Arginine is a semiessential amino acid involved in several metabolic pathways and the production of a number of biologically active compounds (9). Specifically, arginine contributes to the removal of excess ammonia from the body and the synthesis of muscle protein, other amino acids, and creatine (6,8,12,38). Perhaps of most physiological significance, arginine is the precursor of nitric oxide (NO) and thus plays an important role in endothelium-dependent vasodilation (5,6,12). Therefore, one of the proposed benefits of arginine supplementation is increased blood flow to the myocardium and skeletal muscle (6,8-10,22,37,39).
The majority of studies that have examined the effects of arginine on measures of exercise capacity, cardiac performance, and hemodynamics have used subjects with cardiovascular (10,22,24,31,39) or pulmonary diseases (34,37). In general, these investigations have reported improvements in time to exhaustion, exercise tolerance, endothelial function, and blood flow (10,22,24,31,34,37,39). For example, Maxwell et al. (31) examined the effects of 2 weeks of oral arginine (6.6 g·d−1) supplementation on vascular function and exercise capacity in patients with coronary artery disease and reported significantly greater flow-mediated vasodilation (5.5 ± 4.5 to 8.0 ± 4.9%) and total exercise time (545 ± 239 to 664 ± 763 seconds) during incremental treadmill walking compared with placebo. Mehta et al. (34) found a reduction in mean pulmonary artery pressure (−15.8 ± 3.6%) and pulmonary vascular resistance (−27.6 ± 5.8%) after an intravenous infusion of arginine (0.5 g·kg−1 of body weight) in subjects with pulmonary hypertension. Thus, the findings of these previous studies (10,22,24,31,34,37,39) have indicated that arginine supplementation can improve vascular function and exercise capacity in clinical populations.
There are limited data regarding the effects of arginine supplementation in healthy subjects, and the results of these investigations (2,5,8,28,32,40,41) have not been consistent. In particular, previous studies have demonstrated that arginine supplementation (5.2-6.0 g·d−1) improved performance-related variables such as upper body strength (8), resistance to fatigue during repeated isokinetic muscle actions (41), and the anaerobic threshold (11), and peak (8) and mean power (7) during cycle ergometry. Furthermore, intravenous infusion of arginine (3-30 g·d−1) has been shown to increase glucose clearance during prolonged exercise (32), reduce exercise-induced increases in plasma lactate and ammonia (40), decrease peripheral arterial resistance, and inhibit platelet aggregation (5) in healthy individuals. In contrast, other studies have reported that oral supplementation with arginine (2.8-6.0 g·d−1) had no effect on time to exhaustion or maximal aerobic capacity during cycle ergometry (2) and treadmill walking (8). In addition, it has been shown that the chronic oral ingestion of arginine (2.8-6.0 g·d−1) did not affect plasma lactate and ammonia responses during fatiguing workbouts on a cycle ergometer (2,28). It is possible that the discrepancies among these studies (2,5,8,28,32,40,41) reflected differences in doses and route of arginine administration (oral vs. intravenous infusion), types of activities performed, and intensities of the variables measured (i.e., submaximal vs. maximal).
Grape seed extract is another ergogenic aid that has been shown to improve flow-mediated vasodilation through the increased production of NO (13). Previous in vitro studies have demonstrated antioxidant and endothelium-relaxing properties associated with grape seed extract (16,17), but like arginine, little is known regarding its effects on exercise performance in healthy individuals. Based on the previous findings regarding the effects of grape seed extract (13,16,17) and arginine (5,7,8,11,32,40,41) supplementation, a combination of the 2 may act synergistically to increase muscle blood flow, reduce exercise-induced increases in plasma levels of lactate and ammonia, and potentially delay the onset of neuromuscular fatigue. No previous investigations, however, have determined the benefits of arginine supplementation in conjunction with grape seed extract on exercise performance. Therefore, the purpose of the present study was to examine the effects of daily oral administration of arginine-based supplements for 4 weeks on the physical working capacity at the fatigue threshold (PWCFT). Based on the results of previous studies (7,11,41), we hypothesized that the arginine supplement would delay the onset of neuromuscular fatigue and increase PWCFT.
Experimental Approach to the Problem
This study used a randomized, double-blind, placebo-controlled, parallel design. During the first laboratory visit (PWCFT before supplementation [PRE]), each subject performed an incremental test to exhaustion on an electronically braked cycle ergometer and was randomly assigned to 1 of 3 groups: (a) placebo (n = 19); (b) 1.5 g arginine (n = 14); or (c) 3.0 g arginine (n = 17). Table 1 provides the ingredients for the supplement and placebo pills. The subjects were asked to ingest 1 dose (4 pills) on an empty stomach every morning immediately after waking with 16 oz. of water. After 28 days of either supplementation or placebo, the subjects returned to the laboratory and ingested 1 dose 60 minutes before the POST (PWCFT after 4 weeks of supplementation) test. The subjects were tested for their POST incremental test to exhaustion with the same protocol used for the PRE test. No dietary restrictions were enforced during the course of this study, and the subjects were encouraged to continue with their normal exercise and dietary habits. In addition, each subject completed a 3-day food log during the first and last weeks of supplementation period to ensure there were no significant changes in dietary habits.
Sixty-one men volunteered to participate in this investigation. Of the 61 subjects, 50 (mean age ± SD = 23.9 ± 3.0) provided valid PWCFT values PRE and POST supplementation. The subjects were untrained in aerobic exercise and engaged in no more than 4 hours of recreational activity per week. In addition, the subjects did not report or exhibit (a) a history of medical or surgical events that could have significantly affected the study outcome, including cardiovascular disease, metabolic, renal, hepatic, or musculoskeletal disorders; (b) use of any medication that could have significantly affected the outcome of the study; (c) use of nutritional supplements that could have significantly affected the outcome of the study; and (d) participation in another clinical trial or ingestion of another investigational product within 30 days of enrollment. The study was approved by the University Institutional Review Board for Human Subjects, and all participants completed a health history questionnaire and signed a written informed consent document before testing.
Determination of o2peak
Each subject performed an incremental test to exhaustion on a Calibrated Quinton (Corval 400) electronically braked cycle ergometer (Quinton Instruments Inc., Seattle, WA, USA) at a pedal cadence of 70 rpm. Seat height was adjusted so that the subject's legs were at near full extension during each pedal revolution. In addition, toe clips were used to ensure that each subject maintained pedal contact throughout the ride. All subjects wore a nose clip and breathed through a 2-way valve (2700; Hans Rudolph, Kansas City, MO, USA). Expired gas samples were collected and analyzed using a calibrated TrueMax 2400 metabolic cart (Parvo Medics, Sandy, UT, USA) with O2, CO2, and ventilatory parameters expressed as 30-second averages. The metabolic cart was calibrated before each test. Each subject was fitted with a Polar Heart Watch system (Polar Electro Inc., Lake Success, NY, USA) to monitor heart rate throughout the test. The test began at 80 W, and the power output increased by 30 W every 2 minutes until voluntary exhaustion or until the subject could no longer maintain a pedal cadence of 70 rpm despite strong verbal encouragement. O2peak was the highest O2 value in the last 30 seconds of the exercise test that met at least 2 of the following 3 criteria (14): (a) 90% of age-predicted max heart rate; (b) respiratory exchange ratio > 1.1; and (c) a plateau of oxygen uptake (<150 ml·min−1 in O2 over the last 30 seconds of the test). The test-retest reliability for O2peak testing from our laboratory indicated the intraclass correlation coefficient (ICC) was R = 0.95, with no significant mean difference between test and retest values.
A bipolar (20-mm center-to-center) surface electrode (circular 4-mm diameter silver/silver chloride, BIOPAC Systems, Inc., Santa Barbara, CA, USA) arrangement was placed on the dominant leg over the vastus lateralis muscle at one-third of the distance between the lateral superior border of the patella and the anterior superior iliac spine according to the recommendations of the SENIAM Project (20). These points were measured with the subject in the standing position with the dominant leg fully extended. In addition, the electrode-placement site was located 5 cm lateral to the reference line so that they would lie over the vastus lateralis muscle (30). A standard goniometer (Smith & Nephew Rolyan, Inc., Menomonee Falls, WI, USA) was used to orient the electrodes at a 20° angle to the reference line to approximate the pennation angle of the vastus lateralis (1,18,26). The reference electrode was placed over the iliac crest. Before electrode placement, the skin at each electrode site was shaved, carefully abraded, and cleaned with alcohol. Interelectrode impedance was less than 2,000 Ω. The electromyographic (EMG) signals were amplified (gain: ×1,000) using differential amplifiers (EMG 100, Biopac Systems, Inc, bandwidth = 10-500 Hz), digitally bandpass filtered (fourth-order Butterworth) at 10-500 Hz, and the amplitude (microvolts root mean square, μVrms) values were calculated using custom LabVIEW software (version 8.5, National Instruments, Austin, TX, USA).
Determination of Physical Working Capacity at the Fatigue Threshold
The method used to determine the PWCFT values was consistent with the protocol of deVries et al. (15). During each 2-minute power output of the incremental cycle ergometer test to exhaustion, 6, 10-second EMG samples were recorded from the vastus lateralis muscle. The EMG amplitude values for each of the 10-second epochs were plotted across time for each power output of the test (Figure 1). The PWCFT was defined as the average of the highest power output that resulted in a nonsignificant (p > 0.05; single-tailed t-test) slope coefficient for the EMG amplitude vs. time relationship, and the lowest power output that resulted in a significant (p < 0.05) positive slope coefficient (Figure 1). Of the 122 maximal tests performed (61 subjects × 2 tests each), 13 (10.7% of the 122 tests involving 11 of the subjects) resulted in the subject reaching exhaustion before exhibiting a statistically significant positive slope for the EMG amplitude vs. time relationship during any of the 2-minute power outputs. Thus, in this study, PRE and POST PWCFT data were available for 50 of the original 61 subjects. These findings were consistent with those of Housh et al. (21) who also reported that in approximately 10% of the tests, a PWCFT could not be identified. The test-retest reliability for PWCFT testing from our laboratory indicated the ICC was R = 0.95, with no significant mean difference between test and retest values.
A 1-way analysis of variance (ANOVA) was used to examine differences between the groups (1.5 g arginine, 3.0 g arginine, and placebo) for the PRE PWCFT data. An analysis of covariance (ANCOVA) was then used to determine differences between groups for the adjusted POST PWCFT values with PRE PWCFT as the covariate. The total caloric (kilocalories) and macronutrient (grams of protein, carbohydrate, and fat) intake was analyzed with separate 3 (Group: 1.5 g arginine, 3.0 g arginine, and placebo) × 2 (Time: day 0 and 28) mixed-factorial ANOVAs. An alpha of p ≤ 0.05 was considered statistically significant for all comparisons.
A 1-way ANOVA indicated that there were significant (p < 0.05) mean group differences for PRE PWCFT values. The results of the ANCOVA for the adjusted POST PWCFT values covaried for the PRE-test scores indicated that the 1.5 g (mean ± SEM = 211.5 ± 7.9 W; 95% CI = 195.5-227.5 W) and 3.0 g (199.4 ± 7.6 W; 95% CI = 184.2-214.6 W) arginine groups were significantly greater than the placebo group (171.6 ± 7.1 W; 95% CI = 157.2-185.9 W) (Figure 2). In addition, the 3 × 2 mixed factorial ANOVAs resulted in no significant group × time interactions, main effects for group, or main effects for time for total kilocalories, or macronutrients consumed.
Theoretically, the PWCFT test estimates the highest power output that can be sustained for an extended period of time without neuromuscular evidence of fatigue (i.e., slope coefficient of zero for the EMG amplitude vs. time relationship) during cycle ergometry. In the present investigation, the supplements that contained 1.5 and 3.0 g of arginine resulted in significantly greater POST supplementation PWCFT values than the placebo. Furthermore, mean PWCFT values for the 1.5 and 3.0 g supplement groups increased from PRE to POST measurements by 22.4 and 18.8%, respectively, whereas the placebo group did not change (−1.6%). Although no previous studies have examined the effects of arginine on the onset of neuromuscular fatigue, recent investigations (7,11,41) have reported significant changes in other performance-related variables with the daily administration of arginine-based supplements. For example, Chen et al. (11) reported a 17% mean increase (mean ± SD = 0.85 ± 0.07 to 0.94 ± 0.06 L·min−1) in anaerobic threshold in a sample of healthy middle-aged and elderly men after 1 week (5.2 g·d−1) of ingesting an arginine-based supplement. In healthy college-aged men, the arginine containing (6 g) supplement, GAKIC (glycine-arginine-α-ketoisocaproic acid), increased the mean resistance to fatigue (up to 28%) during 35 continuous concentric followed by eccentric isokinetic muscle actions of the leg extensors at 90°·s−1 (41) and attenuated the decline in mean power during repeated bouts of supramaximal cycle ergometry (7). Recent studies (10,37,39) that have examined the effects of arginine supplementation have also demonstrated increased blood flow and exercise capacity in subjects with cardiovascular and pulmonary diseases. For example, Ceremużyński et al. (10) showed that arginine supplementation (6 g·d−1 for 3 days) resulted in greater mean exercise time to maximal ST-segment depression and increased maximal workload in patients with a history of myocardial infarction. Six weeks of arginine supplementation (5.6-12.6 g·d−1) has also been shown to increase mean distance walked in 6 minutes and forearm blood flow during isometric hand grip exercise in subjects with congestive heart failure (39). Furthermore, 1 week of arginine supplementation (0.5 g per 10 kg of body weight, taken 3 times per day) has been shown to increase o2peak (0.83 ± 0.09 to 0.90 ± 0.09 L·min−1) and peak power output (82 ± 6 to 92 ± 7 W) in patients with precapillary pulmonary hypertension (37). Thus, the findings of the present investigation, and those of previous studies (7,10,11,37,39,41), indicated that supplementation with arginine or arginine-based supplements significantly increased exercise capacity and performance in healthy and clinical populations.
The physiological mechanisms responsible for the ergogenic effects of arginine supplementation on neuromuscular fatigue and other performance-related variables have not been fully identified. A number of previous studies (5,22,24,34,39), however, have suggested that the beneficial hemodynamic effects of arginine in healthy and clinical populations may be multifactorial. For example, the increased peripheral blood flow found by Rector et al. (39) after 6 weeks of arginine supplementation (5.6-12.6 g·d−1) was associated with a significant decrease (1.9 ± 1.1 to 1.5 ± 1.1 pmol·L−1) in the potent vasoconstrictor, endothelin. Lerman et al. (24) demonstrated increased coronary blood flow and decreased plasma endothelin after 6 months of arginine supplementation (9 g·d−1). Koifman et al. (22) reported that intravenous infusion of arginine (20 g) increased stroke volume (68 ± 18 to 76 ± 23 mL) and cardiac output (4.1 ± 2.1 to 4.7 ± 1.4 L·min−1), with no change in heart rate (60 ± 7 to 61 ± 9 b·min−11) and decreased mean arterial blood pressure (102 ± 11 to 89 ± 10 mm Hg) and systemic vascular resistance. The authors (22) attributed these changes to an arginine-induced increase in NO production. Furthermore, Bode-Böger et al. (5) reported increased femoral artery blood flow (43.5%) and reduced systolic and diastolic blood pressure with the infusion of arginine (30 g) that were accompanied by increased urinary NO−3, possibly because of increased NO synthesis. Thus, the improved exercise performance in healthy and clinical populations associated with arginine supplementation (5,22,24,34,39) may be because of hemodynamic changes such as increased coronary and peripheral blood flow because of the inhibition of endothelin or increased production of NO.
Previous studies (3,36) have shown that exercise-induced increases in specific metabolic byproducts of muscular contraction lead to altered muscle contractility, which can ultimately affect force production and initiate fatigue. Recent findings (40) have suggested that arginine supplementation may improve exercise performance by attenuating the increase in lactate and other metabolic byproducts associated with the onset of fatigue. For example, Schaefer et al. (40) examined the acute effects of arginine (3 g) on plasma metabolite concentrations during fatiguing cycle ergometry and reported significantly reduced peak plasma lactate (8.2 ± 1.1 to 7.1 ± 0.7 mmol·L−1) and ammonia (73.1 ± 9.1 to 60.6 ± 8.2 μmol·L−1) concentrations. Although venous and arterial values do not always represent interstitial and intracellular concentrations, they provide insight into the rates of metabolite accumulation in the cellular and extracellular environments of the working muscle (33). Furthermore, it has been suggested (27,35,36) that the decrease in intracellular pH as a result of lactate accumulation may provide the physiological signal responsible for the recruitment of additional motor units to maintain force or power output during a fatiguing task and, thus, also contribute to the corresponding fatigue-related increases in EMG amplitude associated with the PWCFT test. Therefore, it is possible that the 1.5- and 3.0-g supplement groups in the present investigation had significantly greater POST supplementation PWCFT values (211.5 ± 7.9 and 199.4 ± 7.6 W, respectively) than the placebo (171.6 ± 7.1 W) because of a reduction in lactate production and the maintenance of cellular pH associated with arginine supplementation (40).
In addition to arginine, the supplement in the present study contained grape seed extract. Grape seed extract contains procyanidins, which possess antioxidant properties and endothelium-relaxing effects in vitro, possibly through the enhanced production of NO in endothelial cells (13,16,17). The exact physiological mechanisms of procyanidins are not fully understood, although their activity is related to increased levels of cyclic GMP leading to activation of endothelial NO synthase and is blocked by NO synthase inhibitors (17). There are limited data, however, regarding the effects of supplementation with grape seed extract in human subjects. Lu and Robinson (29) demonstrated significant decreases in systolic (134.1 ± 1.9 to 125.8 ± 2.7 mm Hg) and diastolic (79.1 ± 2.1 to 73.4 ± 2.2 mm Hg) blood pressure after 8 weeks of grape seed extract (300 mg·d−1) supplementation in subjects with prehypertension. Thus, it is possible that the ingestion of grape seed extract and arginine in the present investigation led to increased production of NO and enhanced blood flow to the exercising muscles.
In the present investigation, the supplements also used polyethylene glycol (PEG) as a delivery system for arginine. Polyethylene glycol is a nontoxic, water-soluble polymer that has commonly been used to enhance the absorption and delivery of various substances including medications (4), vitamins (23), electrolytes (25), and nutritional supplements (19). Specifically, PEG may increase the uptake efficiency of nutritional supplements and result in similar improvements in performance compared with the ingestion of a larger dose of the supplement alone (19). For example, Herda et al. (19) examined the effects of creatine monohydrate plus PEG (PEG creatine) on muscular strength, endurance, and power output after 4 weeks of supplementation. The authors (19) reported that the PEG creatine (1.25 and 2.50 g·d−1 doses) resulted in significant increases in bench press and leg press strength and that the strength increases were equal to those of a larger dose of creatine monohydrate (5 g·d−1) without PEG. Therefore, the findings of Herda et al. (19) and others (4,23,25) have suggested that PEG may aid in the absorption and use of various substances and enhance the ergogenic effects of nutritional supplements. Thus, the results of these studies (4,19,23,25) may explain why the smaller doses of arginine (1.5 and 3.0 g·d−1) used in the present investigation, compared with the doses (5.2-12.6 g·d−1) of previous studies (7,10,11,39,41), resulted in improved exercise performance when combined with PEG.
In summary, the findings of the present investigation showed that the arginine containing supplements (1.5 or 3.0 g) resulted in significantly greater POST supplementation PWCFT values than the placebo. These findings were likely attributable to reduced concentrations of metabolic byproducts, such as lactate or ammonia, or the improved blood flow associated with increased NO synthesis and decreased endothelin production with arginine and grape seed extract supplementation. Future studies should examine the effects of supplements containing arginine on other performance-related variables including fatigue thresholds derived from metabolic parameters.
The results from this study indicated that supplementation of arginine, grape seed extract, and PEG for 4 weeks delayed the onset of neuromuscular fatigue (PWCFT) during cycle ergometry in untrained men. Thus, these findings supported the use of arginine-based supplements, at the dosages examined in the present investigation, as an ergogenic aid for untrained individuals.
This study was funded by a research grant from General Nutrition Corporation. The results of the present study do not constitute endorsement of the product by the authors or the NSCA.
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