Skip to main content
NCBI home page
Gut logoLink to Gut
. 2000 Sep;47(3):382–386. doi: 10.1136/gut.47.3.382

Effect of vasoactive intestinal polypeptide (VIP) antagonism on rat jejunal fluid and electrolyte secretion induced by cholera and Escherichia coli enterotoxins

F Mourad 1, C Nassar 1
PMCID: PMC1728044  PMID: 10940276

Abstract

BACKGROUND—The enteric nervous system is important in the pathophysiology of intestinal fluid secretion induced by cholera toxin (CT), Escherichia coli heat labile (LT), and heat stable (STa) toxins. The neurotransmitters involved are not fully elucidated. Vasoactive intestinal polypeptide (VIP), a potent intestinal secretagogue present in the enteric nervous system, is increased after exposure of the cat intestine to CT. Whether VIP is involved in the pathogenesis of cholera and other toxins in not known.
AIM—To study in vivo the effect of VIP antagonism on jejunal fluid secretion induced by CT, LT, and STa.
METHODS—CT, LT (25 µg), or 0.9% NaCl was instilled in an isolated 25 cm segment of rat jejunum, and the VIP antagonist (VIPa) [4Cl-D-Phe6, Leu17]-VIP (0.2 or 2 µg/kg/min) or 0.9% NaCl was given intravenously. Two hours later, single pass in vivo jejunal perfusion was performed to assess fluid movement. In STa experiments, intravenous VIPa or 0.9% NaCl was given and 30 minutes later the jejunal segment was perfused with a solution containing STa 200 µg/l.
RESULTS—VIPa had no effect on basal intestinal fluid absorption. CT induced net fluid secretion (median −68 µl/min/g dry intestinal weight (interquartile range −80 to −56)) which was dose dependently reversed by VIPa (6.2 (−16 to 34) and 29 (17 to 42); p<0.01). Similarly, LT induced secretion (−63 (−73 to −30)) was attenuated by VIPa (0.2 µg/kg/min) (−15 (−24 to −1); p<0.01) and totally reversed to normal levels by VIPa (2 µg/kg/min) (37 (28-56); p<0.01 compared with LT and not significant compared with normal controls). STa induced secretion (−17 (−19 to −2)) was also reversed by VIPa (12 (9-23) and 14 (0-26); p<0.01).
CONCLUSION—VIP plays an important role in CT, LT, and STa induced intestinal secretion and may be the final putative neurotransmitter in the pathophysiology of these toxins.


Keywords: cholera toxin; Escherichia coli toxins; intestinal secretion; vasoactive intestinal polypeptide; enteric nervous system

Full Text

The Full Text of this article is available as a PDF (133.0 KB).

Figure 1  .

Figure 1  

Open in a new tab

Effect of the VIP antagonist [4Cl-D-Phe6, Leu17 ]VIP given intravenously at a dose of 0.2 and 2 µg/kg/min (VIPa0.2 and VIPa2, respectively) on cholera toxin (CT) induced secretion. Results are expressed as median (interquartile range); positive values denote absorption and negative values denote secretion. **p<0.01 compared with controls; ††p<0.01 compared with CT and controls.

Figure 2  .

Figure 2  

Open in a new tab

Effect of the VIP antagonist [4Cl-D-Phe6, Leu17 ]VIP given intravenously at a dose of 0.2 and 2 µg/kg/min (VIPa0.2 and VIPa2, respectively) on Escherichia coli heat labile toxin (LT) induced secretion. Results are expressed as median (interquartile range); positive values denote absorption and negative values denote secretion. **p<0.01 compared with controls; ††p<0.01 compared with LT and controls; ‡‡p<0.01 compared with LT and p>0.05 compared with controls.

Figure 3  .

Figure 3  

Open in a new tab

Effect of the VIP antagonist [4Cl-D-Phe6, Leu17 ]VIP given intravenously at a dose of 0.2 and 2 µg/kg/min (VIPa0.2 and VIPa2, respectively) on Escherichia coli heat stable toxin (STa) induced secretion. Results are expressed as median (interquartile range); positive values denote absorption and negative values denote secretion. **p<0.01 compared with controls; ††p<0.01 compared with STa and controls; ‡p<0.05 compared with STa and p<0.01 compared with controls.

Figure 4  .

Figure 4  

Open in a new tab

Effect of the VIP antagonist [4Cl-D-Phe6, Leu17 ]VIP given intravenously at a dose of 0.2 and 2 µg/kg/min (VIPa0.2 and VIPa2, respectively) on VIP induced decrease in fluid absorption at 0.02 and 0.2 µg/kg/min given intravenously. Results are expressed as median (interquartile range). *p<0.05, ***p>0.05 and **p<0.01 compared with controls; †p<0.05 compared with VIP0.2 and controls

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aimi Y., Kimura H., Kinoshita T., Minami Y., Fujimura M., Vincent S. R. Histochemical localization of nitric oxide synthase in rat enteric nervous system. Neuroscience. 1993 Mar;53(2):553–560. doi: 10.1016/0306-4522(93)90220-a. [DOI] [PubMed] [Google Scholar]
  2. Allescher H. D., Kurjak M., Huber A., Trudrung P., Schusdziarra V. Regulation of VIP release from rat enteric nerve terminals: evidence for a stimulatory effect of NO. Am J Physiol. 1996 Oct;271(4 Pt 1):G568–G574. doi: 10.1152/ajpgi.1996.271.4.G568. [DOI] [PubMed] [Google Scholar]
  3. Beubler E., Horina G. 5-HT2 and 5-HT3 receptor subtypes mediate cholera toxin-induced intestinal fluid secretion in the rat. Gastroenterology. 1990 Jul;99(1):83–89. doi: 10.1016/0016-5085(90)91233-v. [DOI] [PubMed] [Google Scholar]
  4. Beubler E., Kollar G., Saria A., Bukhave K., Rask-Madsen J. Involvement of 5-hydroxytryptamine, prostaglandin E2, and cyclic adenosine monophosphate in cholera toxin-induced fluid secretion in the small intestine of the rat in vivo. Gastroenterology. 1989 Feb;96(2 Pt 1):368–376. doi: 10.1016/0016-5085(89)91560-6. [DOI] [PubMed] [Google Scholar]
  5. Burleigh D. E., Kirkham S. E. Lack of effect of three putative vasoactive intestinal peptide receptor antagonists on vasoactive intestinal peptide-induced secretory responses in rat colon. Eur J Pharmacol. 1993 Nov 9;249(2):239–242. doi: 10.1016/0014-2999(93)90439-o. [DOI] [PubMed] [Google Scholar]
  6. Cassuto J., Fahrenkrug J., Jodal M., Tuttle R., Lundgren O. Release of vasoactive intestinal polypeptide from the cat small intestine exposed to cholera toxin. Gut. 1981 Nov;22(11):958–963. doi: 10.1136/gut.22.11.958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cassuto J., Jodal M., Tuttle R., Lundgren O. On the role of intramural nerves in the pathogenesis of cholera toxin-induced intestinal secretion. Scand J Gastroenterol. 1981 Apr;16(3):377–384. doi: 10.3109/00365528109181984. [DOI] [PubMed] [Google Scholar]
  8. Castagliuolo I., LaMont J. T., Letourneau R., Kelly C., O'Keane J. C., Jaffer A., Theoharides T. C., Pothoulakis C. Neuronal involvement in the intestinal effects of Clostridium difficile toxin A and Vibrio cholerae enterotoxin in rat ileum. Gastroenterology. 1994 Sep;107(3):657–665. doi: 10.1016/0016-5085(94)90112-0. [DOI] [PubMed] [Google Scholar]
  9. Christophe J., Svoboda M., Lambert M., Waelbroeck M., Winand J., Dehaye J. P., Vandermeers-Piret M. C., Vandermeers A., Robberecht P. Effector mechanisms of peptides of the VIP family. Peptides. 1986;7 (Suppl 1):101–107. doi: 10.1016/0196-9781(86)90171-3. [DOI] [PubMed] [Google Scholar]
  10. Clements J. D., Finkelstein R. A. Isolation and characterization of homogeneous heat-labile enterotoxins with high specific activity from Escherichia coli cultures. Infect Immun. 1979 Jun;24(3):760–769. doi: 10.1128/iai.24.3.760-769.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cox H. M., Cuthbert A. W. Secretory actions of vasoactive intestinal polypeptide, peptide histidine isoleucine and helodermin in rat small intestine: the effects of putative VIP antagonists upon VIP-induced ion secretion. Regul Pept. 1989 Sep-Oct;26(2):127–135. doi: 10.1016/0167-0115(89)90004-9. [DOI] [PubMed] [Google Scholar]
  12. Eklund S., Jodal M., Lundgren O., Sjöqvist A. Effects of vasoactive intestinal polypeptide on blood flow, motility and fluid transport in the gastrointestinal tract of the cat. Acta Physiol Scand. 1979 Apr;105(4):461–468. doi: 10.1111/j.1748-1716.1979.tb00111.x. [DOI] [PubMed] [Google Scholar]
  13. Eklund S., Jodal M., Lundgren O. The enteric nervous system participates in the secretory response to the heat stable enterotoxins of Escherichia coli in rats and cats. Neuroscience. 1985 Feb;14(2):673–681. doi: 10.1016/0306-4522(85)90318-5. [DOI] [PubMed] [Google Scholar]
  14. Eklund S., Karlström L., Rökaeus A., Theodorsson E., Jodal M., Lundgren O. Effects of cholera toxin, Escherichia coli heat stable toxin and sodium deoxycholate on neurotensin release from the ileum in vivo. Regul Pept. 1989 Dec;26(3):241–252. doi: 10.1016/0167-0115(89)90192-4. [DOI] [PubMed] [Google Scholar]
  15. Eklund S., Sjöqvist A., Fahrenkrug J., Jodal M., Lundgren O. Somatostatin and methionine-enkephalin inhibit cholera toxin-induced jejunal net fluid secretion and release of vasoactive intestinal polypeptide in the cat in vivo. Acta Physiol Scand. 1988 Aug;133(4):551–557. doi: 10.1111/j.1748-1716.1988.tb08440.x. [DOI] [PubMed] [Google Scholar]
  16. Field M., Graf L. H., Jr, Laird W. J., Smith P. L. Heat-stable enterotoxin of Escherichia coli: in vitro effects on guanylate cyclase activity, cyclic GMP concentration, and ion transport in small intestine. Proc Natl Acad Sci U S A. 1978 Jun;75(6):2800–2804. doi: 10.1073/pnas.75.6.2800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Field M. Modes of action of enterotoxins from Vibrio cholerae and EScherichia coli. Rev Infect Dis. 1979 Nov-Dec;1(6):918–926. doi: 10.1093/clinids/1.6.918. [DOI] [PubMed] [Google Scholar]
  18. Giannella R. A. Suckling mouse model for detection of heat-stable Escherichia coli enterotoxin: characteristics of the model. Infect Immun. 1976 Jul;14(1):95–99. doi: 10.1128/iai.14.1.95-99.1976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Goyal R. K., Hirano I. The enteric nervous system. N Engl J Med. 1996 Apr 25;334(17):1106–1115. doi: 10.1056/NEJM199604253341707. [DOI] [PubMed] [Google Scholar]
  20. Griffiths S. L., Critchley D. R. Characterisation of the binding sites for Escherichia coli heat-labile toxin type I in intestinal brush borders. Biochim Biophys Acta. 1991 Oct 10;1075(2):154–161. doi: 10.1016/0304-4165(91)90246-d. [DOI] [PubMed] [Google Scholar]
  21. Hughes J. M., Murad F., Chang B., Guerrant R. L. Role of cyclic GMP in the action of heat-stable enterotoxin of Escherichia coli. Nature. 1978 Feb 23;271(5647):755–756. doi: 10.1038/271755a0. [DOI] [PubMed] [Google Scholar]
  22. Keast J. R., Furness J. B., Costa M. Distribution of certain peptide-containing nerve fibres and endocrine cells in the gastrointestinal mucosa in five mammalian species. J Comp Neurol. 1985 Jun 15;236(3):403–422. doi: 10.1002/cne.902360308. [DOI] [PubMed] [Google Scholar]
  23. Lenz H. J., Silverman T. A. Effects of cerebral TRH on intestinal water transport: role of vagal, muscarinic, and VIP pathways. Am J Physiol. 1995 Jul;269(1 Pt 1):G138–G143. doi: 10.1152/ajpgi.1995.269.1.G138. [DOI] [PubMed] [Google Scholar]
  24. Llewellyn-Smith I. J., Song Z. M., Costa M., Bredt D. S., Snyder S. H. Ultrastructural localization of nitric oxide synthase immunoreactivity in guinea-pig enteric neurons. Brain Res. 1992 Apr 17;577(2):337–342. doi: 10.1016/0006-8993(92)90294-j. [DOI] [PubMed] [Google Scholar]
  25. Lundgren O., Svanvik J., Jivegård L. Enteric nervous system. I. Physiology and pathophysiology of the intestinal tract. Dig Dis Sci. 1989 Feb;34(2):264–283. doi: 10.1007/BF01536062. [DOI] [PubMed] [Google Scholar]
  26. Mourad F. H., O'Donnell L. J., Dias J. A., Ogutu E., Andre E. A., Turvill J. L., Farthing M. J. Role of 5-hydroxytryptamine type 3 receptors in rat intestinal fluid and electrolyte secretion induced by cholera and Escherichia coli enterotoxins. Gut. 1995 Sep;37(3):340–345. doi: 10.1136/gut.37.3.340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nilsson O., Cassuto J., Larsson P. A., Jodal M., Lidberg P., Ahlman H., Dahlström A., Lundgren O. 5-Hydroxytryptamine and cholera secretion: a histochemical and physiological study in cats. Gut. 1983 Jun;24(6):542–548. doi: 10.1136/gut.24.6.542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Nzegwu H. C., Levin R. J. Luminal capsaicin inhibits fluid secretion induced by enterotoxin E. coli STa, but not by carbachol, in vivo in rat small and large intestine. Exp Physiol. 1996 Mar;81(2):313–315. doi: 10.1113/expphysiol.1996.sp003935. [DOI] [PubMed] [Google Scholar]
  29. Rolfe V. E., Levin R. J. Vagotomy inhibits the jejunal fluid secretion activated by luminal ileal Escherichia coli STa in the rat in vivo. Gut. 1999 May;44(5):615–619. doi: 10.1136/gut.44.5.615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rolfe V., Levin R. J. Enterotoxin Escherichia coli STa activates a nitric oxide-dependent myenteric plexus secretory reflex in the rat ileum. J Physiol. 1994 Mar 15;475(3):531–537. doi: 10.1113/jphysiol.1994.sp020091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rolston D. D., Borodo M. M., Kelly M. J., Dawson A. M., Farthing M. J. Efficacy of oral rehydration solutions in a rat model of secretory diarrhea. J Pediatr Gastroenterol Nutr. 1987 Jul-Aug;6(4):624–630. doi: 10.1097/00005176-198707000-00023. [DOI] [PubMed] [Google Scholar]
  32. Sack R. B. Enterotoxigenic Escherichia coli: identification and characterization. J Infect Dis. 1980 Aug;142(2):279–286. doi: 10.1093/infdis/142.2.279. [DOI] [PubMed] [Google Scholar]
  33. Schulzke J. D., Riecken E. O., Fromm M. Distension-induced electrogenic Cl- secretion is mediated via VIP-ergic neurons in rat rectal colon. Am J Physiol. 1995 May;268(5 Pt 1):G725–G731. doi: 10.1152/ajpgi.1995.268.5.G725. [DOI] [PubMed] [Google Scholar]
  34. Sjöqvist A., Fahrenkrug J., Jodal M., Lundgren O. The effect of splanchnic nerve stimulation and neuropeptide Y on cholera secretion and release of vasoactive intestinal polypeptide in the feline small intestine. Acta Physiol Scand. 1988 Jul;133(3):289–295. doi: 10.1111/j.1748-1716.1988.tb08410.x. [DOI] [PubMed] [Google Scholar]
  35. Spangler B. D. Structure and function of cholera toxin and the related Escherichia coli heat-labile enterotoxin. Microbiol Rev. 1992 Dec;56(4):622–647. doi: 10.1128/mr.56.4.622-647.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Turvill J. L., Mourad F. H., Farthing M. J. Crucial role for 5-HT in cholera toxin but not Escherichia coli heat-labile enterotoxin-intestinal secretion in rats. Gastroenterology. 1998 Oct;115(4):883–890. doi: 10.1016/s0016-5085(98)70260-4. [DOI] [PubMed] [Google Scholar]
  37. Waldman D. B., Gardner J. D., Zfass A. M., Makhlouf G. M. Effects of vasoactive intestinal peptide, secretin, and related peptides on rat colonic transport and adenylate cyclase activity. Gastroenterology. 1977 Sep;73(3):518–523. [PubMed] [Google Scholar]

Articles from Gut are provided here courtesy of BMJ Publishing Group

RESOURCES