Role of L-Arginine and Tetrahydrobiopterin in Attenuation of Vascular Ang1-8 Reactivity via Endothelial PI3K/AKT/eNOS Signaling Pathways in HgCl2-Induced Vascular Dysfunction. An Ex-Vivo Study.

Abstract

Vascular endothelial dysfunction because of environmental mercuric chloride (HgCl₂) exposure is well known to induce cardiovascular diseases and heightened vascular responsiveness to angiotensin II (Ang 1-8). The PI3K/AKT/eNOS signaling pathway is essential for preserving endothelial NO bioavailability. Nevertheless, the reasons underlying this dysfunction during oxidative stress are inadequately elucidated. This study explored the roles of L-arginine (LA) and tetrahydrobiopterin (BH₄) both alone and in combination on Ang1-8-induced vascular responses via the endothelial PI3K/AKT/eNOS pathway against HgCl₂ -induced vascular dysfunction in rat aortic rings. In comparison to control (CT) rings; HgCl₂ markedly modified Ang1-8 vascular reactivity, consistent with eNOS uncoupling and oxidative dysregulation. Inhibition of PI3K or AKT further amplified these effects, thereby confirming the vasoprotective role of the PI3K/AKT/eNOS system. The co-administration of LA and BH₄ significantly restored both Emax and pD₂ values in the presence of HgCl₂ and inhibitors, indicating improved NO bioavailability and re-coupled eNOS activity. Treatments of LA and BH4 together sustained endothelial PI3K/AKT/eNOS signaling and alleviate HgCl₂-induced vascular hyperreactivity to Ang1-8 through restoration of NO/cGMP-mediated relaxation, reduces oxidative damage, and enhances antioxidant capacity. These results highlight a potential therapy strategy focused on resolving substrate-cofactor coupling and reinstating endothelial signaling to mitigate heavy metal-induced vascular dysfunction.