Inorganic nitrite and chronic tissue ischaemia: a novel therapeutic modality for peripheral vascular diseases

Abstract

Ischaemic tissue damage represents the ultimate form of tissue pathophysiology due to cardiovascular disease, which is the leading cause of morbidity and mortality across the globe. A significant amount of basic research and clinical investigation has been focused on identifying cellular and molecular pathways to alleviate tissue damage and dysfunction due to ischaemia and subsequent reperfusion. Over many years, the gaseous molecule nitric oxide (NO) has emerged as an important regulator of cardiovascular health as well as protector against tissue ischaemia and reperfusion injury. However, clinical translation of NO therapy for these pathophysiological conditions has not been realized for various reasons. Work from our laboratory and several others suggests that a new form of NO-associated therapy may be possible through the use of nitrite anion (sodium nitrite), a prodrug which can be reduced to NO in ischaemic tissues. In this manner, nitrite anion serves as a highly selective NO donor in ischaemic tissues without substantially altering otherwise normal tissue. This surprising and novel discovery has reinvigorated hopes for effectively restoring NO bioavailability in vulnerable tissues while continuing to reveal the complexity of NO biology and metabolism within the cardiovascular system. However, some concerns may exist regarding the effect of nitrite on carcinogenesis. This review highlights the emergence of nitrite anion as a selective NO prodrug for ischaemic tissue disorders and discusses the potential therapeutic utility of this agent for peripheral vascular disease.

Figure 1

Sources and metabolic fate of nitric oxide. Diagram illustrating substrate and cofactors required for nitric oxide formation along with end target reaction molecules and salvage pathways.

Figure 2

Illustration of a physiologically healthy vessel compared with a diseased vessel and the effect nitrite therapy has on diseased vessels. The healthy vessel on the left is capable of adequately regulating blood flow to perfuse distal tissues. When this same vessel becomes dysfunctional due to atherosclerosis, vascular responsiveness is lost concomitant with luminal stenosis leading to reduced blood flow and oxygen delivery in distal tissues. Nitrite is able to augment collateral vessel perfusion and increase blood vessel growth thereby increasing blood flow to ischaemic tissues.