Nitrate tolerance and the links with endothelial dysfunction and oxidative stress

Abstract

Identification of nitric oxide as the molecule responsible for endothelial dependant vasodilatation has led to an explosion of interest in endothelial function. Oxidative stress has been identified as an important factor in the development of tolerance to organic nitrates. This review examines the evidence supporting this recently developed theory and how mechanisms of nitrate tolerance may link with the wider picture of primary nitric oxide resistance.

Long-term hyperglycaemia impairs vascular smooth muscle cell function in women with type 1 diabetes mellitus

“…Since GTN reacts readily with superoxide radicals, one plausible factor for the impaired action of exogenous NO might be oxidative stress, induced by long-term poor glycaemic control. 34 HbA 1C , but not plasma glucose, was independently correlated with NMD in a negative manner. A negative correlation has previously been reported between NMD and short-term glycaemic control in patients with type 1 diabetes, 35 but to our knowledge this is the first study to find a negative independent correlation between long-term glycaemic control and NMD in DM.…”

Deconstructing endothelial dysfunction: soluble guanylyl cyclase oxidation and the NO resistance syndrome

“…Nitroglycerin must be enzymatically converted to NO and nitrite, and the role of NO formation in the mechanism of nitroglycerin-dependent vasodilation is debatable. Sustained exposure to nitroglycerin (nitrates) results in pharmacological tolerance or resistance within days; the mechanisms of tolerance are incompletely understood, but a contributing role of increased oxidant stress and superoxide production has been proposed (22). It is intriguing to speculate that sGC oxidation might contribute, at least in part, to nitrate tolerance.…”

Nitroxyl Anion Donor, Angeli’s Salt, Does Not Develop Tolerance in Rat Isolated Aortae

“…Specifically, they may involve reduced biotransformation of organic nitrates to NO ⅐ , physiological counterregulatory mechanisms (eg, neurohormonal activation), desensitization of sGC, increased activity of phosphodiesterase 1A1, and increased production of reactive oxygen species leading to scavenging of NO ⅐ and a decreased bioavailability. 14,15 Given that HNO donors, such as AS, spontaneously donate HNO via a process that does not require biotransformation and are not susceptible to scavenging by superoxide, we hypothesize that tolerance will not develop to this class of nitrovasodilator. Conversely we predict that HNO donors may induce cross-tolerance to organic nitrates, given the ability of HNO to inhibit aldehyde dehydrogenase (ALDH), 16,17 an enzyme that has been implicated recently in the biotransformation of GTN in the vasculature.…”