Nitrite potentiates the vasodilatory signaling of S-nitrosothiols

Abstract

Nitrite and S-nitrosothiols (SNOs) are both byproducts of nitric oxide (NO) metabolism and are proposed to cause vasodilation via activation of soluble guanylate cyclase (sGC). We have previously reported that while SNOs are potent vasodilators at physiological concentrations, nitrite itself only produces vasodilation at supraphysiological concentrations. Here, we tested the hypothesis that sub-vasoactive concentrations of nitrite potentiate the vasodilatory effects of SNOs. Multiple exposures of isolated sheep arteries to S-nitroso-glutathione (GSNO) resulted in a tachyphylactic decreased vasodilatory response to GSNO but not to NO, suggesting attenuation of signaling steps upstream from sGC. Exposure of arteries to 1 μM nitrite potentiated the vasodilatory effects of GSNO in naive arteries and abrogated the tachyphylactic response to GSNO in pre-exposed arteries, suggesting that nitrite facilitates GSNO-mediated activation of sGC. In intact anesthetized sheep and rats, inhibition of NO synthases to decrease plasma nitrite levels attenuated vasodilatory responses to exogenous infusions of GSNO, an effect that was reversed by exogenous infusion of nitrite at sub-vasodilating levels. This study suggests nitrite potentiates SNO-mediated vasodilation via a mechanism that lies upstream from activation of sGC.

L-NAME releases nitric oxide and potentiates subsequent nitroglycerin-mediated vasodilation

“…Rodent and sheep (below) protocols were pre-approved by the Institutional Animal Care and Use Committee of Loma Linda University, and were in accordance with guidelines of the American Physiological Society and the National Institutes of Health. Female Sprague-Dawley rats weighing 301±5 g were surgically instrumented as previously reported [16], except that the flow probe was placed around the mesenteric instead of the femoral artery. After surgical instrumentation, isoflurane was discontinued and anesthesia was maintained with an intraperitoneal injection (i.p.)…”

“…For both rat and sheep arteries the endothelium was kept intact. Arterial rings were mounted in organ bath chambers as described previously [16]. To inhibit endothelial NOS in rat mesenteric arteries, L-NAME (100 μmol/L) was added to the baths 15 min before contraction with 10 μmol/L serotonin.…”

“…NOx and nitrite concentrations were determined by triiodide-based chemiluminescence (280i, Sievers, Boulder, CO) as previously described [16]. Briefly, overall NOx concentrations were measured by direct injection of the sample into triiodide and nitrite concentrations were taken as the portion of the signal that was eliminated by prior reaction of the sample with acid sulfanilamide.…”

“…However, these nitrodilators represent a wide range of chemical classes, molecular sizes, and stoichiometries, and the mechanisms by which they lead to sGC activation remain unclear. Numerous attempts to ascribe their vasodilatory activity to the release of their NO moiety have failed [12,15,16], casting doubt on their role as NO donors or prodrugs. These discrepancies highlight a critical gap in our understanding of the mechanisms by which nitrodilators lead to sGC activation.…”

Comparação dos efeitos anti-hipertensivos da S-nitrosoglutationa livre e nanoencapsulada em modelo animal de hipertensão

“…(LUNDBERG; WEITZBERG; GLADWIN, 2008). No entanto, atualmente é conhecida a participação do nitrato e do nitrito como via alternativa para a síntese de NO, a via nitrato-nitrito-NO, principalmente em situação de hipóxia (DUNCAN et al, 1995;ZWEIER et al, 1995 As funções biológicas dos nitrosotióis aparentemente são muito similares às do NO, assim, os nitrosotióis são considerados reservatórios endógenos de NO, preservando sua função biológica por mais tempo e permitindo sua atuação em locais distantes da sua síntese (GIUSTARINI et al, 2003;LIU et al, 2018;PERRIN-SARRADO et al, 2019). Além de possuir efeito vasodilatador (KASHIBA et al, 1999), os nitrosotióis exibem atividade inibitória frente à agregação plaquetária (RADOMSKI et al, 1992), inibem a proliferação do musculo liso (GARG; HASSID, 1993) e a adesão de leucócitos ao endotélio vascular (GLUCKMAN et al, 2000).…”