Colonic Vascular Conductance Increased by Daikenchuto via Calcitonin Gene-Related Peptide and Receptor-Activity Modifying Protein 1
Colonic Vascular Conductance Increased by Daikenchuto via Calcitonin Gene-Related Peptide and Receptor-Activity Modifying Protein 1
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DOI：
10.1016/j.jss.2008.02.057
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发表时间：
2008-11-01
影响因子：
2.2
通讯作者：
Kasai, Shinichi
中科院分区：
文献类型：
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作者：
Kono, Toru;Koseki, Takashi;Kasai, Shinichi
背景Daikencyuto（DKT）是一种传统的日本药物（Kampo），是由干日本胡椒、加工过的生姜、人参和麦芽糖粉的提取物粉末混合而成，已被用于治疗麻痹性肠梗阻。DKT可能通过上调降钙素基因相关肽（CGRP）增加胃肠动力。CGRP也是最强的血管活性物质。在本研究中，我们研究了DKT是否对大鼠结肠血流量有任何影响。实验在禁食麻醉和人工通气的Wistar大鼠上进行。记录全身平均动脉血压和心率。采用非接触式激光组织血流仪测量结肠血流中的红细胞流量，并计算结肠血管传导性（CVC），即流量与平均动脉血压的比值。我们研究了使用阻滞剂药物引起反应的四种关键生理机制：CGRP 1受体阻滞剂（CGRP（8-37））、一氧化氮合酶抑制剂、血管活性肠多肽（VIP）受体阻滞剂（[4-Cl-DPhe 6，Leu 17]-VIP）和P物质受体阻滞剂（Spantide）。采用逆转录-聚合酶链反应（RT-PCR）检测降钙素受体样受体、受体活性修饰蛋白1、降钙素基因相关肽1受体组分和降钙素基因相关肽（CGRP）的mRNA。剖腹手术后，将套管插入近端结肠以施用DKT并测量远端结肠的CVC。DKT的结肠内给药（10、100和300 mg/kg）增加CVC（基础CVC，0.10 mL/mmHg）（分别为0.14、0.17和0.17 mL/mmHg），并且在45 min或（10 mg/kg时为0.17 mL/mmHg）或75和60 min（100和300 mg/kg时分别为0.23和0.21 mL/mmHg）。CGRP（8-37）可完全消除DKT引起的充血，而一氧化氮合酶抑制剂可部分减轻DKT引起的充血。[4-Cl-DPhe 6，Leu 17]-VIP和Spantide对充血无影响。日本胡椒在45 min或更晚时显著增加CVC，而人参仅在15 min时显示出显著增加。逆转录聚合酶链反应显示降钙素受体样受体、受体活性修饰蛋白1和CGRP的mRNA在大鼠结肠中表达，并被DKT上调。本研究表明，DKT增加CVC，这主要是由CGRP及其受体成分介导的。(c)2008年爱思唯尔公司All rights reserved.
Background. Daikencyuto (DKT) is a traditional Japanese medicine (Kampo) and is a mixture of extract powders from dried Japanese pepper, processed ginger, ginseng radix, and maltose powder and has been used as the treatment of paralytic ileus. DKT may increase gastrointestinal motility by an up-regulation of the calcitonin gene-related peptide (CGRP). CGRP is also the most powerful vasoactive substance. In the present study, we investigated whether DKT has any effect on the colonic blood flow in rats.Materials and methods. Experiments were performed on fasted anesthetized and artificially ventilated Wistar rats. Systemic mean arterial blood pressure and heart rate were recorded. Red blood cell flux in colonic blood flow was measured using noncontact laser tissue blood flowmetry, and colonic vascular conductance (CVC) was calculated as the ratio of flux to mean arterial blood pressure. We examined four key physiological mechanisms underlying the response using blocker drugs: CGRP1 receptor blocker (CGRP(8-37)), nitric oxide synthase inhibitor, vasoactive intestinal polypeptide (VIP) receptor blocker ([4-Cl-DPhe6, Leu17]-VIP), and substance P receptor blocker (spantide). Reverse transcription-polymerase chain reaction was used for the detection of mRNA of calcitonin receptor-like receptor, receptor-activity modifying protein 1, the component of CGRP 1 receptor and CGRP. After laparotomy, a cannula was inserted into the proximal colon to administer the DKT and to measure CVC at the distal colon.Results. Intracolonal administration of DKT (10, 100, and 300 mg/kg) increased CVC (basal CVC, 0.10 mL/mmHg) from the first 15-min observation period (0.14, 0.17, and 0.17 mL/mmHg, respectively) and with peak response at either 45 min (0.17 mL/mmHg by 10 mg/kg), or 75 and 60 min (0.23 and 0.21 mL/mmHg by 100 and 300 mg/kg, respectively). CGRP(8-37) completely abolished the DKT-induced hyperemia, whereas nitric oxide synthase inhibitor partially attenuated the DKT-induced hyperemia. [4-Cl-DPhe6, Leu17]-VIP and spantide did not affect the hyperemia. Japanese pepper significantly increased CVC at 45 min or later, whereas ginseng radix only showed a significant increase at 15 min. Reverse transcription-polymerase chain reaction showed that mRNA for calcitonin receptor-like receptor, receptor-activity modifying protein 1, and CGRP were expressed in rat colon and up-regulated by DKT.Conclusions. The present study demonstrated that DKT increased CVC, which was mainly mediated by CGRP and its receptor components. (c) 2008 Elsevier Inc. All rights reserved.