Sodium nitrite induces tolerance in the mouse aorta: Involvement of the renin-angiotensin system, nitric oxide synthase, and reactive oxygen species

Abstract

Nitrites have emerged as promising therapeutic agents for cardiovascular diseases, alongside nitrates. While chronic use of organic nitrates is well recognized to lead to vascular tolerance, the tolerance associated with nitrite therapy remains incompletely understood. The aim of the present study was to investigate vascular tolerance to sodium nitrite and the underlying molecular mechanisms. Endothelium-denuded aortic rings isolated from male Balb/C mice were incubated with either the EC₅₀ (10⁻⁴ mol/L) or EC₁₀₀ (10⁻² mol/L) concentration of sodium nitrite for 15 min to induce tolerance. The EC₁₀₀ concentration of sodium nitrite induced vascular tolerance. Pre-incubation with captopril and losartan effectively reversed sodium nitrite-induced tolerance. Similarly, pre-incubation with L-NAME and L-arginine prevented sodium nitrite-induced tolerance. Increased levels of reactive oxidative species (ROS) and reduced bioavailability of nitric oxide (NO) were observed in tolerant aortas. Increased superoxide dismutase (SOD) activity and decreased catalase activity were also verified in tolerant aortas. Both captopril and L-NAME prevented the increased levels of ROS observed in tolerant aortas. Furthermore, pre-incubation with catalase effectively prevented sodium nitrite-induced tolerance. Our findings suggest that sodium nitrite induces vascular tolerance through a signaling pathway involving the renin-angiotensin system, nitric oxide synthase, and ROS. This study contributes to the understanding of the interaction between nitrites and vascular tolerance and highlights potential targets to overcome or prevent this phenomenon.