Clinical Science and Molecular Medicine (1975) 49, 503-506.
SHORT COMMUNICATION
Arterial catecholamines in hypoxic exercise in man
L. J. CLANCY, J . A. J. H . CRITCHLEY,") A. G . LEITCH, B. J. KIRBY,
A. UNGAR") A N D D. C. F L E N L E Y
Department of Medicine at the Royal Infirmary, University of Edinburgh, and
Department of Pharmacology, University of Edinburgh, Edinburgh, Scotland
(Received 14 August 1975)
aline potentiates the ventilatory response to hypoxia
in resting man probably by a direct action on the
arterial chemoreceptors (Cunningham, Hey, Patrick & Lloyd, 1963). It has been postulated (Cunningham, Spurr & Lloyd, 1968) that catecholamines
play a role in the increased ventilatory drive in
hypoxic exercise. However, there are no data, to our
knowledge, for the concentrations of arterial plasma
catecholamines in normal man during hypoxic
exercise. Accordingly, this study was undertaken to
furnish such data during mild and moderate hypoxic
exercise.
SummarY
1. We measured the minute ventilation and arterial blood catecholamine concentrations in four
normal men standing and at two levels of moderate
treadmill exercise breathing 14% oxygen or air.
2. Minute ventilation was significantly higher
during hypoxic exercise than during normoxic
exercise at an oxygen uptake of 1500 ml/min.
3. Arterial plasma noradrenaline during hypoxic
exercise at an oxygen uptake of 1500 ml/min was
significantly greater than at rest.
4. Arterial plasma noradrenaline during normoxic
exercise at an oxygen uptake of 1500 ml/min was not
elevated above the resting concentration.
5 . The results are compatible with the suggestion
that increased concentrations of arterial plasma noradrenaline contribute to the hypoxic potentiation
of the respiratory response to moderate exercise.
Methods
Four healthy non-athletic men, aged 22-40 years,
gave informed consent to the study. A catheter was
inserted into the left brachial artery to enable arterial
blood sampling for measurement of blood gas
tensions, pH and catecholamines. We determined
minute ventilation
oxygen uptake (VoJ and
carbon dioxide output (Vcoz), and, using a Varian
M3 mass spectrometer, continuously recorded endtidal oxygen and COz tensions.
Resting measurements were made while the subject
stood on a treadmill before exercising and are
therefore not basal. Each subject had been breathing
14% oxygen or air for 20 min before any sampleswere
obtained.
The exercise studies consisted of four separate 30
min periods in a day with intervals of at least 30 min
at rest. Each subject walked at 1.5 and 2.0 m/s on a
level treadmill, breathing 14% oxygen or air, and
Key words: catecholamines, exercise.
(vE),
Introduction
The respiratory minute volume is proportional to
oxygen uptake in sub-maximal steady-state exercise
(Grodins, 1950) and the respiratory response is
potentiated by breathing a low oxygen mixture
(Asmussen & Nielsen, 1958). Both exercise (Vendsalu, 1960) and hypoxia (Cunningham, Becher &
Kreuger, 1965)raise the concentrations of catecholamines in plasma. Intravenous infusion of noradrenCorrespondence: Dr L. J. Clancy, Department of Medicine,
Royal Infirmary, Edinburgh EH3 9XW, Scotland.
503
L. J. Clancy et al.
504
steady-state measurements were made during
minutes 7, 23 and 26 of each period. The mean value
of the three measurements was taken as the value for
that individual.
Analytical methods and apparatus were as previously described (King, Cooke, Leitch & Flenley,
1973). Plasma catecholamines were estimated by a
spectrophotofluorimetric (trihydroxyindole) technique (Vendsalu, 1960) after extraction on to an
Amberlite CG-120 column and elution with hydrochloric acid. As arterial plasma concentrations were
low, the eluates were concentrated by low-temperature evaporation under vacuum. We obtained a 90%
recovery rate when 60-600 pmol of noradrenaline or
adrenaline was added to a 10 ml plasma sample from
a resting subject breathing air. Spectrophotofluorimetric assay gave a standard deviation of 0.5 nmol/l
on twelve replicate estimates on a single sample of
concentration 5.0 nmol/l.
The differences between mean values were compared by Student’s t-test.
period standing and the mean values for each exercise
period are shown in Table 1 .
Catecholamines
Noradrenaline. When the subjects were standing,
the plasma noradrenaline concentrations were consistently greater when breathing 14% oxygen than
when breathing air but the differences were not
statistically significant (P> 0.1). Walking at 1.5 m/s
while breathing 14% oxygen or air did not significantly elevate plasma noradrenaline but plasma
noradrenaline was significantly elevated (P< 0.01)
when subjects walked at 2.0 m/s breathing 14%
oxygen. Normoxic walking at 2.0 m/s did not
significantly elevate plasma noradrenaline ( P > 0.1).
Adrenaline. The adrenaline concentrations did not
exceed 15% of the total catecholamines in any of our
experiments and so remained undetectable at rest
and during exercise.
Ventilation
Results
The gas tensions, pH and plasma noradrenaline
concentrations of arterial blood, the m-inute ventilation (VE)and oxygen consumption (VoJ for each
VEwas not consistently altered by breathing 14%
oxygen at rest. Duringexercise VEwas greater in each
subject at both levels of exercise when breathing 14%
oxygen than when breathing air. The regression
TABLE
1 . Respiratory and arterial blood data for four normal men standing and walking at two speeds, breathing 14% oxygen
or air
Results are expressed as the mean value and range for individuals. n=number of measurements.
Minute Respiratory
Plasma
Oxygen uptake ventilation exchange noradrenaline
(ml/min)
(l/min)
ratio
(nmol/l)
Speed n
(m/s)
Breathing
14% oxygen
Breathing
air
0
4
1.5
12
2
12
0
28 1
(237-373)
1012
(827-1291)
1414
(1167-1677)
Po2
(kPa)
10.2
0.96
(8.7-1 1.5) (0.79-1.3)
28.0
0.92
(22.1-28.4) (0.86498)
2.45
(0.9-3’6)
2.52
(1.9-3.0)
7.8
(7.1-8.0)
6.6
(6.4-6.7)
47.0
1.08
(43’948.9) (0.95-1.3)
6.13
(4.2-10.8)
6.8
(6.1-8.3)
PCO~
(kPa)
4.8
(44-5.5)
PH
7.42
(7.46-7.39)
5.0
7.41
(4.5-5.3) (7447.4)
5.0
(4.1-5.2)
7.43
(7.45-7.4)
4
346
(293-408)
10.9
0.78
(9.6-1 1.5) (0.71487)
1.85
(0.8-3.1)
12.7
5.0
(11.6-13.2) (4.8-5.3)
7.43
(7.46-7.40)
1.5
12
1040
(868-1275)
26.0
0.83
(21’6-27.5) (0.78491)
255
(1.9-3.3)
13.1
5.2
(12.8-13.3) (4.9-5.6)
7.42
(7’44-740)
2
12
1584
(1336-1973)
42.5
0.95
(38.747.7) (0.89-1.06)
42
(1.7-9.8)
12.6
5.1
(11.3-13.5) (4.5-5.7)
744
(7.46-7.42)
Noradrenaline in hypoxic exercise
equations for the VE- Voz relationship were VE =
(0.032 & 04lo3) Vo2- (2.03 k4.26), correlation coefficient 0.91 for the hypoxic line and pE = (0.02rt
0.004)Vo2+(5.15 f 4.26), correlation coefficient 0.84,
for the normoxic line. The 95 % coddence limits of
these lines overlap when Vo2is less than 1100 ml/min
but are clearly separated when Poz is 1500 ml/min,
showing that VE is significantlygreater during hypoxia at the higher exercise levels. The mean arterial POZ
was similar during the two hypoxic exercise periods
(Table 1) but one subject hyperventilated during
hypoxia when walking at 2.0 mls. He achieved the
highest minute ventilation and arterial noradrenaline
concentrations, had a respiratory exchange ratio of
1.3, but did not have the highest oxygen uptake. He
also hyperventilated during hypoxia when standing
and his respiratory exchange ratio was then 1.34.
Discussion
Hypoxic stimulation of ventilation both at rest
and on exercise is eliminated by removal of the carotid bodies in man (Lugliani, Whipp, Seard & Wasserman, 1971). The work of Cunningham et al. (1963) in
man and Joels & White (1968) in cats showed that
infused noradrenaline significantly altered ventilation
only during hypoxaemia. These studies suggested
that the arterial chemoreceptors may play a direct
role in the ventilatory response to infused noradrenaline. Studies in man (Stone, Keltz, Sarkar &
Singzon, 1973) have shown that the ventilatory response to infused noradrenaline is not blocked by
pentolamine or propranolol despite adequate inhibition of the blood pressure response with a-receptor
blockade. In contrast, Wasserman, Whipp & Castagna (1974) showed that isoprenaline-induced hyperventilation can be blocked in the dog by propranolol
and is independent of inspired oxygen tension and
indeed of the carotid bodies. The latter authors
believe that the hyperpnoea is likely to be due to the
increased cardiac output that they observed. The
mechanism of action of circulating noradrenaline
therefore remains uncertain. We believe that the
balance of evidence suggests that in man noradrenaline has an action similar to hypoxia and is likely
to act through the carotid bodies.
We were therefore interested to establish the concentrations of noradrenaline in the blood perfusing
the carotid bodies. We have based our studies on
estimates of catecholamines in arterial plasma
because it has been shown (Ginn & Vane, 1968) that
505
20-30 % of circulating noradrenaline is removed in
one passage through the lungs and that 90% of both
noradrenaline and adrenaline is cleared from arterial
blood on passing through the skin and muscle (Celander & Mellander, 1955). Thus the concentration of
noradrenaline in a peripheral venous sample merely
represents the local release of noradrenaline from the
tissue drained by the superficial vein subjected to
venepuncture.
Cunningham et al. (1963) and Patrick (1964)
infused noradrenaline at doses from 5 to 12 pglmin
in normal resting men. Estimates of circulating
noradrenaline were not made in these studies. However, assuming cardiac output to be about 5 l/min
and accepting the usual clearance of noradrenaline
by lungs and tissues, we estimate that the increase in
arterial plasma noradrenaline at an infusion rate of
5 pglmin was of the order of 54-7.5 nmol/l in their
studies, which is twice the increase we saw in hypoxic
exercise. Reference to the ventilatory response curves
of Patrick (1964) shows by interpolation that ventilation was increased by about 50% when noradrenaline
was infused at 5 pglmin at the gas tensions that obtained in our experiments. His studies were made at
rest and although it seems possible that noradrenaline would exert a greater influence during hypoxic
exercise (Horbein & ROOS,1962) we suggest that
even if the sensitivity to noradrenaline remained
unchanged the increased concentrations seen may
have contributed to the increase in ventilation in our
subjects during hypoxic exercise.
Acknowledgments
We thank Professor K. W. Donald for laboratory
facilities, Miss E. Paxton for technical help and Sister
A. McLay for nursing help. L.J.C. held an S.H.H.D.
Research Fellowship and J.A.J.H.C. held a Faculty
of Medicine Gunning Research Scholarship.
References
ASMUSSEN,
E. & NIELSEN,
M. (1958) Pulmonary ventilation
and effect of oxygen breathing in heavy exercise. Acta
Physiologica Scandinauica, 43, 365-378.
CELANDER,
0. & MELLANDER,S. (1955) Elimination of
adrenaline and noradrenaline from the circulating blood.
Nature (London), 176,913-974.
CUNNINGHAM,
D.J.C., HEY,E.N., PATRICK,
J.M. & LLOYD,
B.B. (1963) The effect of noradrenaline infusion on the
relation between pulmonary ventilation and the alveolar
PO2 and PC02 in man. Annals of the New York Academy
of Sciences, 109,756-770.
CUNNINGHAM,
D.J.C., SPURR,D. & LLOYD,B.B. (1968)
506
L. J. Clancy et al.
The drive to ventilation from arterial chemoreceptors in
hypoxic exercise. Arterial Chemoreceptors, pp. 301-323.
Ed. Torrence, R.W. Blackwell Scientific Publications,
Oxford.
F. (1965)
CUNNINGHAM,
W.L., BECHER,E.J. & KREUGER,
Catecholamines in plasma and urine at high altitude.
Journal of Applied Physiology, 20, 607.
GINN,R. & VANE,J.R. (1968) Disappearance of catecholamines from the circulation. Narure (London), 219, 740742.
GRODINS,F.S. (1950) Analysis of factors concerned in
regulation of breathing. Physiological Reviews, 30, 220239.
HORBEIN,
T.F. & Roos, A. (1962) Effect of mild hypoxia on
ventilation during exercise. Journal of Applied Physiology,
17, 239-242.
JOELS,N. & WHITE,H. (1968) The contribution of the arterial
chemoreceptors to the stimulation of respiration by adrenaline and noradrenaline in the cat. Journal of Physiology
(London), 197, 1-24.
KING, A.J., COOKE,N.J., LEITCH,A.G. & FLENLEY,
D.C.
(1973) The effects of 30% oxygen on the respiratory
response to treadmill exercise in chronic respiratory failure.
Clinical Science, 44, 151-162.
LUGLIANI,R., WHIPP, B.J., SEARD,C. & WASSERMAN,
K.
(1971) Effect of bilateral carotid body resection on ventilatory control at rest and during exercise in man. New
England Journal of Medicine, 20,1103-1 11 1.
PATRICK,
J. (1964) Some factors affecting respiration in man.
D.Phil. thesis, Oxford.
STONE,D.J., KELTZ,H., SARKAR,
T.K. & S ~ G Z O J.
N ,(1973)
Ventilatory response to alpha-adrenergic stimulation and
inhibition. Journal of Applied Physiology, 34, 619-623.
VENDSALU,
A. (1960) Plasma concentrations of adrenaline
and noradrenaline during muscular work. Acra PhysioZogica
Scandinavica, 49 (Suppl. 173), 57-69.
WASSERMAN,
K., WHIPP,B.J. & CASTAGNA,
J. (1974) Cardiodynamic hyperpnoea: hyperpnoea secondary to cardiac
output increase. Journal of Applied Physiology, 36,4514164.