Advertisement

Selective Pharmacological Inhibition of Inducible Nitric Oxide Synthase in Experimental Septic Shock

  • L. Liaudet
  • M. D. Schaller
  • F. Feihl
Conference paper
Part of the Yearbook of Intensive Care and Emergency Medicine book series (YEARBOOK, volume 1998)

Abstract

In spite of major advances in the care of critically ill patients, septic shock remains a commonly fatal condition, with a mortality rate averaging 50% [1], Recent progress in the understanding of the pathophysiology of septic shock has prompted an intense search for new therapeutic modalities. In particular, the recognition that an enhanced production of the vasodilator nitric oxide (NO) from an inducible isoform of NO synthase (iNOS) plays a major role in sepsis-induced hypotension, has suggested that the pharmacological inhibition of iNOS might be of great therapeutic value in this setting [2]. In this article, we will review the current state of knowledge regarding the inhibition of NO production in experimental septic shock, by focusing on the most recent data obtained with the newly developed selective inhibitors of iNOS.

Keywords

Nitric Oxide Septic Shock Multiple Organ Dysfunction Syndrome Amino Guanidine Nitric Oxide Synthesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Bone RC (1991) The pathogenesis of sepsis. Ann Intern Med 115: 457–469PubMedGoogle Scholar
  2. 2.
    Szabo C (1995) Alterations in nitric oxide production in various forms of circulatory shock. New Horizons 3: 2–32PubMedGoogle Scholar
  3. 3.
    Thiemermann C (1997) Nitric oxide and septic shock. Gen Pharmacol 29: 159–166PubMedCrossRefGoogle Scholar
  4. 4.
    Kilbourn RG, Traber DL, Szabo C (1997) Nitric oxide and shock. Disease-a-Month 43: 281–348CrossRefGoogle Scholar
  5. 5.
    Cobb JP, Danner RL (1996) Nitric oxide and septic shock. JAMA 275: 1192–1196PubMedCrossRefGoogle Scholar
  6. 6.
    Kilbourn RG, Szabo C, Traber DL (1997) Beneficial versus detrimental effects of nitric oxide synthase inhibitors in circulatory shock: lessons learned from experimental and clinical studies. Shock 7: 235–246PubMedCrossRefGoogle Scholar
  7. 7.
    MacMicking JD, Nathan C, Horn G, et al (1995) Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81: 641–650PubMedCrossRefGoogle Scholar
  8. 8.
    Salzman AL (1995) Nitric oxide and the gut. New Horizons 3: 33–45PubMedGoogle Scholar
  9. 9.
    Szabo C (1996) DNA strand breakage and activation of poly-ADP ribosyltransferase: a cytotoxic pathway triggered by peroxynitrite. Free Rad Biol Med 21: 855–869PubMedCrossRefGoogle Scholar
  10. 10.
    Kilbourn RG, Gross SS, Jubran A, et al (1990) NG-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide. Proc Natl Acad Sci USA 87: 3629–3632PubMedCrossRefGoogle Scholar
  11. 11.
    Kilbourn RG, Jubran A, Gross SS, et al (1990) Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun 172: 1132–1138PubMedCrossRefGoogle Scholar
  12. 12.
    Thiemermann C, Vane J (1990) Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipopolysaccharides in the rat in vivo. Eur J Pharmacol 182: 591–595PubMedCrossRefGoogle Scholar
  13. 13.
    Magder S, Vanelli G (1994) Venous circuit adaptations during high cardiac output sepsis in pigs. Am J Respir Crit Care Med 149: A654 (Abst)Google Scholar
  14. 14.
    Avontuur JAM, Bruining H, Ince C (1995) Inhibition of nitric oxide synthesis causes myocardial ischemia in endotoxemic rats. Circ Res 76: 418–425PubMedGoogle Scholar
  15. 15.
    Cobb JP, Natanson C, Hoffman WD, et al (1992) N-Amino-L-Arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin. J Exp Med 176: 1175–1182PubMedCrossRefGoogle Scholar
  16. 16.
    Robertson FM, Offner PJ, Ciceri DP, Bechker WK, Pruitt BA (1994) Detrimental hemodynamic effects of nitric oxide synthase inhibition in septic shock. Arch Surg 129: 149–156PubMedCrossRefGoogle Scholar
  17. 17.
    Spain DA, Wilson MA, Garison RN (1994) Nitric oxide synthase inhibition exacerbates sepsis-induced renal hypoperfusion. Surgery 116: 322–331PubMedGoogle Scholar
  18. 18.
    Shultz P, Raij L (1992) Endogenously synthesized nitric oxide prevents endotoxin-induced glomerular thrombosis. J Clin Invest 90: 1718–1725PubMedCrossRefGoogle Scholar
  19. 19.
    Statman R, Cheng W, Cunningham JN, et al (1994) Nitric oxide inhibition in the treatment of the sepsis syndrome is detrimental to tissue oxygenation. J Surg Res 57: 93–98PubMedCrossRefGoogle Scholar
  20. 20.
    Harbrecht BG, Billiar TR, Stadler J, et al (1992) Nitric oxide synthesis serves to reduce hepatic damage during acute murine endotoxemia. Crit Care Med 20: 1568–1574PubMedCrossRefGoogle Scholar
  21. 21.
    Evans T, Carpenter A, Silva A, Cohen J (1994) Inhibition of nitric oxide synthase in experimental Gram-negative sepsis. J Infect Dis 169: 343–349PubMedCrossRefGoogle Scholar
  22. 22.
    Liaudet L, Rosselet A, Schaller MD, Markert M, Perret C, Feihl F (1998) Nonselective versus selective inhibition of inducible nitric oxide synthase in experimental endotoxic shock. J Infect Dis (In press)Google Scholar
  23. 23.
    Minnard EA, Shou J, Naama H, Cech A, Gallagher H, Daly JM (1994) Inhibition of nitric oxide synthesis is detrimental during endotoxemia. Arch Surg 129: 142–148PubMedCrossRefGoogle Scholar
  24. 24.
    Boughton-Smith NK, Hutcheson IR, Deakin AM, Whittle BJR, Moncada S (1990) Protective effect of S-nitroso-N-acetyl-penicillamine in endotoxin-induced acute intestinal damage in the rat. Eur J Pharmacol 191: 485–488PubMedCrossRefGoogle Scholar
  25. 25.
    Wright CE, Rees DD, Moncada S (1992) Protective and pathological roles of nitric oxide in endotoxin shock. Cardiovasc Res 26: 48–57PubMedCrossRefGoogle Scholar
  26. 26.
    Traber DL (1996) Presence and absence of nitric oxide synthase in sepsis. Crit Care Med 24: 1102–1103PubMedCrossRefGoogle Scholar
  27. 27.
    Liaudet L, Feihl F, Rosselet A, Markert M, Perret C (1996) Beneficial effects of L-canavanine, a selective inhibitor of inducible nitric oxide synthase, during rodent endotoxemia. Clin Sci 90: 369–377PubMedGoogle Scholar
  28. 28.
    Moore WM, Webber RK, Jerome GM, Tjoeng FS, Misko TP, Currie MG (1994) L-N6-(1- Iminoethyl)lysine: a selective inhibitor of inducible nitric oxide synthase. J Med Chem 37: 3886–3888PubMedCrossRefGoogle Scholar
  29. 29.
    Southan GJ, Szabo C, O’Connor MP, Salzman AL, Thiemermann C (1995) Amidines are potent inhibitors of nitric oxide synthases: preferential inhibition of the inducible isoform. Eur J Pharmacol 291: 311–318PubMedCrossRefGoogle Scholar
  30. 30.
    Misko TP, Moore WM, Kasten T, et al (1993) Selective inhibition of the inducible nitric oxide synthase by aminoguanidine. Eur J Pharmacol 233: 119–125PubMedCrossRefGoogle Scholar
  31. 31.
    Southan GJ, Szabo C, Thiemermann C (1995) Isothioureas: potent inhibitors of nitric oxide synthases with variable isoform selectivity. Br J Pharmacol 114: 510–516PubMedGoogle Scholar
  32. 32.
    Southan GJ, Zingarelli B, O’Connor M, Salzman A, Szabo C (1996) Spontaneous rearrangement of aminoalkylisothioureas into mercaptoalkylguanidines, a novel class of nitric oxide synthase inhibitors with selectivity towards the inducible isoform. Br J Pharmacol 117: 619–632PubMedGoogle Scholar
  33. 33.
    Southan GJ, Szabo C (1996) Selective pharmacological inhibition of distinct nitric oxide synthase isoforms. Biochem Pharmacol 51: 383–394PubMedCrossRefGoogle Scholar
  34. 34.
    Fink MP, Heard SO (1990) Laboratory models of sepsis and septic shock. J Surg Res 49: 186–196PubMedCrossRefGoogle Scholar
  35. 35.
    Liaudet L, Fishman D, Markert M, Perret C, Feihl F (1997) L-canavanine improves organ function and tissue adenosine triphosphate levels in rodent endotoxemia. Am J Respir Crit Care Med 155: 1643–1648PubMedGoogle Scholar
  36. 36.
    Rosselet A, Feihl F, Markert M, Perret C, Liaudet L (1998) Selective iNOS inhibition is superior to norepinephrine in the treatment of rat endotoxic shock. Am J Respir Crit Care Med (In press)Google Scholar
  37. 37.
    Kengatharan KM, De Kimpe SJ, Thiemermann C (1996) Role of nitric oxide in the circulatory failure and organ injury in a rodent model of Gram-positive shock. Br J Pharmacol 119: 1411–1421PubMedGoogle Scholar
  38. 38.
    Wu CC, Chen SJ, Szabo C, Thiemermann C, Vane JR (1995) Aminoguanidine attenuates the delayed circulatory failure and improves survival in rodent models of endotoxic shock. Br J Pharmacol 114: 1666–1672PubMedGoogle Scholar
  39. 39.
    Szabo C, Bryk R, Zingarelli B, et al (1996) Pharmacological characterization of guanidinoethyl- disulphide (GED), a novel inhibitor of nitric oxide synthase with selectivity towards the inducible isoform. Br J Pharmacol 118: 1659–1668PubMedGoogle Scholar
  40. 40.
    Thiemermann C, Ruetten H, Wu CC, Vane JR (1995) The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase. Br J Pharmacol 116: 2845–2851PubMedGoogle Scholar
  41. 41.
    Fatehihassanabad Z, Burns H, Aughey E, et al (1996) Effects of L-canavanine, an inhibitor of inducible nitric oxide synthase, on endotoxin-mediated shock in rats. Shock 6: 194–200Google Scholar
  42. 42.
    Cai M, Sakamoto A, Ogawa R (1996) Inhibition of nitric oxide formation with L-canavanine attenuates endotoxin-induced vascular hyporeactivity in the rat. Eur J Pharmacol 295: 215–220PubMedCrossRefGoogle Scholar
  43. 43.
    Teale DM, Atkinson AM (1994) L-canavanine restores blood pressure in a rat model of endotoxic shock. Eur J Pharmacol 271: 87–92PubMedCrossRefGoogle Scholar
  44. 44.
    Ruetten H, Southan GJ, Abate A, Thiemermann C (1996) Attenuation of endotoxin-induced multiple organ dysfunction by 1-amino-2-hydroxy-guanidine, a potent inhibitor of inducible nitric oxide synthase. Br J Pharmacol 118: 261–270PubMedGoogle Scholar
  45. 45.
    Fishman D, Liaudet L, Lazor R, Feihl F, Perret C (1997) L-canavanine, an inhibitor of inducible nitric oxide synthase, improves venous return in endotoxemic rats. Crit Care Med 25: 469–475PubMedCrossRefGoogle Scholar
  46. 46.
    Wu CC, Ruetten H, Thiemermann C (1996) Comparison of the effects of aminoguanidine and N-omega-nitro-L-arginine methyl ester on the multiple organ dysfunction caused by endotoxaemia in the rat. Eur J Pharmacol 300: 99–104PubMedCrossRefGoogle Scholar
  47. 47.
    Arkovitz MS, Wispe JR, Garcia VF, Szabo C (1996) Selective inhibition of the inducible isoform of nitric oxide synthase prevent pulmonary transvascular flux during acute endotoxemia. J Ped Surg 31: 1009–1015CrossRefGoogle Scholar
  48. 48.
    Sorrells DL, Friend C, Koltuksuz U, et al (1996) Inhibition of nitric oxide with aminoguanidine reduces bacterial translocation after endotoxin challenge in vivo. Arch Surg 131: 1155–1163PubMedCrossRefGoogle Scholar
  49. 49.
    Hock CE, Yin K, Yue G, Wong PYK (1997) Effects of inhibition of nitric oxide synthase by aminoguanidine in acute endotoxemia. Am J Physiol 272: H843–H850PubMedGoogle Scholar
  50. 50.
    Yen MH, Liu YC, Hong HJ, Sheu JR, Wu CC (1997) Role of nitric oxide in lipopolysaccharide-induced mortality from spontaneously hypertensive rats. Life Sci 60: 1223–1230PubMedCrossRefGoogle Scholar
  51. 51.
    Gardiner SM, Kemp PA, March JE, Bennett T (1996) Influence of aminoguanidine and the endothelin antagonist, SB 209670, on the regional haemodynamic effects of endotoxaemia in conscious rats. Br J Pharmacol 118: 1822–1828PubMedGoogle Scholar
  52. 52.
    Huang TP, Nishida T, Kamiike W, et al (1997) Role of nitric oxide in oxygen transport in rat liver sinusoids during endotoxemia. Hepatology 26: 336–342PubMedCrossRefGoogle Scholar
  53. 53.
    Szabo C, Southan GJ, Thiemermann C (1994) Beneficial effects and improved survival in rodent models of septic shock with S-methylisothiourea sulfate, a potent and selective inhibitor of inducible nitric oxide synthase. Proc Natl Acad Sci USA 91: 12472–12476PubMedCrossRefGoogle Scholar
  54. 54.
    Aranow JS, Zhuang J, Wang H, Larkin V, Smith M, Fink MP (1996) A selective inhibitor of inducible nitric oxide synthase prolongs survival in a rat model of bacterial peritonitis: comparison with two nonselective strategies. Shock 5: 116–121PubMedCrossRefGoogle Scholar
  55. 55.
    Schwartz D, Mendonca M, Schwartz I, et al (1997) Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats. J Clin Invest 100: 439–448PubMedCrossRefGoogle Scholar
  56. 56.
    Nava E, Palmer RMJ, Moncada S (1991) Inhibition of nitric oxide synthesis in septic shock: how much is beneficial? Lancet 338: 1555–1557PubMedCrossRefGoogle Scholar
  57. 57.
    Meyer J, Traber LD, Nelson S, et al (1992) Reversal of hyperdynamic response to continuous endotoxin administration by inhibition of NO synthesis. J Appl Physiol 73: 324–328PubMedGoogle Scholar
  58. 58.
    Meyer J, Lentz CW, Stothert JC, Traber LD, Herndon DN, Traber DL (1994) Effects of nitric oxide synthesis inhibition in hyperdynamic endotoxemia. Crit Care Med 22: 306–312PubMedCrossRefGoogle Scholar
  59. 59.
    Rengasamy A, Johns RA (1993) Regulation of nitric oxide synthase by nitric oxide. Mol Pharmacol 44: 124–128PubMedGoogle Scholar
  60. 60.
    Filippov G, Bloch DB, Bloch KD (1997) Nitric oxide decreases stability of mRNAs encoding soluble guanylate cyclase subunits in rat pulmonary artery smooth muscle cells. J Clin Invest 100: 942–948PubMedCrossRefGoogle Scholar
  61. 61.
    Salzman AL, Menconi MJ, Unno N, et al (1995) Nitric oxide dilates tight junctions and deletes ATP in cultured Caco-2BBe intestinal epithelial monolayers. Am J Physiol 268: G361–G373PubMedGoogle Scholar
  62. 62.
    Teale DM, Atkinson M (1992) Inhibition of nitric oxide synthesis improves survival in a murine peritonitis model of sepsis that is not cured by antibiotics alone. J Antimicrob Chemother 30: 839–842PubMedCrossRefGoogle Scholar
  63. 63.
    Wei XQ, Charles IG, Smith A, et al (1995) Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 375: 408–411PubMedCrossRefGoogle Scholar
  64. 64.
    Laubach VE, Shesely EG, Smithies O, Sherman PA (1995) Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. Proc Natl Acad Sci USA 92: 10688–10692PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • L. Liaudet
  • M. D. Schaller
  • F. Feihl

There are no affiliations available

Personalised recommendations