Metabolic changes in muscle on long-term alprenolol therapy Muscle biopsies from the vastus muscle were taken at rest and immediately after upright bicycle exercise at 50% of the individual Vo 2max • before and during 6 wk of alprenolol treatment (200 to 400 mg twice daily) in 6 untrained patients with essential hypertension. Resting muscle concentrations (mmole . kg-I. wet weight) of glycogen. glucose. lactate. and high-energy phosphates [adenosine triphosphate (ATP) and creatine phosphate (CP)] were not affected by alprenolol treatment. but after 10 min of exercise the glycogenolysis increased and depletion of ATP and CP was enhanced. The relationship between blood and muscle lactate was altered by alprenolol. indicating that alprenolol prevents lactate translocation from the muscle to the blood. The results show that during moderate exercise. leg muscle metabolism is influenced by long-term antihypertensive therapy.
M. Frisk-Holmberg, M.D., L. Jorfeldt, M.D., A. Juhlin-Dannfelt, M.D., and J. Karlsson, Ph.D. Uppsala. Linkoping. Huddinge. and Stockholm. Sweden Section of Clinical Pharmacology. Medical Faculty. Uppsala University; Departments of Clinical Physiology. Linkoping University Hospital and Huddinge University Hospital; and Laboratoryfor Human Performance. Karolinska Hospital. Stockholm
The importance of the adrenergic nervous system to intermediate metabolism has been documented. f3-Adrenoceptors are involved in lipid mobilization from adipose tissue 5 , 10 and it has been reported that skeletal muscle glycogenolysis is enhanced by propranolol, 13 indicating involvement of f3-adrenoceptors. The metabolic consequences of f3-adrenoceptor blockade in the clinical situation are not, however, fully understood. 6 Long-term treatment with alprenolol has been found to influence skeletal muscle metabolism during exercise,8 e.g., attenuation of lactate release from the leg and of blood lactate concentration and reduction in the exerciseinduced lipolysis.
Supported by grants from Tore Nilsson's Foundation for Medical Research, Johan and Alice Gronberg's Foundation for Medical Research, and Swedish Medical Research Council (04139). Received for pUblication April 7, 1979. Accepted for publication April 25, 1979. Reprint requests to: Marianne Frisk-Holmberg, Section of Clinical Pharmacology, Box 573, Biomedicum, S-75 I 23 Uppsala, Sweden.
566
Little is known about the effects of long-term f3-blocking on skeletal muscle metabolism with respect to glycogen utilization during exercise, adenosine triphosphate (A TP) and creatine phosphate (CP) levels, and the relationship between muscle and blood lactate, which is of interest since some patients treated with 13blockers complain of muscle fatigue. Our aim was to elucidate this question by studying a group of patients on long-term alprenolol therapy. Patients, procedure, and methods
Our subjects were 6 male patients with essential hypertension corresponding to World Health Organization Stages I and II. Without therapy all had diastolic blood pressures within the range of 95 to 120 mm Hg. All were known responders to alprenolol and they were included in the study if blood pressure returned to pretreatment values when the antihypertensive medication was discontinued for 6 wk. During the last week of this period an exercise test was
0009-9236/79/110566+06$00.60/0 © 1979 The C. V. Mosby Co.
Volume 26 Number 5
performed and maximal oxygen uptake (Vo2max ) determined. 2 All subjects were regarded as untrained; their anthropometric data are given in Table 1. In addition to a physical examination and eye fundal inspection, blood tests, chest x-ray, electrocardiogram, and a renogram were performed. Except for hypertension the patients were regarded as healthy. The study, which was conducted in a randomized single-blind fashion, included 2 consecutive periods of 6 wk, 1 with antihypertensive doses (0.2 to 0.4 gm twice daily) of alprenolol, the other with placebo. During the investigation the patients maintained the same diet and did not change their physical activity programs. At the end of the placebo and alprenolol treatment periods, the patients were examined at rest before exercise and at the end of lO-min sitting exercise on an electrically braked bicycle ergometer. The workload corresponded to 50% of the subject's V02max ' The subjects arrived at the laboratory in the morning after an overnight fast and abstinence from smoking. The morning dose of alprenolol or placebo was taken about 4 hr before the examinations. Muscle biopsies were taken from lateral vastus muscle according to the procedures described by Bergstrom 3 and Karlsson. 12 The samples (about 15 mg fresh weight) were frozen in liquid nitrogen within 5 sec and subsequently stored at - 60° or colder until analyzed for ATP, CP, glycogen, glucose-6-phosphate (G-6-P), and lactate .12 A separate biopsy was taken for histochemical determination of percentage of slow- and fast-twitch fibers (types I and II) in the muscleY For lactate determination capillary samples were taken in duplicate at rest and during the last minute of exercise. Lactate was determined by an adaptation to fingertip blood of a microfluorometric procedure. S, 12 Thus, 50 JLI blood were precipitated in I ml ice-cold perchloric acid, 0.6 molell. After centrifugation the protein-free extract was analyzed as previously described. s Venous blood was drawn for alprenolol determination. Heart rate and arterial blood pressure were measured. The latter was expressed as mean arterial pressure. 14 Standard statistical methods were used in analyzing the data using the paired t test. 1 Com-
Muscle metabolism during beta blockade
4
567
blood lactate placebo p-blocker
2
rest
exercise
Fig.!. Blood lactate concentrations (mmolell) at rest and during exercise with placebo and with alprenolol treatment.
parison of regression lines was done by analysis of covariance. 1 The 95% limit of probability was accepted as indicating statistical significance. Data are expressed as mean ± SEM. Results
Drug level, blood pressure, and heart rate. The steady-state concentrations of alprenolol were within reported therapeutic ranges (median, 12 pg/l; range, 5 to 181 pgll; Table I). The response to treatment was adequate. The mean arterial pressure at rest fell from 127 to 107 mm Hg (p < 0.01). The resting heart rate fell from 86 ± 4 to 63 ± 3 bpm (p < 0.01) and the heart rate during exercise, from 138 ± 6 to 107 ± 2 bpm (p < 0.01). Blood and muscle lactate. The blood lactate levels at rest were not influenced by treatment (see Fig. 1) (placebo, 1.07 ± 0.16 mmole/Z; .a-blockade, 0.94 ± 0.09 mmole/l). During exercise, however, the blood concentrations were lower during the alprenolol period than in the placebo period (Fig. 1) (2.34 ± 0.49 and 3.43 ± 0.36 mmole/l, respectively; p < 0.02). Muscle lactate at rest was not influenced by alprenolol (Fig. 2)-placebo, 1.24 ± 0.10 mmole/kg wet muscle; .a-blockade, 0.94 ± 0.09 mmole/kg wet muscle. During exercise the muscle lactate was increased by .a-blockade in 3 subjects and slightly decreased in the others (Fig. 3). The mean effect of f3-blockade on muscle lactate was not significant. The ratio between muscle lactate concentrations during exercise on and off treatment did, however, correlate positively with the decrease in heart rate
568
Frisk-Holmberg et al.
Clin. Pharmacal. Ther. N avember 1979
rest
placebo
p-blocker
0>
-"
-5
E E
exercise
100
80
glucose
G- 6 - P
lactate
ATP
cp
glycogen
Fig. 2. Concentrations of muscle metabolites (mmole/kg wet muscle) at rest and during exercise with placebo and with alprenolol (mean ± SEM). *p < 0.05.
during blockade (y = -0.360 + 0.049 . x; r = 0.83; p < 0.01) (Fig. 4). There were 2 different regression lines between muscle and blood lactate during exercise (Fig. 3), 1 for placebo (y = 2.02 + 0.45 . x; r = 0.95) and 1 for alprenolol treatment (y = 1.40 + 0.22 . x; r = 0.82). During alprenolol treatment the regression line shifted downward, indicating a higher muscle/blood lactate ratio. The blood/muscle lactate ratio and percentage of slow-twitch fibers did not correlate. Muscle glycogen, glucose, G-6-P, ATP, and CPo The concentrations of these metabolites in the muscle at rest were not changed by alprenolol (Fig. 2); also, the concentrations of glycogen, glucose, and G-6-P during exercise were not influenced by ,8-blockade; but the levels of ATP and CP fell (p < 0.05). At the end of the exercise period alprenolol treatment
further reduced ATP from 5.6 ± 0.7 to 4.6 ± 0.6 mmole/kg wet muscle (p < 0.05) and CP, from 12.8 ± 2.0 to 10.3 ± 2.1 mmole/kg wet muscle (p < 0.05). Discussion
Our results indicate that during moderate physical exercise that corresponds to many daily activities, leg muscle metabolism is influenced by long-term antihypertensive treatment with alprenolol in clinically recommended doses. The depletion of the high-energy phosphates ATP and CP and the accumulation of lactate in skeletal muscle seem to be augmented. The ATP and CP reductions indicate impaired resynthesis. Most of the energy supply to skeletal muscle during exercise is derived from 3 sources: glycogen, glucose, and fatty acids-
Volume 26 Number 5
mainly blood-borne free fatty acids (FFA). During short exercise periods, as in this study, the contribution of glycogen to the energy supply is relatively greatY The resynthesis of ATP and CP would thus be sensitive to limitations of glycogenolysis. Our data do not support any influence on glycogen utilization by alprenolol. Skeletal muscle glycogenolysis is reported to be enhanced by ,a-blockade in animal experiments with propranolol. 13 In our previous study8 the glucose exchange in the leg was determined during the same type of exercise, and although the glucose uptake tended to be lower during alprenolol treatment, the difference was not statistically significant. The uptake of FFA into muscle depends on arterial concentration. Long-term antihypertensive alprenolol treatment lowers arterial FFA concentrations 4 • 8 and would thus bring about a reduced arterial substrate inflow to the exercising skeletal muscle. This could be one explanation for further depletion of ATP and CP. Normally an increase in muscle glycogenolysis is accompanied by a rise in muscle lactate levels and increased lactate release from the muscle to the bloodstream. The relation between muscle lactate level and lactate release to the blood is linear ll at approximate muscle lactate concentrations of less than 5 mmole/kg wet weight. Release does not increase beyond this level, the maximal capacity for lactate release from the skeletal muscle being about 5 mmole/ min. There is a linear relationship between blood lactate and leg muscle lactate up to a muscle lactate concentration of about 5 mmole/ kg wet weight. 12 We did not measure lactate release, but only leg muscle and blood lactate. Muscle lactate concentration during exercise in the placebo situation was within the range of 1.44 to 6.13 mmole/kg wet weight, and as in earlier studies there was a linear relationship between blood and muscle lactate. II. 12 The 2 patients who had the highest muscle lactate concentrations in the placebo situation had the highest muscle lactate levels on alprenolol treatment. An approximately linear relationship was found between blood and muscle lactate during alprenolol treatment but the regression line was shifted downward. This can
Muscle metabolism during beta blockade
5
569
blood lactate. mmol,1
/
4 /
3
/
/~
2 0
•
1
~
placebo Jl-blocker at rest
0 0
4
8
12
muscle lactate, mmol{kg wet muscle
Fig. 3. Relationship between blood lactate and muscle lactate concentrations with placebo and alprenolol during exercise. There are 2 different regression lines-placebo: y = 2.02 + 0.45 . x; r = 0.95; alprenolol: y = 1.4 + 0.22 . x; r = 0.82.
be due to 1 or more of the following possibilities: (1) reduced lactate production in the exercising muscles, (2) translocation hindrance for the lactate between muscle cell and blood, and/or (3) enhanced uptake and metabolism of blood lactate outside the leg. In an earlier study8 we found that the release of lactate from the exercising leg was decreased by alprenolol; a similar finding after treatment with another nonselective ,a-blocker (propranolol) has been reported,I6 Reduced blood concentration of lactate can therefore be due to decreased release. It can be estimated that approximately 7 mmole lactate are released from the leg during a lO-min exercise period in the control situation and 4 mmole, during alprenolol treatment. In our study, assuming a distribution volume of 10 I, there would be an estimated accumulation of lactate in the leg of 19 and 28 mmole, respectively. (The comparison is justified since the type of exercise and the work loads were approximately the same in the previous and present studies). These estimations suggest enhanced lactate production with alprenolol. This is in accord with increased glycogenolysis. 13 Combining data from our previous8 , II and present studies it is evident that the release of
570
Frisk-Holmberg et al.
Clin. Pharmacal. Ther. N avember 1979
Fig. 4. Relationship between relative change in muscle lactate and the decrease in heart rate induced by alprenolol during exercise. Regression line equation: y = '-0.36 + 0.049 . x; r = 0.83; P < 0.01. Numbers 1 to 6 refer to individual patients (see Table I).
Table I. Anthropometric data of the patients * Age Patient*
(yr)
Weight (kg)
I 2 3 4 5 6 Mean ± SEM
41 38 32 26 26 31
85 70 80 70 75 95
Height (em)
174 165 181 179 175 176
V0 2rnax
(I/min)
W50 '7c (watts)t
2.6 3. I 2.3 3.2 2.8 2.0 2.7 ± 0.2
90 110 80 110 100 70 93 ± 7
ST (%):j:
Alprenolol plasma level (pg/I)
46 57 29 47 51 34
181 6.3 5.1 24.4 6.0 17.7
'Patient I received 0.4 gm alprenolol twice daily over 6 wk; Patients 2 to 6 received 0.2 gm twice daily. tWork load at 50% of Vo 2max ' :j:Slow-twitch fibers in the muscle.
lactate is reduced by alprenolol despite unchanged or even increased lactate production and concomitant higher lactate concentration in the muscle. Thus, alprenolol seems to prevent the lactate translocation from muscle cell to blood. This might occur as the result of an action on the cell membrane, or through changes in the local perfusion, or both. Alprenolol and other f3-blockers have been shown to induce a "membrane effect, "15 such as reducing the "ion flux" over cell membrane (whether this includes ions like lactate is not known). Nonoptimal adaptation of the microcirculation to the local metabolism has been discussed as a pos-
sible explanation for the limitation of lactate release in normal subjects. 11 It is also possible that alprenolol influences local circulation and thus induces impaired adaptation of the microcirculation. The alprenolol-induced decrease of heart rate correlated with the changes in muscle lactate metabolism; this relationship was also applied to plasma concentration. Since we have foundS that the change in lactate release induced by alprenolol correlates with plasma concentrations, these findings indicate that the f3-adrenoceptors of the myocardium and the skeletal muscle have similar characteristics.
Muscle metabolism during beta blockade
Volume 26 Number 5
References I. Afifi R, Azen so: Statistical analysis. A computer oriented approach. New York, 1972, Academic Press. Inc. 2. Astrand PG, Rhyming I: A calculation of aerobic capacity (physical fitness) from pulse rate during submaximal work. 1 Appl Physiol 7:218-221, 1954. 3. Bergstrom 1: Muscle electrolytes in man. Scand 1 Clin Lab Invest 14 (supp\. 68):4-36, 1962. 4. Bjomtorp P: The treatment of angina pectoris with a new ,B-receptor blocking agent (H 56/98). Acta Med Scand 182:285-291, 1967. 5. Brody TM, McNeill 1H: Adrenergic receptors for metabolic responses in skeletal and smooth muscles. Fed Proc 29:1375-1378, 1970. 6. Day IL: The metabolic consequences of adrenergic blockade. A review. Metabolism 24:9871000, 1975. 7. Ervik M: Gas chromatographic determination of the secondary amine alprenolol and its trifluoroacetyl derivate, at nanogram levels in biological fluids. Acta Pharm Suec 6:393-400, 1969. 8. Frisk-Holmberg M, 10rfeldt L, 1uhlin-Dannfelt A: Influence of alprenolol on hemodynamic and metabolic response to prolonged exercise in subjects with hypertension. CLIN PHARMACOl THER 6:675-685, 1977. 9. Gollnik PO, Armstrong RB, Saubert CW IV,
10. II. 12. 13.
14. 15. 16.
17.
571
Piehl K, Saltin B: Enzyme actIVIty and fiber composition in skeletal muscle of untrained and trained man. 1 Appl PhysioI33:312-319, 1972. Himms-Hagen 1: Adrenergic receptors for metabolic responses in adipose tissue. Fed Proc 29:1388-1399, 1970. 10rfeldt L, 1uhlin-Dannfelt A, Karlsson 1: Lactate release from human skeletal muscle during exercise. 1 Appl Physiol 44:350-352, 1978. Karlsson 1: Lactate and phosphagen concentrations in working muscle of man. Acta Physiol Scand (supp\. 358):1, 1971. Nazar K, Brzezinska S, Lyszczarz 1, et al: Sympathetic control of the utilization of energy substrates during long-term exercise in dogs. Arch Int Physiol Biochim 79:873-880, 1971. Rushmer RF .. Cardiovascular dynamics, ed. 2, Philadelphia and London, 1968, W. B. Saunders Co., Ltd. Seeman PM: Membrane stabilization of drugs. Int Rev Neurobiol 9:145-221, 1966. Trapp-Jensen J, Clausen JP, Nou J, Larsen CA, Kropsgaard AR, Christianson NJ: The effect of beta-adrenoreceptor blockers on cardiac output, liver blood flow and skeletal muscle blood flow in hypertensive patients. Acta Physiol Scand (supp\. 440):30, 1976. Wahren J: Substrate utilization by exercising muscle in man. Prog Cardiol 2:255-280, 1973.
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M. Frisk-Holmberg, M.D., L. Jorfeldt, M.D., A. Juhlin-Dannfelt, M.D., and J. Karlsson, Ph.D. Uppsala. Linkoping. Huddinge. and Stockholm. Sweden Section of Clinical Pharmacology. Medical Faculty. Uppsala University; Departments of Clinical Physiology. Linkoping University Hospital and Huddinge University Hospital; and Laboratoryfor Human Performance. Karolinska Hospital. Stockholm
The importance of the adrenergic nervous system to intermediate metabolism has been documented. f3-Adrenoceptors are involved in lipid mobilization from adipose tissue 5 , 10 and it has been reported that skeletal muscle glycogenolysis is enhanced by propranolol, 13 indicating involvement of f3-adrenoceptors. The metabolic consequences of f3-adrenoceptor blockade in the clinical situation are not, however, fully understood. 6 Long-term treatment with alprenolol has been found to influence skeletal muscle metabolism during exercise,8 e.g., attenuation of lactate release from the leg and of blood lactate concentration and reduction in the exerciseinduced lipolysis.
Supported by grants from Tore Nilsson's Foundation for Medical Research, Johan and Alice Gronberg's Foundation for Medical Research, and Swedish Medical Research Council (04139). Received for pUblication April 7, 1979. Accepted for publication April 25, 1979. Reprint requests to: Marianne Frisk-Holmberg, Section of Clinical Pharmacology, Box 573, Biomedicum, S-75 I 23 Uppsala, Sweden.
566
Little is known about the effects of long-term f3-blocking on skeletal muscle metabolism with respect to glycogen utilization during exercise, adenosine triphosphate (A TP) and creatine phosphate (CP) levels, and the relationship between muscle and blood lactate, which is of interest since some patients treated with 13blockers complain of muscle fatigue. Our aim was to elucidate this question by studying a group of patients on long-term alprenolol therapy. Patients, procedure, and methods
Our subjects were 6 male patients with essential hypertension corresponding to World Health Organization Stages I and II. Without therapy all had diastolic blood pressures within the range of 95 to 120 mm Hg. All were known responders to alprenolol and they were included in the study if blood pressure returned to pretreatment values when the antihypertensive medication was discontinued for 6 wk. During the last week of this period an exercise test was
0009-9236/79/110566+06$00.60/0 © 1979 The C. V. Mosby Co.
Volume 26 Number 5
performed and maximal oxygen uptake (Vo2max ) determined. 2 All subjects were regarded as untrained; their anthropometric data are given in Table 1. In addition to a physical examination and eye fundal inspection, blood tests, chest x-ray, electrocardiogram, and a renogram were performed. Except for hypertension the patients were regarded as healthy. The study, which was conducted in a randomized single-blind fashion, included 2 consecutive periods of 6 wk, 1 with antihypertensive doses (0.2 to 0.4 gm twice daily) of alprenolol, the other with placebo. During the investigation the patients maintained the same diet and did not change their physical activity programs. At the end of the placebo and alprenolol treatment periods, the patients were examined at rest before exercise and at the end of lO-min sitting exercise on an electrically braked bicycle ergometer. The workload corresponded to 50% of the subject's V02max ' The subjects arrived at the laboratory in the morning after an overnight fast and abstinence from smoking. The morning dose of alprenolol or placebo was taken about 4 hr before the examinations. Muscle biopsies were taken from lateral vastus muscle according to the procedures described by Bergstrom 3 and Karlsson. 12 The samples (about 15 mg fresh weight) were frozen in liquid nitrogen within 5 sec and subsequently stored at - 60° or colder until analyzed for ATP, CP, glycogen, glucose-6-phosphate (G-6-P), and lactate .12 A separate biopsy was taken for histochemical determination of percentage of slow- and fast-twitch fibers (types I and II) in the muscleY For lactate determination capillary samples were taken in duplicate at rest and during the last minute of exercise. Lactate was determined by an adaptation to fingertip blood of a microfluorometric procedure. S, 12 Thus, 50 JLI blood were precipitated in I ml ice-cold perchloric acid, 0.6 molell. After centrifugation the protein-free extract was analyzed as previously described. s Venous blood was drawn for alprenolol determination. Heart rate and arterial blood pressure were measured. The latter was expressed as mean arterial pressure. 14 Standard statistical methods were used in analyzing the data using the paired t test. 1 Com-
Muscle metabolism during beta blockade
4
567
blood lactate placebo p-blocker
2
rest
exercise
Fig.!. Blood lactate concentrations (mmolell) at rest and during exercise with placebo and with alprenolol treatment.
parison of regression lines was done by analysis of covariance. 1 The 95% limit of probability was accepted as indicating statistical significance. Data are expressed as mean ± SEM. Results
Drug level, blood pressure, and heart rate. The steady-state concentrations of alprenolol were within reported therapeutic ranges (median, 12 pg/l; range, 5 to 181 pgll; Table I). The response to treatment was adequate. The mean arterial pressure at rest fell from 127 to 107 mm Hg (p < 0.01). The resting heart rate fell from 86 ± 4 to 63 ± 3 bpm (p < 0.01) and the heart rate during exercise, from 138 ± 6 to 107 ± 2 bpm (p < 0.01). Blood and muscle lactate. The blood lactate levels at rest were not influenced by treatment (see Fig. 1) (placebo, 1.07 ± 0.16 mmole/Z; .a-blockade, 0.94 ± 0.09 mmole/l). During exercise, however, the blood concentrations were lower during the alprenolol period than in the placebo period (Fig. 1) (2.34 ± 0.49 and 3.43 ± 0.36 mmole/l, respectively; p < 0.02). Muscle lactate at rest was not influenced by alprenolol (Fig. 2)-placebo, 1.24 ± 0.10 mmole/kg wet muscle; .a-blockade, 0.94 ± 0.09 mmole/kg wet muscle. During exercise the muscle lactate was increased by .a-blockade in 3 subjects and slightly decreased in the others (Fig. 3). The mean effect of f3-blockade on muscle lactate was not significant. The ratio between muscle lactate concentrations during exercise on and off treatment did, however, correlate positively with the decrease in heart rate
568
Frisk-Holmberg et al.
Clin. Pharmacal. Ther. N avember 1979
rest
placebo
p-blocker
0>
-"
-5
E E
exercise
100
80
glucose
G- 6 - P
lactate
ATP
cp
glycogen
Fig. 2. Concentrations of muscle metabolites (mmole/kg wet muscle) at rest and during exercise with placebo and with alprenolol (mean ± SEM). *p < 0.05.
during blockade (y = -0.360 + 0.049 . x; r = 0.83; p < 0.01) (Fig. 4). There were 2 different regression lines between muscle and blood lactate during exercise (Fig. 3), 1 for placebo (y = 2.02 + 0.45 . x; r = 0.95) and 1 for alprenolol treatment (y = 1.40 + 0.22 . x; r = 0.82). During alprenolol treatment the regression line shifted downward, indicating a higher muscle/blood lactate ratio. The blood/muscle lactate ratio and percentage of slow-twitch fibers did not correlate. Muscle glycogen, glucose, G-6-P, ATP, and CPo The concentrations of these metabolites in the muscle at rest were not changed by alprenolol (Fig. 2); also, the concentrations of glycogen, glucose, and G-6-P during exercise were not influenced by ,8-blockade; but the levels of ATP and CP fell (p < 0.05). At the end of the exercise period alprenolol treatment
further reduced ATP from 5.6 ± 0.7 to 4.6 ± 0.6 mmole/kg wet muscle (p < 0.05) and CP, from 12.8 ± 2.0 to 10.3 ± 2.1 mmole/kg wet muscle (p < 0.05). Discussion
Our results indicate that during moderate physical exercise that corresponds to many daily activities, leg muscle metabolism is influenced by long-term antihypertensive treatment with alprenolol in clinically recommended doses. The depletion of the high-energy phosphates ATP and CP and the accumulation of lactate in skeletal muscle seem to be augmented. The ATP and CP reductions indicate impaired resynthesis. Most of the energy supply to skeletal muscle during exercise is derived from 3 sources: glycogen, glucose, and fatty acids-
Volume 26 Number 5
mainly blood-borne free fatty acids (FFA). During short exercise periods, as in this study, the contribution of glycogen to the energy supply is relatively greatY The resynthesis of ATP and CP would thus be sensitive to limitations of glycogenolysis. Our data do not support any influence on glycogen utilization by alprenolol. Skeletal muscle glycogenolysis is reported to be enhanced by ,a-blockade in animal experiments with propranolol. 13 In our previous study8 the glucose exchange in the leg was determined during the same type of exercise, and although the glucose uptake tended to be lower during alprenolol treatment, the difference was not statistically significant. The uptake of FFA into muscle depends on arterial concentration. Long-term antihypertensive alprenolol treatment lowers arterial FFA concentrations 4 • 8 and would thus bring about a reduced arterial substrate inflow to the exercising skeletal muscle. This could be one explanation for further depletion of ATP and CP. Normally an increase in muscle glycogenolysis is accompanied by a rise in muscle lactate levels and increased lactate release from the muscle to the bloodstream. The relation between muscle lactate level and lactate release to the blood is linear ll at approximate muscle lactate concentrations of less than 5 mmole/kg wet weight. Release does not increase beyond this level, the maximal capacity for lactate release from the skeletal muscle being about 5 mmole/ min. There is a linear relationship between blood lactate and leg muscle lactate up to a muscle lactate concentration of about 5 mmole/ kg wet weight. 12 We did not measure lactate release, but only leg muscle and blood lactate. Muscle lactate concentration during exercise in the placebo situation was within the range of 1.44 to 6.13 mmole/kg wet weight, and as in earlier studies there was a linear relationship between blood and muscle lactate. II. 12 The 2 patients who had the highest muscle lactate concentrations in the placebo situation had the highest muscle lactate levels on alprenolol treatment. An approximately linear relationship was found between blood and muscle lactate during alprenolol treatment but the regression line was shifted downward. This can
Muscle metabolism during beta blockade
5
569
blood lactate. mmol,1
/
4 /
3
/
/~
2 0
•
1
~
placebo Jl-blocker at rest
0 0
4
8
12
muscle lactate, mmol{kg wet muscle
Fig. 3. Relationship between blood lactate and muscle lactate concentrations with placebo and alprenolol during exercise. There are 2 different regression lines-placebo: y = 2.02 + 0.45 . x; r = 0.95; alprenolol: y = 1.4 + 0.22 . x; r = 0.82.
be due to 1 or more of the following possibilities: (1) reduced lactate production in the exercising muscles, (2) translocation hindrance for the lactate between muscle cell and blood, and/or (3) enhanced uptake and metabolism of blood lactate outside the leg. In an earlier study8 we found that the release of lactate from the exercising leg was decreased by alprenolol; a similar finding after treatment with another nonselective ,a-blocker (propranolol) has been reported,I6 Reduced blood concentration of lactate can therefore be due to decreased release. It can be estimated that approximately 7 mmole lactate are released from the leg during a lO-min exercise period in the control situation and 4 mmole, during alprenolol treatment. In our study, assuming a distribution volume of 10 I, there would be an estimated accumulation of lactate in the leg of 19 and 28 mmole, respectively. (The comparison is justified since the type of exercise and the work loads were approximately the same in the previous and present studies). These estimations suggest enhanced lactate production with alprenolol. This is in accord with increased glycogenolysis. 13 Combining data from our previous8 , II and present studies it is evident that the release of
570
Frisk-Holmberg et al.
Clin. Pharmacal. Ther. N avember 1979
Fig. 4. Relationship between relative change in muscle lactate and the decrease in heart rate induced by alprenolol during exercise. Regression line equation: y = '-0.36 + 0.049 . x; r = 0.83; P < 0.01. Numbers 1 to 6 refer to individual patients (see Table I).
Table I. Anthropometric data of the patients * Age Patient*
(yr)
Weight (kg)
I 2 3 4 5 6 Mean ± SEM
41 38 32 26 26 31
85 70 80 70 75 95
Height (em)
174 165 181 179 175 176
V0 2rnax
(I/min)
W50 '7c (watts)t
2.6 3. I 2.3 3.2 2.8 2.0 2.7 ± 0.2
90 110 80 110 100 70 93 ± 7
ST (%):j:
Alprenolol plasma level (pg/I)
46 57 29 47 51 34
181 6.3 5.1 24.4 6.0 17.7
'Patient I received 0.4 gm alprenolol twice daily over 6 wk; Patients 2 to 6 received 0.2 gm twice daily. tWork load at 50% of Vo 2max ' :j:Slow-twitch fibers in the muscle.
lactate is reduced by alprenolol despite unchanged or even increased lactate production and concomitant higher lactate concentration in the muscle. Thus, alprenolol seems to prevent the lactate translocation from muscle cell to blood. This might occur as the result of an action on the cell membrane, or through changes in the local perfusion, or both. Alprenolol and other f3-blockers have been shown to induce a "membrane effect, "15 such as reducing the "ion flux" over cell membrane (whether this includes ions like lactate is not known). Nonoptimal adaptation of the microcirculation to the local metabolism has been discussed as a pos-
sible explanation for the limitation of lactate release in normal subjects. 11 It is also possible that alprenolol influences local circulation and thus induces impaired adaptation of the microcirculation. The alprenolol-induced decrease of heart rate correlated with the changes in muscle lactate metabolism; this relationship was also applied to plasma concentration. Since we have foundS that the change in lactate release induced by alprenolol correlates with plasma concentrations, these findings indicate that the f3-adrenoceptors of the myocardium and the skeletal muscle have similar characteristics.
Muscle metabolism during beta blockade
Volume 26 Number 5
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