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.