The effects of a novel dihydrothienopyridine Ca antagonist S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)-thieno [2,3-b]pyridine-5-carboxylate (S-312-d), on the amount of amino acid release during cerebral ischemia and delayed neuronal death in the hippocampal CA1 region of stroke-prone spontaneously hypertensive rats were studied and compared with those of nimodipine. The released amino acids were measured by high-performance liquid chromatography after microdialysis. Cerebral ischemia was produced by occlusion of the bilateral common carotid arteries for 20 min. Intraduodenal administration of 0.3 mg/kg of S-312-d at 60 min before the carotid occlusion significantly decreased the ischemic release of glutamate and taurine, but did not influence their basal release. However, nimodipine did not inhibit the ischemic glutamate release even at a dose of 10 mg/kg. Similar peripheral hemodynamic effects were observed before and during bilateral carotid occlusion in groups treated with S-312-d or nimodipine. During the carotid occlusion, almost no cerebral blood flow was observed in either group. Therefore, the inhibitory effect of S-312-d on ischemic amino acid release probably arises from its potent direct action on neuronal cells. The neuronal cell densities of the CA1 subfield at 7 days after 20-min bilateral carotid occlusion significantly decreased in the vehicle-control group compared with the sham-operated group. Intraperitoneal administration of 0.1 mg/kg of S-312-d at 60 min before ischemia prevented the decrease of neuronal cell density compared with the vehicle control. These results show that S-312-d can offer marked neuronal protective effects against ischemic injury.