cytochrome-c-t and Arrhythmias--Cardiac

Hyperthyroidism, known to have deleterious effects on heart function, and is associated with an enhanced metabolic state, implying an increased production of reactive oxygen species. Tamoxifen is a selective antagonist of estrogen receptors. These receptors make the hyperthyroid heart more susceptible to ischemia/reperfusion. Tamoxifen is also well-known as an antioxidant. The aim of the present study was to explore the possible protective effect of tamoxifen on heart function in hyperthyroid rats. Rats were injected daily with 3,5,3'-triiodothyronine at 2mg/kg body weight during 5 days to induce hyperthyroidism. One group was treated with 10mg/kg tamoxifen and another was not. The protective effect of the drug on heart rhythm was analyzed after 5 min of coronary occlusion followed by 5 min reperfusion. In hyperthyroid rats not treated with tamoxifen, ECG tracings showed post-reperfusion arrhythmias, and heart mitochondria isolated from the ventricular free wall lost the ability to accumulate and retain matrix Ca(2+) and to form a high electric gradient. Both of these adverse effects were avoided with tamoxifen treatment. Hyperthyroidism-induced oxidative stress caused inhibition of cis-aconitase and disruption of mitochondrial DNA, effects which were also avoided by tamoxifen treatment. The current results support the idea that tamoxifen inhibits the hypersensitivity of hyperthyroid rat myocardium to reperfusion damage, probably because its antioxidant activity inhibits the mitochondrial permeability transition.

Topics: Animals; Arrhythmias, Cardiac; Cytochromes c; Estrogen Antagonists; Female; Hyperthyroidism; Mitochondria, Heart; Myocardial Reperfusion Injury; Oxidative Stress; Rats; Rats, Wistar; Tamoxifen; Thiobarbituric Acid Reactive Substances

The mitogen-activated protein kinases (MAPKs) play an important role in ischemia/reperfusion (I/R) injury. Previous evidence suggests that p38 MAPK inhibition before ischemia is cardioprotective. However, whether p38 MAPK inhibition during ischemia or reperfusion provides cardioprotection is not well known. We tested the hypothesis that p38 MAPK inhibition at different times during I/R protects the heart from arrhythmias, reduces the infarct size, and attenuates ventricular dysfunction. Adult Wistar rats were subject to a 30-minute left anterior descending coronary artery occlusion, followed by a 120-minute reperfusion. A p38 MAPK inhibitor, SB203580, was given intravenously before left anterior descending coronary artery occlusion, during ischemia, or at the onset of reperfusion. The results showed that SB203580 given either before or during ischemia, but not at the onset of reperfusion, decreased the ventricular tachycardia/ventricular fibrillation (VT/VF) incidence and heat shock protein 27 phosphorylation, and increased connexin 43 phosphorylation. The infarct size and cytochrome c level was decreased in all SB203580-treated rats, without the alteration of the total Bax/Bcl-2 expression. The ventricular function was improved only in SB203580-pretreated rats. These findings suggest that timing of p38 MAPK inhibition with respect to onset of ischemia is an important determinant of therapeutic efficacy.

Topics: Administration, Intravenous; Animals; Arrhythmias, Cardiac; Cytochromes c; Disease Models, Animal; Enzyme Inhibitors; Imidazoles; Male; Myocardial Infarction; Myocardial Reperfusion Injury; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pyridines; Rats; Rats, Wistar; Time Factors; Ventricular Function

Microtubule disruption contributes to cellular and organic dysfunction, and is implicated in ischemia/reperfusion (I/R) injury. The purpose of this study was to explore the effects of taxol, a microtubule stabilizer, on cardiac functional recovery during reperfusion.. Left ventricular developed pressure, left ventricular end-diastolic pressure, maximal time derivatives of pressure and the severity of ventricular arrhythmias were analyzed in isolated rat heart. Microtubule structure was immunohistochemically measured. Apoptosis and necrosis was identified with TUNEL or TTC staining, respectively. Mitochondrial permeability transition pore (mPTP) mRNA expression was examined by real-time polymerase chain reactions. mPTP opening, reactive oxygen species (ROS), and oxidative enzyme activities were measured with fluorometric or spectrophotometric techniques. Intracellular calcium concentration ([Ca(2+) ](i) ) and Ca(2+) transients were examined by Fura-2-AM and Fluo-3-AM, respectively. Cytosolic cytochrome c, sarcoplasmic reticulum Ca(2+) -ATPase (SERCA2), ryanodine receptors (RyR), phospholamban (PLB), and PLB phosphorylation were analyzed by Western blot. Effective refractory period (ERP) and afterpotential-mediated activity were detected using microelectrode.. Taxol improved the functional recovery of post-I/R. Taxol preserved the intact microtubule structure in reperfusion. mPTP mRNA expression was unchanged while the mPTP opening was reduced by taxol, and this effect was accompanied by the decreased ROS level caused by oxidative enzymes activities' changes. Taxol reduced apoptosis and the level of cytosolic cytochrome c in reperfusion. Taxol also promoted rapid recovery of [Ca(2+) ](i) , prevented reduction of the amplitude of Ca(2+) transients and shortened the decay time of Ca(2+) transients. The protein expression of SERCA2, RyR, and PLB remained unchanged in reperfusion. Taxol prevented the increase of Phospho-Thr17-PLB and Phospho-Ser16-PLB in reperfusion. In addition, taxol facilitated rapid recovery of ERP and counter-acted afterpotential-mediated activity.. Taxol may effectively improve cardiac functional recovery during reperfusion via inhibiting mPTP opening, ameliorating abnormal calcium homeostasis, and reducing the substrates associated with arrhythmias.

Topics: Action Potentials; Animals; Apoptosis; Arrhythmias, Cardiac; Calcium Signaling; Calcium-Binding Proteins; Cytochromes c; Dose-Response Relationship, Drug; In Vitro Techniques; Membrane Potential, Mitochondrial; Microtubules; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocardial Contraction; Myocardial Reperfusion Injury; Myocardium; Necrosis; Oxidative Stress; Paclitaxel; Perfusion; Phosphorylation; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Recovery of Function; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Time Factors; Tubulin Modulators; Ventricular Function, Left; Ventricular Pressure

We investigated the contribution of dexamethasone treatment on the recovery of postischemic cardiac function and the development of reperfusion-induced arrhythmias in ischemic/reperfused isolated rat hearts. Rats were treated with 2 mg/kg of intraperitoneal injection of dexamethasone, and 24 hours later, hearts were isolated according to the 'working' mode, perfused, and subjected to 30 min global ischemia followed by 120 min reperfusion. Cardiac function including heart rate, coronary flow, aortic flow, and left ventricular developed pressure were recorded. After 60 min and 120 min reperfusion, 2 mg/kg of dexamethasone significantly improved the postischemic recovery of aortic flow and left ventricular developed pressure from their control values of 10.7 +/- 0.3 ml/min and 10.5 +/- 0.3 kPa to 22.2 +/- 0.3 ml/min (p < 0.05) and 14.3 +/- 0.5 kPa (p < 0.05), 19.3 +/- 0.3 ml/min (p < 0.05) and 12.3 +/- 0.5 kPa (p < 0.05), respectively. Heart rate and coronary flow did not show a significant change in postischemic recovery after 60 or 120 min reperfusion. In rats treated with 0.5 mg/kg of actinomycin D injected i.v., one hour before the dexamethasone injection, suppressed the dexamethasone-induced cardiac protection. Electrocardiograms were monitored to determine the incidence of reperfusion-induced ventricular fibrillation. Dexamethasone pretreatment significantly reduces the occurrence of ventricular fibrillation. Cytochrome c release was also observed in the cytoplasm. The results suggest that the inhibition of cytochrome c release is involved in the dexamethasone-induced cardiac protection.

Topics: Animals; Anti-Inflammatory Agents; Arrhythmias, Cardiac; Coronary Circulation; Cytochromes c; Dactinomycin; Dexamethasone; Dose-Response Relationship, Drug; Electrocardiography; Heart; Injections, Intraperitoneal; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Rats; Rats, Sprague-Dawley; Ventricular Fibrillation

Topics: Arrhythmias, Cardiac; Biological Phenomena; Cytochromes c; Heart; Humans; Physiological Phenomena