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- secret ion 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 dis tal colon. Rat distal colon was prepared either by stripping away the muscularis propria with the neural ganglia, or by leaving it intact. T he tissue was mounted in Ussing chambers and short circuited. 5-HT rec eptor agonist-induced changes (d) in I-sc were recorded in the presenc e 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-methox ytryptamine-induced changes in I-sc were antagonized by greater than o r equal to 0.3 mu M tropisetron with pA(2) values 6.5 and 6.4, respect ively. The 5-HT4, antagonist, SC 53606, antagonized the 5-HT-induced r esponse with a pA(2) of 7.2. 5-HT1-like (methysergide), 5-HT1p (N-acet yl-5-hydroxytryptophyl 5-hydroxytryptophan amide (5-HTP-DP)), 5-HT2A ( ketanserin) and 5-HT3 (ondansetron) receptor antagonists had no signif icant 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-i nduced Delta I-sc in the unstripped colon preparation were antagonized by the 5-HT3 antagonist, ondansetron (0.3 nM), and 2-methyl-5-HT acti vity 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.