Pharmacological characterization of neurotensin receptors in the rat isolated portal vein using analogues and fragments of neurotensin.
The contractile effects of the tridecapeptide neurotensin (NT) and several NT fragments and analogues were evaluated and compared in the rat isolated portal vein. The removal of the sequence pGlu1-Leu2-Tyr3-Glu4-Asn5-Lys6-Pro7 produced practically no change in the myotropic activity of NT while the deletion of Leu13 or the last 3 C-terminal amino acids (e.g. Tyr11, Ile12 and Leu13) gave compounds with very low agonist activity (NT(1-12)) or devoid completely of affinity and intrinsic activity (NT(1-10)). Replacing Tyr11 with Ala, Leu, D-Tyr or D-Phe markedly decreased the stimulant effect of NT but did not confer to the molecule antagonistic properties. On the other hand, the substitution of Try11 with D-Trp or Tyr(Me) gave NT analogues which behave as specific and competitive antagonist of the contractile effect of NT in the portal vein. pA2 values of [D-Trp11]-NT and [Tyr(Me)11]-NT measured in the venous preparation were similar to those found in the coronary vasculature of the rat. Taken all together, these results suggest that: (1) the minimum structure required for the full expression of the myotropic activity of NT in the rat portal vein is -Arg9-Pro10-Tyr11-Ile12-Leu13-OH; (2) Tyr11 appears to be closely involved in the process of NT receptor activation since its replacement with D-Trp or Tyr(Me) produced specific and competitive antagonist of NT; (3) the receptors mediating the contractile effect of NT in the rat portal vein appear to be pharmacologically similar to those found in the coronary vessels of the rat. The possibility for the existence of different types of NT receptor in other tissues is discussed.
D000818:Animals; D004347:Drug Interactions; D005260:Female; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009496:Neurotensin / Q000031:analogs & derivatives* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011169:Portal Vein / Q000187:drug effects; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects*; D018028:Receptors, Neurotensin
D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D018028:Receptors, Neurotensin; D009496:Neurotensin