ABSTRACT
BACKGROUND: Ischemia/reperfusion (I/R) injury triggers cardiac dysfunctions via creating reactive oxygen species (ROS). Because xanthine oxidase (XO) is one of the major enzymes that generate ROS, inhibition of XO is expected to suppress ROS-induced I/R injury. However, it remains unclear whether XO inhibition really yields cardioprotection during I/R. The protective effects of the XO inhibitors, topiroxostat and allopurinol, on cardiac I/R injury were evaluated.MethodsâandâResults:Using isolated rat hearts, ventricular functions, occurrence of arrhythmias, XO activities and thiobarbituric acid reactive substances (TBARS) productions and myocardial levels of adenine nucleotides before and after I/R, and cardiomyocyte death markers during reperfusion, were evaluated. Topiroxostat prevented left ventricular dysfunctions and facilitated recovery from arrhythmias during I/R. Allopurinol and the antioxidant, N-acetylcysteine (NAC), exhibited similar effects at higher concentrations. Topiroxostat inhibited myocardial XO activities and TBARS productions after I/R. I/R decreased myocardial levels of ATP, ADP and AMP, but increased that of xanthine. While topiroxostat, allopurinol or NAC did not change myocardial levels of ATP, ADP or AMP after I/R, all of the agents decreased the level of xanthine. They also decreased releases of CPK and LDH during reperfusion. CONCLUSIONS: Topiroxostat showed protective effects against I/R injury with higher potency than allopurinol or NAC. It dramatically inhibited XO activity and TBARS production, suggesting suppression of ROS generation.
Subject(s)
Myocardial Reperfusion Injury/drug therapy , Nitriles/therapeutic use , Pyridines/therapeutic use , Allopurinol/pharmacology , Allopurinol/therapeutic use , Animals , Arrhythmias, Cardiac/drug therapy , Nitriles/pharmacology , Protective Agents/pharmacology , Protective Agents/therapeutic use , Pyridines/pharmacology , Rats , Reactive Oxygen Species/metabolism , Thiobarbituric Acid Reactive Substances/metabolism , Ventricular Dysfunction, Left/prevention & control , Xanthine Dehydrogenase/antagonists & inhibitorsABSTRACT
Besides its antiarrhythmic effect on atrial fibrillation, bepridil protects tissue, yet its effect on apoptosis has never been fully tested. We examine the effect of bepridil on apoptosis of HL-1 cells expressing E334K myosin-binding protein C (MyBPC), a model cell of apoptosis. Bepridil was compared with amiodarone, and its effects on the expression of pro- and anti-apoptotic protein and apoptosis of HL-1 cells expressing mutant E334K MyBPC-green fluorescent protein (GFP) was analyzed using Western blot and a flow cytometer. Bepridil decreased the protein levels of both Bax and cytochrome c of cells expressing E334K MyBPC-GFP with no changes in p53 and Bcl-2, while amiodarone decreased cytochrome c but did not influence Bax except in its highest concentration. It also decreased the number of Annexin-V positive cells of HL-1 cells expressing E334K MyBPC-GFP, and decreased apoptosis of HL-1 cells expressing E334K MyBPC-GFP.
ABSTRACT
The effects of cilnidipine on the serum uric acid level and urinary NO excretion in hypertensive patients were investigated. Blood and urine samples of 16 hypertensive outpatients were collected before and 2 months after cilnidipine therapy (10 mg). The serum uric acid level decreased significantly after cilnidipine treatment, while the uric acid-creatinine clearance ratio was unaffected. The cilnidipine medication produced a significant increase in urinary NO excretion, although amlodipine did not change it significantly. Therefore, cilnidipine has a profound antihypertensive effect and may reduce the serum uric acid level and increase NO production in the kidney.
