Lecci A, Giuliani S, Tramontana M, Meini S, De Giorgio R, Maggi C A
Pharmacology Research Department A. Menarini Pharmaceuticals, Florence, Italy.
Naunyn Schmiedebergs Arch Pharmacol. 1996 May;353(6):671-9. doi: 10.1007/BF00167186.
In urethane-anaesthetized rats, moderate colonic distention (0.5 ml) induced reflex rhythmic contractions (5 mm Hg amplitude and 1.1 cycles/min frequency). Senktide (1-10 nmol/kg, i.v.), a tachykinin NK3 receptor selective agonist, transiently suppressed distension-induced contractions. SR 142,801 (1-10 mumol/kg i.v.), a non-peptide tachykinin NK3 receptor antagonist, had no effect on distension-induced contractions but prevented the inhibitory effect of senktide. Infusion of N-omega-nitro-1-arginine methyl esther hydrochloride (L-NAME, 20 mumol/ml/h, i.v) increased the amplitude of colonic contractions and decreased the inhibitory effect of senktide. Hexamethonium (15 mumol/ml/h, i.v.) or atropine (1 mumol/ml/h, i.v.) inhibited the distension-induced contractions. In hexamethonium- or atropine-treated rats, senktide (10 nmol/kg) transiently and selectively enhanced the amplitude of contractions. Also SR 142,801 (10 mumol/kg), but not its inactive enantiomer SR 142,806, increased both amplitude and frequency of contractions. During continuous infusion of L-NAME and hexamethonium or atropine both frequency and amplitude of distension-induced colonic contractions were higher than when in hexamethonium or atropine only. Senktide (10 nmol/kg) had no effect and SR 142,801 (10 mumol/kg) produced a slight enhancement of colonic contractions. Infusion of sodium nitroprusside (3 mumol/ml/h, i.v.) decreased amplitude and frequency of distension-induced contractions. SR 142,801 had no effect in the presence of the nitric oxide (NO) donor. We conclude that tachykinins acting through NK3 receptors exert at least four different actions on colonic motility activated by distension: 1) a hexamethonium-resistant, NO-dependent, suppressant effect on contractions; 2) a hexamethonium-sensitive, NO-independent inhibitory effect on the amplitude of contractions; 3) a hexamethonium-resistant, NO-independent inhibitory effect on the amplitude of contractions and 4) a hexamethonium resistant and L-NAME-sensitive excitatory effect on amplitude of contractions. The prevalent inhibitory effect evoked in normal conditions along with the excitatory activity induced by SR 142,801 on hexamethonium-resistant colonic motility indicates that tachykinins, acting through neuronal NK3 receptors, activate NO-dependent and NO-independent inhibitory neurotransmission in the rat colon.
在氨基甲酸乙酯麻醉的大鼠中，适度的结肠扩张（0.5毫升）可诱发反射性节律性收缩（幅度为5毫米汞柱，频率为1.1次/分钟）。速激肽NK3受体选择性激动剂森克肽（1 - 10纳摩尔/千克，静脉注射）可短暂抑制扩张诱导的收缩。非肽类速激肽NK3受体拮抗剂SR 142,801（1 - 10微摩尔/千克，静脉注射）对扩张诱导的收缩无影响，但可阻止森克肽的抑制作用。静脉注射N-ω-硝基-L-精氨酸甲酯盐酸盐（L-NAME，20微摩尔/毫升/小时）可增加结肠收缩的幅度，并降低森克肽的抑制作用。六甲铵（15微摩尔/毫升/小时，静脉注射）或阿托品（1微摩尔/毫升/小时，静脉注射）可抑制扩张诱导的收缩。在六甲铵或阿托品处理的大鼠中，森克肽（10纳摩尔/千克）可短暂且选择性地增强收缩幅度。同样，SR 142,801（10微摩尔/千克），而非其无活性对映体SR 142,806，可增加收缩的幅度和频率。在持续输注L-NAME以及六甲铵或阿托品的过程中，扩张诱导的结肠收缩的频率和幅度均高于仅使用六甲铵或阿托品时。森克肽（10纳摩尔/千克）无作用，而SR 142,801（10微摩尔/千克）可轻微增强结肠收缩。静脉注射硝普钠（3微摩尔/毫升/小时）可降低扩张诱导的收缩的幅度和频率。在一氧化氮（NO）供体存在的情况下，SR 142,801无作用。我们得出结论，通过NK3受体起作用的速激肽对扩张激活的结肠运动至少有四种不同作用：1）对收缩的六甲铵抗性、NO依赖性抑制作用；2）对收缩幅度的六甲铵敏感性、NO非依赖性抑制作用；3）对收缩幅度的六甲铵抗性、NO非依赖性抑制作用；4）对收缩幅度的六甲铵抗性和L-NAME敏感性兴奋作用。在正常情况下普遍存在的抑制作用以及SR 142,801对六甲铵抗性结肠运动诱导的兴奋活性表明，通过神经元NK3受体起作用的速激肽可激活大鼠结肠中NO依赖性和NO非依赖性抑制性神经传递。
