Gastrointestinal motility, prokinetic benzamides and serotonin : a study on the guinea-pig colon

The prokinetic substituted benzamides stimulate gastrointestinal motility in animal models and in man. Studies done on the isolated guinea-pig ileum have led to the hypothesis that the benzamides act through facilitation of cholinergic transmission due to stimulation of serotonin4 (5-HT ₄ ) receptors on the intramural enteric neurons. However, many questions as to their mode of action remain. The substituted benzamides are known to interfere with a variety of 5-HT receptor types. In this thesis the pharmacological action and interaction of substituted benzamides and 5-HT on the guinea-pig proximal colon were studied. This preparation was found to be endowed with 5-HT ₃ and 5-HT ₄ receptors on the nerves, mediating contraction via the release of acetylcholine and a non-cholinergic neurotransmitter (probably substance P, which stimulates smooth muscle NK ₁ receptors), and 5-HT _2A receptors on the smooth muscle. The benzamides cisapride and R 76 186 were found to be agonists at this 5-HT ₄ receptor, but cisapride was also found to have an additional direct effect on the smooth muscle. Furthermore, an unknown neuronal 5-HT ₂ - like receptor was found to mediate relaxation involving nitric oxide (NO) and adenosine triphosphate (ATP). Cisapride and some other benzamides, were found to selectively enhance the ATP-mediated relaxation. It is thus proposed that the benzamides do not only facilitate the excitatory cholinergic transmission, but also the inhibitory purinergic transmission. As in peristalsis coordinated contraction and relaxation are important, the benzamides might thus promote peristalsis by enhancing both relaxation and contraction on demand. An in vivo model for faecal pellet propulsion in the guinea-pig distal colon was developed to investigate this hypothesis in future studies.