Excitatory neurotensin receptors on the smooth muscle of the rat fundus: possible implications in gastric motility.
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. 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. 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. 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 concentration-response curve to the right and downwards. Desensitization with a priming concentration of neurotensin (approx. EC50) caused a substantial blockade of its excitability. 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. Pretreatment of the fundus strip with verapamil 0.3-1 microM antagonized in a concentration-dependent fashion the neurotensin-induced contractions but not the muscular contractions caused by acetylcholine. 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.
Huidobro-Toro
J P
JP
Kullak
A
A
D000818:Animals; D001030:Apamin / Q000494:pharmacology; D005748:Gastric Fundus / Q000187:drug effects / Q000502:physiology*; D005769:Gastrointestinal Motility; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009496:Neurotensin / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D018028:Receptors, Neurotensin; D017981:Receptors, Neurotransmitter / Q000502:physiology*; D013329:Structure-Activity Relationship; D013779:Tetrodotoxin / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D018028:Receptors, Neurotensin; D017981:Receptors, Neurotransmitter; D001030:Apamin; D009496:Neurotensin; D013779:Tetrodotoxin; D014700:Verapamil