COMPARISON OF THE SECRETORY ACTIONS OF 5-HYDROXYTRYPTAMINE IN THE PROXIMAL AND DISTAL COLON OF THE RAT

The ability of 5-hydroxytryptamine (5-HT) to induce a secretory response in rat proximal and distal colon was examined both in-vivo and in-vitro by measuring transintestinal electrical activity. In-vivo 5-HT caused a dose-dependent increase in the potential difference (PD) in both regions of the colon (maximum PD change = 7.2 +/- 0.5 (n = 17)mV in proximal colon and 9.2 +/- 0.7 (n = 17)mV in distal colon), an effect that was also observed in stripped (outer muscle layers removed) colonic sheets where the PD change was found to result from a rise in short-circuit current (SCC, maximum change = 150 +/- 24 (n = 15)mu A cm(-2) in proximal colon and 126 +/- 10 (n = 19)mu A cm(-2) in distal colon). The effects of 2-methyl-5-hydroxytryptamine (2-Me-5-HT), a relatively selective agonist at 5-HT3 receptors, and 5-methoxytryptamine (5-MT), an agonist at all 5-HT receptors except 5-HT3, were also tested, their specificity of action being confirmed by their actions on cardiovascular function in-vivo. 2-Me-5-HT produced a similar response to 5-HT in proximal colon, but was less effective in the distal region, particularly in-vitro where it failed to induce any significant change in electrical activity. In contrast, 5-MT was more effective in the distal colon. Frusemide 3 (10(-3) M) inhibited the rise in SCC induced by both 2-Me-5-HT and 5-MT, indicating that, like 5-HT, these agonists stimulated electrogenic Cl- secretion. The 5-HT3 antagonist granisetron abolished the effects of 2-Me-5-HT, both in-vivo (8.6 x 10(-8) molkg(-1)) and in-vitro (1.4 x 10(-6) M, 1.4 x 10(-4) M), but only caused a slight inhibition of the response to 5-HT in-vivo and no inhibition at all in stripped colonic sheets. It is concluded that although 5-HT induces a secretory response in both proximal and distal colon, the mechanisms responsible differ, with 5-HT3 receptors making a greater contribution in the proximal region.