Complex actions of neurotensin in ascending and sigmoid colonic muscle: Involvement of enteric mediators.

The brain-gut peptide neurotensin has complex effects on gastrointestinal smooth muscle. Our objective was to elucidate the mechanisms underlying neurotensin contractions in human colon. Discrete concentration response curves to neurotensin were obtained in strips of circular muscle and taenia coli from "normal" ascending and sigmoid colon segments, in the presence and absence of various pharmacological inhibitors. Potency of neurotensin in all regions was similar (pD(2) ~7). Atropine and the selective muscarinic receptor antagonists, methoctramine and darifenacin, had no effect on neurotensin contractions. In ascending colon circular muscle, responses were enhanced by indomethacin (indicating inhibitory prostaglandin mechanisms) and by tetrodotoxin (TTX), hexamethonium and L-NAME, suggesting nicotinic and enteric inhibitory neurotransmission, with involvement of nitric oxide. In sigmoid circular muscle, neurotensin responses were also enhanced by TTX and hexamethonium, but were attenuated in the presence of mepyramine, MEN10627 and CP99994, suggesting inhibitory neuronal mechanisms and involvement of histamine and tachykinins, respectively; L-NAME and the GABA(B) receptor antagonist, CGP36742, were without effect. The transcripts of NTS1 and NTS3 receptors, but not NTS2 receptors, were detected in sigmoid colon circular muscle and taenia coli. No age and gender differences in NTS1 mRNA expression were found. In conclusion, neurotensin contracts circular muscle strips from ascending and sigmoid regions of the human colon via direct (muscle) and indirect (neuronal/non-neuronal mechanisms). The enteric mediators influenced by neurotensin are regionally specific. In taenia coli strips from both ascending and sigmoid colon, neurotensin contractions were unchanged in the presence of inhibitors, suggesting direct actions only.