Download PDF
Horm Metab Res 2010; 42(4): 261-267
DOI: 10.1055/s-0029-1246190
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Increase of Plasma Insulin by Racecadotril, an Inhibitor of Enkephalinase, in Wistar Rats

H. T. Wu1 , 2 , C. K. Chang3 , K. C. Cheng4 , C. H. Chang5 , 6 , C. H. Yeh7 , J. T. Cheng2 , 6 , 7
  • 1Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
  • 2Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
  • 3Department of Surgery, Mackay Memorial Hospital, and Graduate Institute of Injury Prevention and Control, Taipei Medical University, Taipei City, Taiwan
  • 4Department of Psychosomatric Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima City, Japan
  • 5Department of Neurosurgery, Chi-Mei Medical Center, Yong Kang City, Tainan County, Taiwan
  • 6Department of Medical Research, Chi-Mei Medical Center, Yong Kang City, Tainan County, Taiwan
  • 7Institute of Medical Science, College of Health Science, Chang Jung Christian University, Guei-Ren, Tainan, Taiwan
Further Information

Publication History

received 09.11.2009

accepted 14.12.2009

Publication Date:
08 February 2010 (online)

Also available at
    Permissions and Reprints

Abstract

Racecadotril is known as an inhibitor of enkephalinase. Increase of plasma insulin by racecadotril has been observed in rats while the mechanism of the action remains obscure. In the present study, intravenous injection of male Wistar rats with racecadotril significantly decreased blood glucose levels. However, this effect of racecadotril was not modified by naloxone at the dose sufficient to block opioid receptors. Thus, the blood glucose-lowering action of racecadotril might be through an endogenous opioid independent mechanism. Otherwise, we found that C-peptide content was also raised by racecadotril in parallel with the increase of insulin in Wistar rats. Thus, the blood glucose-lowering action of racecadotril was related to insulin secretion, but not through the inhibition of plasma insulin degradation. In addition, racecadotril showed no direct effect on insulin secretion in isolated islets or cultured HIT-T15 β cells. The increase of plasma insulin and blood glucose-lowering action induced by racecadotril were reduced by pretreatment with atropine and enhanced by physotigmine. Direct inhibition of cholinesterase was not observed in brain homogenates treated with racecadotril. Moreover, actions of racecadotril were significantly reduced in rats receiving hemicholinium-3 at a sufficient dose to decrease endogenous acetylcholine. Activation of cholinergic tone is possibly involved in the blood glucose-lowering effect of racecadotril. Our results suggested that racecadotril increased insulin secretion to lower blood glucose mainly via regulation of parasympathetic tone in Wistar rats.

Key words

racecadotril - insulin release - C-peptide - HIT-T15 β-cells - cholinesterase - parasympathetic nerve

References

  • 1 Matheson AJ, Noble S. Racecadotril.  Drugs. 2000;  59 829-835 ; Discussion 36–37
    Google Scholar
  • 2 Xu F, Yang L, Xu G. A rapid and validated HPLC method to quantify racecadotril metabolite, thiorphan, in human plasma using solid-phase extraction.  J Chromatogr B Analyt Technol Biomed Life Sci. 2008;  861 130-135
    Google Scholar
  • 3 Xu Y, Huang J, Liu F, Gao S, Guo Q. Quantitative analysis of racecadotril metabolite in human plasma using a liquid chromatography/tandem mass spectrometry.  J Chromatogr B Analyt Technol Biomed Life Sci. 2007;  852 101-107
    Google Scholar
  • 4 Nagpal J, Gogia S. Racecadotril.  Indian Pediatr. 2004;  41 1218-1224
    Google Scholar
  • 5 Farthing MJ. Novel targets for the control of secretory diarrhoea.  Gut. 2002;  50 ((Suppl 3)) III15-18
    Google Scholar
  • 6 Baumer P, Danquechin Dorval E, Bertrand J, Vetel JM, Schwartz JC, Lecomte JM. Effects of acetorphan, an enkephalinase inhibitor, on experimental and acute diarrhoea.  Gut. 1992;  33 753-758
    Google Scholar
  • 7 Hinterleitner TA, Petritsch W, Dimsity G, Berard H, Lecomte JM, Krejs GJ. Acetorphan prevents cholera-toxin-induced water and electrolyte secretion in the human jejunum.  Eur J Gastroenterol Hepatol. 1997;  9 887-891
    Google Scholar
  • 8 Bergmann JF, Chaussade S, Couturier D, Baumer P, Schwartz JC, Lecomte JM. Effects of acetorphan, an antidiarrhoeal enkephalinase inhibitor, on oro-caecal and colonic transit times in healthy volunteers.  Aliment Pharmacol Ther. 1992;  6 305-313
    Google Scholar
  • 9 Duval-Iflah Y, Berard H, Baumer P, Guillaume P, Raibaud P, Joulin Y, Lecomte JM. Effects of racecadotril and loperamide on bacterial proliferation and on the central nervous system of the newborn gnotobiotic piglet.  Aliment Pharmacol Ther. 1999;  13 ((Suppl 6)) 9-14
    Google Scholar
  • 10 Turck D, Berard H, Fretault N, Lecomte JM. Comparison of racecadotril and loperamide in children with acute diarrhoea.  Aliment Pharmacol Ther. 1999;  13 ((Suppl 6)) 27-32
    Google Scholar
  • 11 Prado D. A multinational comparison of racecadotril and loperamide in the treatment of acute watery diarrhoea in adults.  Scand J Gastroenterol. 2002;  37 656-661
    Google Scholar
  • 12 Vetel JM, Berard H, Fretault N, Lecomte JM. Comparison of racecadotril and loperamide in adults with acute diarrhoea.  Aliment Pharmacol Ther. 1999;  13 ((Suppl 6)) 21-26
    Google Scholar
  • 13 Roge J, Baumer P, Berard H, Schwartz JC, Lecomte JM. The enkephalinase inhibitor, acetorphan, in acute diarhoea. A double-blind, controlled clinical trial versus loperamide.  Scand J Gastroenterol. 1993;  28 352-354
    Google Scholar
  • 14 Liu IM, Chi TC, Chen YC, Lu FH, Cheng JT. Activation of opioid mu-receptor by loperamide to lower plasma glucose in streptozotocin-induced diabetic rats.  Neurosci Lett. 1999;  265 183-186
    Google Scholar
  • 15 Tzeng TF, Lo CY, Cheng JT, Liu IM. Activation of mu-opioid receptors improves insulin sensitivity in obese Zucker rats.  Life Sci. 2007;  80 1508-1516
    Google Scholar
  • 16 Pasternak GW. Multiple morphine and enkephalin receptors: biochemical and pharmacological aspects.  Ann N Y Acad Sci. 1986;  467 130-139
    Google Scholar
  • 17 Evans AA, Tunnicliffe G, Knights P, Bailey CJ, Smith ME. Delta opioid receptors mediate glucose uptake in skeletal muscles of lean and obese-diabetic (ob/ob) mice.  Metabolism. 2001;  50 1402-1408
    Google Scholar
  • 18 Liu IM, Liou SS, Chen WC, Chen PF, Cheng JT. Signals in the activation of opioid mu-receptors by loperamide to enhance glucose uptake into cultured C2C12 cells.  Horm Metab Res. 2004;  36 210-214
    Google Scholar
  • 19 Rougeot C, Messaoudi M, Hermitte V, Rigault AG, Blisnick T, Dugave C, Desor D, Rougeon F. Sialorphin, a natural inhibitor of rat membrane-bound neutral endopeptidase that displays analgesic activity.  Proc Natl Acad Sci U S A. 2003;  100 8549-8554
    Google Scholar
  • 20 Chang CH, Tsao CW, Huang SY, Cheng JT. Activation of imidazoline I(2B) receptors by guanidine to increase glucose uptake in skeletal muscle of rats.  Neurosci Lett. 2009;  467 147-149
    Google Scholar
  • 21 Chien CS, Cheng SC, Wu HT, Tsao CW, Cheng JT. Insulin resistance induced by glucosamine in fructose-fed rats.  Horm Metab Res. 2009;  41 542-547
    Google Scholar
  • 22 Voss G, Sachsse K. Red cell and plasma cholinesterase activities in microsamples of human and animal blood determined simultaneously by a modified acetylthiocholine-DTNB procedure.  Toxicol Appl Pharmacol. 1970;  16 764-772
    Google Scholar
  • 23 Tzeng TF, Liu IM, Lai TY, Tsai CC, Chang WC, Cheng JT. Loperamide increases glucose ultilization in streptozotocin-induced diabetic rats.  Clin Exp Pharmacol Physiol. 2003;  30 734-738
    Google Scholar
  • 24 Cheng JT, Liu IM, Tzeng TF, Tsai CC, Lai TY. Plasma glucose-lowering effect of beta-endorphin in streptozotocin-induced diabetic rats.  Horm Metab Res. 2002;  34 570-576
    Google Scholar
  • 25 Holzer P. Opioid receptors in the gastrointestinal tract.  Regul Pept. 2009;  155 11-17
    Google Scholar
  • 26 Olson GA, Olson RD, Kastin AJ. Endogenous opiates: 1994.  Peptides. 1995;  16 1517-1555
    Google Scholar
  • 27 Yu BC, Chang CK, Su CF, Cheng JT. Mediation of beta-endorphin in andrographolide-induced plasma glucose-lowering action in type I diabetes-like animals.  Naunyn Schmiedebergs Arch Pharmacol. 2008;  377 529-540
    Google Scholar
  • 28 Ulger F, Bozkurt A, Bilge SS, Ilkaya F, Dilek A, Bostanci MO, Ciftcioglu E, Güldogus F. The antinociceptive effects of intravenous dexmedetomidine in colorectal distension-induced visceral pain in rats: the role of opioid receptors.  Anesth Analg. 2009;  109 616-622
    Google Scholar
  • 29 Lecomte JM, Costentin J, Vlaiculescu A, Chaillet P, Marcais-Collado H, Llorens-Cortes C, Leboyer M, Schwartz JC. Pharmacological properties of acetorphan, a parenterally active “enkephalinase” inhibitor.  J Pharmacol Exp Ther. 1986;  237 937-944
    Google Scholar
  • 30 Erdos EG, Skidgel RA. Neutral endopeptidase 24.11 (enkephalinase) and related regulators of peptide hormones.  FASEB J. 1989;  3 145-151
    Google Scholar
  • 31 Hou JC, Min L, Pessin JE. Insulin granule biogenesis, trafficking and exocytosis.  Vitam Horm. 2009;  80 473-506
    Google Scholar
  • 32 Gilon P, Henquin JC. Mechanisms and physiological significance of the cholinergic control of pancreatic beta-cell function.  Endocr Rev. 2001;  22 565-604
    Google Scholar
  • 33 Gautam D, Han SJ, Hamdan FF, Jeon J, Li B, Li JH, Cui Y, Mears D, Lu H, Deng C, Heard T, Wess J. A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo.  Cell Metab. 2006;  3 449-461
    Google Scholar
  • 34 Iismaa TP, Kerr EA, Wilson JR, Carpenter L, Sims N, Biden TJ. Quantitative and functional characterization of muscarinic receptor subtypes in insulin-secreting cell lines and rat pancreatic islets.  Diabetes. 2000;  49 392-398
    Google Scholar
  • 35 Liu KY, Wu YC, Liu IM, Yu WC, Cheng JT. Release of acetylcholine by syringin, an active principle of Eleutherococcus senticosus, to raise insulin secretion in Wistar rats.  Neurosci Lett. 2008;  434 195-199
    Google Scholar
  • 36 Aquilonius SM, Hartvig P. Clinical pharmacokinetics of cholinesterase inhibitors.  Clin Pharmacokinet. 1986;  11 236-249
    Google Scholar
  • 37 Anderson DC, King SC, Parsons SM. Pharmacological characterization of the acetylcholine transport system in purified Torpedo electric organ synaptic vesicles.  Mol Pharmacol. 1983;  24 48-54
    Google Scholar
  • 38 Zhao X. Effect of HC-3 on electroacupuncture-induced immunoregulation.  Zhen Ci Yan Jiu. 1995;  20 59-62
    Google Scholar
  • 39 Fischbach GD, Frank E, Jessell TM, Rubin LL, Schuetze SM. Accumulation of acetylcholine receptors and acetylcholinesterase at newly formed nerve-muscle synapses.  Pharmacol Rev. 1978;  30 411-428
    Google Scholar

Correspondence

J. T. Cheng

Department of Medical

Research Chi-Mei Medical Center

Yong Kang City

Tainan County

73101 Taiwan

Phone: +886/6/331 8516

Fax: +886/6/238 6548

Email: m980103@mail.chimei.org.tw

      >