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Carbohydrate availability affects ammonemia during exercise after β2-adrenergic blockade


Medicine & Science in Sports & Exercise: May 2000 - Volume 32 - Issue 5 - p 940-945
Basic Sciences: Original Investigations

MATTHYS, D., W. DERAVE, P. CALDERS, and J.-L. PANNIER. Carbohydrate availability affects ammonemia during exercise after β2-adrenergic blockade. Med. Sci. Sports Exerc., Vol. 32, No. 5, pp. 940–945, 2000.

Purpose β-Adrenergic blockade increases blood ammonia concentration during exercise. The purpose of this study was to assess the role of decreased carbohydrate availability in this process.

Methods Wistar rats (N = 47) were injected intravenously with a selective β2-adrenoceptor blocker (ICI 118,551), placebo, or β2-blocker + glucose 1 h before a treadmill exercise test. Blood samples were taken to measure the concentration of ammonia, glucose, lactic acid, free fatty acids (FFA), glycerol, branched-chain amino acids (BCAA), and muscle samples for determination of glycogen content.

Results β2-adrenergic blockade shortened running time to exhaustion (23 ± 4.3 min compared to 44 ± 5.2 min with placebo), increased blood ammonia levels (146.7 ± 16.21 μmol·L−1 compared to 47.5 ± 0.92 μmol·L−1 with placebo) and prevented exercise-induced glycogen breakdown in soleus and gastrocnemius muscles. Pre-exercise supplementation of glucose during β2-blockade restored exercise-induced glycogen breakdown and reduced blood ammonia concentration during exercise (66.5 ± 5.65 mmol·L−1) but did not improve exercise capacity (26 ± 3.2 min) when compared with β2-blockade alone.

Conclusion The results suggest that the enhanced rise in blood ammonia concentration during exercise after β-blockade is caused by impaired carbohydrate availability.

Department of Pediatric Cardiology, Institute of Kinesiology and Sport Sciences, and Laboratory of Normal and Pathological Physiology, University of Ghent, B-9000 Ghent, BELGIUM

Submitted for publication October 1998.

Accepted for publication June 1999.

Address for correspondence: D. Matthys, M.D., Department of Pediatric Cardiology, University Hospital, De Pintelaan 186, B-9000 Ghent, Belgium. E-mail:

The mechanisms responsible for the reduction in exercise capacity in the presence of β-blockers have not yet been elucidated, but they may be related to their metabolic effects (35). The administration of β-blocking drugs has an effect on the metabolism of lipids, carbohydrates, and ammonia during exercise. β-blocker administration has been reported to inhibit exercise-induced lipolysis, which leads to reduced availability of fatty acids (2,8,12,15,24,32). The effect of β-blockade on muscle glycogen utilization is more controversial, but at least in some experimental conditions β-blockade was shown to inhibit muscle glycogenolysis during exercise (34). The reduction in exercise capacity in the presence of β-adrenergic blockers may therefore be related to a reduction in the availability of substrates for energy metabolism in skeletal muscle (24).

Furthermore, β-adrenergic blockade is known to increase the blood ammonia concentration during exercise (5,17,26,27), and hyperammonemia has been associated with fatigue during prolonged exercise (3). In addition, previous studies have shown that the accumulation of blood ammonia during exercise is increased in conditions of reduced carbohydrate availability (6,10,14,30,37,38).

The aim of the present study was to investigate whether the exercise-induced hyperammonemia after β-blockade is related to decreased carbohydrate availability, e.g., because of impaired glycogenolysis. In view of the fact that the exercise-induced hyperammonemia is more pronounced after the administration of nonselective β1+2-blockers than after cardioselective β1-blockers (17,27) and that skeletal muscle adrenoreceptors are mainly of the β2-type (23), we used a selective β2-adrenoceptor antagonist (ICI 118,551) in the present study. Experiments were done with and without supplementation of glucose in addition to the β-adrenergic blockade, to investigate the effects of improved carbohydrate availability during β-blockade.

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Animals and Exercise Protocols

This study was conducted in conformity with the policies and guiding principles in the care and use of animals of the American College of Sports Medicine. Female Wistar rats (body mass approximately 180 g at the start of the experiment) were provided with water and food ad libitum and were trained on a motor-driven treadmill. Exercise training consisted of running at 1.2 km·h1 and 0% grade for 15 min 5 d·wk−1 for 3 wk. After training, rats were randomly divided into three groups, receiving either 1-mL saline (group “SAL”;N = 13), 1 mg·kg bw1 ICI 118,551 (group “β2”;N = 13), or 1 mg·kg bw1 ICI 118,551 in combination with 100-mg glucose (group “β2+GLU”;N = 13). ICI 118,551 is a potent selective β2-adrenoceptor antagonist (4). Rats were injected via a cannula inserted under local anesthesia in the tail vein 1 h before the experiment started. Of each group, six rats were sacrificed at rest and seven rats started running until exhaustion on a treadmill (1.2 km·h1 and 5% grade). Exhaustion was defined as the time point when animals were unable to keep pace with the treadmill despite motivation by an electric shock grid placed at the back of the treadmill lane. For the purpose of comparison a post-hoc SAL group (N = 8) ran for 23 min, the time when the β2-blocked rats reached exhaustion.

Rats were sacrificed by decapitation either in resting conditions or immediately following exercise, and blood was collected for the measurement of ammonia, branched-chain amino acids (BCAA), glucose, free fatty acids (FFA), glycerol, and lactic acid. The skin of the right hind limb was removed and the soleus (SOL), the white superficial part of the gastrocnemius (WG), and the red, deep medial part of the gastrocnemius (RG) were cut out, trimmed of connective tissue and visible blood, and freeze clamped with aluminum clamps precooled in liquid N2. Muscle samples were stored at −80°C until they were analyzed. The fiber type profiles of the muscle samples are well documented (11) and were chosen to represent the major fiber types. The relative distributions of muscle fibers characterized as type I, IIA, IID/X, and IIB are approximately 84:7:9:0 in SOL, 51:35:13:1 in RG, and 0:0:8:92 in WG.

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Ammonia was measured immediately with the Ammonia test Kit II in combination with the Ammonia Checker II (Menarini, Italy). Enzymatic methods were used for the determination of lactate, glycerol, glucose (Boehringer Mannheim, Germany), and FFA (Biomérieux, France). For the determination of BCAA, the samples were prepared by the addition of succinate buffer to reach a pH of 7.4 and centrifuged at 7000 rpm for 90 min. The remaining protein was removed by the addition of sulfosalicylic acid and after neutralization to pH 2.2, amino acids were analyzed by ion exchange column chromatography (LKB Biochrom, Cambridge, UK). BCAA concentration was calculated by summing the individual concentrations of leucine, isoleucine, and valine. Muscle glycogen was converted to glucose by acid hydrolysis and glucose concentration was measured by an enzymatic method (cf. above).

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Statistical Analysis

The differences between the parameter means of the different groups were analyzed by ANOVA I followed by Duncan’s multiple comparison test. Significance was established at P < 0.05. Data are expressed as means ± SEM.

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Exercise Performance

Running time to exhaustion was 44 ± 5.2 min in SAL. Administration of the β2-blocker or of the β2-blocker + glucose reduced time to exhaustion to 23 ± 4.3 min (P < 0.01) and 26 ± 3.2 min (P < 0.01), respectively. The exercise times to exhaustion in the β2 and the β2+GLU group were not significantly different.

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Metabolites in Blood and Plasma


Blood ammonia concentration at rest did not differ between groups (Table 1, Fig. 1). It increased during exercise in each group except in SAL 23-min exercise. Blood ammonia was significantly higher in β2 23 min exercise compared with that in SAL 23-min exercise (P < 0.01), β2+GLU 26-min exercise (P < 0.01), and SAL 44-min exercise (P < 0.01).

Table 1

Table 1

Figure 1

Figure 1

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At rest plasma glucose concentration was significantly higher in β2+GLU than in the other two groups (Table 1). During exercise there were no differences among the three groups. Plasma glucose concentration decreased significantly during exercise only in β2+GLU (P < 0.05)

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Plasma lactate concentration at rest did not differ among groups (Table 1). It increased during exercise in each group except in SAL 23-min exercise.

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At rest, plasma FFA levels were not significantly different in the three groups (Table 1). During exercise plasma FFA increased in SAL and β2+GLU but not in β2. After 23 min, plasma FFA levels were significantly lower in β2 than in SAL (P < 0.05).

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Plasma glycerol concentration at rest did not differ among groups and increased during exercise in all groups (P < 0.01) (Table 1).

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Plasma BCAA levels were not significantly different among the three groups at rest and during exercise (Table 1).

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Glycogen Content in Skeletal Muscle

In resting animals muscle glycogen content did not differ between SAL and β2 (Table 1, Fig. 1). Administration of glucose during β-blockade resulted in significantly higher resting glycogen concentrations compared with those in SAL and β2 in the three muscles studied. During exercise to exhaustion, muscle glycogen decreased significantly in SAL 44 min and β2+GLU 26 min in all three muscles, whereas in the β2 group, glycogen content at exhaustion did not differ from pre-exercise values in any of the muscles. Glycogen degradation in SAL occurred in a different way according to muscle type: in soleus muscle, glycogen stores are nearly emptied after 23 min and no further degradation is observed at exhaustion. In white gastrocnemius muscle, glycogen degradation occurred between 23 min and exhaustion. In red gastrocnemius muscle, glycogen progressively decreases from rest to exhaustion.

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It has been suggested that fatigue and impaired endurance work capacity during exercise under β-blockade may result from changes in amino acid metabolism and accumulation of ammonia (5,17,26,27). The purpose of the present study was to investigate further the mechanisms causing the greater rise in blood ammonia during exercise after β-blockade, and in particular to assess the role of decreased carbohydrate availability in this process

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The β-adrenoreceptor in skeletal muscle is mainly of the β2-type (23). Stimulation of these β2-adrenoceptors by epinephrine promotes glycogenolysis at rest and during exercise (18). A reduction in muscle glycogenolysis during exercise can therefore be anticipated during β2-adrenoceptor blockade. However, data on the effect of β-blockade on glycogen utilization in skeletal muscle during prolonged exercise are inconsistent insofar as even in a single species (the rat) increased (21), unchanged (12) and decreased (34) glycogenolysis have all been reported. According to Gorski and Pietrzyk (13), the differences in the effectiveness of the blockade depend on the duration and intensity of exercise, the type of muscle and the degree of engagement of the various muscles during exercise.

Our results are in agreement with the results of Trudeau et al. (34), who also used selective β2-blockade and treadmill exercise to exhaustion in rats. They observed decreased glycogen utilization in soleus muscle, which is predominantly composed of slow-twitch fibers but not in superficial vastus lateralis or gastrocnemius lateralis muscle, predominantly composed of fast-twitch fibers. In the present study muscle glycogen breakdown was inhibited by β2-blockade in all muscles, regardless of fiber type distribution (Table 1). According to Chasiotis et al. (7) β-blockade with propranolol decreases glycogen degradation by inhibiting the exercise-induced rise in cAMP in skeletal muscle cells. Assuming that the decreased muscle glycogenolysis is not fully compensated by increased uptake of glucose from the blood, it can be concluded that the inhibition of glycogenolysis during β2-blockade leads to reduced muscle glucose availability.

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In the present study, the lower FFA levels in β2-blocked rats suggests that blockade of β-adrenergic receptors with ICI 118,551 limits the availability of fatty acids for energy metabolism in active skeletal muscle during exercise (Table 1). This is in agreement with the results of previous investigations, which have shown that β-blocker administration inhibits exercise-induced lipolysis (2,8,12,15,24,32). Skeletal muscle triglyceride breakdown is mainly controlled through β2-receptors, whereas adipose tissue lipolysis appears to be controlled mainly through β1-adrenoceptors (8). In rats the adipocyte lipolytic receptor does not fit into the β12-adrenoceptor classification, and has been designated as β3-adrenoceptor (1,40). ICI 118,551, the β-adrenergic blocker used in the present experiments, has been shown to have not only β2- but also β3-antagonistic properties in rodents (33).

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Previous reports have demonstrated that nonselective β1+2-blockade enhances exercise-induced hyperammonemia (5,17,26,36), while selective β1-blockade did not or only to a lesser degree (17,27). In addition, inhalation of a β2-adrenoceptor agonist in healthy young adults resulted in reduced blood ammonia levels during exercise (28). We hypothesize that the enhanced rise in blood ammonia after β2-blockade is caused by impaired carbohydrate availability, caused by the effect of β2-blockade on glycogenolysis.

The accumulation of blood ammonia during exercise is increased in conditions of reduced carbohydrate availability and in patients with McArdle’s disease who cannot use muscle glycogen as an energy source during exercise because of myophosphorylase deficiency (6,10,14,30,37,38). Increased production and release of ammonia into the blood could be explained either by an increased oxidation of BCAA in active muscle or through an increased rate of AMP deamination. Wagenmakers et al. (38) showed that the branched-chain ketoacid dehydrogenase complex, the regulatory enzyme in the oxidative pathway of BCAA metabolism in muscle, was activated to a much greater extent during exercise when initial muscle glycogen was depleted as compared with a carbohydrate loaded state. Increased blood ammonia accumulation during exercise may therefore be the consequence of an accelerated muscle oxidation of BCAA in these circumstances (38). A similar mechanism may apply to the β-adrenergic blocked state, since Lamont et al. (22) have shown that β-adrenergic blockade stimulates the exercise-induced increase in leucine oxidation in humans. They also found that the magnitude of this effect was more pronounced with nonselective β1+2-blockade than in the presence of selective β1-blockade, which agrees with their different effects on blood ammonia accumulation during exercise.

A second mechanism to explain the increased blood ammonia concentration during exercise in conditions of reduced carbohydrate availability is through the reactions of the purine nucleotide cycle (6,31). A deficiency of glycogen during exercise would result in an imbalance between utilization and resynthesis of ATP, resulting in increased levels of ADP and AMP. Both ADP and AMP are known to be potent activators of AMP deaminase, and increased levels of ADP and AMP could therefore cause an increased rate of AMP deamination to IMP and ammonia (6,31). This mechanism could also apply to the beta blocked state, since Broberg et al. (5) found the increase in ammonia production after β-adrenergic blockade to be directly related to the increase in adenine nucleotide loss occurring as a consequence of impaired ATP resynthesis.

To further investigate whether ammonia accumulation during β2-blockade results from reduced carbohydrate availability, we have included a third experimental group in which glucose was administered 1 h before exercise to improve carbohydrate availability during β-blockade.

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β-Blockade + Glucose

Supplementation of glucose to β2-blocker before exercise resulted in increased muscle glycogen content at rest and a significant glycogen degradation during exercise, despite the β-blockade. It is well documented that carbohydrate supplementation 0.5 to 1 h preceding exercise results in markedly elevated plasma glucose and insulin levels at the start of exercise (9,25). The elevated initial glycogen levels in the β2+GLU group can be attributed to the effect of hyperglycemia and hyperinsulinemia on muscle glycogen synthesis. During exercise after glucose infusion, carbohydrate availability in the contracting muscles is probably increased both by increased muscle glycogenolysis (9) and by increased muscle glucose uptake (25). The stimulatory effect of pre-exercise glucose administration on exercise-induced glycogen breakdown has been described previously (9) and is probably caused by the high initial glycogen levels promoting glycogenolysis (18,20). The significant fall in blood glucose levels in the β2+GLU group during exercise suggests that the muscle glucose uptake is increased in these circumstances.

Blood ammonia levels during exercise after β2-blockade are more than two-fold lower in the group that received glucose compared with the one without glucose supplementation. A similar reduction of the exercise-induced hyperammonemia after glucose infusion was previously observed in our laboratory during nonselective β-adrenergic blockade in exercising dogs (26), but such an effect was absent in the experiments of Van Baak and Mooij (36) in human volunteers. The smaller increase in blood ammonia, together with the enhanced muscle glycogen breakdown during exercise observed in the present experiments after glucose supplementation during β2-adrenergic blockade (Fig. 1), suggests that ammonia production during β2-blockade is less pronounced when carbohydrates are readily available as energy sources. Increased carbohydrate availability could reduce the production of ammonia during exercise either by decreasing the formation of purine nucleotide catabolites (as shown in patients with McArdle’s disease) (29) or by decreasing the activation of the BC-complex (38) and hence the oxidation of BCAA.

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Decreased physical work capacity is commonly observed after the administration of β-blocking agents and is generally more pronounced during nonselective β1+2-blockade compared with selective β1-blockade (8,12,24,32,35). Only a few studies used selective β2-adrenoceptor blockade. In humans, Hespel et al. (19) observed a nonsignificant reduction in exercise duration after oral treatment with the selective β2-blocker ICI 118,551. In rats Trudeau et al. (34) found a marked reduction in running time to exhaustion during treadmill exercise, using the same drug, and this was confirmed in the present experiments using a similar experimental protocol. This reduced endurance work capacity may result from changes in ammonia metabolism since a rise in the blood ammonia concentration can lead to an increase in ammonia in critical regions of the brain with resulting central nervous dysfunction (central fatigue) (3,16,39). The reduction in running times observed in our rats under selective β2-blockade (23 ± 4.3 min compared to 44 ± 5.2 min with placebo) could therefore be caused by the very high blood ammonia levels (>140 μmol·L1).

Surprisingly, time-to-exhaustion was not improved when glucose was supplemented during β2-blockade (26 ± 3.2 min in β2+glucose compared to 23 ± 4.3 min in β2), despite lower blood ammonia levels. However, the decreased exercise capacity in the presence of β-blockers may also be related to some other effects of β-blockade, such as a decreased oxygen transport to the contracting muscle (hemodynamic effects), the inhibition of other β2-mediated metabolic processes (lipolysis), or to effects of β-blockers not directly related to energy metabolism, such as changes in ionic equilibrium (35).

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In exercising rats under β2-blockade (1) exercise capacity is reduced (2), hyperammonemia is enhanced and (3) muscle glycogen breakdown is inhibited. The supplementation of glucose before exercise under β2-blockade seems to restore carbohydrate utilization and to reduce blood ammonia concentration during exercise, but it does not improve exercise capacity. We hypothesize that reduced carbohydrate availability during β-adrenergic blockade causes the increased production and release of ammonia.

The authors are grateful to P. Hespel and W. Samyn for their expert technical assistance in muscle glycogen assessment (P.H.) and chemical analyses (W.S.), and to W. Eechaute for the statistical analysis.

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