GPLC - glicina propionil-L-carnitina

mistersalvo · 03-04-2010, 07:32 PM

Glycine propionyl-L-carnitine increases plasma nitrate/nitrite in resistance trained men

Department of Health and Sport Sciences, University of Memphis, Memphis, TN, USA

Abstract

We have recently demonstrated that oral intake of glycine propionyl-L-carnitine (GPLC) increases plasma nitrate/nitrite (NOx), a surrogate measure of nitric oxide production. However, these findings were observed at rest, and in previously sedentary subjects.
Purpose

In the present study, we sought to determine the impact of oral GPLC on plasma NOx at rest and in response to a period of reactive hyperemia in resistance trained men.
Methods

Using a double blind, crossover design, 15 healthy men (24 ± 4 years) were assigned to GPLC (3 g/d PLC + 1044 mg glycine) and a placebo in random order, for a four-week period, with a two-week washout between condition assignment. Blood samples were taken from subjects at rest and at 0, 3, and 10 minutes following an ischemia-reperfusion protocol (six minutes of upper arm cuff occlusion at 200 mmHg followed by rapid reperfusion with cuff removal). Blood samples were taken from a forearm vein from the same arm used for the protocol and analyzed for total nitrate/nitrite. Data are presented as mean ± SEM.
Results

A condition main effect (p = 0.0008) was noted for NOx, with higher values in subjects when using GPLC (45.6 ± 2.8 μmol·L-1) compared to placebo (34.9 ± 1.2 μmol·L-1). No time main effect was noted (p = 0.7099), although values increased approximately 12% from rest (37.7 ± 2.7 μmol·L-1) to a peak at 10 minutes post protocol (42.3 ± 3.3 μmol·L-1). The interaction effect was not significant (p = 0.8809), although paired time contrasts revealed higher values for GPLC compared to placebo at 3 (48.2 ± 6.7 vs. 34.9 ± 2.4 μmol·L-1; p = 0.033) and 10 (48.8 ± 5.9 vs. 35.7 ± 2.1 μmol·L-1; p = 0.036) minutes post protocol, with non-statistically significant differences noted at rest (41.8 ± 4.5 vs. 33.6 ± 2.5 μmol·L-1; p = 0.189) and at 0 minutes (43.6 ± 5.1 vs. 35.4 ± 2.7 μmol·L-1; p = 0.187) post protocol. An analysis by subject (collapsed across time) indicated that 11 of the 15 subjects experienced an increase in NOx with GPLC treatment.
Conclusion

These findings indicate that short-term oral GPLC supplementation can increase NOx in resistance trained men. However, as with many dietary supplements, there exist both "responders" and "non-responders" to treatment. Future work may focus on the mechanisms for the discrepancy in response to GPLC supplementation for purposes of NOx elevation.
Introduction

Nitric oxide (NO•) is an important signaling molecule, promoting vasodilation by acting on vascular smooth muscle [1]. In addition, NO• has been linked to other physiological functions such as inhibition of platelet aggregation and platelet adhesion [2]. In these ways, NO• mediates increased blood flow at rest [3-5] and during exercise [4,6,7], which may have implications for those with chronic ischemic disease as well as for athletes interested in enhancing blood flow to working skeletal muscle (e.g., endurance athletes, bodybuilders).

Nitric oxide is synthesized from L-arginine by the endothelium in the vascular system [2] and has been reported to increase in response to acute exercise [8-13]. This is true for dynamic [4], as well as for isometric [7] exercise, in which reperfusion is present following cessation of the contraction. Moreover, chronic exercise training has been reported to result in an increase in plasma nitrate/nitrite (NOx) levels [14-16], a surrogate marker of NO•.

Aside from exercise, pharmaceutical agents have been used with success to induce NO• biosynthesis, in an attempt to promote vasodilation (for review please see [17]). Treatments have sometimes included high dosages of L-arginine, often provided via intravenous injection. This has led to the development of several nutritional supplements, often containing small amounts of L-arginine, which are purported to have "drug-like" action, ultimately leading to increased NO•. While the fitness industry is inundated with advertisements for such products, the scientific data are scant. We have recently demonstrated an increase in plasma NOx in healthy sedentary subjects following oral treatment with a novel carnitine agent, glycine propionyl-L-carnitine (GPLC; [18]). This finding extends recent work of Lofreddo et al. [19] who reported an increase in blood NOx in response to 6 grams per day of PLC given via IV infusion to patients with peripheral arterial disease. Other reports suggest vasodilatation actions with PLC [20], in addition to glycine [21] treatment independently. However, our initial findings using oral GPLC were observed at rest, and in previously sedentary subjects, individuals who quite possibly have lower resting NOx levels compared to well-trained subjects; hence, may have a greater potential for responding to GPLC treatment. To our knowledge, no studies have been done to evaluate the efficacy of nutritional supplements to increase NOx levels in a sample of potential users (e.g., resistance trained athletes). Therefore, in the present study, our purpose was to determine the impact of oral GPLC on plasma NOx at rest and in response to a period of reactive hyperemia in resistance trained men. Using a double blind, randomized, crossover design, we hypothesized that plasma NOx would be higher with GPLC treatment compared to placebo, at rest and in response to the ischemia-reperfusion protocol.
Methods
Subjects

Fifteen healthy, resistance trained men participated in this investigation. Subjects completed a medical history, diet and supplementation history, and physical activity questionnaire to determine eligibility. No subject was a smoker or used anti-inflammatory drugs or antioxidant supplements before (for a minimum of six months) or during the study period. Subjects were young (24 ± 4 yrs; mean ± SD), and of average height (177 ± 5 cm), weight (83 ± 4 kg), and body fat percentage (14 ± 5 %). Subjects were considered to be well-trained and performed resistance exercise for 5 ± 2 hrs per week for 8 ± 5 yrs. They were instructed not to deviate from their current training regimen during the course of the study with the exception of refraining from exercise for the 48 hours prior to each testing day. All experimental procedures were performed in accordance with the Helsinki Declaration. The University of Memphis Human Subjects Committee approved all experimental procedures. All subjects provided both verbal and written consent prior to participating in this study.
Conditions

Subjects were randomly assigned in double-blind manner using a cross-over design to GPLC and a placebo. Each intake period consisted of four weeks, with a two-week washout period between condition assignments. Subjects were instructed to ingest a total of six capsules per day of GPLC or placebo (at two separate times – morning and evening). Based on recent evidence indicating that carnitine uptake is enhanced with carbohydrate feeding [22,23], subjects were instructed to take capsules along with a carbohydrate rich meal. GPLC is a USP grade nutritional supplement as of March 2006, consisting of a molecular bonded form of propionyl-L-carnitine (PLC) and the amino acid glycine (GlycoCarn™, Sigma-tau HealthScience S.p.A, Rome, Italy). In the total 4.5 g/d dosage of GPLC, the actual PLC content was equal to 3 g and the glycine content was equal to 1044 mg (the remainder of the capsule consisted primarily of cellulose). The short term (8–9 week) safety of GPLC supplementation at the dosage provided (4.5 g/d) was established in our initial work [18], where we noted no adverse changes in subjects' complete blood count or blood chemistry panel data. Capsules were manufactured by Jarrow Formulas (Los Angeles, CA), were identical in appearance, and were provided to subjects in unlabeled bottles every two weeks. Compliance to intake was determined based on capsule counts upon bottle return.
Results

Of the 16 subjects who started the study, only data from 15 subjects were included in the analysis. One subject failed to return to the lab for the second testing session; therefore, data for this subject were excluded. Compliance to GPLC and placebo intake was ≥ 97% for both conditions based on capsule counting upon return of bottles. Subjects indicated their compliance to our recommendation of maintenance of their specific exercise regimen during the course of the study period. The mean daily intake of kilocalories (2750 ± 195 vs. 2801 ± 217; p = 0.86), protein grams (155 ± 14 vs. 157 ± 15; p = 0.91), carbohydrate grams (330 ± 23 vs. 340 ± 34; p = 0.76), and fat grams (87 ± 9 vs. 81 ± 7; p = 0.60) during the week prior to GPLC and placebo conditions, respectively, did not differ. Analyses of diet records indicated that no subject regularly consumed nitrate- (e.g., spinach, cabbage, beets, radishes) or nitrite-rich foods during the diet reporting periods; therefore, we do not believe that dietary intake influenced the plasma NOx values.

A condition main effect (p = 0.0008) was noted for NOx, with higher values in subjects when using GPLC (45.6 ± 2.8 μmol·L-1) compared to placebo (34.9 ± 1.2 μmol·L-1). No time main effect was noted for NOx (p = 0.7099), although values increased approximately 12% from rest to a peak at 10 minutes post protocol. The interaction effect for NOx was not significant (p = 0.8809), although paired time contrasts revealed higher values for GPLC compared to placebo at 3 (p = 0.033) and 10 (p = 0.036) minutes post protocol. The interaction data for NOx are presented in Figure 1. An analysis by subject (collapsed across time) indicated that 11 of the 15 subjects experienced an increase in NOx with GPLC treatment.
Conclusion

In summary, our findings indicate that short-term oral GPLC supplementation can increase NOx in resistance trained men. However, there exist both "responders" and "non-responders" to treatment. Findings from this study may have health implications for those with ischemic conditions such as peripheral vascular disease and ischemic heart disease, as increased NOx may allow for enhanced blood flow, in particular during times of physical stress. Moreover, these findings may relate specifically to athletes who seek enhanced blood flow during periods of strenuous exercise, as such a change may be associated with improved physical performance during training and optimal post exercise recovery. Future study is needed to determine what, if any, physiologic benefit is associated with the observed increase in plasma NOx with GPLC supplementation.

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mistersalvo All the Truth Member Messaggi: 2,207 Data registrazione: Jan 2008	03-04-2010, 07:32 PM Glycine propionyl-L-carnitine increases plasma nitrate/nitrite in resistance trained men Department of Health and Sport Sciences, University of Memphis, Memphis, TN, USA Abstract We have recently demonstrated that oral intake of glycine propionyl-L-carnitine (GPLC) increases plasma nitrate/nitrite (NOx), a surrogate measure of nitric oxide production. However, these findings were observed at rest, and in previously sedentary subjects. Purpose In the present study, we sought to determine the impact of oral GPLC on plasma NOx at rest and in response to a period of reactive hyperemia in resistance trained men. Methods Using a double blind, crossover design, 15 healthy men (24 ± 4 years) were assigned to GPLC (3 g/d PLC + 1044 mg glycine) and a placebo in random order, for a four-week period, with a two-week washout between condition assignment. Blood samples were taken from subjects at rest and at 0, 3, and 10 minutes following an ischemia-reperfusion protocol (six minutes of upper arm cuff occlusion at 200 mmHg followed by rapid reperfusion with cuff removal). Blood samples were taken from a forearm vein from the same arm used for the protocol and analyzed for total nitrate/nitrite. Data are presented as mean ± SEM. Results A condition main effect (p = 0.0008) was noted for NOx, with higher values in subjects when using GPLC (45.6 ± 2.8 μmol·L-1) compared to placebo (34.9 ± 1.2 μmol·L-1). No time main effect was noted (p = 0.7099), although values increased approximately 12% from rest (37.7 ± 2.7 μmol·L-1) to a peak at 10 minutes post protocol (42.3 ± 3.3 μmol·L-1). The interaction effect was not significant (p = 0.8809), although paired time contrasts revealed higher values for GPLC compared to placebo at 3 (48.2 ± 6.7 vs. 34.9 ± 2.4 μmol·L-1; p = 0.033) and 10 (48.8 ± 5.9 vs. 35.7 ± 2.1 μmol·L-1; p = 0.036) minutes post protocol, with non-statistically significant differences noted at rest (41.8 ± 4.5 vs. 33.6 ± 2.5 μmol·L-1; p = 0.189) and at 0 minutes (43.6 ± 5.1 vs. 35.4 ± 2.7 μmol·L-1; p = 0.187) post protocol. An analysis by subject (collapsed across time) indicated that 11 of the 15 subjects experienced an increase in NOx with GPLC treatment. Conclusion These findings indicate that short-term oral GPLC supplementation can increase NOx in resistance trained men. However, as with many dietary supplements, there exist both "responders" and "non-responders" to treatment. Future work may focus on the mechanisms for the discrepancy in response to GPLC supplementation for purposes of NOx elevation. Introduction Nitric oxide (NO•) is an important signaling molecule, promoting vasodilation by acting on vascular smooth muscle [1]. In addition, NO• has been linked to other physiological functions such as inhibition of platelet aggregation and platelet adhesion [2]. In these ways, NO• mediates increased blood flow at rest [3-5] and during exercise [4,6,7], which may have implications for those with chronic ischemic disease as well as for athletes interested in enhancing blood flow to working skeletal muscle (e.g., endurance athletes, bodybuilders). Nitric oxide is synthesized from L-arginine by the endothelium in the vascular system [2] and has been reported to increase in response to acute exercise [8-13]. This is true for dynamic [4], as well as for isometric [7] exercise, in which reperfusion is present following cessation of the contraction. Moreover, chronic exercise training has been reported to result in an increase in plasma nitrate/nitrite (NOx) levels [14-16], a surrogate marker of NO•. Aside from exercise, pharmaceutical agents have been used with success to induce NO• biosynthesis, in an attempt to promote vasodilation (for review please see [17]). Treatments have sometimes included high dosages of L-arginine, often provided via intravenous injection. This has led to the development of several nutritional supplements, often containing small amounts of L-arginine, which are purported to have "drug-like" action, ultimately leading to increased NO•. While the fitness industry is inundated with advertisements for such products, the scientific data are scant. We have recently demonstrated an increase in plasma NOx in healthy sedentary subjects following oral treatment with a novel carnitine agent, glycine propionyl-L-carnitine (GPLC; [18]). This finding extends recent work of Lofreddo et al. [19] who reported an increase in blood NOx in response to 6 grams per day of PLC given via IV infusion to patients with peripheral arterial disease. Other reports suggest vasodilatation actions with PLC [20], in addition to glycine [21] treatment independently. However, our initial findings using oral GPLC were observed at rest, and in previously sedentary subjects, individuals who quite possibly have lower resting NOx levels compared to well-trained subjects; hence, may have a greater potential for responding to GPLC treatment. To our knowledge, no studies have been done to evaluate the efficacy of nutritional supplements to increase NOx levels in a sample of potential users (e.g., resistance trained athletes). Therefore, in the present study, our purpose was to determine the impact of oral GPLC on plasma NOx at rest and in response to a period of reactive hyperemia in resistance trained men. Using a double blind, randomized, crossover design, we hypothesized that plasma NOx would be higher with GPLC treatment compared to placebo, at rest and in response to the ischemia-reperfusion protocol. Methods Subjects Fifteen healthy, resistance trained men participated in this investigation. Subjects completed a medical history, diet and supplementation history, and physical activity questionnaire to determine eligibility. No subject was a smoker or used anti-inflammatory drugs or antioxidant supplements before (for a minimum of six months) or during the study period. Subjects were young (24 ± 4 yrs; mean ± SD), and of average height (177 ± 5 cm), weight (83 ± 4 kg), and body fat percentage (14 ± 5 %). Subjects were considered to be well-trained and performed resistance exercise for 5 ± 2 hrs per week for 8 ± 5 yrs. They were instructed not to deviate from their current training regimen during the course of the study with the exception of refraining from exercise for the 48 hours prior to each testing day. All experimental procedures were performed in accordance with the Helsinki Declaration. The University of Memphis Human Subjects Committee approved all experimental procedures. All subjects provided both verbal and written consent prior to participating in this study. Conditions Subjects were randomly assigned in double-blind manner using a cross-over design to GPLC and a placebo. Each intake period consisted of four weeks, with a two-week washout period between condition assignments. Subjects were instructed to ingest a total of six capsules per day of GPLC or placebo (at two separate times – morning and evening). Based on recent evidence indicating that carnitine uptake is enhanced with carbohydrate feeding [22,23], subjects were instructed to take capsules along with a carbohydrate rich meal. GPLC is a USP grade nutritional supplement as of March 2006, consisting of a molecular bonded form of propionyl-L-carnitine (PLC) and the amino acid glycine (GlycoCarn™, Sigma-tau HealthScience S.p.A, Rome, Italy). In the total 4.5 g/d dosage of GPLC, the actual PLC content was equal to 3 g and the glycine content was equal to 1044 mg (the remainder of the capsule consisted primarily of cellulose). The short term (8–9 week) safety of GPLC supplementation at the dosage provided (4.5 g/d) was established in our initial work [18], where we noted no adverse changes in subjects' complete blood count or blood chemistry panel data. Capsules were manufactured by Jarrow Formulas (Los Angeles, CA), were identical in appearance, and were provided to subjects in unlabeled bottles every two weeks. Compliance to intake was determined based on capsule counts upon bottle return. Results Of the 16 subjects who started the study, only data from 15 subjects were included in the analysis. One subject failed to return to the lab for the second testing session; therefore, data for this subject were excluded. Compliance to GPLC and placebo intake was ≥ 97% for both conditions based on capsule counting upon return of bottles. Subjects indicated their compliance to our recommendation of maintenance of their specific exercise regimen during the course of the study period. The mean daily intake of kilocalories (2750 ± 195 vs. 2801 ± 217; p = 0.86), protein grams (155 ± 14 vs. 157 ± 15; p = 0.91), carbohydrate grams (330 ± 23 vs. 340 ± 34; p = 0.76), and fat grams (87 ± 9 vs. 81 ± 7; p = 0.60) during the week prior to GPLC and placebo conditions, respectively, did not differ. Analyses of diet records indicated that no subject regularly consumed nitrate- (e.g., spinach, cabbage, beets, radishes) or nitrite-rich foods during the diet reporting periods; therefore, we do not believe that dietary intake influenced the plasma NOx values. A condition main effect (p = 0.0008) was noted for NOx, with higher values in subjects when using GPLC (45.6 ± 2.8 μmol·L-1) compared to placebo (34.9 ± 1.2 μmol·L-1). No time main effect was noted for NOx (p = 0.7099), although values increased approximately 12% from rest to a peak at 10 minutes post protocol. The interaction effect for NOx was not significant (p = 0.8809), although paired time contrasts revealed higher values for GPLC compared to placebo at 3 (p = 0.033) and 10 (p = 0.036) minutes post protocol. The interaction data for NOx are presented in Figure 1. An analysis by subject (collapsed across time) indicated that 11 of the 15 subjects experienced an increase in NOx with GPLC treatment. Conclusion In summary, our findings indicate that short-term oral GPLC supplementation can increase NOx in resistance trained men. However, there exist both "responders" and "non-responders" to treatment. Findings from this study may have health implications for those with ischemic conditions such as peripheral vascular disease and ischemic heart disease, as increased NOx may allow for enhanced blood flow, in particular during times of physical stress. Moreover, these findings may relate specifically to athletes who seek enhanced blood flow during periods of strenuous exercise, as such a change may be associated with improved physical performance during training and optimal post exercise recovery. Future study is needed to determine what, if any, physiologic benefit is associated with the observed increase in plasma NOx with GPLC supplementation.