mebudipine and Reperfusion-Injury

Reperfusion of the heart after an ischemic insult may lead to potentially lethal arrhythmias and cardimyocyte cell death via apoptosis and necrosis. In addition, previous studies showed that calcium channel blockers may have a protective role in the myocardium against arrhythmia and irreversible tissue injury. Therefore, this study was aimed to investigate the effects of mebudipine on myocardial arrhythmias and tissue injury induced by ischemia/reperfusion injury in isolated rat hearts. Male Wistar rats (250‑300g) were randomly divided to Sham group (without ischemia), control group (ischemia without drug), drug group (ischemia with mebudipine 0.1nM) and vehicle group (ischemia with ethanol 0.01%). The hearts of anaesthetized rats were removed and mounted on Langendorff apparatus and perfused by Krebs‑Henseleit solution under constant pressure of 75 mmHg at 37°C. Impulsive heart rate was monitored with bipolar golden electrodes. The electrocardiographs were recorded throughout the experiment and interpreted using the Lambeth convention. LDH and CPK activities in coronary effluent were analyzed spectrophotometrically. Hematoxilin & Eosin staining was performed for evaluation of microscopic architecture of the myocardium and tissue injury.  Pretreatment with mebudipine significantly decreased the number of ventricular premature beats (VPB) as compared with control group. The similar findings were seen in the number of ventricular tachycardia (VT) and fibrillation (VF) among groups. In addition, mebudipine significantly reduced the severity of arrhythmias in comparison with control hearts.  Moreover, the drug group demonstrated marked improvement in edema and infiltration of inflammatory cells especially with regard to the degree of myonecrosis and cell lysis.Mebudipine diminished the number and the incidence of myocardial arrhythmias induced by reperfusion injury and the severity of tissue injury.

Topics: Animals; Arrhythmias, Cardiac; Creatine Kinase; Heart; Heart Rate; In Vitro Techniques; L-Lactate Dehydrogenase; Male; Myocardium; Nifedipine; Protective Agents; Rats; Rats, Wistar; Reperfusion Injury; Tachycardia, Ventricular; Ventricular Fibrillation

In the present study, we investigated the effects of mebudipine and dibudipine, two new Ca(2+) channel blockers, on primary murine cortical neurons exposed to oxygen-glucose deprivation/reperfusion. The experiments were performed on cells after 11-16 days of culture. To initiate oxygen-glucose deprivation /reperfusion, the culture medium was replaced by glucose-free medium, and the cells were transferred to a humidified incubation chamber in a mixture of 95% N(2) and 5% CO(2) at 37 degrees C for 30 min. The cultures were pretreated with mebudipine and dibudipine 3 h prior to oxygen-glucose deprivation/reperfusion, in order to explore their effects on neurons under oxygen-glucose deprivation conditions. Cell viability and nitric oxide (NO) production were assessed by MTT assay and the modified Griess method, respectively. Exposure of murine cortical neuronal cells to 30 min oxygen-glucose deprivation significantly decreased cell viability and increased NO production. Pretreatment of the cultures with mebudipine and dibudipine significantly increased cell viability and decreased NO generation in a dose-dependent manner. However, the drugs had no protective effect in cells subjected to oxygen-glucose deprivation for 60 min. Pretreatment of cultures with MK-801 (10 microM), a non-competitive NMDA antagonist, decreased neuronal death after 30-min oxygen-glucose deprivation, while application of NBQX (30 microM), a selective AMPA-kainate receptor antagonist, partially attenuated the cell injury. oxygen-glucose deprivation -induced cytotoxicity and NO production were also inhibited by N-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor and MK-801. We conclude that mebudipine and dibudipine could protect cortical neurons against oxygen-glucose deprivation /reperfusion-induced cell injury in a dose-dependent manner, and that this could be mediated partially by decreased NO production.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Cell Death; Cell Survival; Cells, Cultured; Cerebral Cortex; Dizocilpine Maleate; Dose-Response Relationship, Drug; Embryo, Mammalian; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Formazans; Glucose; Hypoxia; Mice; N-Methylaspartate; Neurons; Neuroprotective Agents; NG-Nitroarginine Methyl Ester; Nifedipine; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Quinoxalines; Receptors, Kainic Acid; Reperfusion Injury; Tetrazolium Salts; Time Factors