Exercise-induced dyspnea in patients with heart failure is related to an abnormal increase in ventilation at any metabolic rate (3,11), which persists after cardiac transplantation (2). Exercise hyperpnea in these patients is explained by an increased dead-space ventilation and also by an increased chemosensitivity and sympathetic nervous system activation (2,3,11). Accordingly, β-blocker therapy in heart failure has been reported to decrease the ratio of ventilation (V˙E) to CO2 production (V˙CO2) during exercise, together with a relative increase in end-tidal PCO2 (PetCO2) (1,21,22). To what extent this mechanism may contribute to aerobic exercise symptoms and limitation in various lung diseases and in normal subjects is not exactly known.
In normal subjects, β-blocker intake is associated with a decrease in submaximal exercise V˙E and in maximum O2 uptake (V˙O2max) (17,22). The latter is explained by negative chronotropic and inotropic effects to limit convectional O2 transport to the exercising muscles (17). A relative decrease in cardiac output could indirectly enhance the muscle metaboreflex during exercise, which in turn would increase chemosensitivity and activate the sympathetic nervous system (8).
Therefore, the purpose of the present investigation was to investigate the participation of β-adrenergic receptor-mediated signaling to the central and peripheral chemoreflex and the metaboreflex and its contribution to the ventilatory responses to dynamic exercise in a healthy man.
MATERIALS AND METHODS
Fourteen healthy nonsmoker male subjects, aged 24 ± 6 yr (mean ± SD; body mass index = 24.3 ± 2.6 kg·m−2) gave informed written consent to the study, which was approved by the Ethics Committee of Erasme University Hospital. The subjects had a normal clinical examination. None of them took any drugs.
The subjects were treated with bisoprolol orally, 5 mg, or a placebo, once daily at 7:30 a.m. for 1 wk, after a randomized double-blind crossover design. Bisoprolol is a highly selective β1-adrenoceptor blocker with a 10- to 12-h half elimination life (15). There was a 1-wk washout after the last intake of drug or placebo.
Resting chemoreflex and metaboreflex studies were performed on the sixth day of treatment, at 9:30 a.m., and a cardiopulmonary exercise test (CPET) was performed on the seventh day of treatment, also at 9:30 a.m.
Protocol and interventions.
The participants were studied in the supine resting position in a quiet experimentation room. Muscle sympathetic nerve activity (MSNA) was recorded continuously by obtaining multiunit recordings of postganglionic sympathetic activity, measured from a nerve fascicle in the peroneal nerve posterior to the fibular head. Electric activity in the nerve fascicle was measured using tungsten microelectrodes (shaft diameter 200 μm, tapering to a noninsulated tip of 1-5 μm). A subcutaneous reference electrode was inserted 2 to 3 cm away from the recording electrode, which was inserted into the nerve fascicle. The neural signals were amplified, filtered, rectified, and integrated to obtain a mean voltage display of sympathetic nerve activity.
The subjects breathed across a low-resistance mouthpiece with a nose clip to ensure exclusive mouth breathing during all the sequences. HR was measured continuously by an electrocardiographic lead. Blood pressure (BP) was determined every minute during normoxia, hypoxia, and hyperoxia by an automatic sphygmomanometer (Physiocontrol Collin BP-880). V˙E (pneumotachometer) and PetCO2 (Normocap; Datex, Sheffield, UK) were assessed while the subjects were breathing through the low-resistance mouthpiece, with a nose clip. Arterial saturation in oxygen (SpO2) was estimated continuously by pulse oximetry (Nellcor).
Chemoreflex sensitivity was determined in resting conditions by the measurement of MSNA and V˙E during a 5-min exposure to hyperoxic hypercapnia (7% CO2, FICO2, in O2, central chemoreflex sensitivity) and during a 5-min exposure to isocapnic hypoxia (10% O2 in N2, peripheral chemoreflex sensitivity). The order of the interventions was randomized but kept constant for a given subject.
Maximal voluntary end-expiratory apneas were performed at baseline and at the end of the fifth minute of hypoxia and hypercapnia to eliminate the inhibitory influence of V˙E on chemoreflex-mediated measurements.
Metaboreflex sensitivity was estimated by the measurement of MSNA during a static voluntary contraction of the dominant forearm with a handgrip dynamometer, as previously described (8). The measurement was performed in triplicate before the start of each study. A 5-min baseline period of stable V˙E, with the volunteer breathing room air, was then followed by 3 min of isometric handgrip of the dominant arm at 30% of the maximum voluntary contraction. Each intervention was followed by 3 min of local circulatory arrest to the upper arm without handgrip while the subjects breathed room air. Local circulatory arrest was produced by inflating a standard BP cuff at 200 mm Hg on the upper arm 5 s before the end of the maximum voluntary contraction. The subjects were instructed to relax their grip after the cuff was inflated.
Each intervention was followed by a 10-min recovery period, with the volunteers breathing room air before the next intervention was started. MSNA was recorded continuously during all the interventions. The participants were instructed not to participate in any exercise activities for 24 h after the MSNA study.
Cardiopulmonary exercise test (CPET).
Each subject underwent a physician-supervised standard incremental CPET until the symptom-limited maximum (19). The work rate was increased by 30 W·min−1 after 1 min of pedaling at 0 W. Breath-by-breath volume, O2 and CO2 concentrations, and derived V˙E, V˙O2, and V˙CO2 were determined using the cardiopulmonary exercise system "CPX/D" (Medical Graphics, St Paul, MN). HR was measured using a continuously monitored electrocardiogram. BP was measured at the end of each workload increment using an automatic sphygmomanometer. Pulse oximetric oxygen saturation (SpO2) was measured using a Nonin 8500 M device (Nonin Medical, Minneapolis, MN). V˙O2max was defined as the V˙O2 during the last 30 s of peak exercise and expressed as mL·kg−1·min−1. The anaerobic threshold was detected using the V-slope method (19). Oxygen pulse was calculated by dividing V˙O2 by HR. The ventilatory equivalents for O2 and CO2 were measured by dividing V˙E by V˙O2 during CPET up to the anaerobic threshold and V˙E by V˙CO2, respectively, over the entire CPET. Work efficiency above the anaerobic threshold was calculated by the ratio of change of V˙O2 per unit increase of work rate (ΔV˙O2/Δ work rate).
Sympathetic bursts were identified by careful inspection of the voltage neurogram by a trained observer blinded to subject and intervention, as previously reported (2,8). Sympathetic activity was expressed as burst frequency per minute and as integrated sympathetic activity, which corresponds to burst frequency multiplied by mean burst amplitude and is expressed in arbitrary units. Changes in MSNA during hypoxia, hypercapnia, maximal voluntary contraction, postexercise ischemia, and maximal voluntary end-expiratory apneas were expressed as the percentage of change from baseline. Integrated sympathetic activity depends on neural signal amplification, which varies from one recording to another but remains constant throughout each experiment. Optimal quality tracings for the evaluation of the effects of bisoprolol and placebo on the sympathetic nerve response to hypoxia and to hypercapnia were obtained in 10 and 9 subjects, respectively.
Peripheral chemoreflex sensitivity was expressed as the ratio between the rise in V˙E and the reduction in oxygen saturation during hypoxia [Δ(V˙E hypoxia − V˙E hypoxia)/Δ(SpO2 hypoxia − SpO2 baseline)]. Central chemosensitivity was expressed as the ratio between the rise in V˙E and PetCO2 during hypercapnia [Δ(V˙E hypoxia − V˙E baseline)/Δ(PetCO2 hypoxia − PetCO2 baseline)].
The results are presented as means± SE, except when indicated otherwise. Responses to baseline (mean of the last 3 min), hypoxia, hypercapnia, maximal voluntary contraction, and postexercise ischemia were compared by repeated-measures ANOVA. When the F-ratio of the ANOVA reached a critical P < 0.05 value, modified t-tests were applied to compare specific situations. Due to a technical problem in one subject, hypercapnic responses were calculated only in 13 subjects. The CPET variables with and without bisoprolol were compared by paired t-tests. Ventilatory responses to hypoxia and hypercapnia at rest were related to the V˙E/V˙O2 and V˙E/V˙CO2 slopes during exercise, respectively, using linear regression analysis. The level of statistical significance was fixed at P< 0.05 (20).
All the participants completed the trial. None of them presented any noticeable side effects.
Isocapnic hypoxia increased HR, BP, V˙E, and MSNA, decreased SpO2, all P values <0.05, and did not affect PetCO2. The time course of ventilatory response and changes in SpO2 in response to isocapnic hypoxia was unaffected by bisoprolol, whereas BP and HR remained decreased (Table 1, Fig. 1).
Hyperoxic hypercapnia increased HR, BP, V˙E, SpO2, PetCO2, and MSNA, all P values <0.05. The time course of the V˙E and PetCO2 responses to hyperoxic hypercapnia was unaffected by bisoprolol, whereas BP and HR remained decreased (Table 2, Fig. 2).
Isometric handgrip and posthandgrip ischemia.
Isometric handgrip increased HR, BP, and MSNA, all P values <0.05, and did not affect SpO2 and PetCO2. Posthandgrip ischemia was associated with persistent increases in V˙E, BP, and MSNA, P < 0.05, whereas SpO2 and PetCO2 remained unchanged (Tables 3 and 4).
Bisoprolol and chemosensitivity or metabosensitivity at rest.
Bisoprolol in normoxia decreased HR but had no effect on BP, V˙E, SpO2, PetCO2, or MSNA. There was no interaction between the effects of bisoprolol on these variables and, respectively, hypoxia, hypercapnia, isometric handgrip, and muscle ischemia (Tables 1-4).
Bisoprolol and cardiopulmonary exercise testing.
Bisoprolol decreased V˙O2max, maximum workload, maximum HR, and O2 pulse without effect on the anaerobic threshold, ΔV˙O2/Δ workload or maximum RQ, but with an increase in O2 pulse. The ventilatory equivalents V˙E/V˙CO2 and V˙E/V˙O2 were decreased by bisoprolol (Table 5).
Chemosensitivity and the ventilatory responses to exercise.
Both the V˙E/V˙O2 and V˙E/V˙CO2 slopes were correlated to the ventilatory responses to isocapnic hypoxia and hyperoxic hypercapnia under bisoprolol, not under placebo (Figs. 3 and 4).
The present results show that β-blockade with bisoprolol decreases ventilation at any given level of metabolic rate during dynamic exercise in healthy subjects but does notaffect the central or peripheral chemoreflexes or the muscle metaboreflex. Bisoprolol-induced increase in ventilatory efficiency therefore appears to be of hemodynamic origin.
Bisoprolol decreased aerobic exercise capacity. This is in keeping with previous observations in healthy subjects (6,17) and is essentially explained by negative chronotropic and inotropic effects of β-blockade, leading to decreased maximum cardiac output and associated decreased convectional O2 delivery to the exercising muscles. O2 pulse was increased at exercise after bisoprolol intake, but this is probably related to a predominantly negative chronotropic effect. A decreased exercise capacity could have been related to a decreased β-adrenoreceptor-related lipolysis (17), but the same RQ achieved at maximum exercise also argues against metabolic effects of β-blockade as a cause of earlier lactic acidosis in the present experiments. Exercise with β-blockade has been reported to increase plasma potassium levels, which could be a cause of increased V˙E through muscle afferents stimulation (17). However, the slope of the V˙E to plasma potassium relationship has been reported to be decreased during incremental exercise after β-blocker intake (16) in keeping with reduced ventilatory equivalents recorded in the present experiments. Altered V˙O2 kinetics during exercise after β-blocker intake has been suggested to occur in healthy subjects (9), but thiswas not confirmed in the present study in which the rate of increase in V˙O2 per rate of increase in workload wasnot affected by bisoprolol. Even though this was not directly measured, it appears that the CPET profile recordedafter β-blockade with bisoprolol in the present study would be most likely explained by a limitation of cardiac output due to the selective inhibition of myocardial β1 receptors.
Resting chemosensitivity is related to the ventilatory response to exercise in healthy athletes (12,13) and in patients with heart failure before (3) and after cardiac transplantation (2). The administration of β-blockers in patients with heart failure decreases V˙E/V˙CO2 during exercise (1,21,22). This supports the notion that exercise hyperpnea in heart failure is at least in part β-adrenergic receptor mediated (1,21,22). Isoproterenol or dobutamine increases the ventilatory responses to hypoxia or hypercapnia (14,18). This effect can be inhibited by the administration of β-blockers (14,18). In experimental animals, norepinephrine and epinephrine increase V˙E and carotid sinus nerve discharge (5). This effect can be reduced or abolished by propranolol (5). However, the administration of β-blockers has also been reported to be without effect on the ventilatory responses to hypoxia or to hypercapnia (4,7). A participation of β-adrenergic receptor signaling to the ventilatory response to exercise in healthy subjects thus has remained uncertain until now.
Bisoprolol affected neither the central nor the peripheral chemoreceptor sensitivities, as assessed by unchanged ventilatory responses to hyperoxic hypercapnia and isocapnic hypoxia. This is in agreement with previous observations in healthy subjects (4,7). However, the present results confirm decreased ventilation at any given level of metabolic rate during exercise in β-blocked healthy subjects (4,10,16). The paradox of unchanged chemosensitivity but decreased ventilatory equivalents at exercise with β-blockade could have been explained by an inhibition of the muscle metaboreflex (4). However, the present results clearly show an unchanged metaboreflex after intake of bisoprolol. Therefore, the only possible remaining explanation may be hemodynamic. Wasserman et al. (18) previously introduced the notion of cardiodynamic dyspnea after the intake of isoprenaline. According to these authors, an increased cardiac output at a given level of metabolic rate would require higher ventilation for the maintenance ventilation/perfusion matching and unchanged arterial PCO2. Conversely, decreased cardiac output because of β-blockade would require less ventilation for the maintenance of ventilation perfusion matching.
In the present study, ventilatory equivalents during exercise were correlated to resting ventilatory responses to hypoxia or hypercapnia but only after β-blockade with bisoprolol. Because bisoprolol did not interfere with the resting chemoreflex or metaboreflex ventilatory responses, this intriguing observation may be explained by a decreased interference with the baroreflex. The β-blocked subjects indeed presented with decreased HR and BP that persisted during the entire CPET.
In conclusion, the present study shows that β-blockade in healthy volunteers decreases aerobic exercise capacity and ventilatory equivalents in relation to a decrease in HR and probably also cardiac output without any changes in chemo- or metabosensitivity.
The secretarial assistance of Mrs Amelia Laurent was greatly appreciated.
This research was supported by the Greek State Scholarships Foundation (IKY), the Funds David and Alice Van Buuren, and a grant from Astra-Zeneca.
The results of the present study do not constitute endorsement by the ACSM.
1. Agostoni P, Guazzi M, Busotti M, De Vita S, Palermo P. Carvedilol reduces the inappropriate increase in ventilation during exercise in heart failure patients. Chest
2. Ciarka A, Cuylits N, Vachiery JL, et al. Increased peripheral chemoreceptor sensitivity and exercise ventilation in heart transplant recipients. Circulation
3. Chua T, Clark A, Amadi A, Coats A. Relation between chemosensitivity and the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol
4. Conway MA, Petersen ES. Effects of β-adrenergic blockade on the ventilatory responses to hypoxic and hyperoxic exercise in man. J Physiol
5. Folgering H, Ponte J, Sadig T. Adrenergic mechanisms and chemoreception in the carotid body of the cat and rabbit. J Physiol (Lond)
6. Gullestad L, Hallen J, Medbo JL, Gronnerod O, Holme I, Sejersted O. The effect of acute vs chronic treatment with beta-adrenoceptor blockade on exercise performance, haemodynamic and metabolic parameters in healthy men and women. Br J Clin Pharmacol
7. Heistad D, Wheeler R. Effect of acute hypoxia on vascular responsiveness in man. J Clin Invest
8. Houssiere A, Najem B, Ciarka A, Velez-Roa S, Naeije R, van de Borne P. Chemoreflex and metaboreflex control during static hypoxic exercise. Am J Physiol Heart Circ Physiol
9. Hughson RL. Alterations in the oxygen deficit-oxygen debt relationships with b-adrenergic receptor blockade in man. JPhysiol
10. Jilka SM, Joyner MJ, Nittolo JM, et al. Maximal exercise responses to acute and chronic beta-adrenergic blockade in healthy male subjects. Med Sci Sports Exerc
11. Johnson RL. Gas exchange efficiency in congestive heart failure II. Circulation
12. Martin BJ, Weil JV, Sparks KE, McCullough RE, Grover RF. Exercise ventilation correlates positively with ventilatory chemoresponsiveness. J Appl Physiol
13. Martin BJ, Sparks KE, Zwillich CW, Weil JV. Low exercise ventilation in endurance athletes. Med Sci Sports
14. Pathak A, Velez-Roa S, Xhaet O, Najem B, Van de Borne P. Dose-dependent effect of dobutamine on chemoreflex activity in healthy volunteers. Br J Clin Pharmacol
15. Pritchard BN. Bisoprolol: a new beta-adrenoceptor blocking drug. Eur Heart J
. 1987;8 Suppl M:121-9.
16. Schneider DA, McEniery MT, Solomon C, Jurimae J, Wehr MS. Ventilatory and hyperkalemic responses to incremental exercise after propranolol treatment. J Appl Physiol
17. Van Baak M. Beta-adrenoceptor blockade and exercise. An update. Sports Med
18. Wasserman K, Whipp BJ, Castagna K. Cardiodynamic hyperpnea secondary to cardiac output increase. J Appl Physiol
19. Wasserman K, Hansen JE, Sue DY, Casaburi R, Whipp BJ. Principles of Exercise Testing and Interpretation
. 3rd ed. Baltimore (MD): Lippincott Williams & Wilkins; 1999, pp. 115-42.
20. Winer BJ, Brown DR, Michels K, Mer BJ. Statistical Principles in Experimental Design
. 3rd ed. New York: McGrall-Hill; 1991, pp. 220-83.
21. Witte KK, Thackray SD, Nikitin NP, Cleland JG, Clark AL. The effects of alpha and beta blockade on ventilatory responses to exercise in chronic heart failure. Heart
22. Wolk R, Johnson BD, Somers VK, et al. Effects of beta-blocker therapy on ventilatory responses to exercise in patients with heart failure. J Card Fail