The guinea‐pig distal colon ‐ a sensitive preparation for the investigation of 5‐HT4 receptor‐mediated contractions

Abstract

Experiments were designed to characterize pharmacologically the contractile responses to 5‐hydroxytryptamine (5‐HT) in the guinea‐pig isolated distal colon longitudinal muscle‐myenteric plexus preparation (LMMP). In the presence of methiothepin (100 nm) and granisetron (1 μm), 5‐HT (10 pm −‐ 10 nm) produced concentration‐dependent contractile responses of the guinea‐pig distal colon LMMP, with a pEC50 of 9.2 ± 0.08. Responses to 5‐HT were mimicked by a series of tryptamine analogues, with the following rank order of potency; 5‐HT > 5‐MeOT >> 5‐CT > tryptamine > 2‐Me‐5‐HT. All were found to be full agonists. Responses to 5‐HT were also mimicked by a series of substituted benzamide analogues. Their rank order of potency was 5‐HT > renzapride > cisapride > (S)‐zacopride > (R)‐zacopride > metoclopramide. All were full agonists relative to 5‐HT. The benzimidazolone derivatives, BIMU 1 and BIMU 8 were approximately equipotent partial agonists (intrinsic activities of 0.8 ± 0.07 and 0.5 ± 0.08 respectively) in the guinea‐pig distal colon. Tropisetron produced a rightward displacement of the 5‐HT concentration‐effect curve, yielding an apparent pA2 of 6.4 ± 0.1. The slope of the Schild plot (1.3 ± 0.1) was significantly greater than unity. 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 similar pKB estimates (7.3–7.9) when tested against 5‐MeOT, renzapride and 5‐CT, indicating a common site of action. 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 guinea‐pig distal colon appears to be the most sensitive model to date, making it a useful tool in the investigation of 5‐HT4 receptor‐mediated events. 1993 British Pharmacological Society