INTRODUCTION

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INDUCED METABOLIC ALKALOSIS by sodium bicarbonate (NaHCO₃) ingestion in humans has previously been shown to increase blood Lac concentration ([Lac]) during exercise (10, 33, 37, 46, 63). Unfortunately, the majority of studies exploring the effects of metabolic alkalosis on Lac metabolism have focussed on the possible performance-enhancing capabilities of "bicarbonate loading" (31). Ingestion of NaHCO₃ is thought to enhance performance by buffering the lactic acid produced with exercise, thereby limiting the effects of the decreased intramuscular pH (pH_i; see Ref. 31). Metabolic alkalosis through ingestion or infusion of NaHCO₃ has been shown to enhance performance for short-duration, high-intensity exercise, but the mechanisms have not been elucidated. Different mechanisms have been postulated to explain this, including an increase in muscle Lac production (10, 63) and/or enhanced Lac efflux from the muscle (44). Lactate accumulation results from the conversion of nonoxidized pyruvate to Lac by lactate dehydrogenase (LDH) and as such will be influenced by both pyruvate production from glycogen via glycogen phosphorylase (Phos) and pyruvate oxidation by pyruvate dehydrogenase (PDH; see Refs. 18, 38).

In an effort to discern the possible mechanisms responsible for the increased blood [Lac] with metabolic alkalosis, we chose an oral dose of NaHCO₃, previously shown to induce a significant metabolic alkalosis, to influence plasma [Lac], and to enhance performance (37). Continuous, dynamic constant-rate exercise at low, moderate, and high intensity was chosen to follow the metabolic effects, compare fuel utilization with previously described carbohydrate (CHO) and free fatty acid (FFA) contributions at these power outputs (50), and to maintain the ATP turnover rate constant between conditions. This is the first human in vivo study to examine the key regulatory enzymes, their controllers, and fuel utilization during continuous dynamic constant rate exercise under alkalotic conditions.

The aim of the present study was not to examine the performance effect of an induced metabolic alkalosis during exercise. Rather, the first aim was to determine the effect of metabolic alkalosis on the key regulatory enzymes Phos and PDH and their allosteric regulators. The second aim was to measure the effect of metabolic alkalosis on glycolytic intermediates, muscle pyruvate production, and pyruvate oxidation. The third aim was to measure muscle lactate accumulation, production, and efflux. The last aim was to determine if alkalosis has any effects on glucose uptake and FFA utilization during exercise.

	METHODS

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Subjects

Preexperimental Protocol

Experimental Protocol

View larger version (21K): [in this window] [in a new window]   Fig. 1.   Experimental study protocol. Total of two trials were completed per subject; 0.3 g/kg of either CaCO3 [control (CON)] or NaHCO3 [alkalosis (ALK)] was ingested over the time indicated, each constituting one trial. Leg blood flow and arterial and femoral venous blood samples were taken at the times indicated. Exercise bouts refer to three continuous power outputs of 15 min each. 30, 60, and 75% indicate cycling intensity of 30%, 60% and 75% maximal O2 uptake (O2 max), respectively. Muscle biopsies were taken at the times indicated. Respiratory measurements were taken immediately after blood sample/blood flow.

A radial artery was catheterized with a Teflon catheter (20 gauge, 3.2 cm; Baxter, Irvine, CA) percutaneously after anesthetizing the area with 0.5 ml of 2% lidocaine without epinephrine (6). A femoral vein was catheterized percutaneously for insertion of the thermodilution catheter (model 93-135-6F; Baxter) using the Seldinger technique (6) after administration of 3-4 ml of lidocaine without epinephrine. Both the arterial and femoral venous catheters were maintained patent with sterile, nonheparinized, isotonic saline solution. Arterial and femoral venous blood samples were simultaneously taken at rest, rest postingestion, and during each of the three exercise bouts at 6 and 11 min. Single leg blood flow measurements were made after blood sampling at the same time points. Single leg blood flow was determined using the thermodilution technique, as described by Andersen and Saltin (1). Nonheparinized isotonic saline (10 ml) was injected, and leg blood flow was calculated by a portable CO monitor (Spacelab, Redmond, VA). At least three measurements were recorded at each time point and then averaged.

A total of five percutaneous needle biopsies of the vastus lateralis were taken (1 at rest, 1 at rest postingestion, and 3 during exercise at the end of each power output). The resting biopsies were obtained with the subject lying on a bed. The resting and exercise biopsies were obtained on opposite legs and then were reversed for the second trial. Biopsy sites were prepared by making an incision through the deep fascia under local anesthetic (2% lidocaine without epinephrine), as described by Bergström et al. (5). Respiratory measurements of ventilation (E), O₂ uptake (O₂), CO₂ production (CO₂), and respiratory exchange ratio (RER) were measured at 5 and 11 min of each exercise stage.

Muscle Analysis

Blood Sampling and Analysis

Leg Uptake and Release of Metabolites, O₂, and CO₂

Subjects exercised at a constant rate, and because no significant differences occurred in blood flows or metabolite concentrations between the 6- and the 11-min sampling points at each power output, the two values were averaged to obtain one value for each power output. Reported values are for the single leg only.

Calculations

Intramuscular pH. Intramuscular pH (pH_i) was calculated from the [Lac] and [pyruvate] according to the methods of Sahlin et al. (55).

Lac gradient and [H⁺] gradient. The Lac gradient between the plasma and muscle for both trials was calculated for arterial and femoral venous blood at 75% O_{2 max} only. The Lac gradient between the muscle and arterial plasma was calculated as the difference between the wet weight intramuscular [Lac] and arterial plasma [Lac]. The Lac gradient from muscle-to-femoral venous plasma was calculated as above using the noncorrected venous values. The arterial-to-muscle and femoral venous-to-muscle [H⁺] gradients were calculated as the difference between the respective blood compartment [H⁺] and the calculated intramuscular [H⁺].

Statistical Analysis

	RESULTS

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Muscle Metabolism

Phos. Phos a activity did not change with power output during CON. However, with ALK, Phos a progressively decreased with power output and was significantly lower at 75% O_{2 max} with ALK compared with CON (ALK 37.9 ± 5.1 vs. 48.8 ± 5.0 mmol dry wt · kg¹ · min¹; Fig. 2).

View larger version (22K): [in this window] [in a new window]   Fig. 2.   Phosphorylase (Phos) a, mole fraction % during cycling at the various power outputs. + Significantly different from CON at matched time points. There was a significant main effect of time with each condition. Values are means ± SE.

View this table: [in this window] [in a new window]   Table 1.   Muscle glycogen and glycolytic intermediate contents in vastus lateralis at rest, rest postingestion, and during cycle ergometry at 30, 60, and 75% O2 max after either CON or ALK

View larger version (30K): [in this window] [in a new window]   Fig. 3.   Glycogen utilization for each power output. Data are means ± SE. + Significantly different from CON at matched time points.

Lactate and pyruvate. Intramuscular [Lac] increased with each power output but was significantly higher with ALK at both 60% (ALK 40.9 ± 8.3 vs. CON 26.2 ± 5.0 mmol/kg dry wt) and 75% (ALK 72.8 ± 11.8 vs. CON 65.2 ± 10.1 mmol/kg dry wt) O_{2 max} (Fig. 4). Muscle [pyruvate] increased with each power output and was similar between conditions at 30 and 75% O_{2 max} and significantly higher with ALK during the second power output (Fig. 4).

View larger version (18K): [in this window] [in a new window]   Fig. 4.   Muscle lactate (Lac) and pyruvate concentrations with ALK and CON at rest and during each power output. + Significantly different from CON at matched time points. Values are means ± SE. dw, Dry weight. There was a significant main effect of time for both Lac and pyruvate, specifically at 60 and 75% O2 max.

PDH_a. Resting (ALK 0.55 ± 0.01 vs. CON 0.55 ± 0.08 mmol wet wt · kg¹ · min¹) and rest postingestion (ALK 0.55 ± 0.11 vs. CON 0.53 ± 0.05 mmol wet wt · kg¹ · min¹) PDH_a were not different between conditions. Under both conditions, PDH_a increased progressively with each power output but was significantly higher at 60% O_{2 max} (4.17 ± 0.23 vs. 3.77 ± 0.27) with ALK compared with CON, respectively (Fig. 5).

View larger version (26K): [in this window] [in a new window]   Fig. 5.   Muscle active pyruvate dehydrogenase (PDHa) activity with ALK and CON at rest and during each power output. + Significantly different from CON at matched time points. Data are means ± SE. ww, Wet weight. There was a significant main effect of time for each condition.

View this table: [in this window] [in a new window]   Table 2.   Muscle acetyl group content in vastus lateralis at rest, rest postingestion, and during cycle ergometry at 30, 60, and 75% O2 max after either CON or ALK

ATP, ADP_f, AMP_f, free P_i, and PCr. Muscle ATP concentration ([ATP]) was unaltered by exercise or as a result of ALK. Muscle [ADP_f] and [AMP_f] increased with each power output, but both were significantly higher with ALK at 60 and 75% O_{2 max} (Table 3). Free P_i increased with each power output, but to a significantly greater degree with ALK (Fig. 6). The [PCr] decreased with increasing power output but was significantly more depleted at each power output during ALK compared with CON (Fig. 6).

View this table: [in this window] [in a new window]   Table 3.   Muscle high energy phosphate content in vastus lateralis at rest, rest postingestion, and during cycle ergometry at 30, 60, and 75% O2 max after either CON or ALK

View larger version (17K): [in this window] [in a new window]   Fig. 6.   Phosphocreatine (PCr) and free Pi with ALK and CON at rest and at each power output. There was a significant main effect of time for each condition. + Significantly different from CON at matched time points. Values are means ± SE.

Pyruvate production and oxidation and lactate production and oxidation. Pyruvate production increased with exercise but was significantly higher during both the second and third power outputs with ALK. Pyruvate oxidation increased with exercise similarly between conditions at both 30 and 75% O_{2 max}. At 60% O_{2 max}, pyruvate oxidation was significantly higher during ALK (Table 4). Relative pyruvate oxidation expressed as the percentage of pyruvate produced that was oxidized was similar between conditions for both 30 and 75% O_{2 max}. However, relative pyruvate oxidation was significantly higher during 60% O_{2 max} with ALK (Table 4). Lactate production was similar between conditions during the first two power outputs but was significantly higher at 75% O_{2 max} during ALK (Table 4).

View this table: [in this window] [in a new window]   Table 4.   Muscle pyruvate production, oxidation, and lactate production at 30, 60, and 75% O2 max after either CON or ALK

Blood Metabolites, Blood Flow, and Exchange Across the Leg

View larger version (21K): [in this window] [in a new window]   Fig. 7.   Arterial blood pH, PCO2, and HCO3 during ALK and CON at rest and during each power output. + Significantly different from CON at matched time points. Values are means ± SE.

View this table: [in this window] [in a new window]   Table 5.   Arterial concentration of bloodborne substrates during rest, rest postingestion, and during cycle ergometry at 30, 60, and 75% O2 max after either CON or ALK

Leg blood flow and leg respiratory quotient. Leg blood flow increased progressively with exercise similarly between conditions (Table 6). Leg O₂, CO₂, and leg respiratory quotient were not different between conditions, increasing with each power output (Table 6).

View this table: [in this window] [in a new window]   Table 6.   Leg blood flow, RQ, CO2 production, and O2 uptake at rest, rest postingestion, and during cycle ergometry at 30, 60, and 75% O2 max after either CON or ALK

Blood lactate and flux. Arterial [Lac] increased progressively with each power output but was significantly higher at both 60 and 75% O_{2 max} with ALK (Table 5). Net Lac release across the leg increased with each power output but was significantly higher during 75% O_{2 max} with ALK (Fig. 8).

View larger version (17K): [in this window] [in a new window]   Fig. 8.   Glucose uptake and lactate release across the leg during ALK and CON at rest and for each power output. + Significantly different from CON at matched time points. There was a significant main effect of time for glucose uptake and Lac release. Values are means ± SE.

View larger version (20K): [in this window] [in a new window]   Fig. 9.   Glycerol flux and free fatty acid (FFA) flux across the leg during ALK and under CON conditions at rest and during each power output. + Significantly different from CON at matched time point. There was a significant main effect of time with each condition. Values are means ± SE.

Lactate Gradient, H⁺ Gradient, and pH_i

View this table: [in this window] [in a new window]   Table 7.   Lactate and hydrogen ion gradients from arterial to muscle and femoral venous to muscle during cycle ergometry at 75% O2 max only after either CON or ALK

Respiratory Gas Exchange Variables

View this table: [in this window] [in a new window]   Table 8.   Respiratory variables during cycle ergometry at 30, 60, and 75% O2 max after either CON or ALK

	DISCUSSION

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The present study examined the effects of induced alkalosis on the metabolic responses of skeletal muscle during continuous, dynamic, constant-rate exercise at three power outputs (30, 60, and 75% O_{2 max}). The main effects of alkalosis during this type of exercise occurred during the two higher power outputs and included an enhanced glycogen utilization with a concomitant increase in pyruvate production, increased intramuscular Lac accumulation, enhanced Lac efflux from the exercising leg, and a greater relative activation of Phos than PDH_a.

Lactate production within the muscle is dependent on the balance between the rates of pyruvate production and oxidation. Intramuscular Lac is formed from pyruvate by the action of the near-equilibrium enzyme LDH (47). Although greater pyruvate production was observed at the two highest power outputs, Lac production was elevated over CON values only during 75% O_{2 max} (Table 4). Lactate production at the highest power output resulted from a significant degree of mismatch between the rates of glycogenolysis/glycolysis and maximal PDH_a activation. At 60% O_{2 max}, the absence of an increase in lactate production despite an increased pyruvate production resulted from an enhanced pyruvate oxidation relative to production due to greater PDH_a with ALK. These changes resulted from the effect of alkalosis on the rate-limiting enzymes Phos, phosphofructokinase (PFK), and PDH. The main control points for glycogenolysis/glycolysis involve Phos and PFK, respectively, whereas entry into the oxidative pathway is controlled by PDH_a (47).

Phos

Phos a was significantly reduced at the highest power output with ALK. This reduction presumably reflects the inhibition of Phos kinase a by the increased [H⁺] (Table 3). Previous studies have demonstrated this relationship between [H⁺] and Phos a in intensely exercising muscle (13). However, the mole fraction of Phos in the a form is not the sole determinant of glycogenolytic flux, as previous studies examining the relationship between Phos a transformation and glycogenolysis have demonstrated (14, 18, 34, 54). The present results of a higher glycogen utilization at 75% O_{2 max} (133 ± 6 vs. 113 ± 12; Fig. 3) despite a lower Phos a (Fig. 2) and the observed greater glycogen utilization (132 ± 15 vs. 75 ± 6; Fig. 3) despite similar Phos a (Fig. 2) at 60% O_{2 max} with ALK are in agreement with these previous studies. Additionally, there may have been a hormonal effect throughout exercise due to a decrease in the circulating epinephrine concentration ([epinephrine]) with ALK, which may have contributed to the lower observed Phos a. Bouissou and colleagues (10) observed a 34% reduction in the plasma [epinephrine] and higher intramuscular [Lac] with alkalosis in humans who cycled to exhaustion. The enhanced glycogenolysis despite similar or lower Phos a transformation with ALK likely resulted from posttransformational modulation by increases in the AMP_f, and IMP concentrations and an increase in its substrate free P_i.

AMP and IMP have been shown to stimulate Phos a (2, 54) and Phos b (2, 15). AMP acts on Phos a by reducing the K_m for P_i from 26.8 to 11.8 mM in the presence of as little as 0.01 mM AMP (2, 54). AMP acts in a similar manner on Phos b but with a higher K_m. Both the [AMP_f] and free [P_i] were significantly greater with ALK during the second and third power outputs and were well above the required concentrations for activation (Table 3 and Fig. 6). In support of the close relationship between Phos activity, glycogenolytic flux, and the [AMP_f], other studies using caffeine ingestion (17), increased FFA availability (24, 48), and short-term training (16) have demonstrated glycogen sparing during exercise associated with blunted AMP_f accumulation. The increased [AMP_f] may have augmented activation of both Phos a and Phos b. IMP activates Phos b with a K_m of 1.2 mM (2). IMP concentration ([IMP]) was not measured in the present study but has been shown previously to increase with exercise and when the [ADP_f] increases (64). The [ADP_f] was significantly elevated with ALK, which may have led to an increase in the [IMP], which in turn may have activated Phos b.

ATP and G-6-P are both inhibitors of Phos b. ATP has an inhibitory constant (K_i) of ~2 mM, whereas G-6-P has a K_i of ~0.3 mM (25). In the present study, [ATP] remained constant throughout exercise and between conditions at levels above the K_i. [G-6-P] was significantly lower with ALK at 75% O_{2 max} but remained above the K_i. These combined results should favor a reduction in Phos activity and glycogenolysis. However, it has been previously demonstrated that the inhibition of Phos b by both ATP and G-6-P can be overcome when the [AMP_f] increases sufficiently (18). In addition, previous studies have demonstrated that glycogenolytic flux is closely tied to the availability of its substrate, free P_i, and the allosteric regulator, AMP_f, both of which were elevated with ALK (16, 17).

In summary, Phos activity and therefore glycogenolytic flux results from the combination of covalent, allosteric, and substrate regulation. During ALK, despite a lower transformation of Phos a, glycogenolytic flux was enhanced, and glycogen utilization increased during the second and third power outputs due to the maintenance of flux through posttransformational allosteric activation of Phos a + b by an increased [AMP_f], and possibly [IMP], and an increase in the concentration of its substrate, free P_i.

PFK

[ATP] remained constant between trials and across power outputs, which provided a small degree of inhibition. Also, during the highest power output, intramuscular [H⁺] was significantly elevated for both trials (Table 3), which would provide inhibition, as previous in vitro studies using constant [ATP] with declining pH have demonstrated (22, 65). Human exhaustive exercise protocols have found similar changes reflecting reductions in PFK activity with reduced intramuscular [H⁺] (36, 59). The magnitude of the pH inhibition can be modulated by increases in [F-6-P] and the activators ADP, AMP, and free P_i. Alkalosis led to increases in [F-6-P] and [G-6-P] during the third power output but to a significantly lower magnitude than CON. At this power output, pH_i was significantly lower compared with CON but may have failed to inhibit PFK activity due to positive modulation by the significantly elevated [AMP_f], [ADP_f], and [P_i]. AMP acts by augmenting PFK's affinity for its substrate, F-6-P (9). The increased [F-6-P], although lower than CON, was elevated above the K_m of 0.1-0.2 mM, which could have opposed the pH inhibition by decreasing the affinity of the ATP binding site (39). The accompanying rise in the [G-6-P], although above the K_i for Phos, may have been overridden by the positive modulation of Phos by the increased [AMP_f] and [P_i]. Previous in vitro studies have also demonstrated substantial acceleration of glycolysis with the lowering of the ATP-to-ADP ratio, a situation present with ALK at both 60% (CON 132 vs. ALK 87) and 75% O_{2 max} (CON 80 vs. ALK 55) due to the increase in [ADP_f] (71). The stimulatory effect of an increase in [ADP_f] on PFK activity has been shown to substantially increase with as little as a 2 mM increase in P_i, which also occurred in the present study with ALK (71).

The combined results demonstrate enhanced glycogenolytic/glycolytic flux with ALK due to allosteric upregulation of both Phos and PFK activity, leading to the increased glycogen utilization and pyruvate production at the two highest power outputs.

PDH

Changes in PDH_a at 60% O_{2 max}. In the present study, PDH_a increased with each power output as a result of contraction-induced increases in the [Ca²⁺] (19, 21, 34). However, increases in the [Ca²⁺] cannot be the sole mechanism responsible for the increased PDH_a with ALK, since the power outputs were identical between trials. The elevated PDH_a with ALK resulted from changes in the allosteric regulators acetyl-CoA, ADP_f, H⁺, pyruvate, and the NADH-to-NAD⁺ ratio.

Changes in PDH_a at 75% O_{2 max}. At this power output, PDH_a transformation was similar between conditions and reflects the attainment of maximal PDH_a (Fig. 5). Previous studies have shown maximal activation at this power output (34, 50). The increased pyruvate production with ALK resulted from a slightly higher glycogen utilization. The absence of a difference in the relative pyruvate oxidation rates between conditions was due to the similar rates of PDH_a. The higher lactate production rate observed with ALK resulted from the higher glycogenolytic/glycolytic rate. However, at this power output with ALK, the major fate of the lactate produced was efflux from the muscle and not intramuscular accumulation, which will be discussed later.

Cellular energetics. The rate of mitochondrial ATP production is regulated by O₂ availability and the [NADH]-to-[NAD⁺] and the [ATP]-to-[ADP] × [P_i] ratios (70). O₂ availability was not limiting in the present study in either trial, as neither the mouth O₂ nor O₂ uptake across the leg was different (Tables 6 and 8). However, differences in glycogen and FFA utilization were apparent. During the two higher power outputs with ALK, there was a decrease in FFA utilization, as evidenced by decreased [acetyl-CoA] and the markedly higher glycogen utilization. During CON, the significantly lower glycogen utilization necessitated an increase in FFA utilization to match energy production to ATP demand. The reduced FFA utilization with ALK may have decreased the mitochondrial [NADH], which would necessitate a higher [ADP_f] and [P_i] to drive oxidative phosphorylation according to the equation (70)

(1)

where c³⁺ and c²⁺ are the oxidized and reduced forms of mitochondrial cytochrome c, respectively, and the subscripts i and e refer to the intramitochondrial and extramitochondrial pools of reactants, respectively. This phenomenon of an obligatory increase in the [ADP_f] and [P_i] was observed with ALK during the higher power outputs (Table 3 and Fig. 6). The CK reaction and PCr play key roles in the regulation of oxidative phosphorylation and other metabolic processes as an "energy buffer" and an "energy transport" system between the sites of ATP production and ATP utilization (67). The CK/PCr system is very sensitive to changes in intracellular [ADP_f] and serves to keep this concentration low to prevent the inactivation of cellular ATPases and the net loss of cellular adenine nucleotides (67). In addition to functioning as a "barometer" for the intracellular [ADP_f] and therefore mitochondrial respiration, the CK/PCr system acts as a proton buffer, since the production of ATP consumes both ADP and H⁺, which are both products of ATP hydrolysis

(2)

The coupling of CK with the ATPases at the site of utilization prevents the local acidification at the initiation of exercise before activation of glycogenolysis. The hydrolysis of PCr also liberates free P_i at the onset of exercise, which is essential for the activation of glycogenolysis and glycolysis (3, 67). The increased degradation of PCr usually reflects a lack of mitochondrial-derived ATP from oxidative phosphorylation (70). In the present study, the increased PCr breakdown observed during ALK (Fig. 6) may have resulted from either a reduced [NADH] that accompanied a reduction in FFA utilization (Eq. 1) or may have resulted from a change in the [H⁺] with ALK (Eq. 2). Unfortunately, it is not clear from the present results which mechanism occurred first or what the exact mechanism is. Regardless of the mechanism, it is clear that the increased degradation of PCr led to elevation in the free [P_i], which contributed to the increased glycogenolysis observed with ALK, and is in agreement with previous studies examining the effect of increased FFA availability in rats (26) and humans (24), which have found that the concentrations of ADP, P_i, PCr, and NADH have direct effects on TCA cycle activity, mitochondrial respiration, and glycogen metabolism.

Lactate Metabolism and Transport

Lactate production during ALK at 75% O_{2 max} was increased compared with CON and resulted from the mismatch between the rates of glycogenolysis and PDH_a flux, as evidenced by enhanced pyruvate production and significantly higher glycogen utilization in the absence of a difference in PDH_a between trials (Fig. 3 and Table 4). The similar PDH_a between trials reflects maximal activation and is supported by the similar rates of pyruvate oxidation at this power output (Table 4). Therefore, the only difference between trials at this power output was the augmented CHO utilization and thus glycogenolytic flux, which greatly exceeded the maximal PDH_a flux. Previous studies have demonstrated that a mismatch does exist between the maximal rates of Phos and PDH_a at higher power outputs, resulting in a significant increase in lactate production (34, 51).

Intramuscular lactate accumulation is also a function of the rate of efflux from the muscle (38). ALK significantly increased arterial whole blood [Lac] and plasma [Lac] (Table 5) during both the second and third power outputs and enhanced efflux from the exercising leg during the highest power output only (Fig. 8). Blood [Lac] represents the balance of lactate entry from muscle and uptake by inactive tissue (7). The present results can be explained by both enhanced lactate transport out of the exercising leg and possibly reduced uptake by nonexercising tissue.

Lactate transport across the sarcolemma occurs via a monocarboxylate lactate-proton cotransport protein and as such is the rate-limiting step in lactate efflux (38, 45). Kinetic studies of the transporter using isolated sarcolemmal vesicle preparations have shown it to have a high affinity for L-lactate and to be sensitive to changes in both the Lac and H⁺ concentration gradients (38).

In the present study with ALK, there was an increase in the intramuscular [Lac], but the [Lac] gradient between the muscle and both the arterial plasma and femoral venous plasma compartments was similar between conditions (Table 7). Therefore, the enhanced lactate efflux observed with ALK was not a function of the increase in the intramuscular [Lac]. This means that some other factor likely had an effect on the transporter (8). The most plausible effector is H⁺, as the [H⁺] gradient between muscle and both the arterial and femoral venous blood was significantly elevated with ALK (Table 7; see Refs. 38, 40). ALK also induced a significant elevation in extracellular HCO₃ concentration ([HCO₃]) that may have contributed to the enhanced lactate efflux from the muscle. The importance of external [HCO₃] on lactate efflux has been demonstrated in isolated muscle preparations with low external [HCO₃] yielding reduced lactate efflux (32, 43, 58). In addition, studies employing metabolic alkalosis in exercising humans (10, 27, 33, 37, 46, 63, 69) have consistently demonstrated increases in the appearance of lactate in the plasma when accompanied by increases in [HCO₃]. During ALK in the present study, extracellular [HCO₃] was significantly elevated in both arterial and femoral venous blood at rest postingestion and remained elevated throughout each of the three power outputs, which is an agreement with the above evidence (Table 5). Additionally, decreased lactate uptake by inactive tissue may have contributed to the higher arterial [Lac] with ALK. Uptake by inactive tissue has been shown to occur during exercise (28). Normally, with exercise, the increased blood [H⁺] and [Lac] create an inwardly directed [H⁺] and [Lac] gradient, which facilitates uptake into inactive tissue. However, alkalosis decreases the [H⁺] gradient and therefore may reduce uptake compared with control conditions.

Summary and Conclusions