Effects of low-dose nitrite upon normal, hypoxic and ischaemic vessels

The simple anion inorganic nitrite (NO2 ) has previously been considered a relatively inert nitric oxide (NO) metabolite. However, recent evidence shows that NO2" exhibits an enhanced vasodilator effect in hypoxia. It has been suggested that this effect is mediated by intra-vascular reduction of NO2" to NO by deoxygenated-haemoglobin. This thesis investigated the effects of low-dose NO2" supplementation in man, in three different environments where the actions of NO2" may be potentiated. Firstly, the effect of systemic sodium nitrite (NaNO2) administration upon forearm and pulmonary haemodynamics were assessed in healthy volunteers in both hypoxia and normoxia conditions created by a controlled environmental chamber. The study- infusion resulted in an approximate doubling of plasma NO2", with similar pharmacokinetics observed in both hypoxia and normoxia. Forearm vasodilation occurred in hypoxia but not normoxia. In addition a pulmonary vasodilator effect was present in hypoxia only, and was not dependent upon simultaneous elevation of plasma NO2". The same dose of NaNO2 was given to patients with proven inducible myocardial ischaemia in the second study: a double-blind placebo-controlled clinical trial. Objective markers of myocardial ischaemia were measured by tissue velocity imaging performed during dobutamine stress echocardiography. The results showed that low-dose NaNO2 acts as an anti-ischaemic agent despite no vasodilator effect being present in normoxia. A third set of experiments were performed to assess the potential role of NaNO2 as an ischaemic conditioning agent in a forearm model of ischaemia/reperfusion injury. Here NaNO2 was able to act as a pre-conditioning but not a post-conditioning agent. Two key results subtend this thesis. Firstly, tissue levels of NO2" are more important than intra-vascular levels, as its hypoxia-enhanced actions appear to be modulated from this site. Secondly, NaNO2 may find clinically relevance in the future as a targeted vasodilator, providing a therapeutic effect to tissues in need only