PHARMACOLOGICAL STUDIES ON A NEW DIHYDROTHIENOPYRIDINE CALCIUM-ANTAGONIST .4. PROPHYLACTIC AND THERAPEUTIC EFFECTS OF (3-NITROPHENYL)THIENO[2,3-B]PYRIDINE-5-CARBOXYLATE IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS())

The prophylactic and therapeutic effects of S-312-d 3-nitrophenyl)thie no[2,3-b]pyridine-5-carboxylate, CAS 120056-57-7) were compared with t hose of nimodipine or nicardipine using male stroke-prone spontaneousl y hypertensive rats (SHRSP). The survival rate of SHRSP was dose-depen dently 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 fe d with high Na+ diet died within 40 days after the start of the experi ment. All SHRSP treated with 3 mg/kg S-312-d survived during the 60-da y experiment periods. Marked decreases of body weights and various neu rological symptoms were also inhibited with S-312-d or nimodipine. Mod erate 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 mar kedly inhibited with S-312-d at 1 mg/kg and nimodipine at 10 mg/kg. Hi stological examination of the brain of SHRSP showed that cerebral stro ke lesion including edema, hemorrhage, and/or softening was dose-depen dently 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 o f proteinuria and of occult blood in the urine of SHRSP were also mark edly inhibited with S-312-d or nicardipine. Histological examination o f 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 cor responded to those of S-312-d at 3 mg/kg. Thus, S-312-d can be recomme nded for the treatment of cerebral insufficiency or vasospasm followin g stroke as well as in essential hypertension.