tempo and Myocardial-Ischemia

Focal ventricular tachycardia (VT) in acute myocardial ischemia is closely related to triggered activity (TA), which may be blocked by scavenging reactive oxygen species (ROS).. This study analyzed effects of acutely administered ROS scavenger-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) on VT in vivo and TA in vitro.. Forty-three alpha chloralose anesthetized dogs with coronary artery occlusion were studied. Three-dimensional activation mapping helped to locate the origin of focal or reentrant VT. TEMPO (30 mg/kg intravenously) or vehicle was given. Endocardium excised from the site of origin of VT was studied using standard microelectrode techniques and measures of ROS.. Reentry and focal VT induction were both highly reproducible. TEMPO blocked focal VT in 6 of 11 dogs (P <.05), but 9 of 9 dogs with reentrant VT continued to have VT re-induced after TEMPO. TEMPO did not alter effective refractory period (168 +/- 3 to 171 +/- 3 ms), mean blood pressure (88 +/- 3 to 81 +/- 3 mm Hg), and size of ischemia (42% +/- 3% vs 40% +/- 4%). In vitro, TEMPO (10(-3) M, n = 14) produced no change in action potentials. Nevertheless, TA was reversibly attenuated from 5.3 +/- 1.1 to 0.4 +/- 0.4 complexes with TEMPO (n = 15, P <.05). Lucigenin-enhanced chemiluminescence and dihydroethidium staining showed increased ROS in ischemic endocardium; TEMPO dramatically reduced ROS in ischemic sites.. TEMPO, a scavenger of ROS, prevented triggered activity associated with focal VT during myocardial ischemia in areas of increased ROS. Antioxidant therapy may play an important role in blockade of focal VT under the conditions of myocardial ischemia.

Topics: Animals; Antioxidants; Cyclic N-Oxides; Dogs; Electrocardiography; Electrophysiologic Techniques, Cardiac; Luminescence; Myocardial Ischemia; Purkinje Fibers; Reproducibility of Results; Staining and Labeling; Tachycardia, Ventricular

Use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor has been associated with reduced implantable defibrillator shocks in several multicenter trials, suggesting an antiarrhythmic effect.. The purpose of this study was to determine if lovastatin had an antiarrhythmic effect in a canine model of ischemic and inducible ventricular tachycardia (VT).. Forty-seven alpha-chloralose anesthetized dogs underwent left anterior descending coronary occlusion. Three-dimensional activation mapping identified the mechanism of reinducible VT and the response to lovastatin (0.5 mg/kg IV). The endocardium was excised from foci and studied using standard microelectrode techniques with Tyrode's solution.. Lovastatin blocked focal VT in 8 of 13 dogs (P <.01) compared with only 1 of 12 saline-treated dogs with focal VT. Lovastatin had no effect on reentrant VT. Lovastatin did not alter the effective refractory period, arterial pressure, or percentage of ischemic electrograms. Effective plasma concentration of lovastatin hydroxy acid ranged from 21-157 ng/mL (0.8-3.7 x 10(-7) M). In vitro rapid pacing, mostly with isoproterenol (5 x 10(-7) M) superfusion, produced delayed afterdepolarizations and triggered activity (9 +/- 2 action potentials). Lovastatin (10(-7) M) produced no change in action potentials or delayed afterdepolarizations. However, triggered activity was attenuated to 2 +/- 1 action potentials with lovastatin (P <.05, n = 13) but not with vehicle alone. Triggered activity returned to control after lovastatin washout (20 minutes) as well as with co-superfusion with mevalonic acid (10(-6) M, n = 5). 2,2,6,6-Tetramethylpiperidine-N-oxyl, an antioxidant that enters tissues (10(-3) M, n = 8), prevented triggered activity in a fashion similar to lovastatin.. Lovastatin, in concentrations achievable in human plasma, specifically suppresses triggered activity and focal VT due to ischemia. A prenylated protein downstream from mevalonic acid may act as an antioxidant, producing the antiarrhythmic effect.

Topics: Action Potentials; Adrenergic beta-Agonists; Analysis of Variance; Animals; Anti-Arrhythmia Agents; Antioxidants; Blood Pressure; Body Surface Potential Mapping; Cardiac Pacing, Artificial; Cyclic N-Oxides; Disease Models, Animal; Dogs; Electrophysiologic Techniques, Cardiac; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Isoproterenol; Lovastatin; Male; Mevalonic Acid; Microelectrodes; Myocardial Ischemia; Refractory Period, Electrophysiological; Research Design; Ventricular Fibrillation

In vitro, the stable six-membered ring nitroxide 2,2,6,6-tetramethyl-1-piperidine-N-oxyl (TEMPO) is known to protect the ischemic and reperfused myocardium through a mechanism likely to involve the limitation of free radical damage. In vivo, TEMPO's high rate of reduction into diamagnetic nonactive compounds could limit its pharmacological use and its potential as an ESR probe in oxymetry studies. Recently, beta-phosphorylated nitrones and pyrrolidines have been reported to protect against myocardial reperfusion injury better than their nonphosphorylated analogs. Using hemodynamic, metabolic, and enzymatic indices of reperfusion injury, the efficacy of 2-diethoxyphosphoryl-2,5,5-trimethylpyrrolidinoxyl (TMPPO), a five-membered ring beta-phosphorylated nitroxide, has been compared to that of TEMPO when added at a nontoxic concentration (1 mM) in buffer-perfused isolated rat hearts during low-flow ischemia, total ischemia, and reflow. TMPPO, which is five times as hydrophilic and eight times as resistant to reduction in a biological medium as TEMPO, was more effective in reducing postischemic contracture and myocardial enzymatic leakage. Since a diamagnetic analog of TMPPO was far less protective and both nitroxides showed an antilipoperoxidant effect and acted mainly when administered only at reflow, it was proposed that beta-phosphorylated nitroxides such as TMPPO could be interesting alternatives in pharmacological and ESR applications.

Topics: Animals; Cardiotonic Agents; Creatine Kinase; Cyclic N-Oxides; Cyclopentanes; Electron Spin Resonance Spectroscopy; Heart; Hemodynamics; In Vitro Techniques; L-Lactate Dehydrogenase; Male; Malondialdehyde; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocardium; Perfusion; Phosphorylation; Rats; Rats, Wistar

Lidocaine, a local anaesthetic, has been shown to reduce ventricular arrhythmias associated with myocardial infarction and ischemic myocardial injury and its protective effects has been attributed to its membrane stabilizing properties. Since oxygen radicals are known to be produced during ischemia induced tissue damage, we have investigated the possible antioxidant properties of lidocaine and found that lidocaine does not scavenge O2-. radicals at 1 to 20 mM concentrations. However, lidocaine was found to be a potent scavenger of hydroxyl radicals and singlet oxygen. Hydroxyl radicals were produced in a Fenton type reaction and detected as DMPO-OH adducts by electron paramagnetic resonance spectroscopic techniques. Lidocaine inhibited DMPO-OH adduct formation in a dose dependent manner. The amount of lidocaine needed to cause 50% inhibition of that rate was found to be approximately 80 microM and at 300 microM concentration it virtually eliminated the DMPO-OH adduct formation. The production of OH.-dependent TBA reactive products of deoxyribose was also inhibited by lidocaine in a dose dependent manner. Lidocaine was also found to inhibit the 1O2-dependent 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) formation in a dose dependent manner. 1O2 was produced in a photosensitizing system using Rose Bengal or Methylene Blue as photosensitizers and was detected as TEMP-1O2 adduct by EPR spectroscopy. The amount of lidocaine required to cause 50% inhibition of TEMP-1O2 adduct formation was found to be 500 microM. These results suggest that the protective effect of lidocaine on myocardial injury may, in part, be due to its reactive oxygen scavenging properties.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Cyclic N-Oxides; Dose-Response Relationship, Drug; Electron Spin Resonance Spectroscopy; Free Radical Scavengers; Free Radicals; Lidocaine; Myocardial Ischemia; Reactive Oxygen Species