Estresse oxidativo induzido pelo desacoplamento da no sintase é responsável pela tolerância vascular ao nitrito de sódio

Abstract

The circulating nitrite ions are currently recognized as endogenous nitric oxide (NO) donor and have important functions in cardiovascular system, both in normal and pathophysiological conditions, such as hypoxic vasodilation, cytoprotection after ischemia/reperfusion and regulation of gene and protein expression. Considering these functions, in addition to organic nitrates commonly used in cardiovascular diseases treatment, nitrites are also being used in this therapy. However, the chronic use of nitrates induces vascular tolerance, represented by the reduction of hemodynamic effects of these vasodilators. The association of this phenomenon with nitrites is not known. Therefore, the aim of this study was to evaluate if sodium nitrite induces in vitro tolerance and/or cross tolerance in mice aorta and to investigate the possible cellular mechanisms involved in these processes. Our results demonstrated that, although it does not induce cross tolerance, the sodium nitrite induces tolerance to itself and in an endothelium-independent manner. This phenomenon involves the activation of renin-angiotensin system, which seems to stimulate uncoupling of NO synthase through substrate depletion, leading to increased superoxide anion production. These radicals are converted by superoxide dismutase to hydrogen peroxide (H2O2), which also has its levels increased by decrease in the catalase activity. The H2O2 produced, through its vasoconstriction properties, causes reduction of sodium nitrite vasodilatory effects, which characterizes the occurrence of tolerance.