Browsing by Author "KULLAK, A"

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    EXCITATORY NEUROTENSIN RECEPTORS ON THE SMOOTH-MUSCLE OF THE RAT FUNDUS - POSSIBLE IMPLICATIONS IN GASTRIC-MOTILITY
    (1985) HUIDOBROTORO, JP; KULLAK, A
    Picomolar concentrations of neurotensin caused concentration-dependent contractions of the longitudinal musculature of the fundus of the rat stomach. The EC50 [concentration giving 50% effectiveness] of neurotensin was .apprx. 1.5 nM. On a molar basis neurotensin was about 5-10 times more potent than 5-hydroxytryptamine (5-HT) and .apprx. 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, its 1-8 or 1-11 fragments were completely inactive. Tetrodotoxin did not modify the potency of neurotensin or structurally related analogs 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; densensitization 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 (.apprx. EC50) caused a substantial blockade of its excitability. There was cross-densensitization between neurotensin and the contractile activity of neurotensin 8-13 or xenopsin, but not with angiotensin II, bradykinin, substance P, acethylcholine, 5-HT or histamine. Pretreatment of the fundus strip with verapamil 0.3-1 .mu.M antagonized in a concentration-dependent fashion the neurotensin-induced contractions but not the muscular contractions caused by acetylcholine. Neurotensin activates a specific excitatory receptor probably located on the cell membrane of the smooth muscles of the rat fundus. This receptor is somehow related to a voltage-dependent Ca channel, sensitive to verapamil.
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    EXTRACELLULAR CALCIUM DEPENDENCE OF THE NEUROTENSIN-INDUCED RELAXATION OF INTESTINAL SMOOTH MUSCLES - STUDIES WITH CALCIUM-CHANNEL BLOCKERS AND BAY K-8644
    (1987) KULLAK, A; DONOSO, MV; HUIDOBROTORO, JP
    To investigate whether the neurotensin-induced relaxation of the rat duodenum and ileum is dependent on the external concentration of calcium, the effect of the neuropeptide was studied in isolated intestinal segments superfused with Tyrode solution containing no calcium, 1 or 2.5 mM Ca2+. The neurotensin-induced intestinal relaxation was reduced when the extracellular calcium concentration was lowered. In addition, the inhibitory effect of neurotensin was cancelled when the tissues were incubated in the presence of diltiazem, methoxyverapamil or nifedipine. BAY K-8644, a structural analog of nifedipine that functions as an agonist of the calcium channel, potentiated the neurotensin-induced smooth muscle relaxation. The facilitatory effect of BAY K-8644 was antagonized by nifedipine, indicating competition between the 2 dihydropyridines. Apamin, the K+ channel blocker, antagonized the neurotensin-induced visceral relaxation, displacing the concentration-response curve of the peptide to the right. Furthermore, apamin also blocked the effect of neurotensin when the neuropeptide was assayed in the presence of BAY K-8644. It is concluded that the smooth muscle relaxation induced by neurotensin is dependent on external calcium, suggesting that the activation of the neuropeptide receptor causes an influx of calcium which leads to the opening of K+ channels before smooth muscle relaxation is triggered.
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    INVOLVEMENT OF CALCIUM CHANNELS IN THE CONTRACTILE ACTIVITY OF NEUROTENSIN BUT NOT ACETYLCHOLINE - STUDIES WITH CALCIUM-CHANNEL BLOCKERS AND BAY-K8644 ON THE RAT FUNDUS
    (1986) DONOSO, MV; HUIDOBROTORO, JP; KULLAK, A
    The contractile activity of neurotensin and acetylcholine on rat isolated fundus strips was examined in preparations maintained on 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 for at fundus strips with nifedipine (0.03-3.8 .mu.M), diltiazem (0.5-3.5 .mu.M) or methoxyverapamil (0.3-1.3 .mu.M) 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 by 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.