Adrenomedullin Induces Endothelium-Dependent Vasorelaxation via the Phosphatidylinositol 3-Kinase/Akt-Dependent Pathway in Rat Aorta

H. Nishimatsu, E. Suzuki, D. Nagata, N. Moriyama, H. Satonaka, K. Walsh, M. Sata, K. Kangawa, H. Matsuo, A. Goto, T. Kitamura, Y. Hirata
2001 Circulation Research  
To study the mechanisms by which adrenomedullin (AM) induces endothelium-dependent vasorelaxation, we examined whether AM-induced endothelium-dependent vasodilation was mediated by the phosphatidylinositol 3-kinase (PI3K)/Akt-dependent pathway in rat aorta, because it was recently reported that PI3K/Akt was implicated in the activation of endothelial NO synthase. AM-induced vasorelaxation in thoracic aorta with intact endothelium was inhibited by pretreatment with PI3K inhibitors to the same
more » ... el as that in endothelium-denuded aorta. AM elicited Akt phosphorylation in a time-and dose-dependent manner. AM-induced Akt phosphorylation was inhibited by pretreatment with a calmodulin-dependent protein kinase inhibitor as well as with PI3K inhibitors. When an adenovirus construct expressing a dominant-negative Akt mutant (Ad/dnAkt) was injected into abdominal aortas so that the mutant was expressed predominantly in the endothelium layer, AM-induced vasodilation was diminished to the same level as that in endothelium-denuded aortas. Finally, AM-induced cGMP production, which was used as an indicator for NO production, was suppressed by PI3K inhibition or by Ad/dnAkt infection into the endothelium. These results suggested that AM induced Akt activation in the endothelium via the Ca 2ϩ /calmodulin-dependent pathway and that this was implicated in the production of NO, which in turn induced endothelium-dependent vasodilation in rat aorta. (Circ Res. 2001;89:63-70.)
doi:10.1161/hh1301.092498 pmid:11440979 fatcat:xxcouio3bvdepf7uksqmiai7dq