M. Yamano et al., SEROTONIN (5-HT)(3)-RECEPTOR ANTAGONISM OF 4,5,6,7-TETRAHYDROBENZIMIDAZOLE DERIVATIVES AGAINST 5-HT-INDUCED BRADYCARDIA IN ANESTHETIZED RATS, Japanese Journal of Pharmacology, 65(3), 1994, pp. 241-248
We investigated the mode of the 5-HT3-receptor antagonism of 4,5,6,7-t
etrahydrobenzimidazole derivatives, YM060, YM114 (KAE-393), YM-26103-2
and YM-26308-2, against 5-HT-induced transient bradycardia in anesthe
tized rats. Results were compared with those of ondansetron and granis
etron. 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-re
sponse 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 th
ese compounds inhibited 5-HT-induced bradycardia with a reduced maxima
l response. In contrast, ondansetron displaced the 5-HT dose-response
curve to the right without affecting the maximal response. Judged by t
he apparent DR, values, YM060, YM114, YM-26103-2 and YM26308-2 were ap
proximately 13, 13, 50 and 79 times more potent than ondansetron, resp
ectively, whereas granisetron was equipotent to ondansetron. Single i.
v. doses of YM060 and granisetron inhibited 5-HT-induced bradycardia s
ignificantly 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 vo
n Bezold-Jarisch reflex lasted for 3 -6 hr, whereas ondansetron (700 m
u g/kg, p.o.) antagonized 5-HT3 receptors for only 1 hr. In isolated g
uinea 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 ant
agonists. Furthermore, non-competitive 5-HT3-receptor antagonism of YM
-compounds against the von Bezold-Jarisch reflex at higher doses may b
e reflected in their slow dissociation from the 5-HT3 receptor, and th
at of granisetron may be reflected in its slow metabolism in anestheti
zed rats.