In vitro functional evidence of different neurotensin-receptors modulatingthe motor response of human colonic muscle strips

1 The newly developed non-peptide neurotensin (NT)-receptor antagonists SR 48692 and SR 142948 were used to challenge NT responses of human colonic ci rcular smooth muscle strips in vitro. The presence of NT1 and NT2 receptor transcripts in this tissue was tested by reverse transcriptase polymerase c hain reaction (RT-PCR) analysis. 2 NT potently and dose-dependently contracted muscle strips, with significa nt regional differences in potency and efficacy between the transverse and distal colon: EC50, 3.6 and 7.5 nM; the maximal effect was 70 and 55% of 0. 1 mM carbachol. Colonic responses to NT in both segments were virtually the same in the presence of atropine (1 mu M), levocabastine (10 mu M) or tetr odotoxin (1 mu M). 3 SR 142948 (10 nM - 1 mu M) competitively antagonized NT responses in the transverse and distal colon with similar affinities: pA(2) values 8.71 and 8.45, slopes 0.98 and 0.99. SR 48692 (10 nM-10 mu M) antagonized the NT res ponse competitively in the distal colon (pA(2) 6.55, slope 0.79) and non-co mpetitively in the transverse colon (pA(2) 8.0, slope 0.51). Neither compou nd had any agonist effect. 4 The fact that the specific antagonists prevented NT-evoked atropine- and tetrodotoxin-insensitive mechanical responses of colonic muscle strips is h ighly consistent with the presence in these tissues of non-neuronal NT rece ptors, whose heterogeneity in the transverse segment is supported by the no n-competitive antagonism of SR 48692. The finding of NT1 receptor transcrip t in both transverse and distal colon suggests its identity with the lower affinity site disclosed functionally by SR 48692 in these segments.