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INFLUENCE OF CONTINUOUS FASTING ON RAT COLONIC MOTILITY AND EFFECTS OF PROKINETIC AGENTS, HYDROXY-α-SANSHOOL, AN ACTIVE COMPONENT OF DAIKENCHUTO (TU-100) AND BETHANECHOL: IMPLICATIONS FOR POSTOPERATIVE DIET PROGRESSION.
Kunitsugu Kubota*1, Hiroaki Matsushima1, Akihito Mase1, Masahiro Yamamoto1, Yuji Morine2, Mitsuo Shimada2, Yasuhito Uezono3,4, Toru Kono5,6
1Tsumura Kampo Research Laboratories, Tsumura & Co., Ibaraki, Japan; 2Department of Digestive and Pediatric Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan; 3Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan; 4Division of Supportive Care Research, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Tokyo, Japan; 5Department of Gastroenterological Surgery I, Hokkaido University Graduate School, Hokkaido, Japan; 6Center for Clinical and Biomedical Research, Sapporo Higashi Tokushukai Hospital, Hokkaido, Japan
Background and Aim:
Perioperative fasting is known to delay postoperative recovery. Gastrointestinal motility disorders, such as prolonged ileus, after surgery interfere with nutritional management, which is a critical problem in patients undergoing surgery. The Kampo medicine daikenchuto (TU-100), which is being investigated as a new drug in the US and is widely used for the treatment of paralytic ileus in Japan, has been reported to significantly accelerate ascending colonic draining in healthy humans in a double-blind placebo-controlled study*. Hydroxy-α-sanshool (HAS), a major active ingredient of TU-100, induces a potent rhythmic propulsive movement that causes migration of intracolonic contents. This is classified as a "long distance contraction (LDC)," in the rat proximal colon by blocking KCNK9 channels. In the present study, we investigated the motility pattern changes in rat proximal colons by continuous fasting and studied the influence of treatment with HAS and the muscarinic receptor agonist bethanechol (Beth), a conventional prokinetic.
Methods:
Segments of rat proximal colons in rats fed or fasted for four days were isolated and placed in an organ bath containing aerated Kreb's solution. HAS (10 µM) and Beth (10 µM) were applied on the serosal side of isolated rat proximal colons. Motility was evaluated by measuring the intraluminal pressure, video imaging, and spatiotemporal maps of motility.
Results:
Isolated proximal colon in fed rats exhibited "mixing" movement including retrograde ripple, also called as a "rhythmic propagating ripple (RPR)". However, in fasted rats, the propagative movement from oral side to anal side of proximal colon was the only movement shown as RPR. The frequency of RPR in fasted rats was significantly decreased compared with fed rats. Spontaneous LDCs were not observed in both rats' segments. Beth evoked LDC of 1-2 counts per 20 min in fed rats. The frequency of Beth-induced LDC in fasted rats revealed significant increase than that in fed rats, but the duration of LDC was shortened. In contrast, HAS evoked a periodic LDC of approximately 10 counts per 20 min in fed rats. In fasted rats, the frequency of LDC induced by HAS treatment showed slight decrease compared with that of fed rats. In addition, the shorter duration and variation of LDC were observed in fasted rats by HAS treatment.
Discussion:
Continuous fasting decreased and simplified RPR in proximal colon of rats. This may be related to the absence of intraluminal contents. HAS or Beth treatment evoked LDC movement, but the former was more efficient in fed rats and the latter was good in fasted rats. This confirmed the effects of prokinetic agents may be modified by postoperative oral diet commencement. Further, more efficient prokinetic strategy in postoperative diet progression is desirable.
* Am J Physiol Gastrointest Liver Physiol 298: G970, 2010.
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