ICS 205-930 reduces 5-methoxytryptamine-induced short-circuit current in stripped pig jejunum

The effect of ICS 205-930 on serotonin (5-hydroxytryptamine, 5-HT) and 5-methoxytryptamine (5-MeOT) induced short-circuit current (SCC) was studied in muscle-stripped pig jejunum in vitro. The selective 5-HT4 receptor agonist 5-MeOT and 5-HT both induced a concentration-dependent increase in SCC. The maximal efficacy of 5-HT was twice that of 5-MeOT. ICS 205-930 (Tropisetron) induced a small increase in SCC. Furthermore, ICS 205-930 reduced the 5-MeOT but not the 5-HT induced increase in SCC, except at the 100 microM ICS 205-930 concentration. Pretreatment with bumetanide reduced 5-HT, 5-MeOT, and ICS 205-930 induced peak increases in SCC by 64, 75, and 58%, respectively. Pretreatment with atropine reduced 5-HT, 5-MeOT, and ICS 205-930 induced peak increases in SCC by 38, 75, and 58%, respectively. Pretreatment with hexamethonium reduced 5-HT, 5-MeOT, and ICS 205-930 induced peak increases in SCC by 33, 50, and 36%, respectively. Pretreatment with tetrodotoxin reduced the peak increase in SCC elicited by 5-MeOT and ICS 205-930 by 41 and 50%, respectively. This study demonstrates involvement of a ICS 205-930, hexamethonium, atropine, bumetanide, and tetrodotoxin sensitive receptor in 5-MeOT induced SCC in muscle-stripped pig jejunum in vitro. These data suggest involvement of a neuronal 5-HT4 receptor subtype and acetylcholine in 5-HT elicited SCC and chloride secretion in the pig jejunum.