EFFECT OF TKS159, A NOVEL 5-HYDROXYTRYPTAMINE(4) AGONIST, ON GASTRIC CONTRACTILE ACTIVITY IN CONSCIOUS DOGS

A novel 5-hydroxytryptamine (5-HT)(4) receptor agonist, TKS159, N-[(2S ,4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl] benzamide}, has recently been developed as a gastroprokinetic drug. Cisapride is already used c linically to increase gastric contractions. The stimulatory effects of TKS159 and cisapride on gastric contractions were examined using forc e transducers chronically implanted on the vagally denervated pouch (H eidenhain pouch) and the vagally innervated main stomach in conscious dogs. Contractile activity was analysed by computer and expressed as a motor index. Intravenous administration of TKS159 or cisapride signif icantly increased the motor index in both the main stomach and the Hei denhain pouch during the fed and fasted states. Pharmacological charac terization in the fasted state revealed that the contraction-stimulati ng activity of TKS159 and cisapride on the stomach was significantly i nhibited by atropine, hexamethonium and a 5-HT4 receptor antagonist, S DZ 205-557. Granisetron (a 5-HT3 receptor antagonist) significantly in hibited cisapride-induced, but not TKS159-induced gastric contractions . The plasma motilin concentration was significantly increased after c isapride, but not after TKS159 injection. In conclusion, TKS159 has a contractile-stimulating effect on both the innervated and the denervat ed stomach. It is likely that a cholinergic pathway and 5-HT4 receptor s are involved in producing the contractions, although other mechanism s cannot be excluded. Cisapride has almost the same characteristics, b ut the present findings suggest the involvement of motilin and 5-HT3 r eceptors in the effects of cisapride.