Haldane, Hot Dogs and Halitosis: The Anion Nitrite As an Intrinsic Hypoxic Signaling Molecule and New Therapy for Pulmonary Arterial Hypertension

Abstract

Nitrate and nitrite have traditionally been considered dietary toxins that increase the risk of stomach cancer. In this lecture we discuss how the scientific discovery was made that nitrate and nitrite are in fact natural signaling pathways in the human body. Nitrite is now considered a biological reservoir of nitric oxide (NO), present in plasma, red cells and organ systems, that is reduced to NO during physiological and pathological hypoxia. Current studies by multiple research groups indicate that dietary and NOS-dependent nitrite formation may contribute to critical physiological functions such as blood pressure control, hypoxic vasodilation, mitochondrial respiration and the cellular resilience to ischemic stress. Recent studies suggest that a number of cellular enzymes regulate nitrite reduction to NO at different oxygen tensions, with organ system specificity. The role of molybdenum containing enzymes and heme-globin superfamily proteins - hemoglobin, myoglobin, neuroglobin, cytoglobin and the plant and drosophila hemoglobins - are the subject of active current study, and recent advances in this area of investigation will be reviewed. Studies of cytochrome C oxidase, neuroglobin and plant hemoglobins have identified a role for heme coordination in the control of nitrite reduction to NO (six-to-five coordinate regulation of nitrite binding and reduction). New pre-clinical and clinical studies suggest that inhaled and oral nitrite may be able to prevent and reverse established pulmonary arterial hypertension and phase II proof of concept trials are currently in progress in the US and Europe. It is proposed that the nitrate - nitrite - NO pathway represents a fundamentally conserved pathway for energetics and signaling in biology.