Metformin exaggerates phenylephrine-induced AMPK phosphorylation independent of CaMKKβ and attenuates contractile response in endothelium-denuded rat aorta.

摘要: Abstract Metformin, a widely prescribed antidiabetic drug, has been shown to reduce the risk of cardiovascular disease, including hypertension. Its beneficial effect toward improved vasodilation results from its ability activate AMPK and enhance nitric oxide formation in endothelium. To date, metformin regulation not fully studied intact arterial smooth muscle, especially during contraction evoked by G protein-coupled receptor (GPCR) agonists. In present study, ex vivo incubation endothelium-denuded rat aortic rings with 3 mM for 2 h resulted significant accumulation (∼600 pmoles/mg tissue), as revealed LC–MS/MS MRM analysis. However, did show increase phosphorylation under these conditions. Exposure GPCR agonist (e.g., phenylephrine) enhanced ∼2.5-fold. Importantly, metformin-treated rings, phenylephrine challenge showed an exaggerated ∼9.7-fold, which was associated AMP/ATP ratio. Pretreatment compound C (AMPK inhibitor) prevented induced alone also that after treatment. pretreatment STO-609 (CaMKKβ diminished but Furthermore, attenuation phenylephrine-induced (observed treatment) inhibition CaMKKβ inhibition. Together, findings suggest that, upon endothelial damage vessel wall, uptake underlying vascular muscle would accentuate agonists independent promote vasorelaxation.