Role of superoxide, NO and oxygen in the regulation of energy metabolism and suppression of senile diseases.

Although nitric oxide (NO) rapidly reacts with molecular oxygen under air atmospheric conditions, thereby losing its biological functions, the lifetime of this gaseous radical increases under physiologically low intracellular oxygen tensions. To understand the pathophysiological roles of NO and related molecules in aerobic life, we analyzed the effect of oxygen tensions on the NO-dependent processes in resistance arteries, isolated mitochondria, intact cells and enteric bacteria. Kinetic analysis revealed that NO enhanced the generation of cGMP and induced vasorelaxation of resistance arteries more potently under physiologically low oxygen tensions than under hyperbaric conditions. NO reversibly inhibited the respiration of isolated mitochondria, intact cells and Escherichia coli; the inhibitory effect was more marked under hypoxic conditions than under hyperbaric conditions. Kinetic analysis revealed that NO has pivotal action to increase arterial supply of molecular oxygen for the generation of ATP in peripheral tissues and to suppress energy production in mitochondria and cells in an oxygen-dependent manner. These functions of NO are enhanced by decreasing oxygen tension in situ and suppressed by locally generated superoxide radicals. Thus, cross-talk of NO, superoxide and molecular oxygen constitutes a supersystem by which the energy metabolism in cells and tissues is beautifully regulated in a site-specific manner depending on the relative concentrations of these three radical species.