Aust. N Z. J Med. (1979), 9, pp. 515 520
Limitation of Work Performance in Normal Adult Males in the Presence of Beta-Adrenergic Blockade S. D. Anderson*, P. T. P. Bye?, C. P. Perry:, G. P. Hamor**, G. Theobaldtt and G. NybergT: From the Department of Thoracic Medicine, Royal Prince Alfred Hospital, Sydney
SUInInary: Limitation of work performance in normal adult males in the presence of betaadrenergic blockade. s. D. Anderson, P. T. P. Bye, C. P. Perry, G. P. Hamor. G. Theobald and G. Nyberg, Aust. N.Z. J. Med., 1979. 9, pp. 515-520. The effect on work performance of a single oral dose of the cardio-selective beta-adrenoreceptor blocking agent, metoprolol, was compared with an equipotent dose of the nonselective agent, propranolol, in the same subjects. A number of biochemical and physiological variables including heart rate, oxygen consumption, ventilation, lactate, free fatty acid and glucose levels were measured. Following exercise in the presence of both active drugs, subjects complained of excessive leg fatigue. For the group there was a significant reduction in the total work performed and the maximum heart rate achieved on both drugs. There was a significant correlation between plasma levels of metoprolol, reduction in total work performed and reduction in maximum heart rate. By contrast, after propranolol, there was a wide variation in work performed at a time when the reduction in maximum heart rate was similar for all subjects. This suggests for propranolol that a reduction in heart rate alone is an inappropriate guide to the impairment of work performance. There was a fall in the circulating level of free fatty acids at the end of exercise in the presence of both drugs and it is possible that this biochemical variable contributed to the decrease in work performance. 'Senior Scientific Officer. ?Thoracic Fellow. $Scientific Officer. **Thoracic Fellow. ttTec hnical Officer. $$Research Fellow. Correspondence: Dr. S. D. Anderson, Department of Thoracic Medicine, Page Chest Pavilion, Royal Prince Alfred Hospital, Camperdown, NSW 2050 Accepted for publication: 24 April, 1979
The use of beta-adrenergic blocking agents is now widely established in the management of a variety of conditions including angina pectoris' 2 : hypertension3 4, obstructive cardiomyopathys and migraine.' As early as 1965, Epstein and co-workers7 reported a decreased endurance time in normal subjects exercising on a treadmill after a single intravenous dose of propranolol. In a previous study from.this laboratory patients with angina pectoris reported excessive leg fatigue after bicycle exercise following a single intravenous dose of alprenolol.' In a further study in which normal subjects exercised in the prescnce of a single oral dosc of labetalol hydrochloride it was noted that there ivas a small but significant reduction in the amount of work performed compared with placebo.' It is well known that beta-blocking agents significantly inhibit the tachycardia of exercise and in some cases reduce the normal increase in cardiac output and blood pressure.','' Also these drugs have been reported to have an effect on normal levels of fatty acids'' -I2, lactic acidI3, glucose'" and insulin.12 All these factors may affect work performance. A study in normal subjects exercising in the presence of two beta-blocking agents, metoprolol (a cardio-selective beta-blockerL5) and propranolol (a non-cardio-selective agent'") was carried out in order to document the effects of each of these drugs on work performance and fatigue. Physiological and biochemical variables relevant to exercise performance and energy production were investigated. Subjects and Methods Ten healthy non-smoking male volunteers aged 23 38 years and weighing between 64-91 kg were studied after informed consent was obtained. A control progressive exercise test was performed on an electrically braked bicycle ergometer (Elema Schondnder, Solna, Sweden) during the week prior to the commencement
516
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ANDERSON ET AL.
5
recorded followed by another blood collection. An additional sample of blood was collected to measure circulating levels of propranolol and metoprolol. These were analysed according to the method of Degen and Reiss, 1976.2' The subjects then sat on the bicycle ergometer and commenced progressive exercise to WMAX, the workload being increased by the predetermined increments at one-minute intervals. During exercise expired gas was collected in a 350-litre Tissot Spirometer (Collins, Mass., USA). The gas collected at the highest workload (WMAX) was analysed for oxygen with a paramagnetic analyser (Taylor Servomex, UK) and for carbon dioxide with an infrared analyser (Godart, Utrecht. Holland). The analysis was displayed on an eight-channel recorder (Devices. UK). Ventilation (VE), tidal volume (VT) and frequency of breathing (f) were also recorded. Oxygen consumption (VO,), carbon dioxide production (VCO,) and respiratory exchange ratio (R) at WMAX were calculated. On cessation of exercise (time 102) SBP, DBP and PEFR were measured and a further blood sample was collected. For statistical analysis, values (at time 0, time 80 and time 102) were compared for the same subject on the active and placebo test days. A t-test was used to determine the significance of differences between these values. For illustration and the estimation of correlation coefficients values obtained on the active drugs have been expressed as a percentage of placebo (A/P%).
of each study. The workload was increased by 20 joules/second each minute until the subject could exercise no further. The maximum working capacity (WMAX) was defined as the highest workload which could be sustained for a period of one minute. For the present study the increments in workload were adjusted so that each subject would be able to reach his estimated WMAX at approximately 12 minutes. Cumulative work (CW) was defined as the sum in joules of all workloads performed for any one study. Four tests were conducted over two two-week periods, the subjects attending the laboratory in a fasting state at the same time ofday (8.30 am). Two of the ten subjects were undvai~ablcfor the propranolol study. On arrival at the laboratory (time 0) the subject reclined on a couch and surface electrodes were placed on the chest and back for continuous recording of heart rate (HR) (Quinton Instruments, Seattle, Washington). The systolic blood pressure (SRP) and diastolic blood pressure (DBP) were measured by auscultation, the diastolic measurement being obtained at the time of muffling of the Korotkoff sounds and recorded to the nearest 5 mmHg. Peak expiratory flow rate (PEFR) was measured on a Wright Peak Flowmeter (Airmed, UK). A teflon cannula was inserted in an antecubital vein under local anaesthesia and a three-way tap was connected so that continuous blood sampling could be carried out without use of a tourniquet. Venous blood was collected for the measurement of free fatty acids (FFA), cholesterol, triglycerides, insulin. lactate and glucose according to published rnethods.'h-20 Immediately after the initial blood collection, the drug in its commercially available form (I00 mg bi-metoprolol tartrate or 80 mg propranolol) or its placebo, was administered orally in a double-blind fashion. The subjects remained at rest for the next 80 minutes and then (time 80) further measurements of HR, SBP, DBP and PEFR were
Results
Af Rest Values for the physiological, biochemical and metabolic variables measured at time 0 were within normal limits on the four test days (Table 1). The plasma levels of metoprolol measured 80
TABLE 1 Analysis OF biochemical and haematological variables at rest and immediately pre- and postexercise
-
METOPROLOL Time (min)
so
0
A
P
-
Free fatty acids (pmolhl)
Mean SE
308 54.1
380 49.3
202 33.2
4.46 0.22
4.46 0.21
0.77 0.14
0.80 0.13
11.3 1.61 0.85 NS
8.2 1.04
0.70 0.09
0.70 0.09
5-28 0.13
5.32 0.17
P Mean
Cholcsterol (mmolil)
SE
Triglycerides (mmolil)
Mean SE
P Insulin (pU;ml)
P Lactate (mmolil)
Mean SE
Glucose (mmolil)
Mean SE
0.09
P
P
Haemoglobin (g!dl)
Mean SE
P
13.4
13.6 0.26 NS
0.15
A =active drug: P = placebo; NS = not significant.
A -
-.
419 102
5.23 0.27
4.w 0.13
0.82
1.09 0.20
5.01
0.78
0.78 0.15
0.19
0.15
P
--
PROPRANOLOL 80 A P
- -
525
R8.5
.-
366 95.9
NS
NS
3.94
0.98 0.15
1.02 0.35
0.11
NS
NS
6.5 12.4 1.04 1.61
Limitation of Work Performance in Normal Adult Males in the Presence of Beta-Adrenergic Blockade S. D. Anderson*, P. T. P. Bye?, C. P. Perry:, G. P. Hamor**, G. Theobaldtt and G. NybergT: From the Department of Thoracic Medicine, Royal Prince Alfred Hospital, Sydney
SUInInary: Limitation of work performance in normal adult males in the presence of betaadrenergic blockade. s. D. Anderson, P. T. P. Bye, C. P. Perry, G. P. Hamor. G. Theobald and G. Nyberg, Aust. N.Z. J. Med., 1979. 9, pp. 515-520. The effect on work performance of a single oral dose of the cardio-selective beta-adrenoreceptor blocking agent, metoprolol, was compared with an equipotent dose of the nonselective agent, propranolol, in the same subjects. A number of biochemical and physiological variables including heart rate, oxygen consumption, ventilation, lactate, free fatty acid and glucose levels were measured. Following exercise in the presence of both active drugs, subjects complained of excessive leg fatigue. For the group there was a significant reduction in the total work performed and the maximum heart rate achieved on both drugs. There was a significant correlation between plasma levels of metoprolol, reduction in total work performed and reduction in maximum heart rate. By contrast, after propranolol, there was a wide variation in work performed at a time when the reduction in maximum heart rate was similar for all subjects. This suggests for propranolol that a reduction in heart rate alone is an inappropriate guide to the impairment of work performance. There was a fall in the circulating level of free fatty acids at the end of exercise in the presence of both drugs and it is possible that this biochemical variable contributed to the decrease in work performance. 'Senior Scientific Officer. ?Thoracic Fellow. $Scientific Officer. **Thoracic Fellow. ttTec hnical Officer. $$Research Fellow. Correspondence: Dr. S. D. Anderson, Department of Thoracic Medicine, Page Chest Pavilion, Royal Prince Alfred Hospital, Camperdown, NSW 2050 Accepted for publication: 24 April, 1979
The use of beta-adrenergic blocking agents is now widely established in the management of a variety of conditions including angina pectoris' 2 : hypertension3 4, obstructive cardiomyopathys and migraine.' As early as 1965, Epstein and co-workers7 reported a decreased endurance time in normal subjects exercising on a treadmill after a single intravenous dose of propranolol. In a previous study from.this laboratory patients with angina pectoris reported excessive leg fatigue after bicycle exercise following a single intravenous dose of alprenolol.' In a further study in which normal subjects exercised in the prescnce of a single oral dosc of labetalol hydrochloride it was noted that there ivas a small but significant reduction in the amount of work performed compared with placebo.' It is well known that beta-blocking agents significantly inhibit the tachycardia of exercise and in some cases reduce the normal increase in cardiac output and blood pressure.','' Also these drugs have been reported to have an effect on normal levels of fatty acids'' -I2, lactic acidI3, glucose'" and insulin.12 All these factors may affect work performance. A study in normal subjects exercising in the presence of two beta-blocking agents, metoprolol (a cardio-selective beta-blockerL5) and propranolol (a non-cardio-selective agent'") was carried out in order to document the effects of each of these drugs on work performance and fatigue. Physiological and biochemical variables relevant to exercise performance and energy production were investigated. Subjects and Methods Ten healthy non-smoking male volunteers aged 23 38 years and weighing between 64-91 kg were studied after informed consent was obtained. A control progressive exercise test was performed on an electrically braked bicycle ergometer (Elema Schondnder, Solna, Sweden) during the week prior to the commencement
516
VOL. 9. NO.
ANDERSON ET AL.
5
recorded followed by another blood collection. An additional sample of blood was collected to measure circulating levels of propranolol and metoprolol. These were analysed according to the method of Degen and Reiss, 1976.2' The subjects then sat on the bicycle ergometer and commenced progressive exercise to WMAX, the workload being increased by the predetermined increments at one-minute intervals. During exercise expired gas was collected in a 350-litre Tissot Spirometer (Collins, Mass., USA). The gas collected at the highest workload (WMAX) was analysed for oxygen with a paramagnetic analyser (Taylor Servomex, UK) and for carbon dioxide with an infrared analyser (Godart, Utrecht. Holland). The analysis was displayed on an eight-channel recorder (Devices. UK). Ventilation (VE), tidal volume (VT) and frequency of breathing (f) were also recorded. Oxygen consumption (VO,), carbon dioxide production (VCO,) and respiratory exchange ratio (R) at WMAX were calculated. On cessation of exercise (time 102) SBP, DBP and PEFR were measured and a further blood sample was collected. For statistical analysis, values (at time 0, time 80 and time 102) were compared for the same subject on the active and placebo test days. A t-test was used to determine the significance of differences between these values. For illustration and the estimation of correlation coefficients values obtained on the active drugs have been expressed as a percentage of placebo (A/P%).
of each study. The workload was increased by 20 joules/second each minute until the subject could exercise no further. The maximum working capacity (WMAX) was defined as the highest workload which could be sustained for a period of one minute. For the present study the increments in workload were adjusted so that each subject would be able to reach his estimated WMAX at approximately 12 minutes. Cumulative work (CW) was defined as the sum in joules of all workloads performed for any one study. Four tests were conducted over two two-week periods, the subjects attending the laboratory in a fasting state at the same time ofday (8.30 am). Two of the ten subjects were undvai~ablcfor the propranolol study. On arrival at the laboratory (time 0) the subject reclined on a couch and surface electrodes were placed on the chest and back for continuous recording of heart rate (HR) (Quinton Instruments, Seattle, Washington). The systolic blood pressure (SRP) and diastolic blood pressure (DBP) were measured by auscultation, the diastolic measurement being obtained at the time of muffling of the Korotkoff sounds and recorded to the nearest 5 mmHg. Peak expiratory flow rate (PEFR) was measured on a Wright Peak Flowmeter (Airmed, UK). A teflon cannula was inserted in an antecubital vein under local anaesthesia and a three-way tap was connected so that continuous blood sampling could be carried out without use of a tourniquet. Venous blood was collected for the measurement of free fatty acids (FFA), cholesterol, triglycerides, insulin. lactate and glucose according to published rnethods.'h-20 Immediately after the initial blood collection, the drug in its commercially available form (I00 mg bi-metoprolol tartrate or 80 mg propranolol) or its placebo, was administered orally in a double-blind fashion. The subjects remained at rest for the next 80 minutes and then (time 80) further measurements of HR, SBP, DBP and PEFR were
Results
Af Rest Values for the physiological, biochemical and metabolic variables measured at time 0 were within normal limits on the four test days (Table 1). The plasma levels of metoprolol measured 80
TABLE 1 Analysis OF biochemical and haematological variables at rest and immediately pre- and postexercise
-
METOPROLOL Time (min)
so
0
A
P
-
Free fatty acids (pmolhl)
Mean SE
308 54.1
380 49.3
202 33.2
4.46 0.22
4.46 0.21
0.77 0.14
0.80 0.13
11.3 1.61 0.85 NS
8.2 1.04
0.70 0.09
0.70 0.09
5-28 0.13
5.32 0.17
P Mean
Cholcsterol (mmolil)
SE
Triglycerides (mmolil)
Mean SE
P Insulin (pU;ml)
P Lactate (mmolil)
Mean SE
Glucose (mmolil)
Mean SE
0.09
P
P
Haemoglobin (g!dl)
Mean SE
P
13.4
13.6 0.26 NS
0.15
A =active drug: P = placebo; NS = not significant.
A -
-.
419 102
5.23 0.27
4.w 0.13
0.82
1.09 0.20
5.01
0.78
0.78 0.15
0.19
0.15
P
--
PROPRANOLOL 80 A P
- -
525
R8.5
.-
366 95.9
NS
NS
3.94
0.98 0.15
1.02 0.35
0.11
NS
NS
6.5 12.4 1.04 1.61
