Although regional synthesis of nitric oxide (NO) by the endothelium contributes importantly to local vasodilator tone, we have previously shown that ?NO bioactivity? may be transported in blood, and have biological effects at a distance from the site of entry into the circulation. These endocrine effects of NO are mediated by intravascular NO-stores ? candidates are protein and heme-bound NO species (RXNO) in plasma or erythrocytes and the oxidative NO-metabolite nitrite. Cumulating evidence suggests that nitrite may serve as a major intravascular storage pool for NO. Recent studies by our group show that regional, intra-arterial infusion of nitrite elicits downstream vasodilator response. The mechanism of nitrite reduction in vivo may involve a number of pathways. We have observed that nitrite is reduced to NO by its reaction with deoxyheme proteins. This chemistry suggests a role for hemoglobin and other heme proteins as an oxygen dependent nitrite reductase and further that nitrite ions might contribute to systemic hypoxic vasodilation. Other research groups have proposed pH-dependent mechanisms, the involvement of electron donors such as ascorbic acid, or xanthinoxidase as a reducing agent. The present study will be conducted in two stages (Parts A and B) with the following objectives: Part A will determine 1) whether systemic (intravenous) infusion of nitrite modulates vascular tone in the systemic circulation, 2) whether oxypurinol (a potent inhibitor of xanthine oxidase activity) lowers or ascorbic acid potentiates nitrite-induced vasodilation, 3) elucidate the pharmacokinetic profile of nitrite application in humans and 4) determine phase I data for dosing nitrite in human disease. Part B will determine whether the systemic and pulmonary vascular responses to nitrite infusion are potentiated under hypoxic conditions and are mediated by NO gas per se as measured by NO content in exhaled breath. We began enrolling patients in February 2005. Currently we have enrolled 16 healthy volunteers and completed 11 Part A studies. Due to the study design, data analysis will require completion of the Part A before preliminary results are available.
| Dejam, Andre; Hunter, Christian J; Gladwin, Mark T (2007) Effects of dietary nitrate on blood pressure. N Engl J Med 356:1590;author reply 1590 |
| Dejam, Andre; Hunter, Christian J; Tremonti, Carole et al. (2007) Nitrite infusion in humans and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation. Circulation 116:1821-31 |
