Cardioprotective effects of nitrite during exercise

Abstract

Exercise training has been shown to reduce many risk factors related to cardiovascular disease, including high blood pressure, high cholesterol, obesity, and insulin resistance. More importantly, exercise training has been consistently shown to confer sustainable protection against myocardial infarction in animal models and has been associated with improved survival following a heart attack in humans. It is still unclear how exercise training is able to protect the heart, but some studies have suggested that it increases a number of classical signalling molecules. For instance, exercise can increase components of the endogenous antioxidant defences (i.e. superoxide dismutase and catalase), increase the expression of heat shock proteins, activate ATP-sensitive potassium (K(ATP)) channels, and increase the expression and activity of endothelial nitric oxide (NO) synthase resulting in an increase in NO levels. This review article will provide a brief summary of the role that these signalling molecules play in mediating the cardioprotective effects of exercise. In particular, it will highlight the role that NO plays and introduce the idea that the stable NO metabolite, nitrite, may play a major role in mediating these cardioprotective effects.

Figure 1

Cardioprotective signalling molecules activated by exercise. Short-term and long-term exercise training has been shown to increase the expression and activity of components of the endogenous antioxidant defense system (catalase, SODs), increase the expression of heat shock proteins (HSPs), activate ATP-sensitive potassium (K_ATP) channels, and increase the expression and activity of endothelial nitric oxide synthase (eNOS) resulting in an increase in nitric oxide (NO) levels. Although all of these molecules have been associated with the cardioprotection afforded by exercise training, studies have shown that endogenous antioxidants and HSPs are not necessary for the observed cardioprotection, whereas K_ATP channels and eNOS are necessary.

Figure 2

Hypothesized fate of stored cardiac nitrite during myocardial ischaemia. Nitrite (NO₂⁻) represents a physiologically relevant storage reservoir of NO in blood and tissues that can readily be reduced to NO under pathological conditions such as ischaemic or hypoxic events. Previous studies have indicated that nitrite levels are increased in the plasma following exercise in both rodents and humans. Given that nitrite can be stored in the heart and provide cardioprotection in the setting of myocardial ischaemia by being reduced to NO, it can be hypothesized that the NO generated during exercise from the endothelium can be oxidized to nitrite, transported in the plasma, and stored in the heart or vasculature. In the event of myocardial ischaemia, the nitrite can be reduced back to NO by any of the known reductases found in the heart, thereby increasing the bioavailability of NO and providing cardioprotection in an NO-dependent manner.