ABSTRACT
AIMS: Hypobaric hypoxia (HH), linked to oxidative stress, impairs cardiac function. We synthesized a novel nitronyl nitroxide radical, an HPN derivative (HEPN) and investigated the protective effects of HEPN and HPN against HH-induced heart injury in mice and the underlying mechanisms of action. MAIN METHODS: Mice were administered with HPN (200â¯mg/kg) or HEPN (200â¯mg/kg) 30â¯min before exposed to HH. The cardiac function was measured. Serum AST, CK, LDH and cTnI were estimated. Heart tissue oxidase activity, SOD, CAT, GSH-Px, ROS and MDA were estimated. ATP content, Na+/K+-ATPase and Ca2+/Mg2+-ATPase activity was measured. The expression of HIF-1, VEGF, Nrf2, HO-1, Bax, Bcl-2, Caspase-3 was estimated. KEY FINDINGS: Results showed that pretreatment with HEPN or HPN led to a dramatic decrease in the activity of biochemical markers AST, CK, LDH and cTnI in murine serum. They increased the activity of SOD, CAT and GSH-Px and reduced the level of ROS and MDA in the hearts of mice. HEPN and HPN could increase the expression of Nrf2 and OH-1. They could maintain the ATPase activity. The Bax and Caspase-3 expression as well as the ratio of Bax/Bcl-2 were significantly downregulated and the Bcl-2 expression was upregulated by HPN or HEPN compared to the HH group. They may attenuate the HH-induced oxidant stress via free radical scavenging activity. SIGNIFICANCE: The present study showed that the nitronyl nitroxide radical HEPN and HPN may be potential therapeutic agents for treatment of HH-induced cardiac dysfunction.
Subject(s)
Antioxidants/pharmacology , Cardiotonic Agents/pharmacology , Heart Failure/drug therapy , Hypoxia/drug therapy , Nitrogen Oxides/pharmacology , Animals , Antioxidants/chemical synthesis , Aspartate Aminotransferases/blood , Aspartate Aminotransferases/genetics , Ca(2+) Mg(2+)-ATPase/genetics , Ca(2+) Mg(2+)-ATPase/metabolism , Cardiotonic Agents/chemical synthesis , Casein Kinases/blood , Casein Kinases/genetics , Caspase 3/genetics , Caspase 3/metabolism , Catalase/blood , Catalase/genetics , Gene Expression Regulation/drug effects , Glutathione Peroxidase/blood , Glutathione Peroxidase/genetics , Heart Failure/etiology , Heart Failure/genetics , Heart Failure/physiopathology , Heart Function Tests , Heme Oxygenase-1/genetics , Heme Oxygenase-1/metabolism , Hypoxia/complications , Hypoxia/genetics , Hypoxia/physiopathology , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , L-Lactate Dehydrogenase/blood , L-Lactate Dehydrogenase/genetics , Male , Malondialdehyde/antagonists & inhibitors , Malondialdehyde/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred BALB C , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Nitrogen Oxides/chemical synthesis , Oxidative Stress/drug effects , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Sodium-Potassium-Exchanging ATPase/genetics , Sodium-Potassium-Exchanging ATPase/metabolism , Superoxide Dismutase/blood , Superoxide Dismutase/genetics , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolismABSTRACT
Baicalin belongs to glucuronic acid glycosides and after hydrolysis baicalein and glucuronic acid come into being. It has such effects as clearing heat and removing toxicity, anti-inflammation, choleresis, bringing high blood pressure down, diuresis, anti-allergic reaction and so on. In this study, we investigated whether baicalin ameliorates isoproterenol-induced acute myocardial infarction and its mechanism. Rat model of acute myocardial infarction was induced by isoproterenol. Casein kinase (CK), the MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH), cardiac troponin T (cTnT) and infarct size measurement were used to measure the protective effect of baicalin on isoproterenol-induced acute myocardial infarction. iNOS protein expression in rat was analyzed using western blot analysis. Tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), malondialdehyde (MDA) and superoxide dismutase (SOD) and caspase-3 activation levels were explored using commercial ELISA kits. In the acute myocardial infarction experiment, baicalin effectively ameliorates the level of CK, CK-MB, LDH and cTnT, reduced infarct size in acute myocardial infarction rat model. Meanwhile, treatment with baicalin effectively decreased the iNOS protein expression, inflammatory factors and oxidative stresses in a rat model of acute myocardial infarction. However, baicalin emerged that anti-apoptosis activity and suppressed the activation of caspase-3 in a rat model of acute myocardial infarction. The data suggest that the protective effect of baicalin ameliorates isoproterenol-induced acute myocardial infarction through iNOS, inflammation and oxidative stress in rat.
