PHARMACOLOGICAL STUDIES ON A NEW DIHYDROTHIENOPYRIDINE CALCIUM-ANTAGONIST, S-312-D - THERAPEUTIC EFFECTS OF S-312-D ON CEREBRAL METABOLIC IMPAIRMENT IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

The therapeutic effects of S-312-d on cerebral metabolic impairment were investigated in the stroke-prone spontaneously hypertensive rats (SHRSP) with apparent stroke symptoms. S-312-d was orally administered 10 mg/kg/day (25 mu mol/kg/day) to the SHRSP group (SP-312) for 3 weeks. Several stroke symptoms such as piloerection, hyperreactivity, and limb paralysis in SHRSP were markedly alleviated in SP-312. Their body weight and food intake also increased. The hypotensive and positive chronotropic effects with S-312-d were recovered to pre-drug levels at 24 h after daily administration. The increases of water, Na+ and Ca2+ and the decreases of K+ and Mg2+ in the cortex of SHRSP administered 1% gum arabic solution (SP-cont) were significantly improved in SP-312. The increases of glucose and lactate/pyruvate ratio in the cortex of SP-cont were also significantly reduced in SP-312, while the recoveries of the decreased ATP and creatine phosphate in the cortex of SP-312 were slight. The cholinergic and monoaminergic neurotransmitters in the brain were generally decreased in SP-cont. The decreased acetylcholine (ACh) and choline acetyltransferase activity (CAT) in the cortex of SP-cont were significantly restored in SP-312. In the cortex, the decreased dopamine (DA) in SP-cont was significantly restored, while the decreased norepinephrine (NE) and 5-hydroxytryptamine (5-HT) in SP-cont were only slightly recovered in SP-312. However, the decreased NE and 5-HT in SP-cont showed marked recovery in the hippocampus of SP-312. Many biochemical deteriorations in cerebral organs such as marked edema, increases of Na+ and Ca2+ contents, and decreases of several neurotransmitters in symptomatic SHRSP, which had some characteristic symptoms of stroke, seemed to be improved by the several pharmacological effects resulting from Ca2+ antagonistic effects of S-312-d. These data suggests that S-312-d can prevent the deteriorating metabolic changes in SHRSP following the cerebral stroke. (C) 1994 Wiley-Liss, Inc.