Eddie Weitzberg

A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis

Inorganic nitrite (NO(2)(-)) is emerging as a regulator of physiological functions and tissue responses to ischemia, whereas the more stable nitrate anion (NO(3)(-)) is generally considered to be biologically inert. Bacteria express nitrate reductases that produce nitrite, but mammals lack these specific enzymes. Here we report on nitrate reductase activity in rodent and human tissues that results in formation of nitrite and nitric oxide (NO) and is attenuated by the xanthine oxidoreductase inhibitor allopurinol. Nitrate administration to normoxic rats resulted in elevated levels of circulating nitrite that were again attenuated by allopurinol. Similar effects of nitrate were seen in endothelial NO synthase-deficient and germ-free mice, thereby excluding vascular NO synthase activation and bacteria as the source of nitrite. Nitrate pretreatment attenuated the increase in systemic blood pressure caused by NO synthase inhibition and enhanced blood flow during post-ischemic reperfusion. Our findings suggest a role for mammalian nitrate reduction in regulation of nitrite and NO homeostasis.

The Nitrate–Nitrite–Nitric Oxide Pathway in Mammals

Accumulating evidence suggests that the molecules nitrite and nitrate can be metabolized in vivo to form NO and other bioactive nitrogen oxides. Commensal bacteria play a central role in the bioactivation of nitrate in an entero-salivary bioactivation pathway. A number of nitrite reductase enzymes reduce nitrite to bioactive NO along a physiological oxygen and pH gradient. Nitrite mediates a number of physiological effects including vasodilation, modulation of mitochondrial function, and protection from ischemia–reperfusion injury. Modest dietary intake of nitrate reduces blood pressure, inhibits platelet function, prevents endothelial dysfunction after ischemia–reperfusion, and decreases oxygen cost during exercise. Vegetables protect against cardiovascular disease and diabetes type 2; an effect that may be related to the high nitrate content in this food group.

Luminal Nitric Oxide in the Upper Airways: Implications for Local and Distal Sites of Action

The nose has probably developed primarily to serve as a protection barrier for the lower airways and lungs. The sense of smell is also located in the nose, but may not be vital for the human species. The well-known protective functions of the nose are heating, humidification and filtration of inhaled air. Recently, other protective and regulating functions pertaining to the nasal airways and the paranasal sinuses have been proposed, which involve high nitric oxide (NO) production in the paranasal sinus mucosa. Because this NO can travel with the airstream during inhalation it may play a physiological role not only in the sinuses themselves but also in other parts of the respiratory tract, including the lungs.

Airborne Nitric Oxide in Health and Disease

Publisher Summary Direct measurements of nitric oxide (NO) in biological tissues are difficult to perform because this gas reacts rapidly with hemoglobin or other proteins. Therefore, one must often rely on indirect methods to detect NO synthesis in vivo. These include analysis of nitrate/nitrite or citrulline, immunohistochemical detection of nitric oxide synthase (NOS), and functional studies using NOS inhibitors. Unlike the situation in most biological tissues, where NO is rapidly metabolized, NO, in the gas phase, is fairly stable, especially at low concentrations. Therefore, NO produced in superficial structures of hollow organs diffuses to the lumen and may thus be detectable in gas collected from such organs. This chapter discusses measurements of luminal NO in the airways, gastrointestinal, and urogenital tracts, and its physiological relevance in health and disease.