Kiyoshi Saitoh

Healing of acetic acid-induced gastric ulcer and gastric mucosal PGI2 level in rats

The present study was designed to investigate the changes in gastric mucosal PGI2 level accompanying the healing of acetic acid-induced gastric ulcers in rats. The ulcers, which were observed with an endoscope, were found to undergo periods of decrease, healing and exacerbation during the rats lifetime. The phases were categorized as follows: (1) the reduction period (days 3–50 after ulcer induction, corresponding to 7–14 weeks of age), (2) healing period (days 35–150 after ulcer induction, corresponding to 12–29 weeks of age), (3) first exacerbation period (days 35–231 after ulcer induction, corresponding to 12–40 weeks of age), (4) inactive period (days 231–365 after ulcer induction, corresponding to 40–60 weeks of age), and (5) second exacerbation period (days 365–550 after ulcer induction, corresponding to 60–86 weeks of age). In normal rats, the level of gastric mucosal PGI2 gradually increased with aging between 7 and 20 weeks, then decreased up to 40 weeks. The PGI2 level in the 60-week-old rat did not differ from that in the 40-week-old rat. The PGI2 level was the lowest in the 86-week-old rat. In ulcer-bearing rats, the PGI2 level showed the same pattern of change as that in normal rats, but the level was higher. The above results indicated a marked decrease in PGI2 level between 20 and 40 weeks of age and between 60 and 86 weeks of age in normal and ulcer-bearing rats. These periods corresponded closely to the first and second exacerbation periods, respectively. Thus, it can be postulated that ulcer aggravation may be caused by a marked decrease in gastric mucosal PGI2 generation.

The mode for the manifestation of the inhibitory effects of ifenprodil tartrate on platelet aggregation in vivo and ex vivo.

The mode for the manifestation of the inhibitory effect of ifenprodil tartrate on platelet aggregation in vivo and ex vivo was studied in mice and men, respectively. The ifenprodil level in plasma reached the maximum in 20 min after oral administration of 30 mg ifenprodil tartrate/kg in mice, and it decreased over a 3 hr period after the administration. On the other hand, the maximal inhibitory effect was observed 60 min after the administration. Thus ifenprodil tartrate manifested its inhibitory effect on platelet aggregation only after the maximum plasma concentration of ifenprodil was reached. The same phenomenon was observed with the inhibitory effects of ifenprodil tartrate on platelet aggregation ex vivo in man. To clarify the reason for the delay in the manifestation of the inhibitory effects of ifenprodil, the ifenprodil contents in mouse platelets after the oral administration of the drug was measured. The pattern of change in the ifenprodil contents in platelets was found to resemble closely the pattern of the change in its inhibitory effects, suggesting that the manifestation of the inhibitory effects on platelet aggregation by oral administration of ifenprodil tartrate was directly related to the ifenprodil contents in platelets rather than the ifenprodil level in plasma.

Pharmacological actions of iprazochrome on the vascular system

The pharmacological actions of iprazochrome (IC) on the vascular system were studied, and the following results were obtained: No death nor abnormal behaviors were observed in acute toxicity tests conducted on male and female mice and rats despite the administration of large doses of IC (10,000 mg/kg, p.o. and 80 mg/kg, i.v., respectively). IC inhibited dose-dependently platelet aggregation in vitro induced by arachidonate and ADP, whereas no effect was observed on ADP-induced respiratory depression in mice, which is closely related to platelet aggregation in vivo. The antiserotonergic actions of IC on the isolated external carotid arteries and femoral arteries in dogs observed in a noncompetitive manner were found to be 1/24 to 1/65 that of methysergide. On the other hand, IC showed no inhibitory effect on the paw edema of rats in vivo induced by serotonin. The inhibitory effect of IC on peritoneal dye leakage in mice was less than half that of phenylbutazone. IC prevented apoplexy in stroke-prone SHR (SHRSP) without lowering the blood pressure. Histological changes in the cerebrum of SHRSP were ischemic changes such as swelling of the neurons and shrinkage of the nuclei, mainly in the cerebral cortex and corpus striatum area.