Pharmacological characterization of the 5‐HT receptor‐mediated contraction in the mouse isolated ileum

Abstract

The pharmacological characterization of a 5-HT receptor-mediated contractile response in the mouse isolated ileum is described. In the presence of methysergide (1 microM), 5-hydroxytryptamine (5-HT, 0.3 - 100 microM) produced phasic concentration-dependent contractions of segments of the mouse isolated ileum with a pEC(50) value of 5.47+/-0.09. The 5-HT(3) receptor selective agonists m-chlorophenylbiguanide (0.3 - 100 microM, pEC(50) 5.81+/-0.04), 1-phenylbiguanide (3 - 100 microM, pEC(50) 5.05+/-0.06) and 2-methyl-5-HT (3 - 100 microM, pEC(50) 5.00+/-0.07) acted as full agonists to induce contractile responses. 5-methoxytryptamine (0.1 - 100 microM), RS 67506 (0.1 - 100 microM) and alpha-methyl-5-HT (0.1 - 100 microM) failed to mimic the 5-HT responses. The contractile response to 5-HT was not antagonized by either 5-HT(2) receptor antagonists ritanserin (0.1 microM) or ketanserin (1 microM) nor the 5-HT(4) receptor antagonist SB 204070 (0.1 microM). The 5-HT(3) receptor selective antagonists granisetron (0.3 - 1 nM), tropisetron (1 - 10 nM), ondansetron (10 nM - 1 microM) and MDL 72222 (10 nM - 1 microM) caused rightward displacement of the concentration-response curves to 5-HT. The lower concentrations of the antagonists caused approximate parallel rightward shifts of the concentration-response curves to 5-HT with apparent pK(B) values for granisetron (9.70+/-0. 39), tropisetron (9.18+/-0.20), ondansetron (8.84+/-0.24) and MDL 72222 (8.65+/-0.35). But higher concentrations of antagonists resulted in a progressive reduction in the maximum responses. The contractile response to 5-HT was abolished by tetrodotoxin (0.3 microM); atropine (0.1 and 1 microM) decreased the maximum response of the 5-HT concentration-response curve by approximately 65%. It is concluded that a neuronally located 5-HT(3) receptor mediates a contractile response to 5-HT in the mouse ileum. The 5-HT(3) receptor in the mouse ileum has a different pharmacological profile to that reported for the guinea-pig ileum.