Katsuichi Shuto

Stimulating action of KW-5139 (Leu13-motilin) on gastrointestinal motility in the rabbit

1 The gastrointestinal motor stimulating action of the motilin analogue, KW‐5139 (Leu13‐motilin), was investigated both in the anaesthetized rabbit and in rabbit isolated smooth muscle tissues. 2 KW‐5139 (0.3–10 μg kg−1, i.v.) produced motor stimulating actions in the gastric antrum, ileum and descending colon, the excitatory responses of which were initiated at the same time but declined with different time courses. The rank order of the excitatory response was: descending colon ≥ gastric antrum >> ileum. 3 Atropine (1–3 mg kg−1, i.v.) or naloxone (1 mg kg−1, i.v.) completely suppressed the excitatory response to KW‐5139 in the gastric antrum, but only partially attenuated that in the descending colon. This suggests that the mechanism of the excitatory response is different in the gastric antrum and the descending colon, and that cholinergic neural pathway is involved in the response of the gastric antrum. 4 KW‐5139 (0.1 nM‐1 μm) caused concentration‐dependent contractions of the gastric antrum, duodenum, jejunum, ileum and the descending colon in vitro. In the rabbit intestine, the contractile response to KW‐5139 was strongest in the duodenum and weakest in the ileum. 5 The contractile response to KW‐5139 in the intestinal segments were not affected by tetrodotoxin, but were decreased by verapamil, or pretreatment with a high concentration of porcine motilin, confirming the involvement of motilin receptors in the response to KW‐5139. 6 The present results suggest that the rabbit is a suitable species for the investigation of motilin on gut motility, because of the high responsiveness of the descending colon as well as the upper gastrointestinal tract.

Involvement of disulfide-sulfhydryl interaction in anti-platelet actions of KF4939

We studied on the role of an intramolecular disulfide bond of KF4939 in its anti-platelet actions by using rabbit platelets. The inhibitions of aggregation of platelet-rich plasma (PRP) and washed platelets, and of malondialdehyde production in thrombin-stimulated platelets by KF4939 were counteracted by pretreatment with sulfhydryl compounds, glutathione, 1-cysteine and dithiothreitol. A reduced compound of KF4939 (Red-KF4939) showed nearly equal anti-aggregating activities to those of KF4939 in PRP, it, however, showed low activities to inhibit platelet aggregation and thrombin -stimulated malondialdehyde production in washed platelet suspensions. In addition, the anti-aggregating action of Red-KF4939 was counteracted by pretreatment with sulfhydryl compounds, similarly to that of KF4939. Furthermore, when platelets were treated with KF4939, a significant decrease of protein-bound sulfhydryl groups was observed. We may conclude from these results that the intramolecular disulfide bond plays an essential role in anti-platelet actions of KF4939 and the interaction of the disulfide bond with protein-bound sulfhydryl groups may be involved in the mechanism of anti-platelet actions of KF4939.

Synthesis and in vitro gastrointestinal motility enhancing activity of 3-aryl-2-imidazolidinylidene propanedinitrile derivatives

Abstract Novel N -3-arylated imidazolidinylidene propanedinitrile derivatives 2a–f were prepared by a new intramolecular cyclization method and their AChE inhibitory activity and in vitro gastrointestinal motility enhancing activity were evaluated. All compounds except 2f were found to be potent in both activities.

Effects of Flunarizine on Induced Nystagmus and Cochlear Blood Flow

The effects of flunarizine on induced nystagmus and cochlear blood flow were compared with those of cinnarizine and diphenidol. Flunarizine significantly inhibited caloric (cool water)-induced nystagmus frequency and duration of nystagmus in rabbits at 5 mg/kg i.v., whereas cinnarizine and diphenidol only slightly decreased the frequency of nystagmus at 5 mg/kg, i.v. As for optokinetic stimuli-induced nystagmus in rabbits, flunarizine significantly decreased the amplitude of nystagmus at 2.5 mg/kg i.v., and cinnarizine and diphenidol inhibited nystagmus at 5 mg/kg, i.v. Flunarizine had no effect on nystagmus induced by electrical stimulation of the lateral geniculate body in rabbits at doses up to 5 mg/kg, i.v. Flunarizine increased the cochlear blood flow in anesthetized guinea pigs dose-dependently (0.312-1.25 mg/kg i.v.) On the other hand, cinnarizine (0.625-2.5 mg/kg i.v.) and diphenidol (0.625-2.5 mg/kg i.v.) increased cochlear blood flow, but the duration of action of both cinnarizine and diphenidol was shorter than that of flunarizine at the same dose. As stated above, flunarizine inhibited nystagmus experimentally induced by caloric or optokinetic stimuli. Increased cochlear blood flow suggested that the enhancement of vestibular blood flow might play an important role in the treatment of vestibular dysfunctions with this drug.