Catecholamines contribute to exertional dyspnoea and to the ventilatory response to exercise in normal humans

Size: px

Start display at page:

Download "Catecholamines contribute to exertional dyspnoea and to the ventilatory response to exercise in normal humans"

Irene Burns
6 years ago
Views:

1 European Heart Journal (1997) 18, Catecholamines contribute to exertional dyspnoea and to the ventilatory response to exercise in normal humans A.L. Clarkf, S. Galloway*, N. MacFarlane*f, E. Hendersonf, T. Aitchisoni and J. J. V. McMurrayt * Department of Physiology, University of Glasgow, ^Department of Cardiology, Western Infirmary, %Department of Statistics, University of Glasgow, Glasgow, U.K. Background Exogenous catecholamine administration in humans stimulates ventilation. The present study was designed to investigate whether increased endogenous catecholamine release influences objective measures of ventilation and subjective measures of breathlessness in normal subjects. Methods Yohimbine, a pre-synaptic a 2 adrenoceptor antagonist, or placebo was administered to 10 normal male subjects in a double-blind cross-over fashion. Ventilation and metabolic gas exchange were measured during steady state exercise at 60% of previously determined maximal oxygen consumption. Venous lactate and noradrenaline were measured during exercise. Subjects' sensation of breathlessness and fatigue were recorded using visual analogue scales. Results Plasma noradrenaline was higher following yohimbine administration (at 6 min exercise; Introduction Experimental work in resting animals suggests that catecholamines stimulate ventilation 1 ' 1. Infused catecholamines have a similar effect in resting humans' 2^11. This may be of relevance to pathological conditions such as chronic heart failure where excessive adrenergic drive is associated with an excessive ventilatory response to exercise and dyspnoea. The present study was designed to investigate whether increased endogenous catecholamine release influences objective measures of ventilation and subjective measures of breathlessness in normal subjects. Catecholamine release was increased by pre-treatment with yohimbine. Yohimbine is a presynaptic a 2 adrenoceptor antagonist and thus removes Revision submitted 19 May 1997, and accepted 30 May Correspondence: Dr A. L. Clark, Department of Cardiology, Western Infirmary, Dumbarton Road, Glasgow Gil 6NT, U.K X/97/ $18.00/ ± 0-56 nmol.r' vs 8-74 ± 1-53; P<005). Oxygen consumption was unchanged, but ventilation was greater throughout exercise following yohimbine. The sensation of exertion was greater following yohimbine, and at any given level of ventilation, the sensation of exertion was greater. Conclusions Yohimbine administration causes increased noradrenaline release. This is associated with an increased ventilatory response and an increase in the sensation of exertion during steady state exercise. An increase in circulating noradrenaline might be a mechanism for both increased ventilation and pathological conditions of breathlessness such as chronic heart failure. (Eur Heart J 1997; 18: ) Key Words: Yohimbine, ventilation, exertional dyspnoea. the normal negative feedback of noradrenaline on its own release at adrenergic synapses. Method The study protocol was approved by the local ethics committee. All subjects gave fully informed, signed consent to the study. Ten male subjects aged years were recruited from hospital staff. None was known to have any past medical history, and none was receiving current medication, nor had ever taken a- or y?-adrenoceptor blockers. Subjects were asked to attend on three occasions. At the first visit, subjects undertook an incremental treadmill exercise test to exhaustion with metabolic gas exchange measurements to derive peak Vo 2. This also allowed the subjects to become familiar with the 1997 The European Society of Cardiology

2 1830 A. L. Clark et al. apparatus and with the subjective symptom scaling systems (see below). Subjects attended at the same time of day on two further occasions, separated by at least 72 h. The subjects rested supine, and an intravenous cannula was placed in an antecubital vein. Fifteen milligrammes of yohimbine or matching placebo was administered orally in a double-blind fashion. This dose was chosen to allow peripheral increases in noradrenaline without inducing central nervous system effects 15 ' 61. After a further 45 min resting supine, subjects then undertook fixed-rate submaximal treadmill exercise, consisting of a 2 min warm-up period followed by 6 min at 70% of the predetermined peak Vo 2. Heart rate was measured at 1 min intervals. Metabolic gas exchange During the exercise tests, patients breathed through a one-way valve connected to a metabolic measurements cart (Beckman NMC, Horizon Sensor Medics System, Anaheim, CA, U.S.A.). Every 30 s, minute ventilation (Ve), oxygen consumption (Vo 2 ), carbon dioxide production (Vco 2 ) and respiratory frequency (f) were measured. Tidal volume (Vt; Ve/f) and respiratory exchange ratio (Vco 2 /Vo 2 ) were derived. Subjective symptom scaling The subjects were asked to indicate their sensation of breathlessness using a visual analogue scale and a modified Borg (CR10) scale using the method described by Adams et al. l7] A similar visual analogue scale was used to determine subjects' feelings of exertion or effort. Symptoms were recorded at the end of the 2 min warm-up period and at the end of the 3rd and 6th min of submaximal exercise. Blood sampling Blood was sampled from the indwelling venous cannula. Peripheral venous whole blood lactate concentration was measured with the subjects erect before the onset of treadmill exercise and at the end of the 6th min of constant rate exercise. Lactate was measured by an enzymatic fluorometric analyser (Analox GM7 Analyser, Analox Instruments, London, U.K.). Noradrenaline was measured before administration of treatment (placebo or yohimbine), 45 min post-treatment both supine and erect, and at the end of the 3rd and 6th min of constant rate exercise. Noradrenaline was measured by a radioenzymatic method 181. Statistical methods Statistical analysis of ventilatory data was performed by repeated measures analysis of variance, examining for time effect and treatment-time interactions. All other analyses were by paired t-test with appropriate correction for multiple comparisons. The null hypothesis was rejected when the P value was <005. Results are quoted as means (SEM). Results Noradrenaline Plasma noradrenaline increased during exercise. This increase was greater after yohimbine than after placebo, reaching statistical significance at peak exercise (Fig. 1). Heart rate was significantly higher following yohimbine at 3min (146-9 (4) vs (5-3); /><005) and 6min (167-4 (4-9) vs (5-7); /><005), suggesting an adrenergic effect of yohimbine. Lactate levels were unchanged by yohimbine administration. Metabolic gas exchange There were no differences between pre-exercise and baseline (end of 2 min warm-up) values for any of these variables between the two exercise tests. No treatmenttime interactions were demonstrated, but all variables showed a significant time effect. Oxygen consumption A plateau of oxygen consumption was reached at 3 min of exercise. Mean Vo 2 at 6 min of steady state exercise after placebo was 36-5 ml. kg~'. min~ ' (68% of predetermined peak Vo 2 ). There was no difference between the yohimbine and placebo periods. Minute ventilation Ventilation was significantly greater during exercise with yohimbine compared with placebo (see Fig. 2). There was a trend to an increase in both Vt and f after yohimbine, but neither of these changes reached statistical significance. As a consequence of the greater minute ventilation and unchanged Vo 2 the ventilatory equivalent for oxygen (Ve/Vo 2 ) was greater following yohimbine administration. Carbon dioxide production Vco 2 increased more following yohimbine than with placebo (/ > =005). As a consequence, the respiratory exchange ratio rose more following yohimbine than during the control period. Subjective symptom scaling The modified Borg score was significantly higher at 3 min exercise after yohimbine than after placebo (2-17 (0-41) vs 2-65 (0-41); /><005). The visual analogue scale score for breathlessness tended to be higher after

3 Contribution of catecholamines 1831 a t o c S Rest 1 Rest 2 Standing 4 min 6 min Figure 1 Plasma noradrenaline during exercise following yohimbine administration ( ) or placebo ( ). **P< Time (min) Figure 2 Ventilation expressed as a change from resting values during exercise. Symbols as for Fig. 1. */ > <005 **/»<0-01. yohimbine, but this difference was not statistically significant. The visual analogue scale score for exertion was significantly greater following yohimbine at 3 min (36-6 (6-6) vs 41-9 (6-6); P<005) and 6 min exercise (450 (60) vs 51-8 (5-5); / > <005). Figure 3 shows the relationship between visual analogue scale exertion score and minute ventilation; these results suggest that at any given minute ventilation, the subjective sensation of exertion is greater following yohimbine. Discussion In normal humans, infusion of noradrenaline causes an increase in minute ventilation due to an increase in both minute ventilation and respiratory rate 12 " 41. This action is short lived as hyperventilation relative to arterial blood gases is induced. The consequent fall in arterial carbon dioxide (Paco 2 ) results in a reduction in ventilatory stimulus. If Paco 2 is prevented from falling, prolonged stimulation of ventilation is seen' 9 '. The ventilatory effects of noradrenaline are mediated by peripheral chemoreceptor stimulation, probably via /?,- adrenoceptors 13 ' 101. Clonidine, an a 2 adrenoceptor agonist, seems to have depressive effects on ventilation 1 "- 12 '. The effects of increased noradrenaline release on ventilation and the sensations of fatigue and breathlessness during exercise are not known. We have previously shown that during exercise in normal humans, a sustained rise in ventilation during

4 1832 A. L. Clark et al. Ventilation (l.min Figure 3 The relationship between ventilation and perceived exertion. Following yohimbine, the relationship is shifted to the left. exercise can be maintained, presumably because the fall in Paco 2 is buffered by the continued production of CO 2 by the exercising muscle' 131. The results of the present study show that yohimbine causes an increase in minute ventilation, which is sustained during continued exercise. Yohimbine treatment was associated with an increase in carbon dioxide production and the ventilatory equivalent for O 2. There was no change in Vo 2 and no change in blood lactate, which suggests that yohimbine is causing hyperventilation by an increase in sympathetic stimulation, rather than by any alteration in muscle metabolism. The hyperventilation is accompanied by an increase in the sensations of dyspnoea and effort. Kjaer et al. found that curarised normal subjects at matched workloads had increased plasma noradrenaline levels and perceived exertion scores compared to control' 14 '. It may be that the increased central command to ventilation due to curarisation causes the increased noradrenaline release, but it is possible that increase in catecholamines modulate central perception of exertion. Time course of effect The greatest effect of yohimbine was seen before steady state metabolic gas exchange was reached (see Fig. 2), and yet the yohimbine effect on circulating noradrenaline was seen only towards the end of steady state exercise (Fig. 1), by which time the incremental effect of yohimbine on ventilation was wearing off. Yohimbine has its effects at the level of the synapse, and circulating catecholamines will lag behind release from synapse. There are a number of possible explanations for the time course of the yohimbine effect on ventilation. (1) It may be that catecholamines stimulate ventilation 100 predominantly early in exercise before steady state has been reached. This effect may be mediated predominantly via the carotid chemoreceptors which are known to be particularly influential during this phase of exercise' 15 '. (2) As exercise proceeds and more noradrenaline is released at nerve terminals, levels may rise high enough locally to compete with yohimbine for a 2 - adrenoceptors, preventing further augmentation of catecholamine release. (3) Hyperventilation with a fall in Paco 2 may negate the effect of increased sympathetic drive. Pathophysiological implications The mechanism underlying the dyspnoea and increased ventilatory response to exercise' 16 ' seen in patients with chronic heart failure is unclear' 17 '. There is sympathetic activation in chronic heart failure and there are raised levels of circulating nordrenaline' 18 " 20 '. The levels we induced in normal subjects are similar to those reported from patients with heart failure in some studies' 21 ', although others have reported somewhat higher levels in heart failure patients on exercise' 22 '. Chemoreceptor activity is increased in chronic heart failure' 23 '. The present findings allow speculation that increased circulating noradrenaline is a possible mechanism for both increased ventilation and breathlessness, possibly mediated through increased chemoreceptor activity. Limitations Yohimbine in larger doses than used in this study has been reported to have mood-altering effects' 5 " 6 ',

5 Contribution of catecholamines 1833 which may influence the perception of dyspnoea and effort. By augmenting heart rate, yohimbine could be causing 'cardiodynamic dyspnoea'' 241, although exogenous catecholamines have been associated with increase ventilation in the absence of any heart rate increase' 31. We did not measure either end-tidal or arterial Paco 2, which could have contributed data to support the concept of yohimbine-induced hyperventilation with respect to blood gases. Nevertheless, this study shows that an increase in plasma noradrenaline using yohimbine results in increased ventilation during exercise and an increase in the subjective sensation of dyspnoea. Catecholamines may contribute to the increased ventilation and dyspnoea of disease states. We are grateful to Professor Sheila Jennett for her helpful comments. References [1] Young IM. Some observations on the mechanism of adrenaline hyperpnoea. J Physiol 1957; 135: [2] Wheelan RF, Young IM. The effect of adrenaline and noradrenaline infusions on respiration in man. Br J Pharmacol 1953; 8: [3] Heistad DD, Wheeler RC, Mark AL, Schmid PG, Abbond FM. Effects of adrenergic stimulation on ventilation in man. J Clin Invest 1972; 51: [4] Butland RJA, Pang JA, Geddes DM. The selectivity of the p adrenoceptor for ventilation in man. Br J Clin Pharmacol 1982; 14: [5] Charney DS, Heninger GR, Sternberg DE. Assessment of a 2 adrenergic autoreceptor function in humans: effects of oral yohimbine. Life Sci 1982; 30: [6] Goldberg MR, Hollister AS, Robertson D. Influence of yohimbine on blood pressure, autonomic reflexes and plasma catecholamines in humans. Hypertension 1983; 5: [7] Adams L, Chronos N, Lane R, Guz A. The measurement of breathlessness induced in normal subjects; validity of two scaling techniques. Clin Sci 1981; 61: [8] Da Prada M, Zurcher G. Simultaneous radioenzymatic determination of plasma and tissue adrenaline, noradrenaline and dopamine within the femtomole range. Life Sciences 1976; 19: [9] Barcroft H, Basnayake V, Celander O, et al. The effect of carbon dioxide on the respiratory response to noradrenaline in man. J Physiol 1957; 137: [10] Coles DR, Duff F, Shepherd WHT, Whelan RF. The effect of respiration of infusions of adrenaline and noradrenaline into the carotid and vertebral arteries in man. Br J Pharmacol 1956; 11: [11] Ooi R, Pattison J, Feldman SA. The effects of intravenous clonidine on ventilation. Anaesthesia 1991; 46: [12] Jarvis DA, Duncan SR, Segal IS, Maze M. Ventilatory effects of clonidine alone and in the presence of alfentanil in human volunteers. Anesthesiology 1992; 76: [13] Clark AL, Volterrani M, Piepoli M, Coats AJS. Factors which alter the relationship between ventilation and carbon dioxide production during exercise: implications for the understanding of the increased ventilatory response to exercise in chronic heart failure. Eur J Appl Physiol 1996; 73: [14] Kjaer M, Secher NH, Galbo H. Physical stress and catecholamine release. Balliere's Clinical Endocrin Metab 1987; 2: [15] Wasserman K. Breathing during exercise. N Engl J Med 1978; 298: [16] Buller NP, Poole-Wilson PA. Mechanism of the increased ventilatory response to exercise in patients with chronic heart failure. Br Heart J 1990; 63: [17] Clark AL, Poole-Wilson PA, Coats AJS. Exercise limitation in chronic heart failure: The central role of the periphery. J Am Coll Cardiol 1996; 28: [18] Thomas JA, Marks BH. Plasma norepinephrine in congestive heart failure. Am J Cardiol 1978; 41: 233^13. [19] Francis GS, Goldsmith SR, Cohn JN. The relationship of exercise capacity to resting left ventricular performance and basal plasma norepinephrine levels in patients with congestive heart failure. Am Heart J 1984; 311: [20] Cohn JN, Levine B, Olivari MT et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984; 311: [21] Bayliss J, Norell M, Canepa-Anson R, Sutton G, Poole- Wilson P. Untreated heart failure; clinical and neuroendocrine effects of introducing diuretics. Br Heart J 1987; 57: [22] Rajfer SI, Nemanich JW, Shurman AJ, Rossen JD. Metabolic response to exercise in patients with heart failure. Circulation 1987; 76 (Suppl VI): [23] Chua TP, Clark AL, Amadi A, Coats AJS. Relationship between chemosensitivity and the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol 1996; 27: [24] Wasserman K, Whipp BJ, Costagno J. Cardiodynamic hyperpnea secondary to cardiac output increase. J Appl Physiol 1974; 36:

Effects of Exercise Training on Abnormal Ventilatory Responses to Exercise in Patients with Chronic Heart Failure

EXERCISE AND ABNORMAL VENTILATION IN CHF CHF SEPTEMBER/OCTOBER 2000 243 Effects of Exercise Training on Abnormal Ventilatory Responses to Exercise in Patients with Chronic Heart Failure Patients with chronic