Department of Pharmacology, Menarini Ricerche S.p.A., Florence, Italy.
Neuropeptides. 2010 Jun;44(3):269-72. doi: 10.1016/j.npep.2010.01.002.
The effect of tachykinin neurokinin NK(2) receptors activation on intestinal propulsion and colorectal sensitivity was studied in 7-15 days old newborn rats. In a first set of experiments investigating the intestinal transit, the selective NK(2) receptor agonist, [betaAla(8)]NKA-(4-10) was used. It produced an increase of the small intestinal transit measured by charcoal test of 54%, that was inhibited in a dose-dependent manner by nepadutant ([N(4)-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-L-asparaginyl-L-aspartyl-L-tryptophyl-L-phenylalanyl-L-2,3-diaminopropionyl-L-leucyl]-C-4.2-N-3.5-lactam-C-1.6-N-2.1-lactam), a known selective NK(2) receptor antagonist, orally administered 2-48 h before the challenge with the NK(2) receptor agonist. Nepadutant did not affect the basal intestinal propulsion and showed a good oral bioavailability and long duration of action. In another set of experiments investigating visceral sensitivity, a fixed distension volume of a balloon inserted intrarectally in 14-15 days old newborns rats produced abdominal contractions (AC) that were increased after colonic application of acetic acid (50 microl, 0.5%). In this latter condition nepadutant, at 0.5 and 2.5 mg/kg p.o., significantly reduced the resulting AC. In control rats, untreated with acetic acid, nepadutant did not affect AC evoked by colorectal distension. These findings show for the first time two models to assess intestinal motility and visceral sensitivity in newborn rats and indicate nepadutant as a valuable tool to assess the role of NK(2) receptors in the intestinal propulsive and nociceptive activity in infants.
研究了速激肽神经激肽 NK(2)受体激活对 7-15 日龄新生大鼠肠道推进和结直肠敏感性的影响。在研究肠道转运的第一组实验中，使用了选择性 NK(2)受体激动剂[βAla(8)]NKA-(4-10)。它使炭测试测量的小肠转运增加了 54%，这种增加呈剂量依赖性被 nepadutant([N(4)-(2-乙酰氨基-2-脱氧-β-D-吡喃葡萄糖基)-L-天冬酰胺基-L-天冬酰基-L-色氨酰-L-苯丙氨酰-L-2,3-二氨基丙酰基-L-亮氨酰]-C-4.2-N-3.5-内酰胺-C-1.6-N-2.1-内酰胺)，一种已知的选择性 NK(2)受体拮抗剂，口服给予 NK(2)受体激动剂前 2-48 小时，抑制。Nepadutant 不影响基础肠道推进，具有良好的口服生物利用度和较长的作用持续时间。在另一组研究内脏敏感性的实验中，将一个气球插入 14-15 日龄新生大鼠的直肠内，使其膨胀到一个固定的体积，产生腹部收缩(AC)，然后在结肠应用乙酸(50 微升，0.5%)后增加。在后一种情况下，nepadutant 以 0.5 和 2.5 mg/kg 口服给药，显著减少了由此产生的 AC。在未用乙酸处理的对照大鼠中，nepadutant 不影响结直肠膨胀引起的 AC。这些发现首次证明了两种评估新生大鼠肠道运动和内脏敏感性的模型，并表明 nepadutant 是评估 NK(2)受体在婴儿肠道推进和伤害性活动中的作用的有价值工具。
