lood pressures, plsm ctecholmines, nd oxygen uptke t rest nd during sumximl nd mximl exercise. J. crdiovsc. Phrmc., 4, Frnz, I.-W., Lohmnn, F. W. & Koch, G. (1985). Oxygen uptke nd plsm ctecholmines during sumximl nd mximl exercise fter long-term et-receptor lockde. Int. J. Sports Med., 6, Frisk-Holmerg, M., Jorfeldt, L. & Juhlin-Dnnfelt, A. (1981). Metolic effects in muscle during nti-

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