Effect of a novel 5-hydroxytryptamine3 (5-HT3) receptor antagonist, GK-128, on 5-HT3 receptors mediating contractions and relaxations in guinea-pig distal colon.

1. We investigated 5-hydroxytryptamine3 (5-HT3) receptor-mediating contractions and relaxations in the guinea-pig isolated distal colon using various 5-HT3 receptor agonists and antagonists, including GK-128 (2-[(2-methylimidazol-1-yl) methyl] benzo[f] thiochromen-1-one monohydrochloride hemihydrate). 2. Selective 5-HT3 receptor agonists, 2-methyl-5-HT and m-chlorophenylbiguanide, produced spantide-insensitive contraction and atropine-insensitive contraction and the relaxation. These agonists showed a small, but significant, difference of potency between contraction and relaxation. 3. GK-128 competitively blocked both 2-methyl-5-HT- and m-chlorophenylbiguanide-induced responses with similar potency. The affinities of GK-128 for spantide-insensitive contraction and atropine-insensitive contraction were ten-fold higher than for relaxation. 4. Other selective 5-HT3 receptor antagonists, azasetron and tropisetron, also exhibited higher affinity in contraction than in relaxation, but the extent of their affinity differences was smaller than that observed in GK-128. In contrast, granisetron, ramosetron and ondansetron exhibited no significant differences in their affinity values among the three responses. 5. These results suggest that the 5-HT3 receptors which mediate contraction and relaxation in the guinea-pig distal colon may not be the same, and that GK-128 is a 5-HT3 receptor antagonist with a stronger potency for contraction.