Effects of Ninjin-to on Levels of Calcitonin Gene-Related Peptide and Substance P in Human Plasma

Abstract

Postoperative ileus following laparotomy is a common complication after abdominal surgery and involves an inhibition of bowel transit caused by an impairment of motility. For postoperative ileus, some herbal medicines with experiential gastrointestinal effects have been elucidated pharmacologically. One of them, Dai-kenchu-to, is known to increase gastrointestinal motility and improve ileal function.1) It is thought that the part of the contractile mechanism is mediated by acetylcholine (ACh) release from the ends of cholinergic nerves.2,3) Furthermore, these effects are reported to cause significant increases in the levels of brain-gut peptides such as motilin 4) and vasoactive intestinal peptide (VIP) 5) in human plasma.Ninjin-to is prepared from four crude drugs: Ginseng radix, Glycyrrhizae radix, Atractylodis rhizome, and Zingiberis siccatum rhizoma. This medicine has been used for the treatment of gastroenteritis, esogastritis, gastric atony, gastrectasis, vomiting, and anorexia. Ninjin-to is also reported to enhance gastrointestinal motility, similar to the gastrointestinal prokinetic drugs like cisapride and metoclopramide.6) Moreover, previous study has shown that Ninjin-to not only significantly improved gastrointestinal motility but also showed stronger effects than those of Dai-kenchu-to in a rat model of postoperative ileus. 7) Hence, as well as Daikenchu-to, Ninjin-to may be an effective herbal medicine for postoperative ileus. Naito et al. previously confirmed that Ninjin-to increased the levels of motilin, a powerful inducer of gastrointestinal motor activity and somatostatin, and that it participates in the control of gut motility by exerting both inhibitory and stimulating influences in human plasma.8) These results indicate that the action of Ninjin-to is closely related to changes in motilin and somatostatin levels in plasma.Sensory afferent neurons in the gastrointestinal mucosa regulate neuropeptide [calcitonin gene-related peptide (CGRP) and tachykinins (substance P)] levels and play various physiologic roles. CGRP has several potent biological activities, including vasodilation. It is the most powerful vasoactive substance known and it increases mucosal blood flow.9,10) CGRP is known to coexist with tachykinins in the population of sensory neurons in humans.11) Substance P is widely distributed in the central and peripheral nervous system and in the enteroendocrine cells of the gut 12) and it participates in the regulation of gastrointestinal motility, secretion, and blood flow. 13)At present, the underlying mechanisms of Ninjin-to have not been demonstrated. To determine whether the pharmacologic effects of Ninjin-to on the gastrointestine are due to changes in gastrointestinal mucosa regulatory peptide levels, we examined the temporal effects of Ninjin-to on CGRP-like immunoreactive substances (IS) and substance P-IS levels in plasma as measured by a sensitive enzyme immunoassay (EIA) in healthy subjects. MATERIALS AND METHODSMaterials Ninjin-to (EK-32, lot 01BJ), prepared as a 3.0-g dri...

Comparison of the Effects of Pantethine and Fursultiamine on Plasma Gastrointestinal Peptide Levels in Healthy Volunteers

“…[6][7][8] The traditional herbal medicines Dai-kenchu-to and Ninjin-to, which are used to treat postoperative ileus, have been reported to raise plasma levels of CGRP and SP in humans. 13,14) In this study, we examined the effects of pantethine and fursultiamine on CGRP, VIP, motilin and SP, which are peptides that regulate gastrointestinal motility.…”

“…Synthetic human CGRP and its fragment , VIP, motilin and SP were purchased from Peptide Institute, Inc. (Osaka, Japan). VIP fragment (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) was supplied by Professor H. Yajima (Kyoto University, Kyoto, Japan). Antiserum to CGRP (14160) was purchased from Peptide Institute, Inc. (Osaka, Japan), VIP (T-4116) from Peninsula Laboratories (California, U.S.A.), and motilin (Y121) and SP (Y150) from Yanaihara Institute (Shizuoka, Japan).…”

“…All subjects had no history of gastrointestinal disease and their baseline fasting plasma levels of CGRP-, VIP-, motilin-and SP-IS were within the normal ranges for healthy subjects reported previously. [6][7][8]13,14) The study was approved by the Ethics Committee of Oita Medical University. Each subject received information about the scientific purpose of the study, and gave informed consent.…”

“…An anti-rabbit IgG-(55641, ICN Pharmaceuticals, Inc., Ohio, U.S.A.) coated immunoplate (Nunc-Immuno Module Maxisorp F8, InterMed, Denmark) was used to separate bound and free antigens. Human CGRP fragment (8-37), VIP fragment (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28), motilin and SP were conjugated with b-galactosidase by N-(emaleimido-caproyloxy)-succimide according to the methods of Kitagawa et al 19) The enzyme immunoassays for CGRP-, VIP-, motilin-and SP-IS were specific and highly sensitive, with detection limits of 4.0, 8.0, 0.25 and 0.25 pg/ml, respectively.…”

“…Dai-kenchu-to and Ninjin-to, the traditional herbal medicines used to treat postoperative ileus, have been shown to raise CGRP and SP levels in human plasma. 13,14) The effects of pantethine and fursultiamine on plasma gastrointestinal peptide levels in humans have not been demonstrated. Therefore, we examined the effects of these two compounds on plasma levels of CGRP-, VIP-, motilin-and SP-like immunoreactive substances (IS) in healthy subjects.…”