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 μ m ). 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 EC 50 value of 5.4 μ m . Isobutylmethylxanthine (IBMX, 10 μ m ) 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 EC 50 value of 0.9 μ m . 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 p K B values of 4.8 and 7.0 respectively. 5 The SCC responses to 5‐HT were not inhibited by antagonists selective for 5‐HT 1 (methysergide, methiothepin), 5‐HT 2 (ketanserin) or 5‐HT 3 (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 p K B 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‐HT 4 receptor.