Syr
Hot Italian Goldmember
Acadesine aka AICAR (5-Aminoimidazole-4-carboxamide-1-b-ribosid)
is a very interesting new chemical being investigated for ischemic heart disease (1).
The most interesting part is how this agent regulates adenosine, controls muscle glycogen synthesis in heart,
While it doesnt result very effective in curing ischenia (2), it may works really well for other muscles, namely skeletal muscle mass
"In the heart, we have demonstrated that pharmacologic activation of AMP-activated protein kinase leads to glucose transporter translocation and increased glucose uptake" (3). Will this apply to LBM too?
It seems so: further studies "demonstrated that AICAR increases skeletal muscle glucose uptake in the presence of maximally stimulating doses of insulin, suggesting that the hypoglycemic effect of AICAR is also due to increased cellular glucose uptake. In addition, recent studies have also demonstrated that AICAR-mediated activation of AMPK stimulates skeletal muscle glucose uptake (4, 5). However, these previous studies did not investigate whether AICAR increased muscle glucose uptake by stimulating the translocation of GLUT-4. Thus the present study is not only the first to demonstrate that AICAR increases glucose uptake in the heart but also the first to demonstrate that AICAR causes translocation of GLUT-4 to the cell surface in muscle tissue."
In conclusion, not only Acadesine should prevent prevent glycogen depletion in skeletal muscle cells that occurs after an AAS cycle, but it can increase it during normal excercise and it has an additive effect with insulin, since "there is substantial evidence to suggest that exercise and insulin act to promote glucose transport in the skeletal muscle through different mechanisms" (4).
Lastly "Nitric oxide, which is released in the skeletal muscle during contraction, has also recently been proposed to mediate the contraction-induced increase in muscle glucose transport, although blockade of nitric oxide synthesis failed to inhibit the contraction-induced increase in muscle glucose uptake, suggesting that this pathway is nitric oxide independent" (4)
OK, i'm done. Comments are welcome
_____
(1) J Clin Pharmacol. 1991 Apr
[size=+1]AICA-riboside: safety, tolerance, and pharmacokinetics of a novel adenosine-regulating agent.[/size]
Dixon R, Gourzis J, McDermott D, Fujitaki J, Dewland P, Gruber H.
Gensia Pharmaceuticals, Inc., San Diego, California 92121.
AICA-riboside (5-amino-4-imidazole carboxamide ribonucleoside) is a novel adenosine-regulating agent that is currently being investigated for the treatment of ischemic heart disease. In a placebo-controlled, double-blind study in healthy men, we evaluated the safety and kinetics of the drug after oral and IV administration of 10, 25, 50, and 100 mg/kg doses. At each dose level, four subjects received active drug and two subjects received placebo with a 1-week wash-out period between the IV and oral doses. The drug was well tolerated at all dose levels with only mild and transient side effects reported in some instances by the subjects who received placebo and those patients who received the drug. The post-infusion plasma concentrations of AICA-riboside declined rapidly in a biphasic fashion, and the terminal elimination phase had a harmonic mean t1/2 beta of 1.4 hours. Total plasma clearance (CL), mean residence time (MRTIV), and volume of distribution at steady-state (VSS) were 2.5 L/hr/kg, 0.7 hr, and 1.6 L/kg, respectively. The drug was not protein bound, and there was rapid uptake and phosphorylation in RBCs to its 5'-monophosphate nucleotide. Renal clearance (CLR) was 0.2 L/hr/kg with only 8% of the IV dose excreted in the urine as intact AICA-riboside. Although there was a trend towards a decrease in CL with increasing dose, there were no significant differences (P greater than .05) in the mean estimates of t1/2 beta, CL, CLR, MRTIV and VSS associated with dose. The drug was poorly bioavailable (less than 5%) when administered orally in solution.
Publication Types:
(2) Invalid Link Removed
(3)
Invalid Link Removed
(4)
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(5)
Evidence for 5' AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport
T Hayashi, MF Hirshman, EJ Kurth, WW Winder and LJ Goodyear
[size=-1]Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA.[/size]
The intracellular signaling proteins that lead to exercise-stimulated glucose transport in skeletal muscle have not been identified, although it is clear that there are separate signaling mechanisms for exercise- and insulin-stimulated glucose transport. We have hypothesized that the 5'AMP-activated protein kinase (AMPK) functions as a signaling intermediary in exercise-stimulated glucose uptake. This hypothesis was based on recent studies showing the following: 1) muscle contraction increases AMPK activity and 2) perfusion of rat hindlimb skeletal muscles with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a compound that results in increased AMPK activity, increased insulin-stimulated glucose uptake. In the current study, isolated rat epitrochlearis muscles were treated to contract in vitro (via electrical stimulation for 10 min) and/or incubated in the absence or presence of AICAR (2 mmol/l), insulin (1 micromol/l), or wortmannin (100 nmol/l). Both contraction and AICAR significantly increased AMPK activity, while the enzyme was not activated by insulin. AICAR, contraction, and insulin all increased 3-O-methylglucose (3MG) transport by threefold to fivefold above basal. The phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin completely blocked insulin-stimulated transport, but did not inhibit AICAR- or contraction-stimulated transport. The increase in glucose transport with the combination of maximal AICAR plus maximal insulin treatments was partially additive, suggesting that these stimuli increase glucose transport by different mechanisms. In contrast, there was no additive effect on glucose transport with the combination of AICAR plus contraction. These data suggest that AICAR and contraction stimulate glucose transport by a similar insulin-independent signaling mechanism and are consistent with the hypothesis that AMPK is involved in exercise-stimulated glucose uptake.
is a very interesting new chemical being investigated for ischemic heart disease (1).
The most interesting part is how this agent regulates adenosine, controls muscle glycogen synthesis in heart,
While it doesnt result very effective in curing ischenia (2), it may works really well for other muscles, namely skeletal muscle mass
"In the heart, we have demonstrated that pharmacologic activation of AMP-activated protein kinase leads to glucose transporter translocation and increased glucose uptake" (3). Will this apply to LBM too?
It seems so: further studies "demonstrated that AICAR increases skeletal muscle glucose uptake in the presence of maximally stimulating doses of insulin, suggesting that the hypoglycemic effect of AICAR is also due to increased cellular glucose uptake. In addition, recent studies have also demonstrated that AICAR-mediated activation of AMPK stimulates skeletal muscle glucose uptake (4, 5). However, these previous studies did not investigate whether AICAR increased muscle glucose uptake by stimulating the translocation of GLUT-4. Thus the present study is not only the first to demonstrate that AICAR increases glucose uptake in the heart but also the first to demonstrate that AICAR causes translocation of GLUT-4 to the cell surface in muscle tissue."
In conclusion, not only Acadesine should prevent prevent glycogen depletion in skeletal muscle cells that occurs after an AAS cycle, but it can increase it during normal excercise and it has an additive effect with insulin, since "there is substantial evidence to suggest that exercise and insulin act to promote glucose transport in the skeletal muscle through different mechanisms" (4).
Lastly "Nitric oxide, which is released in the skeletal muscle during contraction, has also recently been proposed to mediate the contraction-induced increase in muscle glucose transport, although blockade of nitric oxide synthesis failed to inhibit the contraction-induced increase in muscle glucose uptake, suggesting that this pathway is nitric oxide independent" (4)
OK, i'm done. Comments are welcome
_____
(1) J Clin Pharmacol. 1991 Apr
[size=+1]AICA-riboside: safety, tolerance, and pharmacokinetics of a novel adenosine-regulating agent.[/size]
Dixon R, Gourzis J, McDermott D, Fujitaki J, Dewland P, Gruber H.
Gensia Pharmaceuticals, Inc., San Diego, California 92121.
AICA-riboside (5-amino-4-imidazole carboxamide ribonucleoside) is a novel adenosine-regulating agent that is currently being investigated for the treatment of ischemic heart disease. In a placebo-controlled, double-blind study in healthy men, we evaluated the safety and kinetics of the drug after oral and IV administration of 10, 25, 50, and 100 mg/kg doses. At each dose level, four subjects received active drug and two subjects received placebo with a 1-week wash-out period between the IV and oral doses. The drug was well tolerated at all dose levels with only mild and transient side effects reported in some instances by the subjects who received placebo and those patients who received the drug. The post-infusion plasma concentrations of AICA-riboside declined rapidly in a biphasic fashion, and the terminal elimination phase had a harmonic mean t1/2 beta of 1.4 hours. Total plasma clearance (CL), mean residence time (MRTIV), and volume of distribution at steady-state (VSS) were 2.5 L/hr/kg, 0.7 hr, and 1.6 L/kg, respectively. The drug was not protein bound, and there was rapid uptake and phosphorylation in RBCs to its 5'-monophosphate nucleotide. Renal clearance (CLR) was 0.2 L/hr/kg with only 8% of the IV dose excreted in the urine as intact AICA-riboside. Although there was a trend towards a decrease in CL with increasing dose, there were no significant differences (P greater than .05) in the mean estimates of t1/2 beta, CL, CLR, MRTIV and VSS associated with dose. The drug was poorly bioavailable (less than 5%) when administered orally in solution.
Publication Types:
- Clinical Trial
- Randomized Controlled Trial
(2) Invalid Link Removed
(3)
Invalid Link Removed
(4)
Invalid Link Removed
(5)
Evidence for 5' AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport
T Hayashi, MF Hirshman, EJ Kurth, WW Winder and LJ Goodyear
[size=-1]Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA.[/size]
The intracellular signaling proteins that lead to exercise-stimulated glucose transport in skeletal muscle have not been identified, although it is clear that there are separate signaling mechanisms for exercise- and insulin-stimulated glucose transport. We have hypothesized that the 5'AMP-activated protein kinase (AMPK) functions as a signaling intermediary in exercise-stimulated glucose uptake. This hypothesis was based on recent studies showing the following: 1) muscle contraction increases AMPK activity and 2) perfusion of rat hindlimb skeletal muscles with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a compound that results in increased AMPK activity, increased insulin-stimulated glucose uptake. In the current study, isolated rat epitrochlearis muscles were treated to contract in vitro (via electrical stimulation for 10 min) and/or incubated in the absence or presence of AICAR (2 mmol/l), insulin (1 micromol/l), or wortmannin (100 nmol/l). Both contraction and AICAR significantly increased AMPK activity, while the enzyme was not activated by insulin. AICAR, contraction, and insulin all increased 3-O-methylglucose (3MG) transport by threefold to fivefold above basal. The phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin completely blocked insulin-stimulated transport, but did not inhibit AICAR- or contraction-stimulated transport. The increase in glucose transport with the combination of maximal AICAR plus maximal insulin treatments was partially additive, suggesting that these stimuli increase glucose transport by different mechanisms. In contrast, there was no additive effect on glucose transport with the combination of AICAR plus contraction. These data suggest that AICAR and contraction stimulate glucose transport by a similar insulin-independent signaling mechanism and are consistent with the hypothesis that AMPK is involved in exercise-stimulated glucose uptake.
