5-Hydroxytryptamine-induced Cl- transport is mediated by 5-HT3 and 5-HT4 receptors in the rat distal colon

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 (d) 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 > alpha-methyl-5-RT much greater than 2-methyl-5-HT. 5-HT and 5-methoxytryptamine-induced changes in I-sc were antagonized by greater than or equal to 0.3 mu M tropisetron with pA(2) values 6.5 and 6.4, respectively. The 5-HT4, antagonist, SC 53606, antagonized the 5-HT-induced response with a pA(2) of 7.2. 5-HT1-like (methysergide), 5-HT1p (N-acetyl-5-hydroxytryptophyl 5-hydroxytryptophan amide (5-HTP-DP)), 5-HT2A (ketanserin) and 5-HT3 (ondansetron) receptor antagonists had no significant effect on the 5-HT response in stripped tissue. 3 mu M forskolin, or 10 mu M 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 Delta I-sc in the unstripped colon preparation were antagonized by the 5-HT3 antagonist, ondansetron (0.3 nM), and 2-methyl-5-HT activity was abolished by pretreatment with tetrodotoxin. In conclusion, 5-HT-induced Delta I-sc is neurally mediated via a 5-HT3 receptor, and non-neurally mediated via a 5-HT4 receptor in the rat distal colon.