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Effects of short-term and long-term treatment with cardioselective and non-selective P-receptor blockade on
carbohydrate and lipid metabolism and on plasma
catecholamines at rest and during exercise
G . KOCH, I.-W. FRANZ AND F. W. LOHMANN
Departments of Physiology and Sports Medicine, Free University, and Department of Medicine, Neukolln Hospital, Berlin,
Federal Republic of Germany
Summary
Introduction
1. The effects on glucose and lipid metabolism and on plasma catecholamines at rest and
during exercise, of 4 weeks treatment with
non-selective ,&blockade (pindolol, 15 mg daily)
and with cardio-selective blockade (metoprolol,
200 mg, and acebutolol, 500 mg, respectively)
were compared in different groups of hypertensive men (mean age 37 years) by single blind
cross-over technique. All patients continued the
treatment with either metoprolol or acebutolol for
another 12-14 months.
2. All antagonists reduced blood pressures
and exercise heart rates in a virtually identical
manner. Whereas lipolysis was similarly inhibited by both selective /3,-antagonists and
non-selective &&blockers,
glycogenolysis in
the muscle was inhibited only by non-selective
P-receptor blockade.
3. The inhibition of glycogen breakdown
resulted in exercise hypoglycaemia and in increases of plasma adrenaline and ACTH, which
probably reflect counter-regulatory mechanisms.
No major metabolic changes occurred after
12-14 months compared with 4 weeks of
treatment.
Information about the metabolic and hormonal
effects of different p-adrenoceptor blockers during exercise is scanty, in particular concerning
conditions after long-term treatment. Increased
glycogen breakdown and lipolysis are required to
meet the augmented metabolic needs during
exercise. Glycogenolysis in the muscle is mainly
mediated by &adrenoceptors whereas PIreceptors are involved in lipolysis. The essential
role played by /3-adrenoceptors in these metabolic
pathways suggests that important differences
might exist between p,-selective and non-selective /?-receptor antagonists, in particular with
respect to carbohydrate metabolism. The purpose
of the present study was to compare the effect of
selective and non-selective blockers on different
variables involved in carbohydrate and lipid metabolism, including the hormones involved in their
regulation. Emphasis was laid on studying the
same patients under identical conditions during
and after standardized ergometer exercise.
Key words: acebutolol, adrenoceptors, blockade,
metaprolol, pindolol.
Abbreviation: ISA, intrinsic sympathetic activity.
Correspondence: Professor G. Koch, Department
of Physiology, Freie Universitat Berlin, Arnimallee 22,
D-1000 Berlin 33, Federal Republic of Germany.
Material and methods
In a first series, two groups of hypertensive
patients, all men, mean age 37 years, were studied
before and after a 4 week treatment with two
different /%blockers, with a single blind cross-over
design: nine men (group 1) received treatment
with pindolol (non-selective, with intrinsic sympathetic activity, ISA) and metaprolol (@,-selective,
without ISA) respectively; 11 patients (group 2)
were treated with pindolol and acebutolol (PIselective, with ISA). The doses .used were:
metoprolol 200 mg, pindolol 15 mg, and acebutolol 500 mg daily. After the initial cross-over
G . Koch, I.- W. Franz and F. W. Lohmann
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Post-exercise
Ergometric
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Post-exercise
FIG. 1. Blood glucose (means & SD) at rest supine, during submaximal and near-maximal work,
and 5 rnin after exercise before (0)and after 4 weeks treatment with pindolol (A)and acebutolol
(a, W) or metaprolol (b, W). The 6 rnin submaximal exercise corresponds to a work load of 100 W,
the 30 min exercise to steady-state work at a heart rate of approximately 130 beatshin.
study, which lasted 8 weeks for each group, all
group 1 patients continued treatment with metaprolol, 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 min. The following variables
were studied both during submaximal and
maximal exercise as well as at rest (supine) before
and 5 min after exercise (sitting): heart rate,
systolic and diastolic blood pressures, and plasma
catecholamines, blood glucose and lactate. In the
pindolol-acebutolol series, in addition, the response of free fatty acids (FFA), glycerol,
ACTH, thyroid-stimulating hormone (TSH),
human growth hormone (HGH) and insulin was
studied. Details of the exercise protocol and the
methods used have been reported previously
[ L21.
Results
however, heart rates were lower (P < 0.05) after
metoprolol and acebutolol than with pindolol.
Carbohydrate metabolism
Pindolol, but neither metoprolol nor acebutolol, resulted in a substantial fall (P < 0.01) in
blood glucose after 30 min of submaximal
exercise, and during maximal work, furthermore,
the post-exercise blood glucose increase was
significantly attenuated (Fig. 1). The reduction in
blood glucose after pindolol was associated with
a rise in peak adrenaline levels. No increase of
adrenaline was observed after either metoprolol
or acebutolol. Even after treatment for 12-15
months metoprolol and acebutolol failed to
reduce exercise glucose or to increase peak
adrenaline levels.
All three antagonists tended to attenuate the
exercise-induced blood lactate increase. At 15
min after exercise blood lactate was significantly
lower after pindolol (P < 0.05).
Blood pressures and heart rates
Lipolysis
All P-receptor antagonists had nearly identical
antihypertensive effects. During exercise, heart
rates were similarly reduced by all drugs; at rest,
Lipolysis was greatly increased during exercise,
as documented by the significantly higher
(P < 0.01) glycerol levels during work. Plasma
P-Receptor blockade and metabolism
glycerol was reduced (P< 0.01) in a virtually
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 the action of acebutolol and pindolol by
25% and 28% respectively.
Regulating hormones
Plasma insulin decreased (P < 0-05) during
exercise, but this response was not affected by
any ,&blocker.
ACTH increased by roughly 100% during
work; this response was not modified by
acebutolol but was 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< 0.05) by pindolol during submaximal work.
The exercise-induced adrenaline increase was
enhanced exclusively by pindolol, peak adrenaline levels being significantly higher (P<
0.05).
Plasma noradrenaline was higher (P< 0.05)
after metoprolol during submaximal exercise
compared with pretreatment and post-pindolol
values. Also, 5 min after exercise post-metoprolol levels were significantly higher (P< 0.01)
than post-pindolol values. Noradrenaline was not
significantly affected by either pindolol or acebutolol.
Except for dopamine, which was found to be
significantly higher after long-term metoprolol
treatment 131, no significant change in catecholamine response was observed after the 12-14
month period compared with the 4 week
treatment.
Discussion
Pindolol but neither metoprolol nor acebutolol
resulted in a substantial exercise-induced hypoglycaemia and concomitant increases of plasma
adrenaline and ACTH. Whereas hypoglycaemia
obviously reflects reduced glycogen breakdown in
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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 &-receptors the inhibitory effect of pindolol,
and the absence of this action with metoprolol
and acebutolol, is due to the non-selective, i.e. the
PI- and &-receptor-blocking, properties of
pindolol.
The insulin response was not modified by any
antagonist: thus insulin does not contribute to the
different blood glucose responses observed.
Lipolysis is mainly mediated by padrenoceptors. In accordance with this concept, lipolysis
was found to be similarly reduced by both the
non-selective antagonist pindolol and the selective
&-blockers metaprolol and acebutolol. The
failure of pindolol to raise resting noradrenaline
and further to augment the exercise-induced rise
of noradrenaline might be one of the factors
contributing to the lower vascular resistance
observed after long-term treatment with pindolol
compared with other P-receptor antagonists
[ l ,41.
The inhibitory effect on carbohydrate metabolism with consecutive hypoglycaemia observed
with non-selective P,-P,-receptor antagonists but
not with selective P,-adrenoceptor blockers suggests that treatment with selective rather than
non-selective antagonists is preferable, particularly in young physically active hypertensive
patients and in patients undergoing preventive or
rehabilitative training programmes.
References
I l l FRANZ,
I.-W., LOHMANN,
F.W. & KOCH, G. (1980) Differential effects of long-term cardioselective and nonselective
/3-receptor blockade on plasma catecholamines during and after
physical exercise in hypertensive patients. Journal of Cardiovascular Pharmacology, 2 , 3 5 4 4 .
121 KOCH, G., JOHANSSON,
U. & ARVIDSON,E. (1980) Radioenzymatic determination of epinephrine, norepinephrine and dopamine in 0.1 ml plasma samples. Plasma catecholamine
response to submaximal and near maximal exercise. Journal of
Clinical Chemistry and Clinical Biochemislry. 18,367-372.
131 FRANZ,
LW., LOHMANN,
F.W. & KOCH, G. (1980) Excessive
plasma dopamine increase at rest and during exercise after
long-term P-adrenoreceptor blockade in hypertensive patients.
British Hear1 Journal, 44,25-29.
141 ATTERHOG,I.H., DUNER,H. & PERNOW.9. (1977) Haemodynamic effects of pindolol in hypertensive patients. Acta
Medico Scandinaoica, Suppl. 606.55-67.