6-cyano-7-nitroquinoxaline-2-3-dione and Myocardial-Ischemia

We have investigated the effects of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK801), a non-competitive N-methyl-D-aspartate (NMDA) ionotropic excitatory amino acid receptor antagonist, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA ionotropic excitatory amino acid receptor antagonist, ketamine and memantine, NMDA receptor channel blockers, on ventricular arrhythmias induced by myocardial ischaemia and myocardial ischaemia-reperfusion. Coronary artery occlusion caused 100 +/- 2% ventricular tachycardia, in saline treated group, and 60 +/- 3% ventricular fibrillation. 66 +/- 6% of the animals recovered from ventricular fibrillation, while in 34 +/- 4% of animals the ventricular fibrillation caused mortality. The incidence of ventricular tachycardia, ventricular fibrillation and mortality was not modified by treatment of rats with MK801 (0.3 mg/kg i.v.), CNQX (1 mg/kg i.v.), ketamine (10 mg/kg) and memantine (1.5 mg/kg), injected 5 min prior to occlusion. Reperfusion caused severe arrhythmias which started within 5 +/- 2 s. For instance, in the saline treated group, the incidence of ventricular tachycardia was 100 +/- 5%, while ventricular fibrillation occurred in 87 +/- 3% of the animals and lasted 90 +/- 12 s. The mortality was 62 +/- 6%. The incidence of ventricular tachycardia, ventricular fibrillation and mortality induced by reperfusion was greatly (P < 0.01) reduced in animals treated with MK801 (0.3 mg/kg i.v.), CNQX (1 mg/kg i.v.), ketamine (10 mg/kg) and memantine (1.5 mg/kg), injected 5 min prior to occlusion. Therefore, reperfusion-induced arrhythmias, but not ischaemia-induced arrhythmias, are sensitive to NMDA/non-NMDA ionotropic excitatory amino acid receptor antagonists.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Arrhythmias, Cardiac; Blood Pressure; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Heart Rate; Ketamine; Male; Memantine; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular; Ventricular Fibrillation

Ca2+ influx and activation of protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) during nonlethal ischemic preconditioning have been implicated in the protection of the heart against subsequent lethal ischemic injury. Thus, we determined if Ca2+ influx, PKC and MAPK also mediate ischemic preconditioning-induced protection in neurons. Preconditioning by exposure of E18 rat cortical cultures to 90 min of nonlethal oxygen-glucose deprivation (OGD) 24 h prior to 180-240 min of lethal OGD was neuroprotective. Exposure to nominally free Ca2+, or blockade of the alpha-amino-hydroxy-5-methyl-isoxazolepropionate (AMPA) receptor with CNQX did not eliminate protection. MAPK activity did not change and PKC activity decreased by 50% relative to normal baseline levels at 0 and 24 h following preconditioning. The sustained decrease in PKC activity was not due to a loss of enzyme as determined from immunoblots using pan and epsilon-, beta- and zeta-specific PKC antibodies. Neuroprotection was maintained with pharmacological inhibition of PKC activity by staurosporine, chelerythrine and calphostin C and MAPK activity by PD 98059 during preconditioning, indicating that activation of these enzymes during preconditioning was not necessary for protection. Therefore, in contrast to cardiac tissue, ischemic preconditioning of neurons does not require activation of PKC and MAP kinase, and protection is maintained with substantial removal of extracellular Ca2+ or blockade of the AMPA receptor.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Brain Ischemia; Calcium; Calcium-Calmodulin-Dependent Protein Kinases; Cells, Cultured; Cerebral Cortex; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Flavonoids; Glucose; Ischemic Preconditioning; Myocardial Ischemia; Myocardium; Neurons; Oxygen; Protein Kinase C; Rats