Effect of Inorganic Nitrite on Cardiac and Skeletal Muscle: Physiology, Pharmacology and Therapeutic Potential

Consumption of green vegetables and beetroot increases the concentration in the bloodstream of a chemical called nitrite. Recent evidence suggests that when the cncentration of this chemical is increased by dietary means muscle works more efficiently and requires less oxygen. We will investigate why this occurs. Heart muscle is another type of muscle and we will investigate whether nitrite has a similar effect in heart muscle. Finally we will investigate whether this can be exploited as a treatment in conditions such as blockage of the arteries of the leg and the heart.

Until recently considered a relatively inert metabolite of nitric oxide, there is now emerging evidence that nitrite can exert very important effects, some of which occur at concentrations close to physiological levels. Amongst these, recent studies indicate that modestly increasing plasma nitrite by dietary means increases the metabolic efficiency of skeletal muscle during exercise. The mechanism responsible is unclear but may involve an effect on the mitochondrial electron transport chain. It is not known whether nitrite exerts similar effects on cardiac muscle. This programme grant comprises a series of mechanistic and clinical studies to 1. Evaluate the mechanism(s) responsible for increased metabolic efficiency in skeletal muscle when plasma nitrite is increased 2. Assess whether nitrite exerts similar effects in cardiac muscle 3. Assess the potential clinical application of these effects for therapeutic purposes. This will include the treatment of intermittent claudication (reversible ischaemia of limb skeletal muscle during exercise), stable angina (reversible ischaemia of cardiac muscle) and heart failure (a syndrome in which reduced cardiac energetic status plays an important pathophysiological role). The applicants bring together a mix of clinical, physiological, pharmacological and molecular skills and the design of the programme ensures strong integration between the clinical and mechanistic studies.