Adaptation of Animals to Different Types of Oxidative Stress: The Role of Mitochondrial Potassium Transport Systems

We studied parameters of the ATP-dependent influx of potassium into mitochondria, which were isolated from rats varying in their resistance to ischemia and from hypoxia-adapted animals. It has been found that in the heart and liver mitochondria, the rates of the ATP-dependent potassium influx and H2O2 production (in case of ATP-inhibited transport) are higher in the hypoxia-resistant rats, as compared to those in the hypoxia-sensitive animals. When adapted to low oxygen, the hypoxia-sensitive rats demonstrated rates of the both processes increasing to the levels observed in the hypoxia-resistant animals. However, the concentration of potassium in the mitochondria of hypoxia-resistant and adapted animals decreased. This indicates that adaptation to hypoxia stimulates not only the influx of potassium into mitochondria, but also K+/H+ exchange. The activation of such a potassium cycle can lower the production of ROS, which plays a crucial role in the lethal cell injury associated with cardiac ischemia and reperfusion. It has been further found that uridine and UMP ( precursors of UDP, a metabolic activator of mitoKATP) greatly decreased the index of ischemic alteration upon 60-min acute ischemia, as well as the size of infarction zone under ischemia-reperfusion conditions. The inhibitors of KATP channels (glibenclamide and 5-HD) reversed the anti-ischemic effect of uridine and UMP. These agents also exerted an anti-arrhythmic effect, which was completely abolished by glibenclamide but not 5-HD. It should be noted that uridine and UMP recovered the levels of ATP, phosphocreatin and glycogen, which were decreased during ischemia, while glibenclamide and 5-HD eliminated these effects. Also demonstrated was the effectiveness of uridine in the reduction of lipopolysaccharide-induced inflammation (another model of oxidative stress).