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