Download Sequential Changes in Plasma Noradrenaline during Bicycle Exercise

Clinical Science ( 1980) 58,3743
Sequential changes in plasma noradrenaline during bicycle
exercise
R . D. S. W A T S O N , C . A. H A M I L T O N , D . H . J O N E S , J . L. REID,’
T. J . S T A L L A R D A N D W. A. L I T T L E R
Department of Cardiovascular Medicine, University of Birmingham and East Birmingham Hospital. and Department of Clinical
Phormocology. Royal Postgraduate Medical School. Hammersmith Hospital. London
(Received 11 January 1979; accepted 20June 1979)
Summary
vascular system. We have examined how plasma
noradrenaline changes during and after bicycle
exercise in both the supine and upright positions in
order to determine the relationship of changes in
sympathetic activity to those of blood pressure and
heart rate, physiological variables which reflect
sympathetic activity.
1. Forearm venous plasma noradrenaline, heart
rate and intra-arterial blood pressure were
measured sequentially during and after upright
bicycle exercise in five normotensive and six hypertensive patients.
2. Plasma noradrenaline increased significantly
between 4 and 8 min during exercise.
3. On stopping exercise blood pressure and
heart rate decreased rapidly whilst plasma noradrenaline increased in each subject to reach a
maximum at a median time of 108 s after exercise.
4. Plasma noradrenaline decreased in five of six
normotensive patients between the end of exercise
and 2 min after exercise performed in the supine
position.
5. Evidence in favour of a reflex increase in
sympathetic activity after upright exercise is
discussed.
Subjects and methods
Upright exercise
Upright exercise was studied in 11 untreated
subjects, five normotensive and six hypertensive;
supine exercise was studied in six patients during
cardiac catheterization.
Patients 1-5 (Table 1) were normotensive
subjects referred for investigation of chest pain.
Mean age was 35 years; four were male and two
(patients 3 and 4) were smokers. Outpatient blood
pressure was 150/95 mmHg or less. Clinical
examination, resting and exercise electrocardiograms were normal and the final diagnosis was
skeletal chest pain.
Patients 6-1 1 (Table 1) had mild to moderate
essential hypertension. Mean age was 46 years;
four were male and patient 10 was a smoker.
Repeated outpatient blood pressure measurements
were greater than 150/95 mmHg and-all were free
of target organ damage (no cerebrovascular or
coronary artery disease; no left ventricular hypertrophy and normal concentrations of plasma
creatine and electrolytes).
Sodium intake was controlled by avoiding added
salt, apart from that used in cooking, for 3 days
before admission. The normotensive subjects were
Key words: blood pressure, exercise, heart rate,
noradrenaline, sympathetic activity.
Introduction
The increase in sympathetic activity during
physical exercise is accompanied by increased
concentrations of venous plasma noradrenaline
(Vendsalu, 1960). Sudden cessation of physical
activity demands rapid homeostasis by the cardioPresent address: Department of Materia Medica,
Stobhill General Hospital, Glasgow G2 1, Scotland,
U.K.
Correspondence: Professor W.A. Littler, Department
of Cardiovascular Medicine, East Birmingham Hospital,
Bordesley Green East, Birmingham B9 5ST,U.K.
37
0143.522 1/80/0 lOO37-07SI .SO/ I
R . D. S. Watson el al.
38
TABLE
1. Details ofpatients 1-1 1 who petformed upright exercise
Patient
no.
Sex
Age
(years)
Body
surface
area
Exercise
workload
M
M
M
I
F
M
M
F
F
M
M
M
I1
Mean 5
SEM
Heart rate
(beats/min)
Systolic blood
pressure (mmHg)
(W)
(m3
2
3
4
5
6
7
8
9
10
Outpatient blood
pressure (mmHg)
Systolic
Diastolic
Control
Exercise
Control
Exercise
79
82
74
75
135
181
133
140
162
178
156
139
120
I24
144
149
132
140
132
186
152
I60
124
172
146
203
220
I86
190
184
262
I89
219
I82
224
193
14457
14956
20557
33
31
46
37
29
46
49
43
44
44
52
2.26
1.97
2.04
1.48
1.83
1.89
1.95
I *42
1.92
1.90
1.74
150
135
I55
70
I70
160
70
55
80
95
75
131
I50
132
I25
140
190
187
I75
157
200
I70
78
95
91
75
86
122
102
101
99
I08
102
41t3
1.855
0.07
1 1 O t 13
16058
96t4
studied during a 3 h attendance at hospital and
observations were commenced 30 min after arterial
cannulation. The hypertensive subjects were
studied 24 h after admission to hospital and whilst
in hospital they received a diet containing 60 mmol
of sodium daily.
Subjects performed upright exercise for 8 rnin on
a bicycle ergometer (Elema Schonander) at a
constant load, determined as the load causing 85%
of maximum heart rate during a previous upright
multistage test to maximum voluntary effort.
Supine exercise
Patients 12- 17 (Table 3) were investigated
during cardiac catheterization. Mean age was 36
years; four were male and patients 12 and 15 were
smokers. They were premedicated with diazepam
(10 mg orally) and sodium intake was not
controlled.
Bicycle exercise was performed for 6 rnin at
constant load, starting 20 min after arterial
cannulation. The workload was determined from a
previous supine exercise test to exhaustion as for
upright exercise.
Arterial pressure and heart rate
Arterial pressure was measured from a fine polyethylene cannula in the brachial artery connected
to a Gaeltec 3EA-a transducer (frequency response
flat to 20 Hz). Heart rate (from electrocardiogram) and blood pressure were recorded on a
Mingograf 81 (Elema Schonander) recorder at 10
100
87
80
97
73
80
97
84+3
111
mm/s. Control observations were made after 10
min rest on the bicycle ergometer, during the last
20 s of each minute during exercise and for 10 rnin
after exercise whilst the subject remained in the
same position. Blood pressure was averaged by
digitizing the last 15 beats recorded.
Plasma noradrenaline
Venous blood (10 ml) was taken into a cooled
syringe from a forearm cannula (Venflon 17G)
without occlusion and transferred to a heparinized
tube in crushed ice until centrifugation at 4°C and
storage at -2OOC within 30 min of sampling.
Plasma noradrenaline was measured within 4
weeks by the method of Henry, Starman, Johnson
& Williams (1975), a radioenzymatic method
utilizing partially purified bovine phenylethanolamine N-methyltransferase. Samples from each
patient were analysed as one batch in duplicate
with internal standards. The method is specific for
noradrenaline and sensitive to 0 . 3 nmol/l. For
upright exercise specimens were obtained immediately before cycling and during minutes 4 and
8 of exercise; after exercise, further specimens were
obtained up to 20 rnin whilst the subject remained
on the ergometer; after exercise, the timing of
samples varied between subjects and was more
frequent in the early post-exercise period; the time
was recorded as the mid-point of sampling. For
supine exercise, specimens were obtained during
the last minute of exercise and at 1 rnin postexercise.
Informed consent for the investigation was
obtained from each patient and the investigations
Plasma noradrenaline during bicycling
were approved by the local Hospital Ethics Committee.
Data analysis
All results are expressed as means f 1 SEM. The
significance of differences in mean values was
tested with a two-tailed Student’s t-test for paired
or unpaired samples as appropriate. The Fisher
exact probability test was used to compare changes
in noradrenaline during supine and upright exercise. (Siegel, 1956.)
Results
Upright bicycle exercise
The average number of blood specimens obtained after exercise was five. In patient 2, three
specimens were obtained within 6 rnin after
exercise before he developed postural hypotension
and had to lie down. Patient 8 became exhausted
after 5 min of exercise.
Personal characteristics are shown in Table 1.
The normotensive subjects were significantly
younger than the hypertensive patients (35 f 3
against 46 f 1 years; P < 0.02) and cycled at a
higher workload (136 f 17 against 85 f 15 W;
0.05
< P < 0.1).
Mean heart rate increased from 84 f 3
beats/min at rest to 144 f 7 beats/min and mean
systolic blood pressure increased from 149 f 6
mmHg at rest to 205 f 7 mmHg during exercise.
Mean plasma noradrenaline (Table 2) before
exercise was 4.18 f 0.94 nmol/l and tended to be
39
higher in the hypertensive than the normotensive
patients (5.55 f 1.50 against 2-54 f 0.48 nmol/l);
the difference was not significant (P > 0.05).
Plasma noradrenaline increased significantly during exercise and the mean concentration at 8 rnin
was 8.92 f 1.73 nmol/l (P< 0.001). In the seven
patients for whom values were available at 4 and
8 rnin during exercise, plasma noradrenaline
increased significantly between these times (at 4
min: 7-44 f 2.66 nm..l/l; at 8 min: 8.80 f 2.54
nmol/l; P < 0.02).
An increase in plasma noradrenaline occurred in
all patients after upright exercise (Table 2). Mean
plasma noradrenaline increased significantly from
8.92 f 1-72 nmol/l at the end of exercise to a
maximum level of 11-89 & 2.23 nmol/l after
exercise (P< 0.01). The increase varied from 0 - 4 7
to 8.15 nmol/l. The median time of the peak
plasma noradrenaline was 108 s after exercise and
varied widely from 39 to 4 18 s.
The range of plasma noradrenaline levels at rest
and during exercise was wide (Table 2). Fig. 1
shows changes in plasma noradrenaline as a
percentage of the maximum in each patient,
together with heart rate and systolic blood pressure.
Observations for patient 2, who had postural
hypotension after exercise, have been excluded. On
stopping exercise, both heart rate and systolic
blood pressure decreased rapidly whereas plasma
noradrenaline tended to increase during the first 2
rnin before decreasing towards control values by
about 12 min. At 6 rnin after exercise, systolic
blood pressure decreased significantly below the
pre-exercise value (control: 149 f 6 mmHg; 6 rnin
post-exercise: 139 f 4 mmHg; P < 0.05); heart
TABLE2. Plasma noradrenaline concentrations and times of maximum values Mer upright
exercise
Patient
Plasma noradrenaline (nmol/l)
no.
Before exercise
During last minute
of exercise
Maximum aRer
exercise
Time of maximum
plasma noradrenaline
aRer exercise
(S)
2
3
4
5
6
7
8
9
10
I1
3.25
4.08
1.89
1.71
1.71
12.82
3.37
3.84
3.19
4.49
5.61
8.27
8.86
4.90
3.54
5.49
23.39
5.79
10.04
6.08
6-67
15.06
11.10
9.92
9.75
4.67
9-92
30.60
6.26
18.19
6.9 1
7.44
16.07
I72
I I5
I78
418
95
95
50
Mean f SEM
4.18 f 0.94
8.92 f 1.73
11.89 f 2.23
138 f 32
I
50
39
203
108
R . D. S . Watson el a / .
40
The disappearance rate of noradrenaline from
plasma was followed in eight patients (nos. 1, 3, 5,
6, 7, 8, 10 and 11). The decline was exponential
with a time constant (ti) which varied from 3.0 to
19.7 (mean 9.2 i-1.9)min.
Supine exercise
Patients’ details are shown in Table 3. Mean
workload was 118 f 19 W; mean exercise heart
rate was 153 C 9 beatshin; mean exercise systolic
blood pressure was 185 f 14 mmHg. When
plasma noradrenaline at the end of exercise was
compared with the concentration 2 min after
stopping, a decrease was observed in five of the six
patients. The fall in mean concentrations, from
4.44 f 1.06 nmol/l at the end of exercise to 3.02 f
1.04 nmol/l 2 min after stopping, was not
statistically significant (0.05 < P < 0.1).
. .150
0
8
4
Cornparisori of supine and upright exercise
12>12
Tinic post-cxcrcisc
(rnin)
FIG. 1. Mean plasma noradrenaline (as a percentage of
the maximum concentration attained), systolic blood
pressure and heart rate during and after upright exercise
in patients 1-1 1. Vertical bars indicate 1 SEM; only the
largest values are indicated during exercise.
rate remained significantly elevated above control
rates up to 10 min after exercise (control heart rate:
84 f 3 beatshin; 10 min post-exercise: 100 f 4
beats/min; P < 0.001).
Changes in plasma noradrenaline between the
end of supine exercise and 2 min post-exercise
(patients 12-17) were compared with changes in
seven of the eleven patients who performed upright
exercise and in whom plasma noradrenaline
measurements were made between 1.5 and 2.5
min after exercise (patients 2, 3,5,6,9, 10 and 11).
After upright exercise, plasma noradrenaline
increased in six of seven patients, whereas after
supine exercise a decrease occurred in five of six
patients. The probability of this distribution, or a
more extreme one, was 0.025 (Fisher exact
TABLE3. Details of patients and plasma noradrenaline concentrations (patients 12-1 7 , who perfortned supitre
exercise)
Subject
no.
Age
Sex
(years)
Body
surface
area
Diagnosis
Workload
(W)
(m3
I2
13
36
42
M
M
2.06
I .98
14
33
F
1.47
I5
41
35
F
16
M
1.78
2.11
17
31
M
2.19
Mean f
SEM
36 f 2
1.93 f O . 1 1
Non-cardiac chest pain
Two vessel coronary artery
disease
Atrial xptal defect (shunt
1.3:1)
Non-cardiac chest pain
Coronary artery disease
excluded
Non-cardiac chest pain
Maximum
exercise
hean rate
(beatshin)
Plasma noradrenaline
At end of
exercise
(nmolll)
2 min rest
post-exercise
(nmol/l)
I40
I30
157
169
5.49
7.21
2.01
7.80
55
I77
7.09
3.66
70
170
118
157
1.95
3.84
1.77
2.4 I
145
I39
I .08
0.47
118 f 19
I53 f 9
4.44 f 1.06 3.02 f 1.04
Plasma noradrenaline during bicycling
probability test). The mean percentage increase in
plasma noradrenaline after upright exercise (21 &
15%) was significantly different from the mean
decrease observed after supine exercise (35 & 12%;
P < 0.025), indicating that the patterns of change
in plasma noradrenaline after upright and supine
exercise were different.
Discussion
It is important to emphasize that the normotensive
subjects were significantly younger than the hypertensive subjccts who performed upright bicycle
exercise; although differences with respect to
exercise heart rate, exercise workload and resting
plasma noradrenaline concentrations were . not
significant, we d o not consider that it is possible to
compare the changes in two groups of this size,
except to demonstrate that they were qualitatively
similar. The high plasma noradrenaline concentrations in patient 6 are unexplained; there were
no clinical features of phaeochromocytoma and
urinary catecholamine excretion was normal.
We attempted to standardize the workload in
each subject, since the increase in plasma noradrenaline during exercise is related to the intensity
of work (Kotchen, Hartley, Rice, Mougey, Jones &
Mason, 1971). This was only partly successful in
that the exercise heart rate varied from 1 1 1 to 18 1
beats/min. However, the approximately twofold
increase in plasma noradrenaline during exercise
suggested that the intensity of exercise was
sufficient to cause a substantial increase in sympathetic activity.
The increase in plasma noradrenaline during
exercise confirms the observations of others
(Vendsalu, 1960; Kotchen et al., 1971). However,
our observations showed that after stopping bicycle
exercise and remaining in the upright position,
plasma noradrenaline increased during the early
post-exercise period in every subject; the increase
between the end of exercise and the maximum concentration of plasma noradrenaline after exercise
was statistically significant. Most investigators
have examined changes in plasma noradrenaline
during, rather than aAer, exercise; however,
Cryssanthopoulos, Barboriak, Fink, Stekiel &
Maksud (1978) noted that plasma noradrenaline
was higher 5 min after exercise than at the end of
exercise, although the increase was not significant.
The timing of the peak plasma noradrenaline
after upright exercise varied considerably between
individuals. Although the exact timing of samples
was not standardized, at least one specimen was
41
taken within 1 min and three specimens within 5
min after exercise. More frequent sampling would
define the peak time more accurately; the fact that
an increase was observed in each subject without
more frequent sampling suggests that the increase
is sustained for 1-2 min.
There are a number of possible explanations of
why plasma noradrenaline concentrations were
highest after exercise. In the' upright position,
reduced venous return to the heart due to pooling
of blood in the vasodilated lower limbs, together
with the fall in blood pressure on stopping exercise,
will result in reduced stimulation of the low
pressure cardiopulmonary and the high pressure
sino-aortic receptors and a reflex increase in
sympathetic vasoconstrictor activity would be
expected. Although the activity of the sino-aortic
baroreflex is inhibited during exercise, its activity
returns quickly on stopping (Bristow, Brown,
Cunningham, Howson, Strange Petersen, Pickering
& Sleight, 1971). Changes in the level of sino-aortic
baroreceptor resistance (Carlsten, Folkow,
Grimby, Hamberger & Thulesius, 1958; Bjurstedt,
Rosenhamer & Tyden, 1975) and alterations in
cardiopulmonary afferent discharge rate have
greater effects on systemic and renal vascular
resistance at low than at high carotid sinus pressures in the dog, indicating an important interaction between the reflexes (Mancia, Shepherd &
Donald, 1976). The observation that the pattern of
change in plasma noradrenaline differed between
supine and upright exercise would support a reflex
increase in sympathetic activity since more marked
pooling of blood after upright exercise would be
expected.
Two other explanations need to be considered;
first, an increase in plasma noradrenaline after
upright exercise could be due to delayed washout
of noradrenaline from the tissues. However, this
mechanism would not explain the difference observed between supine and upright exercise. The
plasma noradrenaline concentrations during
upright exercise were much higher than during
supine exercise and an alternative explanation is
that the mechanisms responsible for clearance of
noradrenaline from the circulation may become
saturated at high plasma concentrations (Vane,
1969); this would explain the fall in plasma noradrenaline after supine exercise but would not
explain the increase observed after upright exercise.
The disappearance rate of noradrenaline in our
patients was considerably longer than that seen
after cessation of a 10 h infusion of noradrenaline
in normal resting subjects (Fitzgerald, Hossman,
42
R . D. S . Watson et al.
Hamilton, Reid, Davies & Dollery, 1978). The
slower decline after exercise is consistent with
continuing sympathetic activity or could be due to
a reduction in noradrenaline clearance.
Although circulating concentrations of noradrenaline at rest are unlikely to have significant
effects on heart rate or blood pressure, those
achieved after exercise were similar to the concentrations, which, after intravenous infusion, caused
an increase in blood pressure (Dargie, Davies,
Dean, Dollery, Maling & Reid, 1977). The delay in
reaching maximal concentrations of plasma noradrenaline after upright exercise may be relevant to
the development of exercise-induced asthma and
arrhythmias. The effects of a-adrenoreceptor antagonists in preventing exercise-induced asthma are
consistent with the existence of an abnormal
balance between a- and Preceptor tone in bronchial smooth muscle in susceptible individuals
(Bianco, Griffin, Kamburoff & Prime, 1974;
Gross, Souhrada & Farr, 1974; Patel, Kerr,
MacDonald & MacKenzie, 1976). Symptoms
occur most commonly after stopping exercise at a
time when plasma noradrenaline concentrations are
higher and it is possible that meceptor effects of
sympathetic stimulation or circulating plasma noradrenaline may explain why bronchoconstriction
becomes more severe at this time. Anderson, Lee,
Campion, Amplatz & Tuna (1972) and Goldschlager, Cake & Cohn (1973) observed that the
highest incidence of ventricular arrhythmias occurred shortly after exercise stress testing, and again it
is possible that the high sympathetic tone and
plasma noradrenaline concentration at this time
may be important in causing arrhythmias. Additionally, plasma free fatty acid changes after exercise
resemble those of plasma noradrenaline, reaching a
maximum within 5 min of stopping exercise
(Carlson & Pernow, 1961); although decreased
effiux from the circulation is partly responsible for
this increase, increased mobilization due to sympathetic activity may contribute (Havel, Naimark
& Borchgrevink, 1963).
Finally, our observations emphasize that the
timing of blood specimens is of critical importance
in comparing the effects of drugs on exerciseinduced changes in plasma noradrenaline, not only
because the sequential changes in plasma noradrenaline are rapid and the timing of the peak
noradrenaline concentration varies considerably
between individuals, but also because the effects of
drugs on plasma noradrenaline Concentrations
during exercise may be different from those on the
concentrations after exercise.
Acknowledgments
We thank Dr S. Hill for technical assistance and
Miss A. Strong for secretarial assistance. We are
grateful for financial support from the Wellcome
Trust, the British Heart Foundation and May and
Baker Ltd.
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