Investigation of the 5‐hydroxytryptamine receptor mediating the ‘maintained’ short‐circuit current response in guinea‐pig ileal mucosa

1 5‐Hydroxytryptamine (5‐HT) stimulated a biphasic increase in short‐circuit current (SCC) in guinea‐pig isolated ileal mucosa. The initial ‘spike’ response to 5‐HT was inhibited by tetrodotoxin (0.3 μm). We have investigated the 5‐HT receptor mechanism(s) controlling the second ‘maintained’ component of the response which remained after treatment with tetrodotoxin. 2 5‐HT stimulated concentration‐related increases in SCC with an EC50 value of 5.4 μm. Isobutylmethylxanthine (IBMX, 10 μm) produced a six fold leftward shift of this concentration‐response curve, suggesting the involvement of a cyclic nucleotide(s) in these responses. 3 In the presence of IBMX, 5‐HT stimulated reproducible increases in SCC with an EC50 value of 0.9 μm. The rank order of potency of indole agonists in these tests was 5‐HT ≥ 5‐methoxytryptamine > 5‐carboxamidotryptamine = α‐methyl‐5‐HT > > 2‐methyl‐5‐HT. 4 The substituted benzamides were partial agonists. Metoclopramide and cisapride produced approximately 20% of the 5‐HT maximum, and renzapride and R,S‐zacopride produced approximately 50% of the 5‐HT maximum. Metoclopramide and cisapride inhibited the SCC responses to 5‐HT with apparent pKB values of 4.8 and 7.0 respectively. 5 The SCC responses to 5‐HT were not inhibited by antagonists selective for 5‐HT1 (methysergide, methiothepin), 5‐HT2 (ketanserin) or 5‐HT3 (ondansetron, ICS205–930) receptors. 6 The SCC responses to 5‐methoxytryptamine, 5‐carboxamidotryptamine, α‐methyl‐5‐HT and R,S‐zacopride, but not 5‐HT, were selectively inhibited by high concentrations of ICS205–930 with apparent pKB values of approximately 6. 7 A possible interpretation of these results is that the ‘maintained’ SCC response to 5‐HT is mediated by a heterogeneous population of 5‐HT receptors. One of these receptors exhibits the characteristics of the putative 5‐HT4 receptor.