β-adrenoceptor blockade and physical activity: cardiovascular and metabolic aspects

Acta Med Scand suppl672:55-62,1983. 55

/I-adrenoceptor blockade and physical activity: cardiovascular and metabolic aspects

Giinter Koch, Ingomar-Werner Franz, Angelika Gubba and Friedrich Wilhelm Lohmann

From the Department of Clinical Physiology, Centrallasarettet, Karlskrona, Sweden, the Departments of Physiology and Sports Medicine, Free University,

and the Department of Medicine, Neukolln Hospital, Berlin, FRG

ABSTRACT. This paper assesses mechanisms that may contribute to the higher incidence of increased muscle fatigue during exercise and reduced exercise performance as observed with selective compared with non-selective b-adrenoceptor antagonists. Pub- lished data and the results obtained in 8 healthy subjects (mean age 23 years) studied before and after acute b-adrenoceptor blockade with pindolol (non- selective, 10 mg) and metoprolol @,-receptor selective, 100 mg) suggest that the differences in the cardiovascular and respiratory effects between the 2 types of antagonists are marginal and cannot explain the discrepancies concerning exercise perception and performance. Conversely, basic differences between the 2 types of antagonists were phnwn in different groups of hypertensive men (mean age 32 years) studied before and after 4 weeks of treatment with pindolol (15 mg), and with metoprolol (200 mg) and acebutolol (cardioselective, 500 mg), by single cross- over technique. Whereas lipolysis was similarly inhibited by both selective and non-selective antagonists, hypoglycaemia occurred only under non- selective blockade. It apparently reflects the inhibition of glycogen breakdown; concomitant rises in plasma adrenaline and ACTH probably reflect counter-regulatory mechanisms.

Key words: /?-receptor blockade, exercise, lipolysis, hypoglycaemia. Acta Med Scand 1983;suppl672:55-62.

INTRODUCTION

Increased muscle fatigue and reduced endurance exercise capacity are commun complaints of physically active patients treated with @-adrenoceptor blocking agents (1); they are apparently more frequent with non-selective than with cardioselective P,-receptor antagonists (2, 3) , or with combinations of@- and a-adrenoceptor blockers (4).

There are several ways in which P-adrenoceptor blockade may interfere with work capacity and per-

formance. All @-receptor antagonists have significant haemodynamic effects, reducing, in particular, exercise heart rate and cardiac output (5, 6) for a given level of oxygen uptake. Muscle blood flow during exercise has also been shown to be significantly reduced (7, 8). Other possible mechanisms by which ap-receptor blockade may affect physical work capacity include the restriction of the b2- adrenoceptor mediated muscle glycogenolysis (9, 10) or the interference with the potassium flux across the muscle cell membrane (1 1 ) .

Recent studies in young physically active hypertensive young subjects suggest that muscle fatigue (2, 10) and the restriction of endurance work capacity (3) are more pronounced during non-selective P1 /P,-adrenoceptor blockade than during treatment with cardioselective P1 -receptor antagonists. Thus, in a double-blind study, complaints were found to be more frequent when the patients were on pindolol than during treatment with metoprolol or acebutol- 01 (2, 10). The purpose of the present study is to re- assess some of the mechanisms that might be re- sponsible for the differences observed. Emphasis was laid on analysing circulatory and metabolic effects of different types of @-receptor blockade. The P-receptor antagonists taken into consideration were pindolol, a non-selective blocker with pronounced intrinsic sympathetic activity (ISA), metoprolol and acebutolol. Both metoprolol and acebutolol are relatively @,-receptor selective; acebutolol has, conversely to metoprolol, a weak intrinsic sympathetic activity.

CARDIO-RESPIRATORY CONSIDERATIONS

Since exercise requires a rise in cardiac output approximately linear with the increase in oxygen uptake the haemodynamic changes induced by P-adrenergic blockade must be considered as a possible mechanism contributing to the differences observed between selective and non-selective anta-

Acta Med Scund suppl672

56 G . Koch et al.

Table I . Changes in some haemodynamic variables and in plasma renin activity usually occurring during treatment with /?-adrrnoceptor antagonists, a-adrenoceptor antagonists and a- /?-adrenoreptor blockers lfrom 6)

/?-receptor blockade a-receptor blockade a- /?-receptor blockade (prazosin)

Heart rate Decreased Icreased or unchanged Decreased or unchanged Cardiac output Stroke volume

Decreased Increased or unchanged Unchanged Unchanged or increased Increased or unchanged Increased or unchanged

Systemic vascular resistance Increased or unchanged Decreased Decreased Arterio - venous oxygen Increased Decreased or unchanged Unchanged or increased difference Left ventricular filling Increased Decreased Unchanged pressure Plasma renin activity Decreased Increased or unchanged Decreased ( P W

gonists. Table I summarises the major basic haemodynamic effects of P-adrenoceptor blockade compared with post-synaptic a- and combined a- P- receptor blockade (6). It is important, however, to realise that the haemodynamic response is widely dependent on the initial circulatory state, particularly with respect to sympathetic activity. This applies especially to left ventricular dynamics which can be considerably deteriorated when the heart is dependent on the adrenergic stimulation as in many cases of left ventricular failure (12).

Haemodynamic evaluations of the effect of different @-receptor antagonists have shown that with- o u t exception they tend to reduce cardiac output, while the arterio-mixed venous oxygen uptake is increased as a compensatory mechanism that ensures unchanged oxygen uptake and transport. The systemic vascular resistance is raised, or at least tends to be raised. These effects are most pronounced during exercise and after an acute blockade, but they subsist during long-term treatment and despite the addition of a vasodilator such as hydralazine (13, 14). The few studies available concerning leg muscle blood flow during exercise suggest that it is reduced to a similar degree as is cardiac output ( 7 3 ) .

It appears that only marginal differences exist among different types of @-receptor antagonists with respect to the degree of reduction of cardiac output and rise in peripheral resistance. This has been con- vincingly shown by Lund-Johansen (5) in a series of long-term studies in different age-matched patient

(Figure 2 ) . Other haemodynamic studies, in particular those by Atterhog et al. (IS), also suggest that pindolol has a haemodynamic profile slightly different from that of other P-receptor antagonists.

Metoprolol Penbutolol Bunitrolol

Atenolol Tirnolol Alprenolol Pindolol

% change

- 10

- 20

Cardiac Index - 30 0 rest supine

re51 Sitting

0 exercise 1oOW

Figure I . Effect of different /?-adrenoceptor antagonists on cardiac index at rest and during exercise in different groups of age matched hypertensives WHO stage 1. Doses were equipotent and treatment lasted for 1 year. (From data reported by Lund-Johansen (S), with permission of the author).

Meloprolol Penbutolol Bunitrolol Atenolol Tirndol Alprenolol Pindolol

%change

+301 20

f 10

0

groups using equipotential doses and reliable 10 Total Peripheral Resistance

methods, i.e. intravascular measurement of pres- 0 rest supine

sures and determination of cardiac output by rest aittlng

0 exercise loow dye-dilution technique. If anything, the non-selective blocking agent pindolol, presumably because of its intr insic sympathetic activity, results in a less pro-

hardly any rise in total systemic vascular resistance

Figure 2 . Effect of different/?-adrenoceptor antagonists on total systemic resistance. Same groups of patients as in Figure I . (The data were recalculated from the data

author). nOunced reduction ofcardiacoutput (Figure 1) and in reported by Lund-Johansen ( 5 ) , with permission of the

Ar’ru Mrd Scand suppl672

Prolonged exercise and /?-receptor blockade 57

It is therefore unlikely that the increased muscle fatigue and the reduced endurance exercise capacity observed in the patients during the treatment with pindolol were caused by haemodynamic peculiar- ities.

hypertensive patients after the acute administration of a /?-receptor antagonist.

METABOLIC ASPECTS

In order to evaluate further the effect of different types of interference with autonomous control on the circulation and on oxygen uptake 8 young healthy subjects aged 22 to 26 years were studied at rest and duringsubmaximal steady stateandmaximalexercise until exhaustion (unpublished observations). Exer- cise was performed seated on an electrodynamical- ly braked bicycle ergometer, the loads were stepwise increased with 6-minutes intervals; the total duration of exercise exceeded 30 minutes in all cases. As can be seen from Table 11 there are no significant differences in maximal oxygen uptake between the control situation and after the acute administration of equipotential doses of metoprol- 01. pindolol, labetalol (a combined a- /?-receptor antagonist) and nifedipine (a slow-channel calcium inhibitor). There is, however, a slight but similar tendency towards lower \;ro2 max values with metoprolol and pindolol compared with the other agents. There is also a distinct trend for ventilation to be lower with the two /?-receptor blockers in particular during maximal work; under all conditions heart rates are substantially lower after /?- receptor blockade than in the control situation or during combined a- /?-receptor blockade or calcium inhibition. The degree of blood pressure reduction obtained in these healthy subjects is noteworthy: it is not seen, or at least not to the same extent, in

Since basic differences in the haemodynamic profile can be excluded as a major cause of the discrepancies observed between non-selective and selectivep- receptor antagonists with respect to muscle fatigue and work capacity, the effects of the 2 types of antagonists on some variables representative for carbohydrate and lipid metabolism and their re- gulation were investigated (2, 10).

In a first series, two groups of hypertensives, all men, mean age 37 years, were studied before and after 4-weeks’ treatment with two different /?- blockers using a single blind cross-over design: 9 men received treatment with pindolol (non-selective, with ISA) and metoprolol @,-selective, without ISA); 11 patients were treated with pindolol and acebutolol @,-selective, with ISA). The doses used were equipotential: metoprolol 200 mg, pindolol 15 mg, acebutolol 500 mg daily. After the initial cross-over study which lasted 8 weeks for each group, all group I patient continued treatment with metoprolol, all group 2 patients with acebutolol. Both groups were studied again 12-14 months later.

At each examination the patients performed submaximal steady state and near-maximal exercise, sitting on a bicycle ergometer. Submaximal exercise lasted 30 minutes. During submaximal and maximal exercise as well as at rest (supine) before and 5

Table 11. Means and standard deviations of heart rates, systolic blood pressures, ventilation and oxygen uptake during submaximal and maximal exercise before (C) and after acute oral administration of metoprolol ( M , 100 mg), pindolol ( P . 10 mg), labetalol ( L , 200 mg) and nifedipine ( N , 10 mg) in young healthy male subjects aged 22-26, *p <0.05, * * p <o.Ol, ***p <0.001 (unpublished observations).

C M P L N

Heart rate (beatslmin) 100 W 123t20 % t 7*** 9 9 t I O * * 1072 14** 1295 I9 200 W 167r22 119+-11*** 123211*** 139-r-13** 164+17 Max 1855 19 141 ?20*** 139% 14*** I64 c22** 185+21

Systolic blood pressure (mm H g ) 100 W 165513 1333: 8*** I 3 1 2 lo*** 132-~10*** 1442 9** 200 W 197t 8 1573: lo*** 154+12*** 1542 12*** 172212*** Max 230t 9 1903: 3*** 178&11*** 183r13*** 1895 7***

100w 33.8? 5.1 32.42 4.0 33.72 4.5 32.22 3.1 36.1-C 4.1 200 w 70.72 12.5 67.22 8.0 65.12 7.7 68.6t 8.9 68.52 7.5 Max 120.5 t 27.0 102.7 t 27.3 * 105.95 20.2* 113.1~18.5 106.32 17.6

Ventilation +, (Ilrnin)

Oxygen uptake qo2 (l/min) 100 W 1.4320.13 1.31 20.12 1.3620.09 1.3320. 11 1.4950.06 200 W 2.5750.21 2.49 r0.09 2.4620.12 2.4620.18 2.5750.09 Max 3.26 20.6 1 3.11 k0.51 3.06r0.51 3.2420.46 3.30 20.46

Acta Med Scand suppl672

58 C. Koch rt al .

minutes after exercise (sitting) the following variables were studied: heart rate, systolic and diastolic blood pressures, and plasma catecholamines, blood glucose and lactate. In the pindolol-acebutolol series, in addition, the responses of free fatty acids (FFA), glycerol, ACTH, thyroid stimulating hormone CSH), human growth hormone (HGH) and insulin were studied. Details of the exercise protocol and the methods used have already been reported ( 2 , 16).

All P-receptor antagonists had almost identical antihypertensive effects. During exercise, heart rates were similarly reduced by all drugs; at rest, however, heart rates were lower (p <0.05) after metoprolol and acebutolol.

gure 3). The reduction of blood glucose after pindolol was associated with a distinct increase of peak adrenaline concentrations (Figure 4). No increase in adrenaline was observed after either metoprolol or acebutolol. Even after 12-15 months’ treatment, metoprolol and acebutolol failed to reduce exercise glucose or to increase peak adrenaline concentrations.

All three antagonists tended to attenuate the exercise induced blood lactate increase. Five minutes after exercise blood lactate was significantly lower after pindolol (p <0.05).

Lipolysis Lipolysis was greatly increased during exercise as documented by the significantly higher (p <0.01)

Carbohydrate metabolism Pindolol, but not metoprolol or acebutolol, resulted in a substantial fall (p < O . O l ) in blood glucose after 30 minutes’ submaximal exercise, and during maxi- ma1 work; furthermore, the post-exercise blood glucose increase was significantly attenuated (Fi-

glycerol concentrations during work (Figure 5 ) . Plasma glycerol was reduced (p CO.01) in a vir- tually identical manner by both acebutolol (27 %) and pindolol (29 %) during steady state exercise. FFA also increased significantly (p <0.05) during work; this increase was attenuated (p <0.05) under

Glucose Glucose ( mg /lo0 m I 1 110-

(mg/lOOml)

-

- o Control

100- A Pindolol Acebutolol

90-

-

Rest 6 30 max. 6 min Ergometric Exercise Post-Exercise

Rest 6 30 max. 5 min Ergometric Exercise Post-Exercise

Figure 3. Blood glucose (means and standard deviations) at rest supine, during submaximal and near-maximal work and 5 minutes after exercise before (0) and after 4 weeks’ treatment with pindolol (A) and acebutolol (B, left panel) and pindolol (A) and metoprolol ( W , right panel) respectively. The 6 minutes’ submaximal exercise corresponds to a

workload of 100 W, the 30 minutes’ exercise to steady state work at a heart rate of about 130 beatshin. Post-pindolol values are significantly (p <0.01) lower than control and post-acebutolol and post-metoprolol values respectively, at 30 minutes and at maximal exercise, and 5 minutes post- exercise.


Prolonged exercise and P-receptor blockade 59

NORADRENALINE (p mol/ml)

ADRENALINE (p mol/ml)

I 6 min 30 rnin max 5 min rest ergometric work I after work

Figure 4. Plasma adrenaline (means and standard deviations) at rest supine, during submaximal and maximal work and 5 minutes after exercise before (C) and after a 4-weeks' treatment with metoprolol (M) and pindolol (P) respectively. For further details see legend to Figure 3.

the action of acebutolol and pindolol by 25 % and 28 %, respectively.

Regulating horrnonrs Plasma insulin decreased (p CO.05) during exercise, but this response was not affected by anyp-blocker.

Glycerol tmmollll 1 n C o n t r o l rn

m

Rest I 6 min m m i n mbx. 5min ergometric work ' after work

Figure 5. Plasma glycerol and free fatty acids (FFA) concentrations (means and standard deviations) at rest supine during submaximal and maximal work, and 5 minutes after exercise, before and after treatment with acebutolol and pindolol respectively. For further details see legend to Figure 3.

t . I . ,--

I 6 min 30 min max I 5 min rest ergometric work after work

Figure 6 . Plasma noradrenaline (means and standard deviations) at rest supine, during submaximal and maximal work, and 5 minutes after exercise, before (C) and after a 4-week treatment with metoprolol (M) and pindolol (P) respectively. For further details see legend to Figure 3.

ACTH increased by roughly 100 % during work; this response was not modified by acebutolol, but grossly enhanced (p <0.01) by pindolol.

Thyroid stimulating hormone levels showed no significant increase during exercise and were not affected by either pindolol or acebutolol. Human growth hormone increased during exercise; this increase was further enhanced (p <O.OS) by pindolol during submaximal work.

As mentioned above, the exercise-induced adrenaline increase was enhanced exclusively by pindolol, peak adrenaline concentrations being significantly higher (p <O.OS).

Plasma noradrenaline was higher (p <O.OS) after metoprolol during submaximal exercise compared with pretreatment and post-pindolol values. In addition, S minutes after exercise, post-metoprolol concentrations were significantly higher (p <0.01) than post-pindolol values. Noradrenaline was not significantly affected by either pindolol or acebutolol treatment.

Except for dopamine, which was found t o be significantly higher after long-term metoprolol treatment (17), no significant changes in catecholamine response were observed after the 12-14 months period compared with the 4-week treatment period.

DISCUSSION AND CONCLUSION

From available published data and the results pre- sented it is evident that differences in the cardiovascular and respiratory effects between the non-

Actu Med Scund suppl672

60 G . Koch et al.

selective P-receptor antagonist pindolol and the cardioselective blockers metoprolol and acebutolol respectively are marginal and can hardlyexplainthedif- ferences between the two types of antagonists with respect to muscle fatigue and endurance exercise capacity.

On the other hand, evidence has been provided for distinct differences in the metabolic effects exerted during prolonged exercise by the two types of antagonists.

Pindolol, but not metoprolol or acebutolol. resulted in a substantial exercise-induced hypoglycaemia and concomitant increase in plasma adrenaline and ACTH. While hypoglycaemia obviously reflects reduced glycogen breakdown in the working muscle under the action of pindolol, the enhanced adrenaline and ACTH responses most probably reflect counter-regulatory mechanisms. Since glycogenolysis is mainly mediated by P,-receptors the inhibitory effect ofpindolol andtheabsence ofthis action with metoprolol and acebutolol, are obviously due to the non-selectivity, i.e. the P,- and p2- receptor blocking properties, of pindolol.

These results seem to be in disagreement with data suggesting that muscle glycogen breakdown is not reduced during exercise by either a selective or a non-selective P-receptor antagonist (18). However, these data were obtained during short-term exercise (I0 minutes) and are thus not relevant for prolonged exercise of the type performed in our series. From Figure 3 it is evident that significant hypoglycaemia occurs only after 30 minutes of exercise.

The insulin response was not modified by any antagonist: insulin thus does not contribute to the different blood glucose responses observed.

Lipolysis is mainly mediated by B,-adrenoceptors. In accordance with this concept, lipolysis was found to be similarly reduced by both the non- selective antagonist pindolol and the Bl-selective blockers metoprolol and acebutolol.

The failure of pindolol to raise resting noradrenaline and to augment the activity-induced rise of noradrenaline further may be one of the factors contributing to the lower vascular resistance observed after long-term treatment with pindolol compared with otherg-receptor antagonists ( 5 , 15).

The inhibitory effect on carbohydrate metabolism with consecutive hypoglycaemia observed with non-selective pl- p,-receptor antagonists but not with selective p,-adrenoceptor blockers may be an important factor causing, or contributing to, the increased muscle fatigue and restricted endurance exercise capacity observed in physically active young subjects. Treatment with selective rather than non-selective antagonists might therefore be preferable in subjects having extensive sport

activities or taking part in preventive training or physical fitness programmes.

DI SCUSSlON Juhlin-Dannfelt and Koch

Koch: What type of blocker did you give your rats?

Juhlin-Dannfelt: It was a non-selective blocker, propranolol. As we did not see any inhibitory effect on muscle glycogen, we did not proceed to a selective blocker.

Hood: The thing that strikes one most is how strongly the pyruvate to lactate cycle can be disturbed in a situation where pyruvate is so badly needed, namely in the depleted liver of the man who drinks alcohol and does not eat. The combination of glycogen depletion and continuing reduction of pyruvate to lactate may lead to severe hypoglycaemia. The question is of great practical importance as so many people drink such a lot and eat so badly.

Juhlin-Dannfrlt: Under good nutritional conditions with full glycogen stores in the liver, the inhibition of gluconeo- genesis we see after consumption of alcohol is of little importance. Several studies have shown that alcoholic hypoglycaemia only occurs during starva- tion and children seem to be more sensitive than adults. There is another situation in which the gluco- neogenesis is of decisive importance. and that is during prolonged physical exertion. We have shown that a small quantity of alcohol in the body suppresses lactate uptake by the liver during work and the exercise-induced hypoglycaemia develops faster. A s regards the inhibitory effect of /3-blockade on glycogenolysis in the heart during exertion, it means that the supply of substrate decreases. Stud- ies of the clinical significance of this are lacking. as far as I know, but one cannot rule out the possibility that it may be important during prolonged exertion. It is important to note, however, that ischaemia in the myocardium may stimulate glycogenolysis and this stimulation occurs in spite of P-blockade. Our results with propranolol have prompted us to plan studies in which we will measure substrate utilisation by the heart in order to see whether the reduced glycogenolysis is com- pensated for by other substrates.

Bjijmtorp: You concluded that P-blockade did not inhibit the adaptation to physical training, but did you not find

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Prolonged exercise and P-receptor blockade 61

that heart weight and enzymes increased after training during P-blockade? Can you explain that?

Juhlin-Dannfelt: That is correct and it applied particularly to the cardiac hypertrophy, which was significantly more pronounced during P-blockade. One explanation for this might be an increased stroke volume during P-blockade. The muscle enzyme values definitely showed no tendency to decrease but there was n o significant increase.

Hiemdahl: A brief comment on the increased dopamine levels reported by Koch. You wondered whether anyone could confirm your results. As you know, we have also studied this question and we found no increase in dopamine during long-term treatment with metoprolol. No subject showed this change during 3 years’ postinfarction treatment. I think this is a methodological problem.

Krwh: I should like to see it as simply a methodological problem. The only thing that makes me hesitate t o offer this explanation is that at the same time as the long-term metoprolol samples were analysed, other samples from patients treated with other agents were analysed. Only the patients who had been on long-term metoprolol showed the dopamine increase.

Hjrrndahl: That, if anything, indicates that it is not an effect ofp-blockade but is a methodological problem. You have probably had a n interference with your plasma-catecholamine assay that we did not have with our HPLC-analyses.

Koch: T o me it is at any rate surprising that this should have happened with metoprolol but not with any other agent or under any other conditions.

In this context it is important t o point out that it is more difficult to assay dopamine than adrenaline or, above all, noradrenaline. Resting plasma levels of dopamine are significantly lower than those of noradrenaline, and during near maximal work there is only a small (scarcely two-fold) increase. The reproducibility of dopamine determination is lower than for the other plasma catecholamines.

Hirrndahl: If I remember correctly. your resting levels were 0.5-1 nmol/l and they increased to 5-6 nmol/l during metoprolol treatment. Our resting levels were 0.1-0.2 nmol/l. They did not increase to any

significant extent during metoprolol treatment, either at rest or during exercise.

Koch: This corresponds exactly to our pretreatment and 4-week treatment results in the metoprolol series, and in our acebutolol series on all occasions, in- cluding the IS-month treatment period.

Areskog: Kaiser e t al. recently published a study in the Inter- national Journal of Sports Medicine in which they compared a selective and a non-selectivep-blocker. They studied the dose-response relationship for the ability to run a certain distance and recorded sub- jective tiredness and the time needed t o run the distance. The selective P-blocker caused less sub- jective tiredness. Also, the people with more slow twitch fibres showed a greater deterioration in their performance than those with fast fibres. Could you comment on these results?

Juhlin-Dannfcdt: The study you refer to demonstrated in an elegant way that the fibre composition of the skeletal muscle influences the individual’s capacity for work. It showed that there are differences between maximal exertion of brief duration and prolonged exertion. In the former case P-blockade even reduced the subject’s stamina compared to the the control situation and this was the case above all in persons with slow fibres. A possible explanation for this may be the previous finding that sympathetic stimulation reduces the tension and duration of maximal contraction in slow fibres whereas the opposite situation applies in the case of fast fibres. The fact that no such effect was observed during selective blockade with atenolol indicates that this is a local p2-effect. As regards more prolonged exertion, the study clearly shows that P-blockade reduces working capacity and that there is no difference between selective and non-selective blockade if the fibre composition is not taken into account. I n the subjects with slow fibres, however, propranolol had a markedly greater effect than atenolol. Although the authors did not draw this conclusion. this is consistent with my findings that propranolol reduces the level of free fatty acids in the blood more than atenolol and . the reduced availability of fat influences above all the slow fibres.

W alldius : As regards prolonged work and the muscles’ energy needs, there are of course very significant quanti- ties of triglycerides stored in the muscle. Is there any reason to suppose that utilisation of these

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62 G . Koch et al.

energy stores is reduced duringp-blockade? Or is it perhaps so that the triglycerides are broken down intracellularly and that these fatty acids interfere with glucose metabolism?

Juhlin-Dannfelt: I d o not know of any studies in which muscle triglycerides have been measured with and without P-receptor blockade.

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Effects of beta-adrenergic blockade on the cardiac response to maximal and submaximal exercise in man. J Clin Invest 1965;44: 1745-53.

2. Franz IW, Lohmann FW, Koch G. Differential effects of long-term cardioselective and nonselective beta- receptor blockade on plasma catecholamines during and after physical exercise in hypertensive patients. J Cardiovasc Pharmacol 1980;2:35-44.

3. Lundborg P, Astrom H, Bengtsson C et al. Effect of @-adrenoceptor blockade on exercise performance and metabolism. Clin Sci 1981;61:299-305.

4. Bjerle P, Fransson L, Koch G, Lindstrom B. Pindolol and labetalol in hypertension: comparison of their antihypertensive effects with particular respect to conditions in the upright posture and during exercise. Cum Ther Res 1980;27:516-26.

5 . Lund-Johansen P. The effect of beta-blocker therapy on chronic hemodynamics. Primary Cardiology 1980;

6. Koch G. Hemodynamic changes after acute and long- term combined alpha-beta-adrenoceptor blockade with labetalol as compared with beta-receptor blockade. J Cardiovasc Pharmacol 1981;3(suppl 1):30-41.

7. Nordenfelt I . Blood flow of working muscles during autonomic blockade of the heart. Cardiovasc Res

8. Trap-Jensen J, Clausen JP, Noer I , LarsenOA, Krogs- gaard AR, Christensen NJ. The effect of beta-adrenoceptor blockers on cardiac output, liver blood flow and skeletal muscle blood flow in hypertensive patients. Acta Physiol Scand 1976;suppl 440:30. (Abstract).

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9. Christlieb AR, Maki PC. The effect of beta-blocker therapy on glucose and lipid metabolism. Primary Cardiology 198O;suppl:47-54.

10. Koch G, Franz IW, Lohmann FW. Effects of short- term and long-term treatment with cardio-selective and non-selective/l-receptor blockade on carbohydrate and lipid metabolism and on plasma catecholamines at rest and during exercise. Clin Sci 1981;suppl 61: 433-5.

1 I . Carlsson E, Fellenius E , Lundborg P, Svensson L. Beta-adrenoceptor blockers, plasma-potassium, and exercise. Lancet 1978;2:424-5. (Letter).

12. Koch G. Beta-receptor and calcium blockade in ischaemic heart disease: effects on systemic and pul- monary hemodynamics and on plasma catecholamines at rest and during exercise. In: Puech P, Krebs T, eds. 4th International Adalat@ Symposium. New therapy of ischemic heart disease. Amsterdam-Oxford-Prince- town: Excerpta Medica, 1980:131-42.

13. Koch G. Haemodynamic adaptation a t rest and during exercise to long-term antihypertensive treatment with combination of beta-receptor blocking and vasodilator agent. Br Heart J 1976;38: 1240-6.

14. Trap-Jensen J, Clausen JP, Hartling 0, Krogsgaard AR, Noer I . Central and peripheral circulation in patients with hypertension treated with propranolol and hydra- lazin. Svenska Lakarsallskapets Handlingar 1976; 85: 181.

15. Atterhog JH, Duner H, Pernow B. Haemodynamic effects of pindolol in hypertensive patients. Acta Med Scand 1977;suppl606:55-62.

16. Koch G, Johansson U, Arvidsson E. Radioenzymatic determination of epinephrine, norepinephrine and dopamine in 0.1 ml plasma samples: plasma catecholamine response to submaximal and near maximal exercise. J Clin Chem Clin Biochem 1980;18:367-72.

17. Franz IW, Lohmann FW, Koch G. Excessive plasma dopamine increase at rest and during exercise after long-term beta-adrenoceptor blockade in hypertensive patients. Br Heart J 1980;44:25-9.

18. Frisk-Holmberg M, Jorfeldt L, Juhlin-Dannfelt A. Metabolic effects in muscle during antihypertensive therapy with beta,- and beta,-beta,-adrenoceptor blockers. Clin Pharmacol Ther 1981 ;30:611-8.


β-adrenoceptor blockade and physical activity: cardiovascular and metabolic aspects

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