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Failure of L-NAME to cause inhibition of nitric oxide synthesis: Role of inducible nitric oxide synthase

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Abstract

We addressed the hypothesis that administration of nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) does not result in a sustained suppression of nitric oxide (NO) synthesis, because of a compensatory expression of inducible nitric oxide synthase (iNOS). L-NAME was administered in the drinking water (0.1–1.0 mg/ml) for 7 days to guinea pigs and rats. Nitric oxide synthesis was assessed by [1] ex vivo formation of nitrite in blood vessels and intestine [2] tissue levels of cGMP [3] iNOS gene expression by RT-PCR [4] NADPH diaphorase staining [5] direct assessment of NO release in tissue explants using a microelectrode/electrochemical detection system. Chronic L-NAME administration elevated intestinal cGMP and nitrite levels in guinea pigs (p<0.05). In rats, intestinal nitrite levels were comparable in control and L-NAME treatment groups, whereas direct assessment of NO release defined a marked increase in the L-NAME group. Chronic L-NAME resulted in an induction of iNOS gene expression in rats and guinea pigs and novel sites of NADPH diaphorase staining in the intestine. We conclude that iNOS expression is responsible for a compensatory increase or normalization of NO synthesis during sustained administration of L-NAME.

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References

  1. Huang PL, Dawson TM, Bredt OS, Snyder SH, Fishman MC. Targeted disruption of the neuronal nitric oxide synthase gene. Cell 1993;75:1273–86.

    Google Scholar 

  2. Voelker CA, Miller MJS, Zhang X-J, Eloby-Childress S, Clark DA, Pierce MR. Perinatal nitric oxide synthase inhibition retards neonatal growth by inducing hypertophic pyloric stenosis in rats. Pediatr Res 1995;38:768–74.

    Google Scholar 

  3. Shang H, Schmidt HHHW, Nakane M, Mitchell JA, Pollock JS, Förstermann U, et al. Characterization and localization of nitric oxide synthesis in non-adrenergic noncholingergic nerves from bovine retractor penis muscles. Br J Pharmacol 1992;106:768–73.

    Google Scholar 

  4. Gardiner SM, Compton AN, Bennett T, Palmer RMJ, Moncada S. Regional hemodynamic changes during ingestion of NG-nitro-L-arginine methyl ester in conscious Brattleboro rats. Br J Pharmacol 1990;101:10–2.

    Google Scholar 

  5. Miller MJS, Sadowska-Krowicka H, Chotinareumol S, Kakkis JL, Clark DA. Amelioration of chronic ileitis by nitric oxide synthase inhibition. J Pharmacol Exp Ther 1993;264:11–6.

    Google Scholar 

  6. McCartney-Francis N, Allen JB, Mizel DE, Albina HE, Xie Q-W, Nathan CF. Suppression of arthritis by an inhibitor of nitric oxide synthase. J Exp Med 1993;178:749–54.

    Google Scholar 

  7. Weinberg JB, Granger DL, Pisetsky DA, Seldin MF, Misukonis MA, Mason SN, et al. The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease; increase nitric oxide production and nitric oxide synthase expression in MRL-1pr/1pr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl L-arginine. J Exp Med 1994;179:651–9.

    Google Scholar 

  8. Greenberg SS, Xie J, Zararain JM, Kapusta DR, Miller MJS. Hydroxocobalamin (Vit B12a) prevents and reverses endotoxin-induced hypotensions and mortality in rodents: role of nitric oxide. J Pharmacol Exptl Ther 1995;273:257–63.

    Google Scholar 

  9. Miller MJS, Grisham MG. Nitric oxide as a mediator of inflammation? — You had better believe it. Med Inflamm 1995;4:387–96.

    Google Scholar 

  10. Furfine ES, Harmon MF, Paith JE, Garvet EP. Selective inhibition of constitutive nitric oxide synthase by L-NG-nitroarginine. Biochemistry 1993;32:8512–7.

    Google Scholar 

  11. Miller MJS, Clark DA. Nitric oxide synthase inhibition can initiate or prevent gut inflammation: role of enzyme source. Agents Actions 1994;41:C231–2.

    Google Scholar 

  12. Miller MJS, Thompson JH, Zhang X-J, Sadowska-Krowicka H, Kakkis JL, Munshi UK, et al. Role of inducible nitric oxide synthase expression and peroxynitrite formation in guinea pig ileitis. Gastroenterology 1995;109:1475–83.

    Google Scholar 

  13. Miller MJS, Munshi UK, Sadowska-Krowicka H, Kakki JL, Zhang X-J, Eloby-Childress, S, et al. Inhibition of calcium-dependent nitric oxide synthase causes ileitis and leukocytosis in guinea pigs. Dig Dis Sci 1994;39:1185–92.

    Google Scholar 

  14. Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 1991;88:4561–655.

    Google Scholar 

  15. Payne D, Kubes P. Nitric oxide donors reduce the rise in reperfusion-induce intestinal mucosal permeability. Am J Physiol 1993;265:G189–95.

    Google Scholar 

  16. Kanwar S, Wallace JL, Befus D, Kubes P. Nitric oxide synthesis inhibition increases epithelial permeability via mast cells. Am J Physiol 1994;266:G222–9.

    Google Scholar 

  17. Miller MJS, Sadowska-Krowicka H, Chotinaruemol S, Wong M, Clark DA, Jeng AY. Anti-inflammatory agents and substance P depletion in experimental ileitis. Med Inflamm 1993;2:293–7.

    Google Scholar 

  18. Kubes P, Wallace JL. Nitric oxide as a mediator of gastrointestinal mucosal injury? — Say it ain't so. Med Inflamm 1995;4:397–405.

    Google Scholar 

  19. Lui X, Lu J, Cha C. The general characteristics of microelectrodes of any planar geometry under steady state conditions. J Electroanalyt Chem 1990;295:15–23.

    Google Scholar 

  20. Ribbons KA, Zhang X-J, Thompson JH, Greenberg SS, Moore WM, Kornmeier CM, et al. Increased nitric oxide synthesis in colitis rhesus macaques. Gastroenterology 1995;108:705–11.

    Google Scholar 

  21. Seago ND, Sadowska-Krowicka H, Zhang X-J, Clark DA, Miller MJS. Role of nitric oxide in a new model of chronic gut inflammation in guinea pigs induced by local injection of Freund's complete adjuvant. Med Inflamm 1995;4:19–24.

    Google Scholar 

  22. Miller MJS, Munshi UK, Zhang X-J, Sadowska-Krowicka H, Savage P, Kakkis JL, et al. Chronic administration of the nitric oxide synthase inhibitor, L-NAME, increases circulating endothelin levels in guinea pigs. Endothelium 1994;3:57–62.

    Google Scholar 

  23. Sandoval M, Liu X, Oliver PD, Zhang X-J, Clark DA, Miller MJS. Nitric oxide induces apoptosis in human colonic epithelial cell line, T84. Med Inflamm 1995;4:248–50.

    Google Scholar 

  24. Fahmi H, Charon D, Mondage M, Chaby R. Endotoxin-induced desensitization of mouse macrophages is mediated in part by nitric oxide production. Infect Immun 1995;63:1863–9.

    Google Scholar 

  25. Rhengasamy A, Johns RA. Regulation of nitric oxide synthase by nitric oxide. Molec Pharmacol 1995;44:124–8.

    Google Scholar 

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accepted by G. Letts

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Miller, M.J.S., Thompson, J.H., Liu, X. et al. Failure of L-NAME to cause inhibition of nitric oxide synthesis: Role of inducible nitric oxide synthase. Inflamm Res 45, 272–276 (1996). https://doi.org/10.1007/BF02280990

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  • DOI: https://doi.org/10.1007/BF02280990

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