L-Arginine and Tetrahydrobiopterin Alleviate Mercury-Induced Vascular Dysfunction by Modulating Angiotensin II Receptors (AT1, AT2) and ACE2 Activity in Rat Aortic Rings

Cardiovascular diseases are often driven by oxidative stress and endothelial dysfunction, particularly under heavy metal exposure such as HgCl2. It disrupts NO signaling and RAS balance, impairing vascular function. L-arginine LA and tetrahydrobiopterin BH4, as essential regulators of eNOS, are potential therapeutic agents for restoring vascular reactivity. This study aimed to evaluate the protective effects of LA and BH4, individually and in combination, on Ang II-induced vascular reactivity in isolated rat aortic rings under normal and HgCl2-induced oxidative stress conditions. The interaction of Ang-II receptors (AT1, AT2) and ACE2 activity were explored. Aortic rings were pre-treated with LA, BH4, or both, followed by stimulation with Ang II (10-11-10-6 M). Pharmacological inhibitors were used to assess the roles of AT1 (1 µM), AT2 (10 µM), and ACE2 (1 µM) receptors. Vascular responsiveness was analyzed through Emax, pD2, and AUC values in the presence and absence of HgCl2 (1 µM). HgCl2 significantly impaired Ang II-induced vasoconstriction. LA and BH4 partially restored vascular responsiveness, with the combination producing the most substantial improvements, indicating synergistic NO-mediated effects. AT1 receptor blockade abolished Ang II responses, confirming its central role, while AT2 inhibition increased contraction, revealing its vasodilatory function. ACE2 inhibition enhanced Ang II-induced contraction, particularly after HgCl2 exposure. Co-treatment with LA and BH4 mitigated this effect, restoring balance.ConclusionLA and BH4 can reverse HgCl2-induced vascular dysfunction by enhancing NO signaling and modulating Ang II receptor pathways. Their combined use offers therapeutic promise in conditions involving oxidative stress and RAS dysregulation.