Carini F, Lecci A, Tramontana M, Giuliani S, Maggi C A
Department of Pharmacology, Menarini Ricerche, via Rismondo 12/A, 50131 Florence, Italy.
Br J Pharmacol. 2001 Aug;133(7):1107-13. doi: 10.1038/sj.bjp.0704164.
In the gastrointestinal tract, tachykinin NK(2) receptors are localized both on smooth muscle and nerve fibres. NK(2) receptor antagonists reduce exaggerated intestinal motility in various diarrhoea models but the site of action contributing to this effect is unknown. In this study we investigated the effects of atropine (1.4 micromol kg(-1), i.v.), hexamethonium (13.5 micromol kg(-1), i.v.), and nepadutant (0.1 micromol kg(-1), i.v.), a selective tachykinin NK(2) receptor antagonist, on distension (0.5 and 1 ml)-, or irritation (acetic acid, 0.5 ml of 7.5% v v(-1))-induced motility in the rat distal colon in vivo. The effects of atropine, hexamethonium or N(omega)-nitro-L-argininemethylester (L-NAME, 1.85 micromol kg(-1), i.v.) on [betaAla(8)]NKA(4-10) (10 nmol kg(-1), i.v.)-induced colonic contractions were also investigated. When the colonic balloon was filled with a subthreshold volume (0.5 ml), the intraluminal instillation of acetic acid triggered a high-amplitude phasic colonic motility which was partially reduced by nepadutant and suppressed by either hexamethonium or atropine. Filling of the balloon with 1 ml evoked reflex (hexamethonium-sensitive), atropine-sensitive phasic colonic motility: nepadutant had no significant effect on the distension-evoked motility. Neither hexamethonium nor atropine significantly reduced [betaAla(8)]NKA(4-10)-induced colonic contractions, whereas nepadutant suppressed them. Following L-NAME pretreatment, [betaAla(8)]NKA(4-10)-induced colonic contractions were inhibited by both atropine and hexamethonium. In hexamethonium-pretreated animals, an atropine-sensitive component of [betaAla(8)]NKA(4-10)-induced colonic contractions was also evident. These results indicate that the application of irritants onto the colonic mucosa induces the release of endogenous tachykinins which enhance excitatory cholinergic mechanisms through the stimulation of NK(2) receptors.
在胃肠道中，速激肽NK(2)受体定位于平滑肌和神经纤维上。NK(2)受体拮抗剂可减轻多种腹泻模型中过度的肠道蠕动，但导致这种作用的作用部位尚不清楚。在本研究中，我们研究了阿托品（1.4微摩尔/千克，静脉注射）、六甲铵（13.5微摩尔/千克，静脉注射）和奈帕度坦（0.1微摩尔/千克，静脉注射），一种选择性速激肽NK(2)受体拮抗剂，对体内大鼠远端结肠由扩张（0.5毫升和1毫升）或刺激（乙酸，0.5毫升7.5%体积/体积）诱导的蠕动的影响。还研究了阿托品、六甲铵或N(ω)-硝基-L-精氨酸甲酯（L-NAME，1.85微摩尔/千克，静脉注射）对[β丙氨酸(8)]NKA(4-10)（10纳摩尔/千克，静脉注射）诱导的结肠收缩的影响。当结肠球囊填充亚阈值体积（0.5毫升）时，腔内滴注乙酸会引发高振幅的阶段性结肠蠕动，奈帕度坦可部分减轻这种蠕动，六甲铵或阿托品可抑制这种蠕动。用1毫升填充球囊会诱发反射性（六甲铵敏感）、阿托品敏感的阶段性结肠蠕动：奈帕度坦对扩张诱发的蠕动没有显著影响。六甲铵和阿托品均未显著降低[β丙氨酸(8)]NKA(4-10)诱导的结肠收缩，而奈帕度坦可抑制它们。L-NAME预处理后，[β丙氨酸(8)]NKA(4-10)诱导的结肠收缩被阿托品和六甲铵均抑制。在六甲铵预处理的动物中，[β丙氨酸(8)]NKA(4-10)诱导的结肠收缩的阿托品敏感成分也很明显。这些结果表明，将刺激物应用于结肠黏膜会诱导内源性速激肽的释放，这些速激肽通过刺激NK(2)受体增强兴奋性胆碱能机制。
