TY - JOUR
T1 - Activation of protein kinase B/Akt and endothelial nitric oxide synthase mediates agmatine-induced endothelium-dependent relaxation
AU - Santhanam, Anantha Vijay R.
AU - Viswanathan, Shivkumar
AU - Dikshit, Madhu
PY - 2007/10/31
Y1 - 2007/10/31
N2 - The ability of agmatine, formed from l-arginine by the enzyme arginine decarboxylase (ADC), to modulate vasomotor function in rat aorta was investigated in the present study. Agmatine-mediated modulation of vasomotor tone was studied in organ chambers, protein expression quantified by Western blot analysis and cyclic guanosine 5′-monophosphate (cGMP) levels measured by radioimmunoassay. Agmatine (10- 10 to 10- 3 M) produced concentration-dependent relaxations (82 ± 5%) in phenylephrine-contracted endothelium intact rat aorta. Relaxations to agmatine were diminished on denudation of endothelium and nitric oxide synthase (NOS) inhibition by l-Nω-nitro arginine or soluble guanylate cyclase inhibition by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (P < 0.001) abolished agmatine-mediated relaxations, while relaxations were insensitive to inducible NOS inhibition by 1400W. Agmatine-treated aorta demonstrated increased protein expression of phosphorylated S473-Akt and phosphorylated S1177-endothelial nitric oxide synthase (eNOS), and elevated the levels of cyclic GMP (P < 0.01). Agmatine-mediated potentiation of relaxations and elevation of cGMP levels was sensitive to phosphatidylinositol 3′-kinase inhibitor, wortmannin. Relaxations to agmatine were also affected by pre-treatment with tetraethylammonium (P < 0.01) or apamin (P < 0.05), and were not affected by charybdotoxin. Relaxations to agmatine were partially affected by pre-treatment of aortic rings with barium chloride (P < 0.05), and glybenclamide (P < 0.05). Results obtained suggest that agmatine activates protein kinase B/Akt to phosphorylate eNOS and elevate cyclic GMP levels to produce vasodilatation of aorta. Agmatine-mediated relaxations in rat aorta seems to be mediated mainly by endothelial NO-mediated activation of small conductance Ca2+-activated K+ channels, and partly by ATP-sensitive and inward rectifying K+ channels.
AB - The ability of agmatine, formed from l-arginine by the enzyme arginine decarboxylase (ADC), to modulate vasomotor function in rat aorta was investigated in the present study. Agmatine-mediated modulation of vasomotor tone was studied in organ chambers, protein expression quantified by Western blot analysis and cyclic guanosine 5′-monophosphate (cGMP) levels measured by radioimmunoassay. Agmatine (10- 10 to 10- 3 M) produced concentration-dependent relaxations (82 ± 5%) in phenylephrine-contracted endothelium intact rat aorta. Relaxations to agmatine were diminished on denudation of endothelium and nitric oxide synthase (NOS) inhibition by l-Nω-nitro arginine or soluble guanylate cyclase inhibition by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (P < 0.001) abolished agmatine-mediated relaxations, while relaxations were insensitive to inducible NOS inhibition by 1400W. Agmatine-treated aorta demonstrated increased protein expression of phosphorylated S473-Akt and phosphorylated S1177-endothelial nitric oxide synthase (eNOS), and elevated the levels of cyclic GMP (P < 0.01). Agmatine-mediated potentiation of relaxations and elevation of cGMP levels was sensitive to phosphatidylinositol 3′-kinase inhibitor, wortmannin. Relaxations to agmatine were also affected by pre-treatment with tetraethylammonium (P < 0.01) or apamin (P < 0.05), and were not affected by charybdotoxin. Relaxations to agmatine were partially affected by pre-treatment of aortic rings with barium chloride (P < 0.05), and glybenclamide (P < 0.05). Results obtained suggest that agmatine activates protein kinase B/Akt to phosphorylate eNOS and elevate cyclic GMP levels to produce vasodilatation of aorta. Agmatine-mediated relaxations in rat aorta seems to be mediated mainly by endothelial NO-mediated activation of small conductance Ca2+-activated K+ channels, and partly by ATP-sensitive and inward rectifying K+ channels.
KW - Akt
KW - Nitric oxide synthase
KW - Potassium channels
KW - Rat aorta
KW - Soluble guanylate cyclase
KW - Vasorelaxation
UR - http://www.scopus.com/inward/record.url?scp=34548800397&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34548800397&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2007.06.031
DO - 10.1016/j.ejphar.2007.06.031
M3 - Article
C2 - 17640632
AN - SCOPUS:34548800397
SN - 0014-2999
VL - 572
SP - 189
EP - 196
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 2-3
ER -