5-HT7 receptors mediate the inhibitory effect of 5-HT on peristalsis in the isolated guinea-pig ileum

Abstract

The study was undertaken to investigate the 5-HT receptor mediating the inhibitory effect of 5-HT on peristalsis in the guinea-pig isolated ileum. The facilitatory and inhibitory effects were measured as the decrease and increase, respectively, in the intraluminal pressure required to trigger peristalsis. In the presence of 5-HT(2/3&4) receptor antagonists ketanserin (0.1 micro M), granisetron (1 micro M) and SB-204070 (1 micro M), a cumulative addition (0.1-100 micro M) of 5-HT or 5-carboxamidotryptamine, but not 2-methyl-5-HT produced a concentration-dependent increase in the threshold required to trigger peristalsis. The 5-HT(7) receptor selective antagonist SB-269970-A (0.01-1 micro M) or methiothepin (0.01-0.1 micro M) concentration-dependently antagonised this response to 5-HT. SB-269970-A (1 micro M) and methiothepin (1 micro M) were also able to restore peristalsis in tissues in which peristalsis was inhibited by a prior addition of 30 micro M of 5-HT. The results indicate an involvement of 5-HT(7) receptors in the inhibitory effect of 5-HT on peristalsis in the guinea-pig ileum.

Figure 1

Schematic diagram of the apparatus used to study peristalsis.

Figure 2

A trace illustrating the inhibitory effect of a cumulative addition of 5-HT on peristalsis in the presence of ketanserin (0.1 μM), granisetron (1 μM) and SB-204070 (1 μM).

Figure 3

A trace illustrating the effect of 30 μM 5-HT on peristalsis and the reversal of the inhibitory effect of 5-HT on peristalsis by 1 μM SB-269970-A. Ketanserin, granisetron or SB-204070 was not present in these experiments.

Figure 4

(a) Concentration–response curves to 5-HT, 5-carboxamidotryptamine (5-CT) and 2-methyl-5-HT (2-Me-5-HT) to inhibit peristalsis in the guinea-pig ileum. The threshold for peristalsis before and after the cumulative addition of the drugs to the serosal side are shown. (b) Effect of an increasing concentration of SB-269970-A (SB) on the inhibitory effect of 5-HT on peristalsis. (c) Effect of an increasing concentration of methiothepin (Meth) on the inhibitory effects of 5-HT on peristalsis. The buffer routinely contained ketanserin (0.1 μM), granisetron (1 μM) and SB-204070 (1 μM) in these experiments (d and e). The inhibitory effect of 30 μM of 5-HT on peristalsis in the guinea-pig ileum and the reversal of the effect by a further addition of 1 μM of SB-269970-A (SB) (d) and methiothepin (Meth) (e). The buffer did not contain ketanserin, granisetron (1 μM) or SB-204070 in these experiments. ^*P<0.001 compared to threshold before treatment with 5-HT. All points indicate the means and vertical bars the s.e.mean of six separate experiments.