Induction by Endotoxin of Nitric Oxide Production in Vascular Smooth Muscle Cells

  • J. C. Stoclet
  • C. A. Schott
  • F. Schneider
  • C. Berton
  • D. Paya


Endotoxin released on lysis of gram-negative bacteria contains a macromolecular glycolipid termed lipopolysaccharide (LPS) which is able to reproduce many of the cardiovascular features of septic shock (Parratt 1989). The persistent loss of vascular tone observed during gram-negative septicemia and after injection of LPS in animals and in humans is often unresponsive to catecholamines and other vasoconstrictor agents and is associated with a high mortality rate (Groeneveld et al. 1986).


Nitric Oxide Nitric Oxide Vascular Smooth Muscle Cell Nitric Oxide Production Cationic Amino Acid 
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  1. Baydoun AR, Bogle RG, Pearson JD, Mann GE (1993) Selective inhibition by dexamethasone of induction of nitric oxide synthase, but not of induction of L-arginine transport, in activated murine macrophage J774 cells. Br J Pharmacol 110: 1401–1406PubMedGoogle Scholar
  2. Baydoun AR, Vileman SM, Jay MT, Mann GE (1994) Induction of L-arginine transport and nitric oxide synthase in cultured rat aortic smooth muscle cells activated with bacterial entodoxin. J Physiol (Lond) 475: 46 PGoogle Scholar
  3. Beasley D, McGuiggin M (1994) Interleukin-i activates soluble guanylate cyclase in human vascular smooth muscle cells through a novel nitric oxide-independent pathway. J Exp Med 179: 71–88PubMedCrossRefGoogle Scholar
  4. Beasley D, Schwartz JH, Brenner BM (1991) Interleukin-i induces prolonged L-arginine dependent cyclic guanosine monophosphate and nitrite production in rat vascular smooth muscle cells. J Clin Invest 87: 602–608PubMedCrossRefGoogle Scholar
  5. Bernard C, Tedgui A (1992) Cytokine network and the vessel wall. Insights into septic shock pathogenesis. Eur Cytokine Netw3: 19–33Google Scholar
  6. Bernard C, Szekely B, Philip I, Wollman E, Payen D, Tedgui A (1992) Activated macrophages depress the contractility of rabbit carotids via an L-arginine-nitric oxide dependent effector mechanism: connection with amplified cytokine release. J Clin Invest 89: 851–860PubMedCrossRefGoogle Scholar
  7. Bogle RG, Baydoun AR, Pearson JD, Moncada S, Mann GE (1992) L-arginine transport is increased in macrophages generating nitric oxide. Biochem J 284: 15–18PubMedGoogle Scholar
  8. Boucher JL, Genet A, Vadon S, Delaforge M, Henry Y, Mansuy D (1992) Cytochrome P-450 catalyzes the oxidation of n-hydroxy-L-arginine by NADPH and 02 to nitric oxide and citrulline. Biochem Biophys Res Commun 187: 880–886PubMedCrossRefGoogle Scholar
  9. Busse R, Mulsch A (1990) Induction of nitric oxide-synthase by cytokines in vascular smooth muscle cells. FEBS Lett 275: 87–90PubMedCrossRefGoogle Scholar
  10. Chamley-Campbell JH, Campbell GR, Ross R (1979) The smooth muscle cell in culture. Physiol Rev 59: 1–61PubMedGoogle Scholar
  11. Chenais B, Yapo A, Lepoivre M, Tenu JP (1993) ISP-Hydroxy-arginine, a reactional intermediate in nitric oxide biosynthesis, induces cytostatis in human and murine tumor cells. Biochem Biophys Res Commun 196: 1558–1565PubMedCrossRefGoogle Scholar
  12. Closs EI, Albritton LM, Kim JW, Cunningham JM (1993 a) Identification of a low affinity, high capacity transporter of cationic amino acids in mouse liver. J Biol Chem 268: 7538–7544Google Scholar
  13. Closs EI, Lyons RC, Mitchell M, James M (1993b) Expression of cationic amino acid transporter in NO-producing macrophages. Endothelium 1: 60Google Scholar
  14. Evans T, Carpenter A, Kinderman H, Cohen J (1993) Evidence of increased nitric oxide production in patients with the sepsis syndrome. Circ Shock 41: 77–81PubMedGoogle Scholar
  15. Fleming I, Gray GA, Julou-Schaeffer G, Parratt JR, Stoclet JC (1990) Incubation with endotoxin activates the L-arginine pathway in vascular tissue. Biochem Biophys Res Commun 171: 562–568PubMedCrossRefGoogle Scholar
  16. Fleming I, Gray GA, Schott CA, Stoclet JC (1991a) Inducible but not constitutive production of nitric oxide by vascular smooth muscle cells. Eur J Pharmacol 200: 375–376PubMedCrossRefGoogle Scholar
  17. Fleming I, Julou-Schaeffer G, Gray GA, Parratt JR, Stoclet JC (1991b) Evidence that an L-arginine/nitric oxide dependent elevation of tissue cyclic GMP content is involved in depression of vascular reactivity by endotoxin. Br J Pharmacol 103: 1047–1052PubMedGoogle Scholar
  18. Fleming I, Dambacher T, Busse R (1992) Endothelium derived kinins account for the immediate response of endothelial cells to bacterial lipopolysaccharide. J Cardiovasc Pharmacol 20 [Suppl 12]: S135–S138PubMedGoogle Scholar
  19. Fleming I, Gray GA, Stoclet JC (1993) Influence of endothelium on induction of the L-arginine-nitric oxide pathway in rat aortas. Am J Physiol 264: H1200–H1207PubMedGoogle Scholar
  20. Gray GA, Julou-Schaeffer G, Oury K, Fleming I, Parratt JR, Stoclet JC (1990) An L-arginine-derived factor mediates endotoxin-induced vascular hyposensitivity to calcium. Eur J Pharmacol 191: 89–92PubMedCrossRefGoogle Scholar
  21. Groeneveld ABJ, Brorisveld W, Thijs LJ (1986) Haemodynamic determinants of mortality in human septic shock. Surgery 99: 140–153PubMedGoogle Scholar
  22. Hecker M, Mitchell JA, Harris HJ, Katsura M, Thiemermann C, Vane JR (1990 a) Endothelial cells metabolize NG-monomethyl-L-arginine to L-citrulline and subsequently to L-arginine. Biochem Biophys Res Commun 167: 1037–1043Google Scholar
  23. Hecker M, Sessa WC, Harris HJ, Anggard EE, Vane JR (1990b) The metabolism of L-arginine and its significance for the biosynthesis of endothelium derived relaxing factor: cultured endothelial cells recycle L-citrulline to L-arginine. Proc Natl Acad Sci USA 87: 8612–8616PubMedCrossRefGoogle Scholar
  24. Julou-Schaeffer G, Gray GA, Fleming I, Schott C, Parratt JR, Stoclet JC (1990) Loss of vascular responsiveness induced by endotoxin involves L-arginine pathway. Am J Physiol 259: H1038–H1043PubMedGoogle Scholar
  25. Knowles RG, Salter M, Brooks SL, Moncada S (1990) Anti-inflammatory glucocorticoids inhibit the induction by endotoxin of nitric oxide synthase in the lung, liver and aorta of the rat. Biochem Biophys Res Commun 172: 1042–1048PubMedCrossRefGoogle Scholar
  26. Low BC, Ross IK, Grigor MR (1993) Characterization of system L and system amino acid transport activity in cultured vascular smooth muscle cells. J Cell Physiol 156: 626–634PubMedCrossRefGoogle Scholar
  27. Mayer B, Brunner F, Schmidt K (1993) Inhibition of nitric oxide synthesis by methylene blue. Biochem Pharmacol 45: 367–374PubMedCrossRefGoogle Scholar
  28. Mitchell JA, Hecker A, Anggard EE, Vane JR (1990) Cultured endothelial cells maintain their L-arginine level despite the continuous release of EDRF. Eur J Pharmacol 182: 573–576PubMedCrossRefGoogle Scholar
  29. Mitchell JA, Kohlhaas KL, Sorrentino R, Warner TD, Murad F, Vane JR (1993) Induction by endotoxin of nitric oxide synthase in the rat mesentery: lack of effect on action of vasoconstrictors. Br J Pharmacol 109: 265–270PubMedGoogle Scholar
  30. Moncada S, Palmer RMJ, Higgs EA (1990) Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 43: 109–142Google Scholar
  31. Nathan C (1992) Nitric oxide as a secretory product in mammalian cells. FASEB J 6: 3051–3064Google Scholar
  32. Parratt JR (1989) Alteration in vascular reactivity in sepsis and endotoxemia. In: Vincent JL (ed) Update in intensive care and emergency medicine, vol 8. Springer, Berlin Heidelberg New York, pp 299–308Google Scholar
  33. Paya D, Gray GA, Fleming I, Stoclet JC (1993 a) Effect of dexamethasone on the onset and persistence of vascular hyporeactivity induced by E. coli lipopolysaccharide in rats. Circ Shock 41: 103–112Google Scholar
  34. Paya D, Gray GA, Stoclet JC (1993b) Effects of methylene blue on blood pressure and reactivity to norepinephrine in endotoxemic rats. J Cardiovasc Pharmacol 21: 926–930PubMedCrossRefGoogle Scholar
  35. Petros A, Bennet D, Vallance P (1991) Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 338: 1557–1558PubMedCrossRefGoogle Scholar
  36. Radomski MW, Palmer RMJ, Moncada S (1990) Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. Proc Natl Acad Sci U S A 87: 10043–10047PubMedCrossRefGoogle Scholar
  37. Rees DD, Cellek S, Palmer RMJ, Moncada S (1990) Dexamethasone prevents the induction by endotoxin of nitric oxide synthase and the associated effects on vascular tone. An insight into endotoxin shock. Biochem Biophys Res Commun 173: 541–547Google Scholar
  38. Schini VB, Junquero DC, Scott-Burden T, Vanhoutte PM (1991) Interleukin-1β induces the production of an L-Arginine derived relaxing factor from cultured smooth muscle cells from rat aorta. Biochem Biophys Res Commun 176: 114–121PubMedCrossRefGoogle Scholar
  39. Schneider F, Lutun P, Hasselman M, Stoclet JC, Tempé JD (1992a) Methylene blue increases systemic vascular resistance in human septic shock. Intensive Care Med 18: 309–311PubMedCrossRefGoogle Scholar
  40. Schneider F, Schott C, Stoclet JC, Julou-Schaeffer G (1992b) L-Arginine induces relaxation of small mesenteric arteries from endotoxin-treated rats. Eur J Pharmacol 211: 269–272PubMedCrossRefGoogle Scholar
  41. Schneider F, Bucher B, Schott C, André A, Julou-Schaeffer G, Stoclet JC (1994) Effect of bacterial lipopolysaccharide on function of rat small femoral arteries. Am J Physiol 266: H191–H198.PubMedGoogle Scholar
  42. Schott CA, Gray GA, Stoclet JC (1993 a) Dependence of endotoxin-induced vascular hyporeactivity on extracellular L-arginine. Br J Pharmacol 108: 38–43Google Scholar
  43. Schott CA, Vetrovsky P, Stoclet JC (1993b) Cationic amino acids inhibit the effects of L-arginine in rat aorta exposed to lipopolysaccharide. Eur J Pharmacol 236: 155–157PubMedCrossRefGoogle Scholar
  44. Schott CA, Bogen CM, Vetrovsky P, Berton CC, Stoclet JC (1994) Exogenous NG-hydroxy-L-arginine causes nitrite production in vascular smooth muscle cells in the absence of nitric oxide synthase activity. FEBS Lett 341: 203–207PubMedCrossRefGoogle Scholar
  45. Stoclet JC, Fleming I, Gray G, Julou-Schaeffer G, Schneider F, Schott CA, Schott C, Parratt JR (1993a) Nitric oxide and endotoxemia. Circulation 87 [Suppl V]: 77–80Google Scholar
  46. Stoclet JC, Berton C, Bogen CM, Schott CA (1993b) L-Arginine transport in vascular smooth muscle cells and its role in lipopolysaccharide-induced NO generation. Endothelium 1 [suppl]: 59Google Scholar
  47. Stuehr DJ, Kwon NS, Nathan CF, Griffith O, Feldman P, Wiseman J (1991) N-Hydroxy-L-arginine is an intermediate in the biosynthesis of nitric oxide from L-arginine. J Biol Chem 266: 6259–6263PubMedGoogle Scholar
  48. Szabo C, Mitchell JA, Thiemermann C, Vane JR (1993 a) Nitric-oxide mediated hyporeactivity of noradrenaline precedes nitric oxide synthase induction in endotoxin shock. Br J Pharmacol 108: 786–792Google Scholar
  49. Szabo C, Wu CC, Gross SS, Thiemermann C, Vane JR (1993b) Interleukin-i contributes to the induction of nitric oxide synthase by endotoxin in vivo. Eur J Pharmacol 250: 157–160PubMedCrossRefGoogle Scholar
  50. Szabo C, Wu CC, Mitchell JA, Gross SS, Thiemermann C, Vane JR (1993 c) Platelet-activating factor contributes to the induction of nitric oxide synthase by bacterial lipopolysaccharide. Circ Res 73: 991–999Google Scholar
  51. Szabo C, Thiemermann C, Wu CC, Peretti M, Vane JR (1994) Attenuation of the induction of nitric oxide synthase by endogenous glucocorticoids accounts for endotoxin tolerance in vivo. Proc Nat Acad Sci U S A (in press)Google Scholar
  52. Thiemermann C, Wu CC, Szabo C, Peretti M, Vane JR (1993) Role of tumour necrosis factor in the induction of nitric oxide synthase in a rat model of endotoxic shock. Br J Pharmacol 110: 77–182Google Scholar
  53. Toda N, Okamura T (1990) Modifications by L-NG-monomethyl arginine ( L-NMMA) of the response to nerve stimulation in isolated dog mesenteric and cerebral arteries. Jpn J Pharmacol 52: 70–173Google Scholar
  54. Wright CE, Rees DD, Moncada S (1992) The protective and pathological roles of nitric oxide in endotoxin shock. Cardiovasc Res 26: 48–57PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • J. C. Stoclet
  • C. A. Schott
  • F. Schneider
  • C. Berton
  • D. Paya

There are no affiliations available

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