Development of endothelin antagonists protecting against ischemic neuronal degeneration

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The present study was aimed at elucidating a neuroprotective action of endothelin (ET) antagonists on ischemic neuronal degeneration with the in vitro and in vivo rat model for brain ischemia. (1) RES-701-1 (ETB antagonist) but not BQ-123 (ETA antagonist) inhibited the release of dopamine from rat striatal slices. (2) Striatal response to the test stimulation remained impaired up to 2 hr after the pulse exposure of ET-1 under conditions of hypoglycemia/hypoxia. We termed this event striatal dopaminergic dysfunction'. RES-701-1 but not BQ-123 led to a recovery from this striatal dysfunction. An inhibitor of nitric oxide synthase closely associated with ETB function improved ET-1 neurotoxicity. (3) The delayd neuronal death occurred in the hippocampus CA1 pyramidal cell layr of rats at 7 days after a 20-min bilateral carotid occlusion according to Pulsinelli's method. RES-701-1 and T-0201 (ETA/ETB antagonist) injected into the lateral ventricle 10 min after reperfusion protected against ischemic neuronal death. (4) The quantitative receptor autoradiographic method we used revealed a dramatic increase in 125-I-ET-1 binding sites in the hippocampus CA1 pyramidal cell layr with neuronal death. The de novo 125-I-ET-1 binding sites were characteristically the ETB receptor.The present findings provide evidence that ETB antagonists could be operative for the treatment of ischemic brain damage.