Nitrite‐derived nitric oxide: a possible mediator of ‘acidic–metabolic’ vasodilation

Abstract

The fundamental, yet poorly understood, physiological mechanism known as 'acidic-metabolic' vasodilation, contributes to local blood flow regulation during hypoxia/ischaemia and increased metabolic activity. The vasodilator nitric oxide (NO) has been suggested to be involved in this event. Besides enzymatic production by NO synthases, a novel mechanism for generation of this gas in vivo was recently described. This involves non-enzymatic reduction of inorganic nitrite to NO, a reaction that takes place predominantly during acidic/reducing conditions. We have studied the effects of physiological amounts of nitrite on NO generation and relaxation of rat aorta in vitro in a situation where environmental pH was reduced to levels seen in tissues during hypoxia/ischaemia. The relaxatory effect of nitrite was increased in an acidic buffer solution (pH 6.6) compared with neutral pH; EC50 for nitrite was reduced from 200 to 40 microM. Nitrite-evoked relaxation was effectively prevented by coadministration of an inhibitor of soluble guanylyl cyclase. The relaxation was further potentiated by the addition of ascorbic acid. In parallel, NO was generated from nitrite in a pH dependent manner with even larger amounts seen after addition of ascorbic acid. NO generation from nitrite correlated to the the degree of relaxation of rat aorta. These results illustrate non-enzymatic release of NO from nitrite at physiological concentrations. This may be an important auto-regulated physiological mechanism involved in the regulation of vascular tone during hypoxia/ischaemia.

NO generation from inorganic nitrate and nitrite: Role in physiology, nutrition and therapeutics

“…But could nitrite be bioactive also at much lower physiological levels? In 2001 Modin et al first reported on vasoactivity from physiological amounts of nitrite (Modin et al, 2001). Rat aortic strips dilated when exposed to low micromolar levels of nitrite, if the medium had been made slightly acidic (pH ~7).…”

Dietary nitrate supplementation enhances short but not longer duration running time-trial performance

“…In contrast, Wilkerson et al (2012) observed no difference in power output during the earlier stages of a 50 mile (total exercise duration: >2 h) cycle ergometry TT, yet the final 10 miles was faster with NO 3 − supplementation. Together, these findings might suggest a potential application of BRJ during higher work rate periods within a longer duration event, perhaps specifically those which require greater type II muscle recruitment or markedly decrease the muscle pH and PO 2 and hence, augment NO 2 − reduction into NO (Modin et al 2001;Cosby et al 2003;Castello et al 2006). This might include facilitating a fast start or finish during competition, or responding to a surge by another competitor.…”

“…This suggests that it is differences in the 'use' rather than the availability of NO 2 − that is important. This might be related to greater acidosis and hypoxia, and thus NO 2 − reduction (Modin et al 2001;Cosby et al 2003;Castello et al 2006), in the 1500 vs. 10,000 m conditions, as a consequence of the relatively greater work rate adopted (~86 vs. 78% V O 2max ; ~6.5 vs. 4.5 mM blood [Lactate]). …”

“…Therefore, the beneficial effects of NO 3 − supplementation might be restricted to, or most pronounced during, exercise where type II fibers are predominantly recruited (Breese et al 2013;Bailey et al 2015;Coggan et al 2015), such as during short duration exercise where a higher relative work rate can be adopted (Essén 1978;Sale 1987). Additionally, hypoxia and acidosis-cellular conditions particularly prevalent at higher work rates (Richardson et al 1995;Robergs et al 2004)-are known to enhance the reduction of NO 2 − into NO (Modin et al 2001;Cosby et al 2003;Castello et al 2006). Consequently, NO 3 − supplementation may be more effective at elevating NO 2 − derived NO, and thus enhancing NO signalling, during short duration exercise tests where a high work rate is adopted, compared with longer duration exercise tests conducted at a lower work rate.…”

Nitrite-mediated renal vasodilatation is increased during ischemic conditions via cGMP-independent signaling

“…A handful of enzymatic and nonenzymatic pathways have been demonstrated to catalyze nitrite reduction to NO in blood and tissues, including deoxyhemoglobin and deoxymyoglobin [6,7], aldehyde oxidase (AO) [8], aldehyde dehydrogenase (ALDH) [9][10][11], xanthine oxidoreductase (XOR) [12,13], and endothelial NO synthase (NOS) [14]. Nitrite has enhanced bioactivity at low oxygen tensions and under acidic conditions [6,15,16], and studies have demonstrated a protective effect of this anion in ischemia-reperfusion injury [17,18].…”