Pharmacological studies on a new dihydrothienopyridine calcium antagonist. 4th communication: prophylactic and therapeutic effects of S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2, 3- b]pyridine-5-carboxylate in stroke-prone spontaneously hypertensive rats.

The prophylactic and therapeutic effects of S-312-d (S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2, 3- b]pyridine-5-carboxylate, CAS 120056-57-7) were compared with those of nimodipine or nicardipine using male stroke-prone spontaneously hypertensive rats (SHRSP). The survival rate of SHRSP was dose-dependently increased by once a day oral administration of S-312-d (0.3, 1, and 3 mg/kg) or nimodipine (10 mg/kg), while all non-treated SHRSP fed with high Na+ diet died within 40 days after the start of the experiment. All SHRSP treated with 3 mg/kg S-312-d survived during the 60-day experiment periods. Marked decreases of body weights and various neurological symptoms were also inhibited with S-312-d or nimodipine. Moderate diuretic effects were observed with S-312-d at doses of 1 and 3 mg/kg. The appearance of urinary occult blood in control SHRSP was markedly inhibited with S-312-d at 1 mg/kg and nimodipine at 10 mg/kg. Histological examination of the brain of SHRSP showed that cerebral stroke lesion including edema, hemorrhage, and/or softening was dose-dependently inhibited with S-312-d. Once a day oral administration of S-312-d (1, 3, or 10 mg/kg) dose-dependently increased the body weights and improved the neurological symptoms of diseased SHRSP. The appearance of proteinuria and of occult blood in the urine of SHRSP were also markedly inhibited with S-312-d or nicardipine. Histological examination of the brain of SHRSP showed that the arbitrary neurotoxic index (ANI) for stroke lesion dose-dependently decreased with S-312-d at 1, 3, and 10 mg/kg as follows: 4.8, 3.0, 2.3. The ANI for non-treated SHRSP was 7.6. The therapeutic effects of nicardipine (ANI 3.9) at 10 mg/kg corresponded to those of S-312-d at 3 mg/kg. Thus, S-312-d can be recommended for the treatment of cerebral insufficiency or vasospasm following stroke as well as in essential hypertension.

Effects of a novel calcium antagonist, S-(+)-methyl-4,7-dihydro-3-isobutyl-6- methyl-4-(3-nitrophenyl)thieno[2,3-b]pyridine-5-carboxylate (S-312-d), on ischemic amino acid release and neuronal injury in stroke-prone spontaneously hypertensive rats.

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.