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. 1993 Apr;108(4):861–864. doi: 10.1111/j.1476-5381.1993.tb13478.x

Inhibitors of nitric oxide synthetase prevent castor-oil-induced diarrhoea in the rat.

N Mascolo 1, A A Izzo 1, F Barbato 1, F Capasso 1
PMCID: PMC1908159  PMID: 7683565

Abstract

1. Castor oil (2 ml orally) produced copious diarrhoea in rats 3 h after its administration. 2. Pretreatment (intraperitoneal, i.p.) of rats with the NO synthesis inhibitors NG-nitro-L-arginine methyl ester (L-NAME, 1-25 mg kg-1) and NG-monomethyl-L-arginine (L-NMMA, 2.5-100 mg kg-1) inhibited or prevented castor-oil-induced diarrhoea. L-Arginine (150-600 mg kg-1, i.p.) administered to rats pretreated with L-NAME 10 mg kg-1, drastically reduced the antidiarrhoeal activity of L-NAME in a dose-related manner. D-Arginine (900 mg kg-1) did not modify the protection by L-NAME. 3. Pretreatment (i.p.) of rats with L-NAME (2.5-25 mg kg-1) decreased the intestinal fluid accumulation and Na+ secretion induced by castor oil. L-Arginine (600 mg kg-1) but not D-arginine (900 mg kg-1) counteracted the inhibitory effect of L-NAME (10 mg kg-1). 4. L-NAME (10 and 25 mg kg-1) had no significant effect on the intestinal transit in normal rats or those given castor oil. 5. These results provide evidence that nitric oxide (NO) could play an important role in castor-oil-induced diarrhoea.

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Selected References

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  1. Amezcua J. L., Dusting G. J., Palmer R. M., Moncada S. Acetylcholine induces vasodilatation in the rabbit isolated heart through the release of nitric oxide, the endogenous nitrovasodilator. Br J Pharmacol. 1988 Nov;95(3):830–834. doi: 10.1111/j.1476-5381.1988.tb11711.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Amezcua J. L., Palmer R. M., de Souza B. M., Moncada S. Nitric oxide synthesized from L-arginine regulates vascular tone in the coronary circulation of the rabbit. Br J Pharmacol. 1989 Aug;97(4):1119–1124. doi: 10.1111/j.1476-5381.1989.tb12569.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boeckxstaens G. E., Pelckmans P. A., Bult H., De Man J. G., Herman A. G., van Maercke Y. M. Evidence for nitric oxide as mediator of non-adrenergic non-cholinergic relaxations induced by ATP and GABA in the canine gut. Br J Pharmacol. 1991 Feb;102(2):434–438. doi: 10.1111/j.1476-5381.1991.tb12191.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boeckxstaens G. E., Pelckmans P. A., Rampart M., Verbeuren T. J., Herman A. G., Van Maercke Y. M. Nonadrenergic noncholinergic mechanisms in the ileocolonic junction. Arch Int Pharmacodyn Ther. 1990 Jan-Feb;303:270–281. [PubMed] [Google Scholar]
  5. Bult H., Boeckxstaens G. E., Pelckmans P. A., Jordaens F. H., Van Maercke Y. M., Herman A. G. Nitric oxide as an inhibitory non-adrenergic non-cholinergic neurotransmitter. Nature. 1990 May 24;345(6273):346–347. doi: 10.1038/345346a0. [DOI] [PubMed] [Google Scholar]
  6. Capasso F., Mascolo N., Autore G., Romano V. Laxatives and the production of autacoids by rat colon. J Pharm Pharmacol. 1986 Aug;38(8):627–629. doi: 10.1111/j.2042-7158.1986.tb03097.x. [DOI] [PubMed] [Google Scholar]
  7. Christinck F., Jury J., Cayabyab F., Daniel E. E. Nitric oxide may be the final mediator of nonadrenergic, noncholinergic inhibitory junction potentials in the gut. Can J Physiol Pharmacol. 1991 Oct;69(10):1448–1458. doi: 10.1139/y91-217. [DOI] [PubMed] [Google Scholar]
  8. Desai K. M., Sessa W. C., Vane J. R. Involvement of nitric oxide in the reflex relaxation of the stomach to accommodate food or fluid. Nature. 1991 Jun 6;351(6326):477–479. doi: 10.1038/351477a0. [DOI] [PubMed] [Google Scholar]
  9. Gaginella T. S., Bass P. Laxatives: an update on mechanism of action. Life Sci. 1978 Sep 11;23(10):1001–1009. doi: 10.1016/0024-3205(78)90659-8. [DOI] [PubMed] [Google Scholar]
  10. Gaginella T. S., Phillips S. F. Ricinoleic acid: current view of an ancient oil. Am J Dig Dis. 1975 Dec;20(12):1171–1177. doi: 10.1007/BF01070759. [DOI] [PubMed] [Google Scholar]
  11. Gardiner S. M., Compton A. M., Bennett T., Palmer R. M., Moncada S. Control of regional blood flow by endothelium-derived nitric oxide. Hypertension. 1990 May;15(5):486–492. doi: 10.1161/01.hyp.15.5.486. [DOI] [PubMed] [Google Scholar]
  12. Gustafsson L. E., Wiklund C. U., Wiklund N. P., Persson M. G., Moncada S. Modulation of autonomic neuroeffector transmission by nitric oxide in guinea pig ileum. Biochem Biophys Res Commun. 1990 Nov 30;173(1):106–110. doi: 10.1016/s0006-291x(05)81028-9. [DOI] [PubMed] [Google Scholar]
  13. Hitchcott P. K., File S. E., Ekwuru M., Neal M. J. Chronic diazepam treatment in rats causes long-lasting changes in central [3H]-5-hydroxytryptamine and [14C]-gamma-aminobutyric acid release. Br J Pharmacol. 1990 Jan;99(1):11–12. doi: 10.1111/j.1476-5381.1990.tb14644.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Knowles R. G., Palacios M., Palmer R. M., Moncada S. Formation of nitric oxide from L-arginine in the central nervous system: a transduction mechanism for stimulation of the soluble guanylate cyclase. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5159–5162. doi: 10.1073/pnas.86.13.5159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Melo M. de F., Thomas G., Mukherjee R. Antidiarrhoeal activity of bisnordihydrotoxiferine isolated from the root bark of Strychnos trinervis (Vell.) Mart. (Loganiaceae). J Pharm Pharmacol. 1988 Jan;40(1):79–82. doi: 10.1111/j.2042-7158.1988.tb05163.x. [DOI] [PubMed] [Google Scholar]
  16. Moncada S., Higgs E. A. Endogenous nitric oxide: physiology, pathology and clinical relevance. Eur J Clin Invest. 1991 Aug;21(4):361–374. doi: 10.1111/j.1365-2362.1991.tb01383.x. [DOI] [PubMed] [Google Scholar]
  17. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  18. Moore P. K., al-Swayeh O. A., Chong N. W., Evans R. A., Gibson A. L-NG-nitro arginine (L-NOARG), a novel, L-arginine-reversible inhibitor of endothelium-dependent vasodilatation in vitro. Br J Pharmacol. 1990 Feb;99(2):408–412. doi: 10.1111/j.1476-5381.1990.tb14717.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mülsch A., Busse R. NG-nitro-L-arginine (N5-[imino(nitroamino)methyl]-L-ornithine) impairs endothelium-dependent dilations by inhibiting cytosolic nitric oxide synthesis from L-arginine. Naunyn Schmiedebergs Arch Pharmacol. 1990 Jan-Feb;341(1-2):143–147. doi: 10.1007/BF00195071. [DOI] [PubMed] [Google Scholar]
  20. Niemegeers C. J., Lenaerts F. M., Janssen P. A. Difenoxine (R 15403), the active metabolite of diphenoxylate (R 1132). 2. Difneozine, a potent, orally active and safe antidiarrheal agent in rats. Arzneimittelforschung. 1972 Mar;22(3):516–518. [PubMed] [Google Scholar]
  21. Palmer R. M., Ashton D. S., Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988 Jun 16;333(6174):664–666. doi: 10.1038/333664a0. [DOI] [PubMed] [Google Scholar]
  22. Piercey M. F., Ruwart M. J. Naloxone inhibits the anti-diarrhoeal activity of loperamide. Br J Pharmacol. 1979 Jul;66(3):373–375. doi: 10.1111/j.1476-5381.1979.tb10840.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Pinto A., Autore G., Mascolo N., Sorrentino R., Biondi A., Izzo A. A., Capasso F. Time course of PAF formation by gastrointestinal tissue in rats after castor oil challenge. J Pharm Pharmacol. 1992 Mar;44(3):224–226. doi: 10.1111/j.2042-7158.1992.tb03586.x. [DOI] [PubMed] [Google Scholar]
  24. Pinto A., Calignano A., Mascolo N., Autore G., Capasso F. Castor oil increases intestinal formation of platelet-activating factor and acid phosphatase release in the rat. Br J Pharmacol. 1989 Apr;96(4):872–874. doi: 10.1111/j.1476-5381.1989.tb11897.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Racusen L. C., Binder H. J. Ricinoleic acid stimulation of active anion secretion in colonic mucosa of the rat. J Clin Invest. 1979 Apr;63(4):743–749. doi: 10.1172/JCI109358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rees D. D., Palmer R. M., Schulz R., Hodson H. F., Moncada S. Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br J Pharmacol. 1990 Nov;101(3):746–752. doi: 10.1111/j.1476-5381.1990.tb14151.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Robert A., Nezamis J. E., Lancaster C., Hanchar A. J., Klepper M. S. Enteropooling assay: a test for diarrhea produced by prostaglandins. Prostaglandins. 1976 May;11(5):809–828. doi: 10.1016/0090-6980(76)90189-1. [DOI] [PubMed] [Google Scholar]
  28. Sakuma I., Stuehr D. J., Gross S. S., Nathan C., Levi R. Identification of arginine as a precursor of endothelium-derived relaxing factor. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8664–8667. doi: 10.1073/pnas.85.22.8664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sarna S. K. Physiology and pathophysiology of colonic motor activity (2). Dig Dis Sci. 1991 Jul;36(7):998–1018. doi: 10.1007/BF01297155. [DOI] [PubMed] [Google Scholar]
  30. Simon B., Cyzgan P., Stiehl A., Kather H. Human colonic adenylate cyclase: effects of bile acids. Eur J Clin Invest. 1978 Oct;8(5):321–323. doi: 10.1111/j.1365-2362.1978.tb00849.x. [DOI] [PubMed] [Google Scholar]
  31. Tsurumi K., Fujimura H. Effect of anti-inflammatory drugs on endotoxin-induced diarrhea in mice. Jpn J Pharmacol. 1983 Feb;33(1):165–173. doi: 10.1254/jjp.33.165. [DOI] [PubMed] [Google Scholar]
  32. Vischer P., Casals-Stenzel J. Influence of prostacyclin and indomethacin on castor oil-induced gastrointestinal effects in rats. J Pharm Pharmacol. 1983 Mar;35(3):152–156. doi: 10.1111/j.2042-7158.1983.tb04295.x. [DOI] [PubMed] [Google Scholar]

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