Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy

Abstract

Beyond an inert oxidation product of nitric oxide (NO) metabolism, current thinking posits a key role for nitrite as a mediator of NO-signaling, especially during hypoxia. This concept has been discussed both in the context of nitrite serving a role as an endogenous modulator of NO-homeostasis, but also from a novel clinical perspective whereby nitrite therapy may replete NO-signaling and prevent ischemic tissue injury. Indeed, the relatively rapid translation of studies delineating mechanisms of action to ongoing and planned clinical trials has been critical in fuelling interest in nitrite biology and several excellent reviews have been written on this topic. In this article we limit our discussions to current concepts, and what we feel are questions that remain unanswered within the paradigm of nitrite being a mediator of NO biology.

Inhalation of Nitric Oxide Prevents Ischemic Brain Damage in Experimental Stroke by Selective Dilatation of Collateral Arterioles

“…24 These phenomena were attributed to the formation of bioactive NO carriers in the lung that circulate in blood and release NO in extrapulmonary blood vessels. The nature of the NO carriers formed during NO inhalation is still undergoing debate and may involve nitrite, 25,26 S-nitroso hemoglobin, [27][28][29][30] or other S-nitrosothiols (eg, of cysteine or glutathione), 27,30 which, among others, may be formed when NO reacts with oxygen to form N 2 O 3 . 31,32 Consistent with this concept, previous studies using iNO or inhaled ethyl nitrite have shown protection in experimental paradigms in which vasoconstriction plays an important pathophysiological role, eg, experimental subarachnoid hemorrhage.…”

Nitrite therapy improves survival postexposure to chlorine gas

“…The last decade has seen many studies document the potential for nitrite to replete NO signaling in acute and chronic diseases afflicting all major organ systems, which are characterized by loss of endogenous NO function (14,18,33). We chose to test nitrite therapy on the basis that endothelial NO synthase-dependent signaling is inhibited, and nitrite levels are decreased during the initial stages (hours) after Cl 2 exposure (Fig.…”

“…In addition to its generation by one of three nitric oxide synthases, multiple studies over the last decade have shown that enzymatic production of NO is complemented by nonenzymatic mechanisms for NO generation from nitrite (18). A functional role for the latter pathway has been demonstrated in both physiological and pathophysiological contexts, and perhaps the most evidence is in therapeutics where the goal is to improve or replete NO bioactivity in ischemic and inflammatory diseases (14,19,33). Consistent with this, our recent studies showed that nitrite administered by intraperitoneal (IP) or IM injections, after Cl 2 exposure prevented acute lung injury and development of reactive airways in rats (28,36).…”

Coronary Microvascular Dysfunction in CAD: Consequences and Potential Therapeutic Applications

“…However, more recent findings have determined that the generation of NO from the reduction of nitrite can occur in vivo, under a variety of physiologic and pathophysiologic conditions (Vitturi & Patel, 2011). Nitrite is cardioprotective after episodes of ischemia and reperfusion in a variety of experimental models, and clinical trials are underway to determine the vasculoprotective and cardioprotective actions of nitrite therapy in patients with cardiovascular disease (Calvert & Lefer, 2009).…”