Towards nitrite as a therapy in cardiovascular disease

Abstract

The nitrite anion has traditionally been considered an inert by-product of nitric oxide (NO) metabolism, but is now thought to be an important source of bioactive NO. Work from our department and others have implicated intrinsic vascular wall heme-proteins in a hypoxia-potentiated release of NO. The experiments presented in this thesis were designed to test the hypothesis that vascular wall myoglobin is one of the responsible proteins, and furthermore that the release of NO in relative hypoxia may be useful therapeutically in conditions such as heart failure and myocardial ischaemia. Experiments using murine aortic rings show that myoglobin is indeed an important vascular wall bioconverter of nitrite. Systemic nitrite infusions in healthy volunteers and patients with advanced heart failure show that this property of nitrite allows it to act as a specific venodilator in the latter condition; potentially overcoming some of the drawbacks of organic nitrates, such as hypotension and tolerance. Finally, studies in healthy volunteers, with and without a common variant of the aldehyde dehydrogenase enzyme, show that nitrite can protect the endothelium from ischaemia-reperfusion injury, depending upon temporal administration of the infusion and the genotype.