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)μA cm−2 in proximal colon and 126 ± 10 (n = 19)μA 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 (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 times 10−8 molkg−1) and in‐vitro (1·4 times 10−6M, 1·4 times 10−4M), 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.
The calcium-calmodulin antagonist 5-iodo-C8-W7 inhibited the PGE2-induced stimulation of cAMP production by isolated enterocytes from rat small intestine. It also reduced the secretory response of intestinal sheets to PGE2, measured as a rise in short-circuit current. It did not however, inhibit the electrical responses to forskolin and dibutyryl cAMP, nor to acetylcholine, a secretagogue whose effect is not mediated by cAMP. It is concluded that the receptor-mediated activation of adenylate cyclase and the subsequent secretory response are dependent upon calcium-calmodulin.
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