Myocardial protection by nitrite

Abstract

Nitrite has long been considered to be an inert oxidative metabolite of nitric oxide (NO). Recent work, however, has demonstrated that nitrite represents an important tissue storage form of NO that can be reduced to NO during ischaemic or hypoxic events. This exciting series of discoveries has created an entirely new field of research that involves the investigation of the molecular, biochemical, and physiological activities of nitrite under a variety of physiological and pathophysiological states. This has also led to a re-evaluation of the role that nitrite plays in health and disease. As a result there has been an interest in the use of nitrite as a therapeutic strategy for the treatment of acute myocardial infarction. Nitrite therapy has now been studied in several animal models and has proven to be an effective means to reduce myocardial ischaemia-reperfusion injury. This review article will provide a brief summary of the key findings that have led to the re-evaluation of nitrite and highlight the evidence supporting the cardioprotective actions of nitrite and also highlight the potential clinical application of nitrite therapy to cardiovascular diseases.

Figure 1

Predominant pathways for the generation of nitric oxide (NO) from nitrite. Nitrite is formed when NO generated from endothelial nitric oxide synthase reacts with molecular oxygen. Nitrite is then stored in the blood stream and myocardium. During conditions of hypoxia and/or ischaemia nitrite stored in the blood and heart is converted to NO via the action of a number of nitrite reductases. In the myocardium, nitrite is thought to be reduced to NO by myoglobin, low pH, hypoxia, and mitochondria. Conversion of nitrite to NO increases myocardial blood flow and directly protects the myocardium against ischaemic injury.

Figure 2

Nitrite homeostasis is determined by nitric oxide (NO) generation from NO synthases and dietary consumption of nitrate. Nitrate enters the stomach and then circulates in the blood and is converted into nitrite via salivary bacteria containing nitrate reductase. Nitrite derived from the diet and NOS activity rapidly accumulates in the plasma and is transported into tissues such as the heart. Nitrite is then stored in the myocardium and is metabolized into NO during hypoxia or ischaemia.