Subject(s)
Anti-Asthmatic Agents/adverse effects , Eye Diseases/chemically induced , Myasthenia Gravis/chemically induced , Omalizumab/adverse effects , Anti-Asthmatic Agents/administration & dosage , Eye Diseases/physiopathology , Humans , Male , Middle Aged , Myasthenia Gravis/physiopathology , Omalizumab/administration & dosageABSTRACT
Proper heart function relies on high efficiency of energy conversion. Mitochondrial oxygen-dependent processes transfer most of the chemical energy from metabolic substrates into ATP. Healthy myocardium uses mainly fatty acids as its major energy source, with little contribution of glucose. However, lactate, ketone bodies, amino acids or even acetate can be oxidized under certain circumstances. A complex interplay exists between various substrates responding to energy needs and substrate availability. The relative substrate concentration is the prime factor defining preference and utilization rate. Allosteric enzyme regulation and protein phosphorylation cascades, partially controlled by hormones such as insulin, modulate the concentration effect; together they provide short-term adjustments of cardiac energy metabolism. The expression of metabolic machinery genes is also dynamically regulated in response to developmental and (patho)physiological conditions, leading to long-term adjustments. Specific nuclear receptor transcription factors and co-activators regulate the expression of these genes. These include peroxisome proliferator-activated receptors and their nuclear receptor co-activator, estrogen-related receptor and hypoxia-inducible transcription factor 1. Increasing glucose and reducing fatty acid oxidation by metabolic regulation is already a target for effective drugs used in ischemic heart disease and heart failure. Interaction with genetic factors that control energy metabolism could provide even more powerful pharmacological tools.
Subject(s)
Energy Metabolism/physiology , Myocardium/metabolism , Acyl Coenzyme A/biosynthesis , Amino Acids/metabolism , Animals , Carbohydrate Metabolism/physiology , Carnitine/metabolism , Citric Acid Cycle/physiology , Ethanol/metabolism , Fatty Acids/metabolism , Gene Expression Regulation, Developmental , Glucose/metabolism , Glycogen/biosynthesis , Glycogenolysis , Glycolysis/physiology , Heat-Shock Proteins/physiology , Hexokinase/metabolism , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/physiology , Ischemic Preconditioning, Myocardial , Ketone Bodies/metabolism , Lactic Acid/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Peroxisome Proliferator-Activated Receptors/physiology , Pyruvic Acid/metabolism , Receptors, Estrogen/physiology , Transcription Factors/physiologyABSTRACT
We used two experimental models to prove that resveratrol (trans-3,4',5-trihydroxystilbene) reduces cardiac ischemic-reperfusion injury by means of a nitric oxide- and adenosine-dependent mechanism. (1). ACUTE EX VIVO: resveratrol (10 microM, 10 min) infusion in Langendorff-perfused normoxic rat hearts significantly increased adenosine release and coronary flow compared with baseline. After 30-min low-flow ischemia, vasodilation, still present at reperfusion, was completely abolished by resveratrol plus adenosine antagonist 8-(p-sulfophenyl)theophylline (SPT, 50 microM) administration. (2). CHRONIC IN VIVO: rats received tap water containing 25 mg/l resveratrol for 15 days or normal water. Twenty-four hours after, their hearts were Langendorff-perfused and submitted to 60-min low-flow ischemia and reperfusion. The resveratrol-treated hearts showed better functional recovery at reperfusion and significant vasodilation, but no variation in high-energy phosphates (31P Nuclear Magnetic Resonance). N(G)-nitro-L-arginine methyl ester (L-NAME, 30 microM), a nonselective nitric oxide synthase inhibitor, or SPT (50 microM) administered for 10 min prior to the low-flow ischemia cancelled the effects. This suggests that long-term moderate resveratrol consumption could play an important role in late cardioprotective effects.
