Jpn. J. Pharmacol. 69, 351-356 (1995)

Characteristics of Inhibitory Effects of Serotonin (5-HT)3-Receptor Antagonists, YM060 and YM114 (KAE-393), on the von Bezold-Jarisch Reflex Induced by 2-Methyl-5-HT, Veratridine and Electrical Stimulation of Vagus Nerves in Anesthetized Rats

Mayumi Yamano, Hiroyuki Ito, Takeshi Kamato and Keiji Miyata

Neuroscience and Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305, Japan

Abstract: We evaluated the inhibitory effects of YM060 {(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]- 4,5,6,7-tetrahydro- 1H-benzimidazole monohydrochloride} and YM114 (KAE-393) {(R)-5-[(1-indolinyl)carbonyl]- 4,5,6,7-tetrahydro- 1H-benzimidazole monohydrochloride} on the von Bezold-Jarisch reflex (BJR) induced by 2-methyl-5-HT, a selective serotonin (5-HT)3-receptor agonist; veratridine, which stimulates chemoreceptors and baroreceptors; and electrical stimulation of vagal efferent nerves in anesthetized rats. Results were compared with those of ondansetron and granisetron. 2-Methyl-5-HT (5-160 microg/kg, i.v.) and veratridine (100-200 microg/kg, i.v.) dose-dependently decreased the heart rate (BJR). YM060, YM114, ondansetron and granisetron dose-dependently inhibited 2-methyl-5-HT (40 microg/kg, i.v.)-induced BJR, with ID50 values of 0.012, 0.060, 0.97 and 0.15 microg/kg, i.v., respectively. Their 5-HT3 receptor blocking potencies against 2-methyl-5-HT-induced BJR were largely consistent with those against 5-HT-induced BJR. In contrast, higher doses (100 microg/kg, i.v.) of YM060, YM114, ondansetron and granisetron did not inhibit veratridine (150 microg/kg, i.v.)-induced BJR. Atropine (300 microg/kg, i.v.) abolished bradycardia induced by electrical stimulation of vagal efferent nerves, whereas YM060, YM114, ondansetron and granisetron had no effect at a dose of I000 microg/kg, i.v. 5-HT (0.625-5.0 microg) injected into the left ventricle also caused a dose-dependent decrease in heart rate, an effect that was abolished by YM060 (0.1 microg/kg, i.v.), atropine (100 microg/kg, i.v.) and vagotomy. These results suggest that YM060 and YM114 are highly potent and selective 5-HT3-receptor antagonists that do not affect veratridine- or electrical stimulation-induced bradycardia in anesthetized rats. They also suggest that 5-HT-induced BJR in anesthetized rats originates from 5-HT3 receptors located on the endings of vagal afferent nerves in the heart.

Keywords: 5-HT3-receptor antagonist, von Bezold-Jarisch reflex, Vagus nerve, Veratridine

Copyright© The Japanese Pharmacological Society 1995

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