ABSTRACT
1. Our method of real-time monitoring of dopamine release from rat striatal slices revealed that endothelin (ET)-3-induced dopamine release was inhibited by NG-methyl-L-arginine (L-NMMA; 1 mM), an inhibitor of nitric oxide (NO) synthase, while NG-methyl-D-arginine (D-NMMA; 1 mM), an inactive isomer of L-NMMA, had no effect. 2. The inhibition of L-NMMA (0.1 mM) became apparent when tissues were pretreated with tetrodotoxin (1 microM) for 30 min and subsequently exposed to ET-3 (4 microM). 3. L-NMMA (0.1 and 1 mM) dose dependently protected against ET-3-triggered hypoxic/hypoglycemic impairment of striatal responses to high K+. 4. Thus, NO may work as a promoter in mediation of the stimulatory and neurotoxic action of ET-3 on the striatal dopaminergic system, presumably by interacting with interneurons in the striatum.
Subject(s)
Corpus Striatum/cytology , Endothelin-3/metabolism , Interneurons/metabolism , Neurotoxins/metabolism , Nitric Oxide/metabolism , Animals , Cell Hypoxia/physiology , Corpus Striatum/metabolism , Dopamine/metabolism , Dopamine/physiology , Endothelin-3/pharmacology , Enzyme Inhibitors/pharmacology , Hypoglycemia/physiopathology , Interneurons/chemistry , Interneurons/drug effects , Male , Organ Culture Techniques , Oxygen/pharmacology , Potassium/pharmacology , Rats , Rats, Wistar , Tetrodotoxin/pharmacology , omega-N-Methylarginine/pharmacologyABSTRACT
Pre-treatment with BAY K 8644, an L-type voltage-gated Ca2+ channels agonist, produced long-term enhancement (LTE) of over 2 h of high K(+)-evoked dopamine release from rat striatal slices. Exposure to BAY K 8644 under Ca(2+)-free conditions did not enhance this release. Thus, a transient activation of L-type voltage-gated Ca2+ channels followed by Ca2+ entry can trigger LTE of the evoked DA release from striatal tissues. This type of LTE in the striatum underlines the importance of presynaptic mechanisms, including L-type voltage-gated Ca2+ channels of 'long-term potentiation' expression.
Subject(s)
Calcium Channels/physiology , Corpus Striatum/metabolism , Dopamine/metabolism , Potassium/pharmacology , 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology , Animals , Calcium Channel Agonists/pharmacology , Electrophysiology , In Vitro Techniques , Ion Channel Gating , Male , RatsABSTRACT
The high K(+)-evoked dopamine release from rat striatal slices remained impaired by 50% up to 2 h after pulse exposure of the tissues to endothelin-3, under conditions of hypoglycemia/hypoxia. This striatal dysfunction was significantly improved by D-2-amino-5-phosphonopentanoic acid, a NMDA receptor antagonist, at a much lower concentration than that providing protection against NMDA-evoked dysfunction. In light of these findings, the important role of glutamatergic mechanisms, especially NMDA receptors, in mediating endothelin neurotoxicity warrants further attention.
Subject(s)
Endothelins/toxicity , Neostriatum/cytology , Neurons/drug effects , Receptors, N-Methyl-D-Aspartate/drug effects , 2-Amino-5-phosphonovalerate/pharmacology , 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/toxicity , Animals , Dopamine/metabolism , In Vitro Techniques , Male , N-Methylaspartate/toxicity , Neostriatum/drug effects , Neostriatum/metabolism , Neurons/metabolism , Nifedipine/pharmacology , Potassium/pharmacology , Potassium Chloride/pharmacology , Rats , Rats, WistarABSTRACT
The protective effect of nebracetam on ischemic neuronal damage was histologically examined in the pyramidal cell layer of the hippocampal CA1 subfield 7 days after operation using stroke-prone spontaneously hypertensive rats (SHRSP) subjected to 10-min bilateral carotid occlusion. Nebracetam (50 and 100 mg/kg), given orally 10 min after reperfusion, dose-dependently protected against ischemic delayed neuronal damage in the SHRSP with occlusion; however, the blood pressure remained unchanged following nebracetam administration. These findings further support the notion that nebracetam protects against ischemic delayed neuronal cell death in the hippocampus.
Subject(s)
Parasympathomimetics/pharmacology , Pyrrolidinones/pharmacology , Animals , Brain Ischemia , Cell Count/drug effects , Hippocampus , Hypertension , Male , Neuroprotective Agents , Pyramidal Cells/cytology , Rats , Rats, Inbred SHRABSTRACT
We examined the role of endothelin (ET) receptor subtypes in mediating the transient and sustained release of dopamine (DA) evoked by ETs and ET-1-induced dopaminergic dysfunction in rat striatal slices. Both phases of the release of DA evoked by ET-1 and ET-3 were inhibited by RES-701-1 (ETB antagonist) but not BQ-123 (ETA antagonist). The high K(+)-evoked DA release from slices remained impaired following a brief exposure to ET-1, under conditions of hypoxia/hypoglycaemia. RES-701-1 but not BQ-123 led to a recovery from ET-1-induced striatal dysfunction. Therefore, ETB receptors are involved in the stimulatory and neurotoxic actions of ETs on the striatal dopaminergic system.
