I Picomolar concentrations of neurotensin caused concentration-dependent contractions of the longitudinal musculature of the fundus of the rat stomach. The EC50 of neurotensin was approximately 1.5 nM. On a molar basis neurotensin was about 5 10 times more potent than 5-hydroxytryptamine (5-HT) and approximately 80 times as active as acetylcholine in producing similar contractions. 2 Studies with structurally related peptides indicated that whereas the carboxy terminal portion of neurotensin was essential for biological activity, a substantial part of its amino terminus end could be removed without affecting its potency. The EC50 for the neurotensin fragment 8-13 was identical to that of neurotensin, however its 1 -8 or 1 -11 fragments were completely inactive. 3 Tetrodotoxin did not modify the potency of neurotensin or structurally related analogues suggesting that the neurotensin receptor is probably located on the smooth muscle membrane. In addition, the potency of neurotensin in contracting the fundus was not modified by pretreatment with atropine, methysergide or diphenhydramine. 4 Fade to the contractile response of neurotensin was followed by the development of tachyphylaxis; desensitization was concentration-dependent and characterized by a shift in the agonist concentrationresponse curve to the right and downwards. Desensitization with a priming concentration of neurotensin (approx. EC O) caused a substantial blockade of its excitability. 5 There was cross-desensitization between neurotensin and the contractile activity of neurotensin 8-13 or xenopsin, but not with angiotensin II, bradykinin, substance P, acetylcholine, 5-HT or histamine.6 Pretreatment of the fundus strip with verapamil 0.3-1 tM antagonized in a concentrationdependent fashion the neurotensin-induced contractions but not the muscular contractions caused by acetylcholine. 7 It is concluded that neurotensin activates a specific excitatory receptor probably located on the cell membrane of the smooth muscles of the rat fundus. In addition, we suggest that this receptor is somehow related to a voltage-dependent calcium channel, sensitive to verapamil.

1The contractile activity ofneurotensin and acetylcholine on rat isolated fundus strips was examined in preparations maintained in Tyrode buffer containing 2.5, 1.0 or 0 mM Ca2 . While the neurotensin contractions depended markedly on the external Ca2+ concentration, the acetylcholine-induced muscular responses were not significantly affected by omission of calcium in the superfusion media.2 Pre-incubation of rat fundus strips with nifedipine (0.03-3.8wM), dialtiazem (0.5-3.511M) or methoxyverapamil (0.3-1.3 ILM) antagonized in a non-surmountable fashion the contractile activity of neurotensin but not of acetylcholine. 3 Pretreatment with Bay K 8644 potentiated in a concentration-dependent fashion the contractile activity of rat fundus strips to neurotensin without modifying to any significant degree the acetylcholine-induced contractions. 4 Nifedipine blocked in a concentration-dependent manner the Bay K 8644-induced potentiation of the neurotensin contractile responses in the fundus. 5 Results demonstrate the dependence on external calcium of the contractile activity of neurotensin and the resistance of the muscarinic response to external calcium manipulations. The coupling of the neurotensin receptor to calcium channels is discussed.

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