Pharmacological characterization of 5‐hydroxytryptamine receptor types in the guinea‐pig proximal colon

It was investigated which 5-hydroxytryptamine (5-HT) receptors mediate the responses to 5-HT in the longitudinal muscle layer of the guinea-pig proximal colon, using selective 5-HT receptor antagonists and the 5-HT analogues α-methyl-5-HT (2-Me-5-HT), 2-methyl-5-HT (2-Me-5-HT), and 5-methoxytryptamine (5-MeOT). 5-HT as well as its analogues induced concentration-related contractions, at low concentrations preceded by relaxations. The 5-HT concentration-contractile response curve was biphasic whilst the curves to α-Me-5-HT, 2-Me-5-HT, and 5-MeOT were monophasic. Tetrodotoxin (TTX) abolished the relaxations, and it inhibited the contractions to all agonists. In the presence of TTX, blockade of either 5-HT2 (ketanserin) or 5-HT3 receptors (ondansetron, tropisetron) reduced the contractions to 5-HT, whereas blockade of both 5-HT receptor types at the same time abolished them. In the absence of TTX, the contractions to 5-HT were inhibited by antagonists at 5-HT2 (ketanserin), 5-HT3 (granisetron, nanomolar concentration of tropisetron) and also 5-HT4 receptors (micromolar concentration of tropisetron). Contractions to α-Me-5-HT did not seem to be sensitive to 5-HT2 receptor blockage with ketanserin, but in the presence of TTX the contractions were abolished by the 5-HT2 receptor antagonist. The 5-HT3 receptor antagonist granisetron abolished contractions to 2-Me-5-HT. In the presence of TTX, the 5-HT2 receptor antagonist ketanserin abolished contractions to 5-MeOT, and in the absence of TTX the contractions to 5-MeOT were highly sensitive blockade of 5-HT4 receptors with tropisetron. Blockage of either 5-HT1 (methiothepin), 5-HT2 (ketanserin), 5-HT3 (ondansetron, granisetron, tropisetron) or 5-HT4 (tropisetron) receptors did not abolish the relaxations to 5-HT or 5-MeOT. In conclusion, 5-HT induces contractions of the longitudinal muscle of the guinea-pig proximal colon, through the stimulation of 5-HT2 receptors on the smooth muscle cells and 5-HT3 receptors and putative neuronal 5-HT4 receptors. 5-HT evokes relaxations via an unknown neuronal receptor.