5-Hydroxytryptamine-induced Cl − transport is mediated by 5-HT 3 and 5-HT 4 receptors in the rat distal colon

Abstract

In the rat distal colon, 5-hydroxytryptamine (5-HT)-induced Cl − secretion is seen as a rise in short circuit current ( I sc). We investigated the 5-HT receptor mediating 5-HT-induced Cl − secretion in the rat distal colon. Rat distal colon was prepared either by stripping away the muscularis propria with the neural ganglia, or by leaving it intact. The tissue was mounted in Ussing chambers and short circuited. 5-HT receptor agonist-induced changes (Δ) in I sc were recorded in the presence and absence of 5-HT receptor antagonists. In stripped preparations, the rank order of potency of agonists was: 5-HT > 5-methoxytryptamine > α-methyl-5-HT ⪢ 2-methyl-5-HT. 5-HT and 5-methoxytryptamine-induced changes in I sc were antagonized by ≥ 0.3 μM tropisetron with pA 2 values 6.5 and 6.4, respectively. The 5-HT 4 antagonist, SC 53606, antagonized the 5-HT-induced response with a pA 2 of 7.2. 5-HT 1-like (methysergide), 5-HT 1P ( N-acetyl-5-hydroxytryptophyl 5-hydroxytryptophan amide (5-HTP-DP)), 5-HT 2A (ketanserin) and 5-HT 3 (ondansetron) receptor antagonists had no significant effect on the 5-HT response in stripped tissue. 3 μM forskolin, or 10 μM 3-isobutyl-1-methyl-xanthine (IBMX), decreased the EC 50 and increased the maximum 5-HT response. The 2-methyl-5-HT and 5-HT-induced ΔI sc in the unstripped colon preparation were antagonized by the 5-HT 3 antagonist, ondansetron (0.3 nM), and 2-methyl-5-HT activity was abolished by pretreatment with tetrodotoxin. In conclusion, 5-HT-induced ΔI sc is neurally mediated via a 5-HT 3 receptor, and non-neurally mediated via a 5-HT 4 receptor in the rat distal colon.