Vasodilation is a phenomenon of the vascular endothelium that depends on the bioavailability of nitric oxide (NO), and is an essential condition for the maintenance of arterial health (5). A number of environmental factors, including physical exercise and diet, are capable of modifying NO bioavailability and endothelial function, being, therefore, the focus of interest in several recent studies (36,40).
A sustained improvement in endothelium-dependent vasodilation has been observed after the chronic performance of physical exercise (30). This benefit is independent of the improvement in factors such as fasting plasma lipids (15), and it depends on the type of exercise and the muscle groups involved in each specific movement (14,28). However, at the molecular level, this improved endothelial function would result from acute adaptive mechanisms of the vascular wall to systematic shear stress, such as the increase in endothelial NO immediately after the effort (29,41). This exercise-related positive effect is produced by increasing several times the level of eNOS Ser1177 phosphorylation, and leads to an increase in the enzyme activity of eNOS and enhanced NO production (17).
However, it is not known whether the occurrence of postprandial phenomena during exercise, such as glucoregulation, may modify NO production or bioavailability.
It has been demonstrated that, under resting conditions, the hyperglycemia and subsequent oxidative stress might acutely worsen the efficacy of the NO-dependent vasodilatory system (33,48); however, under exercise conditions, this association lacks evidence. Under resting conditions, the severity of hyperglycemia ought to be directly related to the deterioration in endothelium-dependent vasodilation (4,32,47), because of a reduction in the production or activity level of NO caused by quenching by free radicals (22,48). However, in an exercise situation, the interaction between the increased demand for substrates and their availability prioritizes the delivery of nutrients to active tissues by means of the NO-dependent vasodilatory system. For this reason, an acute increase in NO might occur after exercise in conjunction with an impaired oxidative state (37).
Research on the glycemic behavior provoked by the pre-exercise intake of different glycemic carbohydrates might thus clarify the importance of glycemia for the NO-dependent vasodilatory system after the exercise. Along these lines, the addition of different doses of fructose to a single supplement of glucose (G) has proven to be an effective dietary strategy for the attenuation of postprandial glycemia, at least under resting conditions (31,42). Furthermore, it is also a dietary combination frequently used by athletes or recreational practitioners. To the best of our knowledge, there are no previous reports on the metabolic effects of the intake of a combination of glucose plus fructose (F) on endothelium-dependent vasodilation stimulated by different types of physical exercises.
This study is based on the hypothesis that the addition of a small dose of fructose to a high-glycemic-index carbohydrate, such as G, ingested before 2 metabolically different exercises can modify subsequent endothelial function.
The aim was therefore to determine changes in endothelial function when a small dose of fructose was consumed with a G supplement, before 2 common forms of aerobic and anaerobic exercises (AEs and AnEs). In addition, to account for this interaction (carbohydrate-exercise-endothelial function) from a metabolic standpoint, the glycemic behavior induced by both G and F was investigated, together with its influence on NO bioavailability and plasma lipid oxidation during a postprandial state that included exercise and recovery periods.
Experimental Approach to the Problem
The subjects initially attended 2 preliminary sessions during which anthropometric, and nutritional assessments, and V̇o2max, and 10 repetition maximum (10RM) tests, were performed. After 2 weeks on a controlled diet, all subjects ingested a dietary supplement of G or F and underwent a single session of aerobic or anaerobic physical exercises. Combinations of these independent variables resulted in 4 possible experimental interventions in a crossover design in which subjects performed all experimental conditions: G + AE, F + AE, G + AnE, and F + AnE. Subjects were allocated to a treatment order in a complete randomized design, and there was a 1-week washout interval between trials. Ischemic reactive hyperemia ([IRH], the most important dependent variable) was measured at rest and at the end of exercise and recovery phases. Blood samples were taken at baseline, during, and after the exercise sessions to determine glycemia, insulinemia, NO, and lipoperoxide (LPO) (dependent variables). In addition, plasma lactate concentrations were measured as an indicator of exercise intensity.
Twenty healthy men who had trained aerobically or anaerobically at least 4 times a week participated in the study; details of background training are provided in Table 1. None of the subjects had received pharmacological treatment or vitamin or mineral supplements during the 2 months before the study. The study design, purpose, and possible risks were explained to the subjects, and written consent was signed. All the procedures employed in the study were approved by the Ethics Committee and Review Board for use of Human Subjects of the Reina Sofía University Hospital.
Endurance Tests and Exercise
All subjects performed a progressive test until exhaustion on a cycloergometer (Ergometrics 800; Ergoline, Barcelona, Spain) under identical environmental conditions (21-24°C; 45-55% relative humidity) to determine their endurance exercise load. The test protocol commenced with 4 minutes of warm-up, at a load of 25 W during the first 2 minutes, followed by 50 W for the other 2; the load was thereafter increased by 25 W·min−1 until exhaustion. The subjects were asked to maintain a constant pedaling rate between 60 and 70 rpm. During the tests, a breath-by-breath automatic system (Oxycon Delta; Jaeger, Höchberg, Germany) measured the following parameters: oxygen and carbon dioxide consumption (V̇o2 and V̇Co2, in l minute-1 standard temperature and pressure [STP]); ventilation (V̇E) (V̇E, in l minute-1 body temperature, ambient preasure, and saturated with water vapor [BPTS]), V̇E/V̇o2, V̇E/V̇Co2, and end-tidal partial pressure of oxygen and carbon dioxide (PETO2 and PECO2). The values given were means calculated for 15-second intervals. The workloads (W) corresponding to the ventilatory thresholds 1 and 2 (VT1 and VT2, respectively) were calculated according to the method proposed by Davis (7).
In the endurance exercise performed during the experimental trials, the subjects pedaled at 25 and 50 W during the first and second minutes, respectively (warm-up phase), before completing a total of 30 minutes at an intensity equivalent to the value of W that they had reached at an equidistant point between VT1 and VT2 during the preliminary V̇o2max test. The same cycloergometer and pedaling rate was used in the endurance trials as in the preliminary tests.
Muscular Strength Tests and Exercise
The 10RM load was calculated on the basis of a halfsquat exercise in a multipower machine (Gervasport, Madrid, Spain), according to the procedure for tests of submaximal force proposed by Kraemer and Fry (24). The sequence employed in this exercise was 3 seconds per repetition (1.5 seconds in eccentric phase and 1.5 seconds in concentric phase) and was controlled by means of a digital metronome (MA-30, Korg, Tokyo, Japan).
The AnE performed during the experimental trials consisted of a bout of 10 series of 10 half squats, with the first and second series being done at 70 and 80% of 10RM, respectively, and the remainder at 90% of 10RM. There was a recovery period of 2 minutes 45 seconds between each series. The total duration of each bout (including exercise and interseries recovery periods) was 30 minutes. The subjects used the same machine and sequence of exercises as in the preliminary 10RM test.
Nutritional Status and Diet
A qualitative-quantitative assessment of the frequency of food intake retrospective to the 4 weeks before the preliminary evaluations was obtained from each subject by a nutritionist. The subjects were thereafter instructed to consume an isocaloric diet, with a moderate glycemic load and glycemic index. The daily serving of vegetables and fruit was set in accordance with the recommended dietary intake of ascorbic acid. This diet was followed throughout the 2 weeks before the first experimental trial and the washout periods between each trial; furthermore, caffeine, alcohol, and foods with high sugar content were not to be consumed during the day before each test. A 24-hour diary of food consumption was kept, to confirm that the dietary recommendations were adhered to, and the composition of the diet was calculated with the aid of food composition tables. The glycemic load and glycemic index were calculated in accordance with the formulas proposed by Liu et al. (26) and Jenkins et al. (21), respectively (Table 2).
Subjects arrived at the laboratory between 08.00 and 09.00, after 10-12 hours of nocturnal fasting. Ischemic reactive hyperemia was measured and a cannula (Vennflon, 16 G, London, United Kingdom) was inserted into the antecubital vein. Twenty milliliters of blood was then drawn off 15 minutes before the beginning of the exercise tests (t−15), and immediately thereafter the subjects ingested a solution of 50 g G (glucose anhydride C6H12O6 99.5%) or 50 g G plus 15 g fructose monosaccharide in 400 mL water. The 50 g of G, which requires no hydrolysis for absorption, was established as the minimal amount of glycemic carbohydrate in the 4 trials, with the purpose that this may provide the same threshold for detecting changes in the glycemic behavior, and endothelial function when fructose was given simultaneously in the F trials. For such a reason, we intentionally used 2 nonisocaloric supplementations like other studies have previously done (19,31). The solutions of G and F had a total concentration of 12.5 and 16.5%, respectively. The quantity of fructose in the combined supplement was determined on the basis of previous reports of its digestibility and absorption under resting and exercise conditions (10,35), and its specific concentration in solution was 3.75%, which is lower than that reported as being capable of being absorbed without causing gastrointestinal symptoms (44). During the 2 hours after the consumption of the supplement (postprandial period), which included a brief digestive rest (t−15-t0), the exercise phase (t0, t15, and t30) and the recovery phase (t45, t75, and t105), venous blood samples were drawn, whereas IRH was measured at the end of the exercise and recovery phases (Figure 1).
The subjects were also requested to avoid performing moderate or severe exercises for 24 hours before each preliminary session and experimental trial, which was controlled by means of a self-recorded exercise questionnaire. Srm-creatine kinase basal values above 200 U·L−1 were considered as an exclusion criterion for the experiment.
Blood Samples and Analytical Assays
Blood samples were collected in tubes containing 1 g−1 ethylenediaminetetraacetic acid (EDTA); the tubes were stored immediately in ice and the plasma separated by centrifugation at 1,500g for 15 minutes at 4°C. The tubes were protected from light at all times. Glucose concentrations were determined by spectrophotometric methods, using a modular analyzer (ISE-4-DDPPEEPP, Hoffmann-La Roche®, Basel, Switzerland). Plasma insulin levels were measured by chemiluminescent microparticle immunoassay using an analyzer (Architect i-4000, Abbott®, Chicago, IL, USA). The levels of LPO were determined in plasma aliquots using a commercially available kit (LPO-586, Oxis International®, Portland, OR, USA). Total nitrite and nitrate (NO) concentrations were determined by colorimetric assay (Nitrate/Nitrite, Colorimetric Assay Kit; Cayman Chemical, Ann Arbor, MI, USA), and plasma lactic acid was measured by enzymatic colorimetric assay using an analyzer (Cobas 400, Hoffman-La Roche®).
Study of Endothelial Function
A Periflux 5000 laser-Doppler monitor (Perimed AB, Stockholm, Sweden) was used to measure IRH; this provides a simple, swift method for measuring changes in acute endothelial reactivity immediately after exercise and during recovery. With the patient lying in the supine position in a room with stable temperature (20-22°C), the blood pressure cuff (HG Erkameter 300, Erka, Bad Tolz, Germany) was placed 5 cm above the elbow, whereas the laser probe was attached to the palmar surface of the second finger of the same dominant hand. After a 5-minute resting period, basal capillary flow was measured for 1 minute (t0). Thereafter, 4-minute distal ischemia was induced by inflating the cuff to suprasystolic pressure (200-220 mmHg). Subsequently, the cuff was deflated, and after 30 seconds, the flow was recorded for 1 minute (td).The data were recorded and stored using PeriSoft for Windows. The values of the area under the curve (AUC) of the t0 and td times were analyzed. These data were used to calculate the increase in postischemic flow by means of the formula: IRH = AUCtd-AUCt0.
Ischemic reactive hyperemia as measured by laser Doppler provides a high degree of reproducibility (38); previous pilot studies yielded an ICC of 0.91. The 10RM test had been regularly used by subjects during the previous year of training, which ensured good reproducibility of measurements (ICC = 0.93); a familiarization period was therefore not deemed necessary. The V̇o2max test was performed using a regularly calibrated gas analyzer; moreover, subjects were accustomed to cyclergometer effort, having used this equipment at least once a week. Biochemical measurements were generally made at the hospital laboratory in accordance with Standard ISO 15189. The laboratory is involved in internal and external quality control programs. External quality control is provided monthly by The Spanish Society of Clinical Biochemistry and Molecular Pathology.
The data are presented as means ± SE. Sample normality was calculated using the Shapiro-Wilk test. The effect of the different interventions (G + AnE, F + AnE, G + AE, and F + AE; independent variables) on IRH, glycemia, insulinemia, NO, LPO, and lactate (dependent variables) was subjected to analysis of variance (ANOVA) with repeated measurement of 2 factors (within): group and time: (4 [group] × 3 [time for endothelial function and NO] or 7 [time for other dependent variables]). A Tukey correction was used to adjust the p value in relation to the number of contrasts performed. Statistical significance was set at p ≤ 0.05; for all the statistical tests, the SPSS 11.5 package for Windows was used.
The glycemic behavior was analyzed as peaks of glycemia, because of its importance on the phenomena related to the endothelial function (i.e., glucoregulation, NO availability, and LPO concentration). In addition, the glycemic response was determined as the incremental area that included only the geometric area ahead of the fall in plasma G concentrations to below basal levels (16). This method was employed to specifically analyze the rise or attenuation of glycemia, depending on the carbohydrates consumed before the exercise trials.
Ischemic Reactive Hyperemia
In the study of endothelial function, IRH was significantly higher when the subjects consumed the F supplement and performed AnE (F + AnE vs. G + AnE; t30 and t105p < 0.05; + 26.30 and +27.23%, respectively, Figure 2A). However, there were no significant differences when they performed the aerobic exercise (Figure 2B).
Glycemic and Insulinemic Response
During the AnE, the F supplement produced a peak value of glycemia but not of insulinemia that was significantly lower than after G alone (−8.60%; F + AnE vs. G + AnE; t15; p < 0.05; Figures 3A and 4A). However, the G area under the curve was lower, but not significantly so, in F + AnE vs. G + AnE (96.10 ± 5.47 and 104.80 ± 5.87, respectively). During the recovery phase, a second peak of glycemia and insulinemia was only observed in F + AnE (t45; F + AnE vs. G + AnE; p < 0.05).
During the aerobic exercise and its recovery phase, no differences were produced in either the glycemic peak (Figure 3B) or the area under the curve (64.80 ± 4.66 and 67.51 ± 5.20; G + AE and F + AE, respectively) by the 2 supplements. However, a higher level of insulinemia was observed at those points in time, when the subjects ingested F (F + AE vs. G + AE; t15 and t45; p < 0.05; Figure 4B).
In AnE, plasma LPO concentrations were not significantly different between F + AnE and G + AnE in any of the analyzed conditions. On the contrary, in aerobic exercise, LPO levels were significantly higher after F at the end of the exercise and recovery phase (F + AE vs. G + AE; t30 and t105; p < 0.05) (Table 3).
A higher concentration of NO was registered at the end of the AnE and the recovery period after F than after G alone (t30 and t105; p < 0.05). At the same points in time, there were no differences between the supplements after aerobic exercise (Table 3), nor was any correlation found between NO and LPO levels under any of the experimental conditions.
Blood lactate was significantly elevated during the phase of recovery from AnE after glucose plus fructose (F + AnE vs. G + AnE; t75 and t105; p < 0.05), whereas no difference was found after the aerobic exercise (Table 4).
The main finding of this study is that the inclusion of fructose in a G supplement ingested before a session of AnE (F + AnE) increases endothelium-dependent vasodilation during the acute recovery period. This increase was preceded by an attenuation of the glycemic peak during the exercise phase and by a nonexponential fall in glycemia on the recovery phase. Furthermore, in F+AnE, a greater bioavailability of NO was observed at the end of the exercise and the recovery phases. Conversely, in aerobic exercise, no differences were observed in IRH, or in glycemic behavior; however, LPO showed a deterioration of the oxidative state.
Endothelial function depends on the equilibrium between the vasodilatory and vasoconstrictor factors (6). NO is regarded as the most important relaxant factor derived from the endothelium (34), and its availability is acutely increased after the shear stress produced in each exercise session (23,45), resulting in a progressive vascular adaptation (18,36,39). Although the intensity of shear stress depends on the variability of the flow (anterograde-retrograde) and the maximal strength exercised during the sessions (12,13,15), metabolic sources of stimulation also influence the acute vasodilatory response to exercise. During the exercise, the distribution of nutrients thus leads to a “functional sympatholysis” that involves an adrenergic attenuation, which gives way to the elevated dilation mediated by NO (1,23).
In the present study, we observed a higher bioavailability of NO and an improved endothelium-dependent vasodilation reflected by IRH after AnE when the subject ingested F. In addition, 2 postprandial conditions were clearly different in this group: (a) A reduction in the glycemic postabsorptive glycemic peak, but more sustained G availability, as shown by a second peak of glycemia in the recovery phase, and (b) a higher residual blood lactate level. On the basis of these findings, we believe that the increase in NO and the improvement in vasodilatory response were related to the glycemic behavior observed, and its interaction with the elevated demand for G during the AnE. Furthermore, in the F + AnE condition, the second peak in plasma G and insulin during acute recovery might reflect a second release of G from the liver, possibly after the metabolic conversion of fructose (25), but it would also mean more prolonged insulin stimulation, leading to the need for greater bioavailability of NO for the distribution of G to active tissues. Several studies have reported that, when carbohydrates are infused, the acute increase in insulin-dependent G transport to metabolically active muscles (2,3) would explain the elevated muscular and endothelial synthesis of NO (43). In line with this, Vincent et al. (46) have reported increases in total blood flow for 60-90 minutes after modest increases in insulin for G exchange.
The hypothesis of higher vasodilation induced by a modified glucoregulation after the inclusion of fructose would also explain why IRH was improved only in AnE, without any evident effects after AE. In the AnE, the elevated metabolic demands of G may have potentiated the NO-mediated G delivery system, according to the postabsorptive availability of the carbohydrate consumed and its regulation by the liver. Meanwhile, in the moderate aerobic exercise, which is partially independent of G as a substrate, it would be reasonable to expect that the availability of the carbohydrate consumed would not modify either glucoregulation or the need to deliver G from the blood.
In addition, the increase in LPO levels was the other differential phenomenon, observed only in the aerobic trial when the subject ingested F. This situation makes it clear that the consumption of the above mentioned combined supplement, before aerobic exercise, produced a deterioration that may have contributed to the fact that no differences were observed in NO bioavailability, and thus, on IRH stimulated by the exercise. Previous reports have shown fructose to be an important inducer of oxidative stress, especially when its quantity or the metabolic situation favors the synthesis of lipid products (8,25). In our study, the lipoperoxidation may be explained by the pathways through which the fructose is metabolized during exercise, rather than by the level of glycemia provoked during the aerobic exercise. An increase in triglycerides has already been reported, after pre-exercise intake of F in aerobic exercise (9). This acute lipidic deregulation supports the theory that the nonoxidative metabolism of fructose, in nonglycolytic exercises, may favor a redox unbalance.
On the other hand, the accumulation of residual lactate observed during recovery from the F + AnE could be explained as a product of the hepatic metabolism of fructose (25), which might offer a complementary explanation for the improvement in endothelial vasodilation. The hypothesis that lactate acts as a vasodilator has also been advanced by other studies of blood flow in various organs, including skeletal muscle (11,20). However, other authors have been unable to confirm such effects on the macrovascular endothelium so far (27), and our experimental design did not allow us to provide any information about the contribution of lactate to endothelial function observed.
In summary, the present study confirms that, in a predominantly glycolytic exercise, different glycemic carbohydrates can improve the metabolic availability of substrates and modify exercise ability to produce an acute vasodilatory response of the endothelium. Our results also demonstrate that a pre-exercise dietary supplement of F may (a) minimize the postabsorptive peak in glycemia and improve G availability during the early recovery phase, (b) favor the increase in the bioavailability of NO, and (c) raise residual blood lactate levels. Future studies using different doses of fructose or combining other glycemic carbohydrates might offer us new information about the influence of the glycemic response on endothelial function after exercise.
The data obtained here highlight the importance of the diet-exercise interaction in the acute stimulus exerted by AnE on endothelial physiology. The addition of a small amount of fructose to a widely used supplement such as G represents a simple and effective strategy for enhancing the vasodilatory effect of exercise, and thus the adaptation of peripheral circulation in sportspeople undergoing a muscular hypertrophy program. This effect of fructose may be especially significant both in sportspeople with demonstrably impaired peripheral endothelial reactivity (e.g., subjects with diabetes or metabolic syndrome), and in sedentary subjects undergoing circulatory and cardiovascular adaptation to a physical exercise program.
This study was supported by grants from the “Consejería de Turismo, Comercio y Deporte de la Junta de Andalucía,” “Fundación Hospital Reina Sofía CajaSur,” and “CIBER Fisiopatologia de la Obesidad y Nutricion” as an initiative of ISCIII. None of the authors had a personal or financial conflict of interest. This work was also supported by grants from the “Andalusian Council of Tourism, Commerce and Sports,” “Reina Sofía Hospital CajaSur Fundation,” and "CIBER Physiopathology of the Obesity and Nutrition as an initiative of Carlos IIIrd Health Institute (ISCIII).
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