Pharmacological studies of neurotensin, several fragments and analogous in the isolated perfused rat heart.
Neurotensin (NT) induced a dose-dependent increase of the coronary perfusion pressure (CPP) in the isolated perfused rat heart. This effect was not modified by pretreating the organ with methysergide (8.5 x 10(-6) M), atropine (3.4 x 10(-6) M), a mixture of phentolamine (3.1 x 10(-6) M) and practolol (1.5 x 10(-5) M), 8-leucine-angiomine (2.9 x 10(-5) M) thus suggesting the existence of specific NT receptors in the coronary vessels of rat. The structure-activity studies performed using several NT fragments and analogues in the isolated perfused rat heart led us to the following conclusions: (1) the minimum structure required for the full expression of the biological activity of NT is H-Arg9-Pro10-Tyr11-Ile12-Leu13-OH; (2) the amino acid Tyr in position 11 appears to play a key role in the process of NT receptor activation. The replacement of Tyr11 with Tyr(Me) gave a compound which inhibits selectively the increase in coronary perfusion pressure induced by NT, but still exhibits some NT-like activity, specially when used in concentrations higher than 10(-6) M. [Tyr(Me)11]NT did not antagonize the stimulant effects of NT in rat stomach strips and guinea pig atria, thus suggesting that the receptors mediating the constrictor effect of NT in coronary vessels of the rat are pharmacologically different from those subserving the stimulant effect of NT in rat stomach strip and guinea pig atria.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004347:Drug Interactions; D005260:Female; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009496:Neurotensin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D010446:Peptide Fragments; D009496:Neurotensin