Circulating nitrite anions are a directly acting vasodilator and are donors for nitric oxide

Abstract

Inhaled nitric oxide (NO) is a pulmonary vasodilator, but also acts systemically, causing negative cardiac inotropic effects and a fall in systemic vascular resistance. Circulating metabolites of NO are presumed to be responsible. We questioned the role of nitrite anions and the manner in which they might contribute to these effects. Nitrite and nitrate anions coexist in blood, while circulating levels of dissolved NO are very low. Nitrate anions are not biologically active, but nitrite anions may have a biological role through the release of NO. In vitro, at 37 degrees C and in aerated Krebs bicarbonate solution, the steady-state concentration of dissolved NO was proportional to the concentration of NO in the gas. Nanomolar concentrations of dissolved NO coexisted with micromolar concentrations of nitrite anions. The idea of an equilibrium between the two in solution was also supported by the observed release of NO from nitrite anions in the absence of gas. With rings of precontracted pig pulmonary arteries (prostaglandin F(2alpha); 10 micromol/l), the steady-state concentration of dissolved NO causing 50% relaxation (EC(50)) was 0.84+/-0.25 nmol/l, corresponding to a gaseous concentration of 2.2 p.p.m. The EC(50) of nitrite was 4.5+/-0.7 micromol/l, a concentration normally found in plasma. The estimated concentration of dissolved NO derived from this nitrite was 4.5 pmol/l, some 100 times lower than would be needed to cause relaxation. The rate of exhalation of NO was increased and pulmonary vascular resistance was reduced by the addition of nitrite solution to the perfusate of isolated perfused and ventilated pig lungs, but only when millimolar concentrations were achieved. Thus circulating nitrite anions are a direct vasodilator, only being a carrier of effective amounts of "free" NO at higher than physiological concentrations.

Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate‐nitrite‐nitric oxide pathway

“…0.08 g) and dogs (0.2 g) had been found to reduce arterial blood pressure by Reichert & Mitchell in 1880 , nitrite concentrations were not thought to increase after nitrate ingestion and accounts of syncope and hypotension due to over‐indulgence in sausages , are more likely to have been a result of nitrite than the suggested nitrate. While high concentrations of acidified nitrite had been shown to relax rabbit aorta strips in 1953 , nitrite was thought to lack any physiological effect until the demonstration of arterial‐venous plasma nitrite gradients in 2000 , dilatation of arterial rings , and in 2003 the dilatation of forearm resistance vessels with a concomitant drop in MABP of ∼7 mmHg . The effect of nitrite appeared to be due to its conversion to NO by deoxyhaemoglobin .…”

“…However, a definite link still remains to be established. From 2001, nitrite was discovered to provide an important alternative source of nitric oxide, particularly when oxygen levels are reduced , such as in the microcirculation, causing vasodilatation and in 2004 in ischaemic hearts, with protective effects . Even then, dietary nitrate was still thought to lack any effect in the circulation as it was not thought to increase circulating nitrite concentrations .…”

Nitrite as regulator of hypoxic signaling in mammalian physiology

“…Nitrite-dependent vasodilation has been demonstrated in the mouse, rat, dog, sheep, primate and human circulation (11, 26, 86–90). In most of these studies the nitrite-dependent vasodilation coincides with NO formation in the red blood cells.…”

“…Concomitantly, the pulmonary vascular resistance was markedly reduced, suggesting the release of NO radicals under these conditions (90). …”

Inorganic nitrite therapy: historical perspective and future directions

“…Importantly, expanded understanding of nitrite as a hypoxia-dependent source of NO and signaling responses suggest that nitrite itself may be an important participant in physiological vasoregulation responses to tissue hypoxia. The loss of nitrite vasodilation upon removal of the endothelial monolayer also implicated this cell compartment as an important source of nitrite reduction within the vasculature [154]. As previously mentioned, multiple nitrite reduction mechanisms are possible within the cardiovascular system.…”