THE GUINEA-PIG DISTAL COLON - A SENSITIVE PREPARATION FOR THE INVESTIGATION OF 5-HT(4) RECEPTOR-MEDIATED CONTRACTIONS

1 Experiments were designed to characterize pharmacologically the cont ractile responses to 5-hydroxytryptamine (5-HT) in the guinea-pig isol ated distal colon longitudinal muscle-myenteric plexus preparation (LM MP). 2 In the presence of methiothepin (100 nm) and granisetron (1 muM ), 5-HT (10 pm - 10 nm) produced concentration-dependent contractile r esponses of the guinea-pig distal colon LMMP, with a pEC50 of 9.2 +/- 0.08. 3 Responses to 5-HT were mimicked by a series of tryptamine anal ogues, with the following rank order of potency; 5-HT>5-MeOT>>5-CT>try ptamine>2-Me-5-HT. All were found to be full agonists. 4 Responses to 5-HT were also mimicked by a series of substituted benzamide analogues . Their rank order of potency was apride>(S)-zacopride>(R)-zacopride>m etoclopramide. All were full agonists relative to 5-HT. 5 The benzimid azolone derivatives, BIMU 1 and BIMU 8 were approximately equipotent p artial agonists (intrinsic activities of 0.8 +/- 0.07 and 0.5 +/- 0.08 respectively) in the guinea-pig distal colon. 6 Tropisetron produced a rightward displacement of the 5-HT concentration-effect curve, yield ing an apparent pA2 of 6.4 +/- 0.1. The slope of the Schild plot (1.3 +/- 0.1) was significantly greater than unity. 7 SDZ 205 557 produced a concentration-dependent shift to the right of the 5-HT concentration -response curve, yielding an estimated pA2 of 7.8 +/- 0.1 and a slope which did not significantly deviate from unity. SDZ 205 557 produced s imilar pK(B) estimates (7.3-7.9) when tested against 5-MeOT, renzaprid e and 5-CT, indicating a common site of action. 8 The pharmacological profile of the 5-HT-evoked contractions of the guinea-pig distal colon LMMP are consistent with activity at the 5-HT4 receptor. Furthermore, of the models of this receptor described in the literature, the guine a-pig distal colon appears to be the most sensitive model to date, mak ing it a useful tool in the investigation of 5-HT4 receptor-mediated e vents.