Propranolol on Blood Pressure, Heart Rate and Hormonal Changes During Graded Treadmill Exercise in Patients with Essential Hypertension

Original Article

Comparison of the Acute Effects of Acebutolol and Propranolol on Blood Pressure, Heart Rate and Hormonal Changes during Graded Treadmill Exercise in Patients with Essential Hypertension

Hideo Matsuura, Satoko Masaoka, Ikuo Kanazawa, Shigeko MURANO,Yukiko TSUCHIOKA and Goro KAJIYAMA

The acute effects of propranolol and acebutolol on blood pressure, heart rate and hormonal changes during graded treadmill exercise were studied in patients with essential hypertension. Both of propranolol (2 mg i.v.) and acebutolol (10 mgi.v.) lowered the pre-exercise hemodynamic parameters and suppressed the elevation of systolic blood pressure, heart rate and pressure-rate product during exercise, but did not show any significant effect on diastolic blood pressure. Although these drugs increased plasma norepinephrine concentration (PNE) at rest and during moderate exercise, they failed to affect PNEat submaximalexercise. Plasma renin activity at rest and during exercise were morestrongly suppressed by propranolol than acebutolol. Plasma aldosterone concentration wasnot affected by these drugs. Propranolol and acebutolol showedsimilar acute effects on blood pressure, heart rate and hormonal profiles at rest and during exercise within the doses used in this study. These results indicate that jSj adrenoceptor selectivity and intrinsic sympathomimeticactivity maynot play an important role in the acute antihypertensive effect at rest and during exercise and that both 8 blockers have beneficial antihypertensive effects during exercise on patients with essential hypertension. Key words: j8 j adrenoceptor selectivity, Intrinsic sympathomimetic activity, Antihypertensive effect

Although the depressor mechanisms of 0- usually evaluated by their effects on the blood adrenoceptor blocking agents ( /S blockers) have not pressure (BP) at rest. On the other hand studies been clarified yet (1, 2), it is not questionable that regarding their effects on BP during exercise (17-22) ft blockers are important and useful for the treat- were made to evaluate the usefulness of anti- ment of essential hypertension (3-8). 02 adrenocep- hypertensive drugs in daily life, and £ blockers have tor blocking action causes increase in peripheral been demonstrated to have the potency to lower BP vascular resistance (9-1 1) and bronchial resistance of hypertensive subjects during exercise (17, 18, 20, (12) through the unopposed a stimulation of 21). Comparativestudies to evaluate the long term smooth muscle cells of the vascular and bronchial effects of nonselective and cardioselective (2 walls. In order to avoid these adverse effects of 0 blockers on hemodynamicand hormonal profiles blockers, 0x selective (cardioselective) 0 blockers during dynamic exercise were undertaken using which have dominant 0j blocking action compared different combinations of these two kinds of /S to 02 blocking action have been developed (13-16). blockers (22-27). Only few comparative study, The efficacy of antihypertensive drugs have been however, has been undertaken between propanolol From The First Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima. Received for publication March 22, 1988. Reprint request to: Hideo Matsuura, MD,The First Department of Internal Medicine, Hiroshima University School of Medicine, 1-2-3, Kasumi, Minami-ku, Hiroshima 734, Japan. 8 Jpn J Med Vol 28, No 1 (January, February, 1989) Pblockers and exercise in hypertensives

and acebutolol. In manyof these studies, exercise 10 mgof acebutolol, respectively. Nosignificant was given on a bicycle ergometer but not on a tread- differences of blood pressure, heart rate and hor- mill because of avoiding noise for measurement of monal backgrounds were observed among these blood pressure, and there have been only few acute three groups (Table 1). comparative studies. Since walking is the most Treadmill exercise (Fig. 1): Two weeks after popular daily exercise, the acute effects of both kinds discontinuing all antihypertensive medication, tread- of /S blockers, propranolol and acebutolol, on the mill exercise was conducted twice with modified hemodynamicsand hormonal profiles at rest and Sheffield's protocol (28) under fasting condition in during graded treadmill exercise were compared in the morning. The end-point of exercise was 90%of this study. the predicted maximumheart rate (submaximal SUBJECTS AND METHODS exercise). Sixty minutes before the first exercise, an indwelling cannula was inserted into an antecubital Subjects: Thirty-nine patients with essential vein for blood sampling and telemetric electro- hypertension (WHO I and II, 6 and 33 patients, cardiogram (ECG) was obtained. They were kept in respectively) composed of 26 menand 13 women a supine position for 60 minutes until the beginning with a meanage of 42.2 years were divided into three of the exercise. BP was measured by the auscultatory groups. Patients were considered to have hyperten- B lo o d S am plin g sion if during three subsequent visits without anti- 10 ' S M R 5 'M l i hypertensive therapy, their sitting blood pressure was more than 160 mmHgin systole and 95 mmHgin I H 一蝣lEsxt e rc ls * *Ii p E xe rc is e *¥ diastole. Secondary hypertension was ruled out by clinical, biochemical and radiological examination. P lac e b o Iv P ro p ra n o lo 1 2 m g !v The purpose and nature of this study were explained A ce b u lo to ! tO m g Iv n ? V and informed consent was obtained from each IV 1 * F Ill patient. Saline was intravenously administered in II II I S u p in e I I I R I S u p in e I I I R placebo group (6 men and 4 women, 41.8±13.7 B O m ln 'si 5 ' ' e o m ln U t I 5 * years old). Propranolol group (10 men and 5 S I S M s I S M women, 42.1 ± 15.2 years old) and acebutolol group Fig. 1. Study protocol of graded treadmill exercise. (10 men and 4 women, 42.5± 12.2 years old) were Si = sitting position, St = standing position, SM= submaximal intravenously administered 2 mgof propranolol and exercise, R= recovery phase. Table 1. Background of Patients P la ce b o P r o p ra n o lo l A c e b u to lo l

n ( M / F ) 1 0 (6 / 4 ) 1 5 (1 0 / 5 ) 1 4 (1 0 / 4 ) w h o i / n 2 / 8 2 / 1 3 2 / 1 2 a g e 4 1. 8 ｱ 13 .7 4 2. 1 ｱ 1 5 . 2 4 2. 5 + 1 2. 2 S B P (m m H g ) 1 5 0 . 2 ｱ 1 1 . 6 1 5 4 . 5 ｱ 2 0 . 2 1 5 7 . 5 + 2 0 . 5 D B P ( m m H g ) 9 7 . 2 ｱ 7 . 0 10 1 . 1 ｱ 13 . 3 10 2 . 7 + 13 . 3 H R (m iir l) 7 5 . 6 ｱ 1 5 . 2 7 2 . 9 ｱ 1 0 . 1 7 4 . 9 + 2 0 . 2 P R P ( x lO ' m m H g -m in - 1) 1 13 . 4 + 2 3 . 0 1 12 . 7 + 20 . 8 1 18 . 5 + 4 3. 9 P N E ( n g - m r l) 0 . 2 3 2 ｱ 0 . 1 1 4 0. 2 4 1 ｱ 0. 1 2 5 0. 2 4 4 + 0. 0 7 3 P R A ( n g -m l- 1!!- 1) 2 . 3 7 + 1. 0 9 2. 0 5 ｱ 1 . 5 2 1. 6 6 + 1 . 0 6 P A C (p g .m r l) 8 0 . 2 ｱ 2 3 . 9 7 9. 2 ｱ 16 . 3 8 0. 9 + 13 . 0 E x e r c ise D u r a tio n (m in ) 13 . 9 ｱ 1 .6 1 4. 0 ｱ 1 . 5 1 4. 0 + 1 . 1

SBP: systolic blood pressure, DBP: diastolic blood pressure, HR: heart rate, PRP: pressure-rate product, PNE:plasma norepinephrine concentration, PRA:plasma renin activity, PAC:plasma aldosterone concentration. 9 Jpn J Med Vol 28, No 1 (January, February, 1989) Matsuura et al

Assay of plasma renin activity and plasma methodusing a mercurysphygmomanometerand heart rate (HR) was obtained from ECGrecording aldosterone concentration: Plasma renin activity every minute from 5 minutes before exercise to 5 (PRA) and plasma aldosterone concentration (PAC) minutes after exercise. Pressure-rate product (PRP) were determined by radioimmunoassay using assay was calculated as the product of systolic BP and HR. kits (CIS, Paris, France). At 5 minutes of recovery, saline as placebo, 2 mg Statistical analysis: Data were shown as of propranolol or 10 mgof acebutolol was intra- mean± SD. The parameters before and after drug venously injected over a period of 10 minutes. Sixty administration in each group were compared with minutes after the patients were kept in a supine posi- the use of Wilcoxonsigned rank test. Differences tion, the second treadmill exercise was performed at a p level of less than 0.05 were regarded to be with exactly the same duration as the first time. significant. Blood samples were drawn just before starting exercise, at 10 minutes of exercise, at the end point RESULTS of exercise and at 5 minutes of recovery. 1. Backgrounds of the patients in each group (Table Determination of plasma norepinephrine con- 1). centration: After plasma was deproteinized by 0.4 N perchloric acid, norepinephrine (PNE) was Three groups were statistically alike in regard to age, sex, hemodynamicand hormonal parameters, absorbed by aluminiumoxide II-III (Merck, and duration of the exercise. Darmstadt, West Germany) at pH 8.4. PNEwas determined by the electrochemical method using a 2. Effects of the repetitive exercises on blood high performance liquid chromatography (Yanaco pressure, heart rate, pressure-rate product and 4000W, Yanagimoto, Kyoto, Japan) after extracting hormonal parameters. PNE from aluminiumoxide II-III by 0.01N HC1. In order to examine the effects of repetitive

Table 2. Effects of repetitive exercise on the hemodynamicand hormonal parameters.

S i S t l O m in S M R 5 m in

15 0 . 2 + l l. 6 14 9 .8 ｱ 1 1 . 5 17 2 . 3 ｱ 1 2 . 9 1 9 2 . 2 + 8 . 6 1 4 2 . 6 + 4 . 9 S B P 1s t m m H g 2 n d 14 6 . 1 ｱ 14 .9 14 3 . 2 ｱ 1 1 . 9 * 1 67 . 9 ｱ 1 6 . 5 1 88 . 4 + 1 3 . 1 1 3 9 . 6 ｱ 1 2 . 7

9 7 2 + 7 0 9 5 .7 ｱ 7 .6 9 6 .4 ｱ 10 . 5 9 6 . 2 ｱ 1 2 . 9 9 3 . 2 ｱ 9 . 6 D B P 1s t 9 5 . 1 + 8 .8 9 5 .0 + 10 . 2 9 3 . 6 ｱ 9 .8 9 3 . 0 ｱ 1 4 . 3 9 4 . 0 ｱ 8 . 3 m m H g 2 n d

7 5 6 + 1 5 . 2 7 9 . 0 ｱ 1 5 . 9 12 5 .3 ｱ 17 . 5 1 57 .7 ｱ 20 . 1 9 5 . 9 ｱ 1 8 . 1 H R 1s t 7 9 7 + 14 .0 * 8 5 .0 ｱ 1 7 .0 * 1 28 . 7 ｱ 1 9 . 1 1 5 7 . 1 ｱ 2 1 . 4 9 7 . 2 ｱ 16 . 1 m in l 2 n d

P R P 1s t 1 1 3 4 + 2 3 .0 1 17 . 9 ｱ 2 5 . 5 2 1 1 . 9 + 3 8 . 1 3 0 2 .2 ｱ 3 0 .8 1 37 . 2 ｱ 3 0 . 4 1 1 6 4 + 2 3 . 2 1 2 1 . 5 ｱ 2 5 . 9 2 1 6 . 2 ｱ 3 9 . 3 2 9 4 . 5 ｱ 3 4 . 4 1 3 5 .0 ｱ 2 1 .3 X l O 2 m m H g - m i n 2 n t

P N E 1 s t 0 2 3 2 + 0 . 1 1 4 n d 0 . 3 6 4 ｱ 0 . 1 4 8 0 . 6 5 8 ｱ 0 . 3 0 3 0 .4 10 ｱ 0 . 13 3 n g -m l 2 n d 0 2 5 7 + 0 . 1 3 9 n d 0 . 3 8 6 ｱ 0 . 1 5 2 0 . 6 7 0 ｱ 0 . 2 7 4 0 .4 0 3 ｱ 0 . 1 3 3

2 3 7 + 1 . 0 9 n d 3 .0 3 ｱ 1 . 1 9 4 .4 0 ｱ 1 . 10 4 . 3 2 ｱ 1 . 4 2 P R A 1 st n g -m l 2 n d 2 . 2 1 + 1 .0 9 n d 2 .6 8 ｱ 1 .2 1 3 .9 1 ｱ 1 . 3 4 * 4 . 1 8 ｱ 1 . <

P A C 1s t 8 0 2 + 2 3 . 9 n d 10 0 . 9 ｱ 2 5 . 2 1 16 .9 + 28 . 1 1 28 .9 ｱ 18 .7 p g -m l 1 2 n d 8 3 2 + 15 . 2 n d 9 8 . 7 ｱ 1 3 . 3 1 1 4 . 3 + 14 .0 12 6 . 1 ｱ 2 5 .0

n d : n o t d e te rm in e d * p < 0 .0 5 v s th e l st e x er cise

Abbreviations used are the same as those shown in Table 1 and Figure 1.

10 Jpn J Med Vol 28, No 1 (January, February, 1989) fi blockers and exercise in hypertensives exercise on the hemodynamic and hormonal 3. Effects of propranolol and acebutolol on blood parameters before and during exercise, saline was pressure, heart rate and pressure-rate product. administered to the placebo group. The first exercise Both ft blockers significantly lowered systolic BP did not showany changes in the pre-exercise values at rest and during exercise, but they failed to lower for hemodynamicand hormonal parameters before diastolic BPwhich showedno change during the the second exercise, except systolic BP and HR exercise (Fig. 2). Propranolol had a more potent (Table 2). The second exercise produced the same depressor effect than acebutolol in the doses used responses in each parameter as during the first in this study, but there was no statistical significance. exercise, except PRAwhich showed a significantly In the placebo group, HRwas increased by 5/min lower value (p <0.05) at the end point of the second exercise. 60 minutes after the first exercise (p <0.05), but propranolol showed a significant decrease in HRat rest (p<0.05) and acebutolol showed a decreasing

thetendency.increaseBothinft HRblockersduringsignificantlyand after suppressedexercise Placebo Propranolol Acebutolol I" } ' |/\ l/\ 400 sb#\ I Isb/ /J\|\, |Isap"' A\| Placebo Propranolol Acebulolol i A /Aå /A iloo-i DBP| I y^1!!.! i_J [-|-fi^p1-1....I

o Hx-' I - , T T i/ 1,#\'l#1 Sf St 10' SM R5' Si SI 10' SM RS' Si St 10' SM R5' t 1OO I > psrf* '** FT* I

Fig. 2. Effects of placebo (n= 10), propranolol (n= 15) a and acebutolol (n= 14) on the changes in blood pressure during exercise. The broken line indicates the time course SI SI 10' SM R51 SI St 101 SM R51 sTt\ 10' SM R5' of parameters before drugs and the solid line indicates that Fig. 4. Effects of placebo (n= 10), propranolol (n= 15) after drugs. Each perpendicular bar indicates the standard and acebutolol (n = 14) on the changes in pressure-rate pro- deviation. **p<0.01, ***p<0.005 vs before drugs. See Table duct during exercise. Each perpendicular bar indicates the 1 and Fig. 1 for abbreviations. standard deviation. *p<0.05, **p<0.01 vs before drugs. See Fig. 1 for abbreviations.

200 Placebo Propronolol Acebutolol 1.5- Placebo Propranolol Acebulolol

? 150. A E | /\ /^ I/r. en 1.0-

I r--""l (å '"I r-""1 I

50 ot^-, . ,__, y * oL-*->-' 1 å i Ii , i i i i i , i , SI St 10- SM R5' SI St 10- SM RS' SI SI 10' SM RS' SI St 10" SM R51 Si St 10- SM R51 SI St 10" SM R51

Fig. 3. Effects of placebo (n= 10), propranolol (n= 15) Fig. 5. Effects of placebo (n= 10), propranolol (n= 15) and acebutolol (n= 14) on the changes in heart rate during and acebutolol (n=14) on the changes in plasma exercise. *p<0.05, **p<0.01 vs before drugs. Each per- norepinephrine concentration during exercise. Each perpendicular bar indicates the standard deviation. See Fig. 1 pendicular bar indicates the standard deviation. *p < 0.05, for abbreviations. **p<0.01 vs before drugs. See Fig. 1 for abbreviations.

Jpn J Med Vol 28, No 1 (January, February, 1989) ll Matsuura et al

(p<0.01, Fig. 3). As the results of the changes in after exercise and returned to the basal level 60 BP and HR by these ft blockers, PRP was minutes after resting. In the placebo group, PRA significantly (p< 0.01) decreased at rest and during after the end-point of the second exercise showed exercise in both groups (Fig. 4). a lower level than that of the first exercise, but there 4. Effects of propranolol and acebutolol on plasma was no statistical difference. Propranolol decreased norepinephrine (Fig. 5). PRA significantly through the second exercise Propranolol significantly increased PNEbefore (p<0.05-p<0.01), but acebutolol showed a de- exercise and acebutolol also significantly increased creasing tendency in PRAas in the case of placebo PNEbefore exercise and at 10 minutes of exercise, (Fig. 6). Although PRA was suppressed by both £ but they failed to increase PNEat the end-point of blockers, the response of PACto exercise wasnot exercise and 5 minutes of recovery. affected by them (Fig. 7). 5. Effects of propranolol and acebutolol on hormonal parameters. In comparison with the changes in the DISCUSSION hemodynamic parameters and PNE, the changes in In recent years, many kinds of antihypertensive PRA and PAC during exercise showed a different drugs have been developed and studied pharmaco- pattern. They continuously increased until 5 minutes logically and clinically. /3 blockers also have many kinds of derivatives and their modesof action have P la c e b o P r o o f a n o lo l A c e b u t o l o l been thought to be different from each other. They

T x 6 have been classified into five groups by Fitzgerald E (29) or three divisions and four groups by Prichard ? (30) according to their properties. Propranolol has ｣ � 4 .2 been classified as a /3 blocker with neither partial 4 c agonist activity nor cardioselectivity. On the other c J^ r a IB 2 hand, acebutolol has been classified as a £ blocker s ft possessing partial agonist activity and cardio- ft selectivity. According to their different properties,

o S I S I l O * S M R 5 ' S I S I l O ' S M R S # S I S t t O ' S M R S ' effects of these drugs on hemodynamicand hormonal profiles at rest and during exercise maydiffer. Fig. 6. Effects of placebo (n= 10), propranolol (n= 15) Since hemodynamic and hormonal profiles during and acebutolol (n = 14) on the changes in plasma renin activity during exercise. Each perpendicular bar indicates the standard exercise are different from those at rest, different deviation. *p<0.05, **p<0.01 vs before drugs. See Fig. 1 types of fi blockers are considered to showmore for abbreviations. easily different effects on these profiles during exercise than at rest. Although pindolol and P l a c e b o P r o p r a n o to l A c e b u t o lo l metoprolol (22, 23), propranolol and metoprolol ? 1 5 0 o > a (24), propranolol and atenolol (25, 26) and nadolol c and atenolol (27) were compared, these studies failed o to demonstrate different hypotensive effects and

o l O O o negative chronotropic effects between these two kinds of £ blockers before and during exercise. oc

$ Kelley (31) also discussed that the effects of < i 5 cardioselective and noncardioselective p blockers K on tachycardia during exercise appeared similar. o S i S i l O ' S M R 5 ' 1 0 S M R 5 S I S t 10 - S M R 5 These previous studies were designed as long term Fig. 7. Effects of placebo (n= 10), propranolol (n= 15) single- or double-blind crossover trials, but our study and acebutol (n = 14) on the changes in plasma aldosterone was designed as an acute open trial. Although pro- concentration during exercise. Each perpendicular bar pranolol and acebutolol were administered to indicates the standard deviation. See Fig. 1 for abbreviations. different groups, the background of patients and the 12 Jpn J Med Vol 28, No 1 (January, February, 1989) P blockers and exercise in hypertensives

changes in all the parameters during the first exercise (3 1) also reported that exercise increased PNE, that in each group were not different. This indicates that the increases were larger in the presence of £ the design of the present study is good for the pur- blockers, and that cardioselective /3 blockers pro- pose of this study. duced larger increases. Onthe other hand, Esler et In studies in which the acute effects of drugs on al. (32) showed that propranolol affected the parameters during exercise are evaluated, it is norepinephrine kinetics, namely inhibition of both important to eliminate the effect of repetitive norepinephrine spillover and clearance, but failed exercise on the parameters. In other words, the to affect PNE at rest in patients with essential reproducibility of hemodynamic and hormonal hypertension. Best et al. (33), however, indicated parameters should be required at rest and during that infusion of propranolol increased PNEdue to exercise after the initial exercise. In our previous inhibition of clearance and no change in spillover study, the reproducibility of these parameters was of norepinephrine in normal healthy men. Although observed in normal subjects (20), and in the current the precise mechanisms of /3 blockers in affecting study, this was also observed in patients with PNEin the resting condition (15) have been con- essential hypertension. Since the blood pressure, troversial, propranolol and acebutolol showed heart rate and hormonal changes were not affected similar significant increases in PNE at rest and by the repetitive treadmill exercise, the effects of during mild exercise but not at submaximal exercise propranolol and acebutolol could be compared. or 5 minutes after exercise. This result indicates that It was reported that intravenous administration cardioselectivity does not affect the increase in PNE of propranolol failed to lower BP (10) or paradoxi- by /3 blocking action. cally elevate BP (9). During handgrip exercise after It was reported that PRAwas significantly sup- intravenous administration of 10 mgof propranolol, pressed by £ blockers (30). Propranolol and elevation of meanarterial BPwasnot affected, acebutolol suppressed the elevation of PRAat rest whichwas due to suppression of cardiac output (CO) and during exercise, but acebutolol could suppress and to compensatory increase in total peripheral PRAless potently than propranolol. Lucsko et al. resistance (TPR) (9). On the other hand, Fleming (34) showed that acebutolol was able to suppress et al. (17) reported that intravenous administration PRA in the supine and standing positions in of propranolol decreased blood pressure due to hypertensives. Weber et al. (35) compared the effects decrease in cardiac output and no change in of /S blockers with different properties and reported peripheral resistance at rest and during exercise. The that p blockers possessing fi2 activity were more causes of this discrepancy have not been elucidated, prominent in affecting PRA. The present results are but in this study a significant depressor effect was in agreement with these previous reports. In spite observed at rest and during exercise after intravenous of the different effects on PRA, propranolol and administration of propranolol and acebutolol. acebutolol showed no effect on PAC.It maybe ex- Although COand TPRwere not measured in this plained by that aldosterone secretion is controlled by study, the depressor effect of these two /3 blockers more efficient mechanisms than the renin system. may be due to decrease in CO. In spite of partial Hansson et al. (19) indicated that long term treat- agonist action and cardioselectivity, acebutolol ment with penbutolol, possessing intrinsic sym- showed the same extent of depressor effect and pathomimetic activity and membrane stabilizing negative chronotropic effect as propranolol during action, lowered PRA and urinary excretion of exercise. These results are compatible with previous aldosterone in hypertensives. Since they did not in- studies (22-27). vestigate the acute effects of penbutolol nor the Franz et al. (22) showed the different effects of effects on PAC, it is difficult to compare the results pindolol and metoprolol on PNE in hypertensive in the study. men. PNEwas elevated by metoprolol during sub- In summary, two different types of /3 blockers maximal exercise and 5 minutes after exercise, but could suppress the elevation of BPduring exercise was not affected by pindolol, except 5 minutes after and their hypotensive effects were nearly the same exercise when norepinephrine was reduced. Kelley within the dose intravenously administered in this Jpn J Med Vol 28, No 1 (January, February, 1989) 13 Matsuura et al

of cardioselective adrenoceptive blocking drug. Br J study. They also showed the same effect on hor- Pharmacol 48: 340P, 1973. monal changes during exercise except PRA. Harms HH, Spoelstra AJG: Cardiac and bronchial ]9 ACKNOWLEDGEMENT: The authors are grateful to adrenoceptor antagonistic potencies of atenolol, metoprolol, acebutolol, practolol, propranolol and Miss YukoOmurafor her excellent secretarial assistance. pindolol in the anesthetized dog. Clin Exper Pharmacol Physiol 5: 53, 1978. REFERENCES Shinebourne E, Fleming J, Hamar J: Effects of beta- 1) Lewis P: The essential action of propranolol in adrenergic blockade during exercise in hypertensive and ischemic heart-disease. Lancet ii: 1217, 1976. hypertension. Am J Med 60: 837, 1976. 2) Lorimer AR, Dunn FG, Jones JV, et al: Beta- Lund-Johansen P: Hemodynamic changes at rest and during exercise in long-term /3-blocker therapy of adrenoceptor blockade in hypertension. AmJ Med 60: 877, 1976. essential hypertension. Acta Med Scand 195: 1 17, 1974. 3) Prichard BNC, Gillan PMS: Use of propranolol Hansson BG, Hokfelt B: Long term treatment of (Inderal) in treatment of hypertension. Br Med J 2: 725, moderate hypertension with penbutolol (Hoe 893d). 1. 1964. Effects on blood pressure, pulse rate, catecholamines in blood and urine, plasma renin activity and urinary 4) Prichard BNC, Gillan PMS: Propranolol in hyperten- aldosterone under basal conditions and following sion. Am J Cardiol 18: 387, 1966. exercise. Europ J Clin Pharmacol 9: 9, 1975. 5) Veterans Administration Cooperative Study Group on Masaoka S, Kubo S, Kanazawa I, et al: Effects of Antihypertensive Agents: Propranolol in the treatment of essential hypertension. JAMA237: 2303, 1977. nifedipine and captopril upon the hemodynamic and hormonal features during treadmill exercise in patients 6) Veterans Administration Cooperative Study Group on with essential hypertension [Abst]. Jpn Circ J 47: 1003, Antihypertensive Agents: Comparison of propranolol 1983. and hydrochlorothiazide for the initial treatment of hypertension. I. Results of short-term titration with Myers MG,De Champlain J: Effects of atenolol and emphasis on racial differences in response. JAMA248: hydrochlorothiazide on blood pressure and plasma 1996, 1982. catecholamines in essential hypertension. Hypertension 5: 591, 1983. 7) Veterans Administration Cooperative Study Group on Antihypertensive Agents: Comparisonof propranolol Franz IW, Lohmann FW, Koch G: Differential effects and hydrochlorothiazide for the initial treatment of of long-term cardioselective and nonselective beta- hypertension. II. Results of long-term therapy. JAMA receptor blockade on plasma catecholamines during and 248: 2004, 1982. after physical exercise in hypertensive patients. J 8) Wikstrand J, Westergren G, Berglund G, et al: cardiovasc Pharmacol 2: 35, 1980. Antihypertensive treatment with metoprolol or Vandongen R, Margetts B, Deklerk N, et al: Plasma hydrochlorothiazide in patients aged 60 to 75 years. catecholamines following exercise in hypertensives treated with pindolol: Comparison with placebo and Report from a double-blind international multicenter study. JAMA 255: 1304, 1986. metoprolol. Br J Clin Pharmacol 21: 627, 1986. 9) MacDonald HR, Sapru RP, Taylor SH, et al: Effect of Morrison SC, Chir B, Kumana CR, et al: Selective and intravenous propranolol on the systemic circulatory nonselective beta-adrenoceptor blockade in hyperten- response to sustained handgrip. AmJ Cardiol 18: 333, sion: Responses to changes in posture, cold and exercise. 1966. Circulation 65: 1171, 1982. 10) Ulrych M, Frohlich ED, Dustan HP, et al: Immediate Leener FHH, Coenen CHM, Zonderland M, et al: hemodynamiceffects of beta-adrenergic blockade with Effects of cardioselective and nonselective /3-blockade propranolol in normotensive and hypertensive man. on dynamic exercise performance in mildly hyperten- Circulation 37: 411, 1968. sive men. Clin Pharmacol Ther 28: 12, 1980. ll) YamamotoJ, SekiyaA: On the present action of pro- Kaiser P, Hylander B, Eliasson K, et al: Effect of beta- pranolol in the rat. Arch Int Pharmacodyn 179: 372, selective and nonselective beta blockade on blood 1969. pressure relative to physical performance in menwith 12) Stephan SA: Unwanted effects of propranolol. AmJ systemic hypertension. AmJ Cardiol 55: 79D, 1985. Cardiol 18: 463, 1966. Wilcox RG, Hampton JR: Comparison between 13) Basil B, Jordan R, Loveless AH, et al: Pharmacological atenolol and nadolol in essential hypertension at rest properties of M&B17803A, a cardioselective jS- and on exercise. Br J Clin Pharmacol 13: 841, 1982. adrenoceptor blocking agent. J Pharmacol 2: 195, 1971. Sheffield LT: Graded exercise test (GXT) for ischemic 14) Ablad B, Carlsson E, Ek L: Pharmacological studies heart disease. A submaximal test to a target heart rate of two new cardioselective adrenergic beta-receptor in exercise testing and training of apparently healthy antagonists. Life Sci 12: 107, 1973. individuals: A handbook for physicians. AmHeart 15) Barrett AM,Carter J, Fitzgerald JP, et al: A new type Assoc, The Committee on Exercise: 35, 1972.

14 Jpn J Med Vol 28, No 1 (January, February, 1989) ft blockers and exercise in hypertensives Matsuura et al

Fitzgerald JP: Perspectives in adrenergic beta-receptor 1981. blockade. Clin Pharmacol Ther 10: 292, 1969. Best JD, Halter JB: Blood pressure and norepinephrine Prichard BNC: /5-adrenergic receptor blockade in spillover during propranolol infusion in humans. Am hypertension, past, present and future. Br J Clin Phar- J Physiol 248: R400, 1985. macol 5: 379, 1978. Lucsko M, GuedonJ: The evaluation of acebutolol in Kelly JG: Choice of selective versus nonselective beta hypertension: Effects on haemodynamics and plasma blockers: Implication for exercise training. AmJ Cardiol renin activity. Clin Trials J 3: 86, 1974. 55: 162D,1985. Weber MA, Stokes GS, Gain JM: Comparison of the Esler M, Jackman G, Leonard P, et al: Effect of pro- effects of renin release of beta-adrenergic antagonists pranolol on noradrenaline kinetics in patients with with differing properties. J Clin Invest 54: 1413, 1974. essential hypertension. Br J Clin Pharmacol 12: 375,

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