[The role of mitochondria in NO-dependent regulation of Na+, K+ -ATP activity in the rat aorta].

Abstract

In experiments in vivo we studied the interaction between two ion-transporting mechanisms of cardiovascular system--Na+, K+ -ATPase of rat aorta and Ca2+ -uptake system of mitochondria in short-term response to different doses of NO donor, nitroglycerine (NG). The activity of the Na+, K+ -ATPase was determined in rat aorta, and mitochondrial uptake of Ca2+ was studied in rat heart mitochondria assuming that metabolism induced by NO in cardiac mitochondria is similar to that in rat aortic mitochondria. The data show a coordinated dose-dependent action of NG on Na+, K+ -ATPase activity as well as Ca2+ -uptake in mitochondria. An activation of Na+, K+ -ATPase by low dose of NG (0.25 mg/kg body weight) is accompanied by the activation of Ca2+ -uptake in mitochondria as a result of inhibition of permeability transition pore. However, further increase of the dose of the drug leads to reciprocal changes of studied parameters: the decrease in Na+ -pump activity below the control level and the increase of Ca2+ -uptake in mitochondria with a peak at 1.0 mg/kg NG, which takes place in parallel with the dramatic rise in the level of ROS and RNS together with their toxic products, nitrosothiols (NT) and free iron (Fe2+) content in mitochondria. Strong correlation between Ca2+ -uptake and Fe2+ -release, Fe2+ -release and OH-radical formation, the rise in OH-radical level and the decrease of that of H2O2 and mitochondrial NT together with the inhibition of Na+, K+ -ATPase favor a hypothesis that oxidative stress in rat aorta is of mitochondrial origin due to an enhanced uptake of Ca2+ into mitochondrial matrix, Fe2+ deliverance and manifold increase in OH-radical formation from decomposition of hydroperoxide in Haber-Weiss reaction and the decomposition of mitochondrial NT via formation of peroxynitrite, both catalysed by Fe2+, with subsequent release of *OH-radical. Effective abolition of Na+, K+ -ATPase inhibition by potent antioxidant melatonine gives the evidence of the oxidative nature of Na+, K+ -ATPase inhibition by nitric oxide in rat aorta.