SEROTONIN (5-HT)(3)-RECEPTOR ANTAGONISM OF 4,5,6,7-TETRAHYDROBENZIMIDAZOLE DERIVATIVES AGAINST 5-HT-INDUCED BRADYCARDIA IN ANESTHETIZED RATS

We investigated the mode of the 5-HT3-receptor antagonism of 4,5,6,7-tetrahydrobenzimidazole derivatives, YM060, YM114 (KAE-393), YM-26103-2 and YM-26308-2, against 5-HT-induced transient bradycardia in anesthetized rats. Results were compared with those of ondansetron and granisetron. YM060 (0.03-0.1 mu g/kg, i.v.), YM114 (0.03-0.3 mu g/kg, i.v.), YM-26103-2 (0.01-0.03 mu g/kg, i.v.), YM-26308-2 (0.01-0.03 mu g/kg, i.v.) and granisetron (0.3-3 mu g/kg, i.v.) displaced the 5-HT dose-response curve to the right, with apparent DR(2) values of 0.068, 0.068, 0.019, 0.011 and 0.69 mu g/kg, i.v., respectively. Higher doses of these compounds inhibited 5-HT-induced bradycardia with a reduced maximal response. In contrast, ondansetron displaced the 5-HT dose-response curve to the right without affecting the maximal response. Judged by the apparent DR, values, YM060, YM114, YM-26103-2 and YM26308-2 were approximately 13, 13, 50 and 79 times more potent than ondansetron, respectively, whereas granisetron was equipotent to ondansetron. Single i.v. doses of YM060 and granisetron inhibited 5-HT-induced bradycardia significantly longer than ondansetron. Moreover, inhibitory effects of p.o. doses of YM060 (3 mu g/kg), YM114 (80 mu g/kg), YM-26103-2 (12 mu g/kg), YM-26308-2 (5 mu g/kg) and granisetron (250 mu g/kg) on the von Bezold-Jarisch reflex lasted for 3 -6 hr, whereas ondansetron (700 mu g/kg, p.o.) antagonized 5-HT3 receptors for only 1 hr. In isolated guinea pig colon, the inhibitory effect of YM-compounds on 5-HT-induced contraction persisted significantly longer than those of ondansetron and granisetron after washout of the bath containing compounds. These results suggest that YM-compounds are highly potent 5-HT3-receptor antagonists. Furthermore, non-competitive 5-HT3-receptor antagonism of YM-compounds against the von Bezold-Jarisch reflex at higher doses may be reflected in their slow dissociation from the 5-HT3 receptor, and that of granisetron may be reflected in its slow metabolism in anesthetized rats.