Effects of neurokinins on human colonic motility

Abstract Neurokinins have been implicated as excitatory neuromessengers involved in the mediation of different reflexes in the mammalian gastrointestinal tract. However, marked interspecies variations in reported receptor distribution and in regional peptide content do not allow the extrapolation of results obtained in animals to the human gastrointestinal tract. To characterize the myogenic and neurogenic mechanical response of human colonic muscle to neurokinins, we studied the inotropic response of muscle strips from the proximal and distal human colon, and the rectum to the NK-1 receptor agonists substance P (SP) and substance P methylester (SPME), to the NK-2 receptor agonists neurokinin A (NKA) and neurokinin A 4–10 (NKA4–10) and to the NK-3 receptor agonist neurokinin B (NKB). Even though all neurokinins caused a dose-dependent inotropic response, NKA was 15–20 times more potent than SP or SPME in all areas of the colon. The efficacy and potency of NKA was highest in distal circular colon. The response to exogenous SP and NKA was partially mediated by actions of these peptides on myenteric nerves, as indicated by the sensitivity of the mechanical response to atropine, tetrodotoxin and hexamethonium. Densensitization to NKA, but not to SP significantly increased the atropine-resistant part of the off response to electrical field simulation. These results suggest the following: (a) NKA is a potent agonist in human colon with a proximal to distal gradient in potency and in efficacy; (b) the response to NK-I, NK-2 and NK-3 agonists involves cholinergic and nicotinic mechanisms; (c) the increase in the atropine resistant off-response after desensitization with NKA is consistent with the existence of inhibitory NK-2 receptors on non-cholinergic myenteric neurons.