Skip to main content
PMC home page
Annals of Surgery logoLink to Annals of Surgery
. 1995 Apr;221(4):339–349. doi: 10.1097/00000658-199504000-00003

Nitric oxide. Novel biology with clinical relevance.

T R Billiar 1
PMCID: PMC1234582  PMID: 7537035

Abstract

OBJECTIVE: The author provides the reader with a view of the regulation and function of nitric oxide (NO), based on the three distinct enzyme isoforms that synthesize NO. SUMMARY BACKGROUND DATA: Nitric oxide is a short-lived molecule exhibiting functions as diverse as neurotransmission and microbial killing. Recent advances in the characterization of the enzymes responsible for NO synthesis and in the understanding of how NO interacts with targets have led to new insights into the many facets of this diverse molecule. METHODS: Nitric oxide is produced by one of three enzyme isoforms of NO synthesis. These enzymes vary considerably in their distribution, regulation, and function. Accordingly, the NO synthesis or lack of NO production will have consequences unique to that isoform. Therefore, this review summarizes the regulation and function of NO generated by each of the three isoforms. RESULTS: Nitric oxide exhibits many unique characteristics that allow this molecule to perform so many functions. The amount, duration, and location of the NO synthesis will depend on the isoform of NO synthase expressed. For each isoform, there probably are disease processes in which deficiency states exist. For induced NO synthesis, states of overexpression exist. CONCLUSIONS: Understanding the regulation and function of the enzymes that produce NO and the unique characteristics of each enzyme isoform is likely to lead to therapeutic approaches to prevent or treat a number of diseases.

Full text

PDF
339

Selected References

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

  1. Abu-Soud H. M., Stuehr D. J. Nitric oxide synthases reveal a role for calmodulin in controlling electron transfer. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10769–10772. doi: 10.1073/pnas.90.22.10769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baek K. J., Thiel B. A., Lucas S., Stuehr D. J. Macrophage nitric oxide synthase subunits. Purification, characterization, and role of prosthetic groups and substrate in regulating their association into a dimeric enzyme. J Biol Chem. 1993 Oct 5;268(28):21120–21129. [PubMed] [Google Scholar]
  3. Billiar T. R., Curran R. D., Harbrecht B. G., Stuehr D. J., Demetris A. J., Simmons R. L. Modulation of nitrogen oxide synthesis in vivo: NG-monomethyl-L-arginine inhibits endotoxin-induced nitrate/nitrate biosynthesis while promoting hepatic damage. J Leukoc Biol. 1990 Dec;48(6):565–569. doi: 10.1002/jlb.48.6.565. [DOI] [PubMed] [Google Scholar]
  4. Boughton-Smith N. K., Hutcheson I. R., Deakin A. M., Whittle B. J., Moncada S. Protective effect of S-nitroso-N-acetyl-penicillamine in endotoxin-induced acute intestinal damage in the rat. Eur J Pharmacol. 1990 Dec 4;191(3):485–488. doi: 10.1016/0014-2999(90)94185-z. [DOI] [PubMed] [Google Scholar]
  5. Bredt D. S., Snyder S. H. Nitric oxide, a novel neuronal messenger. Neuron. 1992 Jan;8(1):3–11. doi: 10.1016/0896-6273(92)90104-l. [DOI] [PubMed] [Google Scholar]
  6. Bucala R., Tracey K. J., Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest. 1991 Feb;87(2):432–438. doi: 10.1172/JCI115014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Burnett A. L., Lowenstein C. J., Bredt D. S., Chang T. S., Snyder S. H. Nitric oxide: a physiologic mediator of penile erection. Science. 1992 Jul 17;257(5068):401–403. doi: 10.1126/science.1378650. [DOI] [PubMed] [Google Scholar]
  8. Busse R., Mülsch A. Induction of nitric oxide synthase by cytokines in vascular smooth muscle cells. FEBS Lett. 1990 Nov 26;275(1-2):87–90. doi: 10.1016/0014-5793(90)81445-t. [DOI] [PubMed] [Google Scholar]
  9. Ceccatelli S., Hulting A. L., Zhang X., Gustafsson L., Villar M., Hökfelt T. Nitric oxide synthase in the rat anterior pituitary gland and the role of nitric oxide in regulation of luteinizing hormone secretion. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11292–11296. doi: 10.1073/pnas.90.23.11292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Charles I. G., Palmer R. M., Hickery M. S., Bayliss M. T., Chubb A. P., Hall V. S., Moss D. W., Moncada S. Cloning, characterization, and expression of a cDNA encoding an inducible nitric oxide synthase from the human chondrocyte. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11419–11423. doi: 10.1073/pnas.90.23.11419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chartrain N. A., Geller D. A., Koty P. P., Sitrin N. F., Nussler A. K., Hoffman E. P., Billiar T. R., Hutchinson N. I., Mudgett J. S. Molecular cloning, structure, and chromosomal localization of the human inducible nitric oxide synthase gene. J Biol Chem. 1994 Mar 4;269(9):6765–6772. [PubMed] [Google Scholar]
  12. Chin J. H., Azhar S., Hoffman B. B. Inactivation of endothelial derived relaxing factor by oxidized lipoproteins. J Clin Invest. 1992 Jan;89(1):10–18. doi: 10.1172/JCI115549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cho H. J., Xie Q. W., Calaycay J., Mumford R. A., Swiderek K. M., Lee T. D., Nathan C. Calmodulin is a subunit of nitric oxide synthase from macrophages. J Exp Med. 1992 Aug 1;176(2):599–604. doi: 10.1084/jem.176.2.599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Christopher T. A., Ma X. L., Lefer A. M. Beneficial actions of S-nitroso-N-acetylpenicillamine, a nitric oxide donor, in murine traumatic shock. Shock. 1994 Jan;1(1):19–24. doi: 10.1097/00024382-199401000-00004. [DOI] [PubMed] [Google Scholar]
  15. Closs E. I., Lyons C. R., Kelly C., Cunningham J. M. Characterization of the third member of the MCAT family of cationic amino acid transporters. Identification of a domain that determines the transport properties of the MCAT proteins. J Biol Chem. 1993 Oct 5;268(28):20796–20800. [PubMed] [Google Scholar]
  16. Cobb J. P., Natanson C., Hoffman W. D., Lodato R. F., Banks S., Koev C. A., Solomon M. A., Elin R. J., Hosseini J. M., Danner R. L. N omega-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. 1992 Oct 1;176(4):1175–1182. doi: 10.1084/jem.176.4.1175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Corbett J. A., Lancaster J. R., Jr, Sweetland M. A., McDaniel M. L. Interleukin-1 beta-induced formation of EPR-detectable iron-nitrosyl complexes in islets of Langerhans. Role of nitric oxide in interleukin-1 beta-induced inhibition of insulin secretion. J Biol Chem. 1991 Nov 15;266(32):21351–21354. [PubMed] [Google Scholar]
  18. Corraliza I. M., Campo M. L., Fuentes J. M., Campos-Portuguez S., Soler G. Parallel induction of nitric oxide and glucose-6-phosphate dehydrogenase in activated bone marrow derived macrophages. Biochem Biophys Res Commun. 1993 Oct 15;196(1):342–347. doi: 10.1006/bbrc.1993.2254. [DOI] [PubMed] [Google Scholar]
  19. Curran R. D., Billiar T. R., Stuehr D. J., Ochoa J. B., Harbrecht B. G., Flint S. G., Simmons R. L. Multiple cytokines are required to induce hepatocyte nitric oxide production and inhibit total protein synthesis. Ann Surg. 1990 Oct;212(4):462–471. doi: 10.1097/00000658-199010000-00009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Dawson V. L., Dawson T. M., London E. D., Bredt D. S., Snyder S. H. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6368–6371. doi: 10.1073/pnas.88.14.6368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Denis M. Tumor necrosis factor and granulocyte macrophage-colony stimulating factor stimulate human macrophages to restrict growth of virulent Mycobacterium avium and to kill avirulent M. avium: killing effector mechanism depends on the generation of reactive nitrogen intermediates. J Leukoc Biol. 1991 Apr;49(4):380–387. doi: 10.1002/jlb.49.4.380. [DOI] [PubMed] [Google Scholar]
  22. Drapier J. C., Hibbs J. B., Jr Murine cytotoxic activated macrophages inhibit aconitase in tumor cells. Inhibition involves the iron-sulfur prosthetic group and is reversible. J Clin Invest. 1986 Sep;78(3):790–797. doi: 10.1172/JCI112642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Drapier J. C., Hirling H., Wietzerbin J., Kaldy P., Kühn L. C. Biosynthesis of nitric oxide activates iron regulatory factor in macrophages. EMBO J. 1993 Sep;12(9):3643–3649. doi: 10.1002/j.1460-2075.1993.tb06038.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Durante W., Sen A. K., Sunahara F. A. Impairment of endothelium-dependent relaxation in aortae from spontaneously diabetic rats. Br J Pharmacol. 1988 Jun;94(2):463–468. doi: 10.1111/j.1476-5381.1988.tb11548.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Furchgott R. F., Zawadzki J. V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373–376. doi: 10.1038/288373a0. [DOI] [PubMed] [Google Scholar]
  26. Garthwaite J., Charles S. L., Chess-Williams R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature. 1988 Nov 24;336(6197):385–388. doi: 10.1038/336385a0. [DOI] [PubMed] [Google Scholar]
  27. Gaston B., Reilly J., Drazen J. M., Fackler J., Ramdev P., Arnelle D., Mullins M. E., Sugarbaker D. J., Chee C., Singel D. J. Endogenous nitrogen oxides and bronchodilator S-nitrosothiols in human airways. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10957–10961. doi: 10.1073/pnas.90.23.10957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Geller D. A., Lowenstein C. J., Shapiro R. A., Nussler A. K., Di Silvio M., Wang S. C., Nakayama D. K., Simmons R. L., Snyder S. H., Billiar T. R. Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3491–3495. doi: 10.1073/pnas.90.8.3491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Geller D. A., Nussler A. K., Di Silvio M., Lowenstein C. J., Shapiro R. A., Wang S. C., Simmons R. L., Billiar T. R. Cytokines, endotoxin, and glucocorticoids regulate the expression of inducible nitric oxide synthase in hepatocytes. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):522–526. doi: 10.1073/pnas.90.2.522. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Gillespie J. S., Liu X. R., Martin W. The effects of L-arginine and NG-monomethyl L-arginine on the response of the rat anococcygeus muscle to NANC nerve stimulation. Br J Pharmacol. 1989 Dec;98(4):1080–1082. doi: 10.1111/j.1476-5381.1989.tb12650.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Granger D. L., Hibbs J. B., Jr, Perfect J. R., Durack D. T. Specific amino acid (L-arginine) requirement for the microbiostatic activity of murine macrophages. J Clin Invest. 1988 Apr;81(4):1129–1136. doi: 10.1172/JCI113427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Green S. J., Meltzer M. S., Hibbs J. B., Jr, Nacy C. A. Activated macrophages destroy intracellular Leishmania major amastigotes by an L-arginine-dependent killing mechanism. J Immunol. 1990 Jan 1;144(1):278–283. [PubMed] [Google Scholar]
  33. Gross S. S., Levi R. Tetrahydrobiopterin synthesis. An absolute requirement for cytokine-induced nitric oxide generation by vascular smooth muscle. J Biol Chem. 1992 Dec 25;267(36):25722–25729. [PubMed] [Google Scholar]
  34. Harbrecht B. G., Billiar T. R., Stadler J., Demetris A. J., Ochoa J. B., Curran R. D., Simmons R. L. Nitric oxide synthesis serves to reduce hepatic damage during acute murine endotoxemia. Crit Care Med. 1992 Nov;20(11):1568–1574. doi: 10.1097/00003246-199211000-00015. [DOI] [PubMed] [Google Scholar]
  35. Harbrecht B. G., Billiar T. R., Stadler J., Demetris A. J., Ochoa J., Curran R. D., Simmons R. L. Inhibition of nitric oxide synthesis during endotoxemia promotes intrahepatic thrombosis and an oxygen radical-mediated hepatic injury. J Leukoc Biol. 1992 Oct;52(4):390–394. doi: 10.1002/jlb.52.4.390. [DOI] [PubMed] [Google Scholar]
  36. Harbrecht B. G., Stadler J., Demetris A. J., Simmons R. L., Billiar T. R. Nitric oxide and prostaglandins interact to prevent hepatic damage during murine endotoxemia. Am J Physiol. 1994 Jun;266(6 Pt 1):G1004–G1010. doi: 10.1152/ajpgi.1994.266.6.G1004. [DOI] [PubMed] [Google Scholar]
  37. Hecker M., Sessa W. C., Harris H. J., Anggård E. E., Vane J. R. 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 U S A. 1990 Nov;87(21):8612–8616. doi: 10.1073/pnas.87.21.8612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Hibbs J. B., Jr, Taintor R. R., Vavrin Z. Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science. 1987 Jan 23;235(4787):473–476. doi: 10.1126/science.2432665. [DOI] [PubMed] [Google Scholar]
  39. Hibbs J. B., Jr, Vavrin Z., Taintor R. R. L-arginine is required for expression of the activated macrophage effector mechanism causing selective metabolic inhibition in target cells. J Immunol. 1987 Jan 15;138(2):550–565. [PubMed] [Google Scholar]
  40. Hoffman R. A., Langrehr J. M., Billiar T. R., Curran R. D., Simmons R. L. Alloantigen-induced activation of rat splenocytes is regulated by the oxidative metabolism of L-arginine. J Immunol. 1990 Oct 1;145(7):2220–2226. [PubMed] [Google Scholar]
  41. Ignarro L. J., Buga G. M., Wood K. S., Byrns R. E., Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9265–9269. doi: 10.1073/pnas.84.24.9265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Inoue Y., Bode B. P., Beck D. J., Li A. P., Bland K. I., Souba W. W. Arginine transport in human liver. Characterization and effects of nitric oxide synthase inhibitors. Ann Surg. 1993 Sep;218(3):350–363. doi: 10.1097/00000658-199309000-00014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Janssens S. P., Shimouchi A., Quertermous T., Bloch D. B., Bloch K. D. Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase. J Biol Chem. 1992 Jul 25;267(21):14519–14522. [PubMed] [Google Scholar]
  44. Karupiah G., Xie Q. W., Buller R. M., Nathan C., Duarte C., MacMicking J. D. Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. Science. 1993 Sep 10;261(5127):1445–1448. doi: 10.1126/science.7690156. [DOI] [PubMed] [Google Scholar]
  45. Kaufman H. S., Shermak M. A., May C. A., Pitt H. A., Lillemoe K. D. Nitric oxide inhibits resting sphincter of Oddi activity. Am J Surg. 1993 Jan;165(1):74–80. doi: 10.1016/s0002-9610(05)80407-6. [DOI] [PubMed] [Google Scholar]
  46. Keaney J. F., Jr, Simon D. I., Stamler J. S., Jaraki O., Scharfstein J., Vita J. A., Loscalzo J. NO forms an adduct with serum albumin that has endothelium-derived relaxing factor-like properties. J Clin Invest. 1993 Apr;91(4):1582–1589. doi: 10.1172/JCI116364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Kilbourn R. G., Jubran A., Gross S. S., Griffith O. W., Levi R., Adams J., Lodato R. F. Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun. 1990 Nov 15;172(3):1132–1138. doi: 10.1016/0006-291x(90)91565-a. [DOI] [PubMed] [Google Scholar]
  48. Kubes P., Granger D. N. Nitric oxide modulates microvascular permeability. Am J Physiol. 1992 Feb;262(2 Pt 2):H611–H615. doi: 10.1152/ajpheart.1992.262.2.H611. [DOI] [PubMed] [Google Scholar]
  49. Kubes P., Suzuki M., Granger D. N. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4651–4655. doi: 10.1073/pnas.88.11.4651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Lancaster J. R., Jr, Langrehr J. M., Bergonia H. A., Murase N., Simmons R. L., Hoffman R. A. EPR detection of heme and nonheme iron-containing protein nitrosylation by nitric oxide during rejection of rat heart allograft. J Biol Chem. 1992 Jun 5;267(16):10994–10998. [PubMed] [Google Scholar]
  51. Lowenstein C. J., Alley E. W., Raval P., Snowman A. M., Snyder S. H., Russell S. W., Murphy W. J. Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9730–9734. doi: 10.1073/pnas.90.20.9730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Malawista S. E., Montgomery R. R., van Blaricom G. Evidence for reactive nitrogen intermediates in killing of staphylococci by human neutrophil cytoplasts. A new microbicidal pathway for polymorphonuclear leukocytes. J Clin Invest. 1992 Aug;90(2):631–636. doi: 10.1172/JCI115903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Marsden P. A., Heng H. H., Scherer S. W., Stewart R. J., Hall A. V., Shi X. M., Tsui L. C., Schappert K. T. Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene. J Biol Chem. 1993 Aug 15;268(23):17478–17488. [PubMed] [Google Scholar]
  54. Matsuyama T., Kimura T., Kitagawa M., Pfeffer K., Kawakami T., Watanabe N., Kündig T. M., Amakawa R., Kishihara K., Wakeham A. Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development. Cell. 1993 Oct 8;75(1):83–97. [PubMed] [Google Scholar]
  55. McCartney-Francis N., Allen J. B., Mizel D. E., Albina J. E., Xie Q. W., Nathan C. F., Wahl S. M. Suppression of arthritis by an inhibitor of nitric oxide synthase. J Exp Med. 1993 Aug 1;178(2):749–754. doi: 10.1084/jem.178.2.749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. McDonald B., Reep B., Lapetina E. G., Molina y Vedia L. Glyceraldehyde-3-phosphate dehydrogenase is required for the transport of nitric oxide in platelets. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11122–11126. doi: 10.1073/pnas.90.23.11122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. McDonald L. J., Moss J. Stimulation by nitric oxide of an NAD linkage to glyceraldehyde-3-phosphate dehydrogenase. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6238–6241. doi: 10.1073/pnas.90.13.6238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. McNamara D. B., Bedi B., Aurora H., Tena L., Ignarro L. J., Kadowitz P. J., Akers D. L. L-arginine inhibits balloon catheter-induced intimal hyperplasia. Biochem Biophys Res Commun. 1993 May 28;193(1):291–296. doi: 10.1006/bbrc.1993.1622. [DOI] [PubMed] [Google Scholar]
  59. Mearin F., Mourelle M., Guarner F., Salas A., Riveros-Moreno V., Moncada S., Malagelada J. R. Patients with achalasia lack nitric oxide synthase in the gastro-oesophageal junction. Eur J Clin Invest. 1993 Nov;23(11):724–728. doi: 10.1111/j.1365-2362.1993.tb01292.x. [DOI] [PubMed] [Google Scholar]
  60. Mellion B. T., Ignarro L. J., Ohlstein E. H., Pontecorvo E. G., Hyman A. L., Kadowitz P. J. Evidence for the inhibitory role of guanosine 3', 5'-monophosphate in ADP-induced human platelet aggregation in the presence of nitric oxide and related vasodilators. Blood. 1981 May;57(5):946–955. [PubMed] [Google Scholar]
  61. Michel T., Li G. K., Busconi L. Phosphorylation and subcellular translocation of endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6252–6256. doi: 10.1073/pnas.90.13.6252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Middleton S. J., Shorthouse M., Hunter J. O. Increased nitric oxide synthesis in ulcerative colitis. Lancet. 1993 Feb 20;341(8843):465–466. doi: 10.1016/0140-6736(93)90211-x. [DOI] [PubMed] [Google Scholar]
  63. Minnard E. A., Shou J., Naama H., Cech A., Gallagher H., Daly J. M. Inhibition of nitric oxide synthesis is detrimental during endotoxemia. Arch Surg. 1994 Feb;129(2):142–148. doi: 10.1001/archsurg.1994.01420260038004. [DOI] [PubMed] [Google Scholar]
  64. Molina y Vedia L., McDonald B., Reep B., Brüne B., Di Silvio M., Billiar T. R., Lapetina E. G. Nitric oxide-induced S-nitrosylation of glyceraldehyde-3-phosphate dehydrogenase inhibits enzymatic activity and increases endogenous ADP-ribosylation. J Biol Chem. 1992 Dec 15;267(35):24929–24932. [PubMed] [Google Scholar]
  65. Montague P. R., Gancayco C. D., Winn M. J., Marchase R. B., Friedlander M. J. Role of NO production in NMDA receptor-mediated neurotransmitter release in cerebral cortex. Science. 1994 Feb 18;263(5149):973–977. doi: 10.1126/science.7508638. [DOI] [PubMed] [Google Scholar]
  66. Morris S. M., Jr, Billiar T. R. New insights into the regulation of inducible nitric oxide synthesis. Am J Physiol. 1994 Jun;266(6 Pt 1):E829–E839. doi: 10.1152/ajpendo.1994.266.6.E829. [DOI] [PubMed] [Google Scholar]
  67. Nakaki T., Nakayama M., Kato R. Inhibition by nitric oxide and nitric oxide-producing vasodilators of DNA synthesis in vascular smooth muscle cells. Eur J Pharmacol. 1990 Dec 15;189(6):347–353. doi: 10.1016/0922-4106(90)90031-r. [DOI] [PubMed] [Google Scholar]
  68. Nakane M., Schmidt H. H., Pollock J. S., Förstermann U., Murad F. Cloned human brain nitric oxide synthase is highly expressed in skeletal muscle. FEBS Lett. 1993 Jan 25;316(2):175–180. doi: 10.1016/0014-5793(93)81210-q. [DOI] [PubMed] [Google Scholar]
  69. Nakayama D. K., Geller D. A., Di Silvio M., Bloomgarden G., Davies P., Pitt B. R., Hatakeyama K., Kagamiyama H., Simmons R. L., Billiar T. R. Tetrahydrobiopterin synthesis and inducible nitric oxide production in pulmonary artery smooth muscle. Am J Physiol. 1994 Apr;266(4 Pt 1):L455–L460. doi: 10.1152/ajplung.1994.266.4.L455. [DOI] [PubMed] [Google Scholar]
  70. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992 Sep;6(12):3051–3064. [PubMed] [Google Scholar]
  71. Nguyen T., Brunson D., Crespi C. L., Penman B. W., Wishnok J. S., Tannenbaum S. R. DNA damage and mutation in human cells exposed to nitric oxide in vitro. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3030–3034. doi: 10.1073/pnas.89.7.3030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Nishida K., Harrison D. G., Navas J. P., Fisher A. A., Dockery S. P., Uematsu M., Nerem R. M., Alexander R. W., Murphy T. J. Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthase. J Clin Invest. 1992 Nov;90(5):2092–2096. doi: 10.1172/JCI116092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Nussler A. K., Billiar T. R. Inflammation, immunoregulation, and inducible nitric oxide synthase. J Leukoc Biol. 1993 Aug;54(2):171–178. [PubMed] [Google Scholar]
  74. Nussler A. K., Billiar T. R., Liu Z. Z., Morris S. M., Jr Coinduction of nitric oxide synthase and argininosuccinate synthetase in a murine macrophage cell line. Implications for regulation of nitric oxide production. J Biol Chem. 1994 Jan 14;269(2):1257–1261. [PubMed] [Google Scholar]
  75. Nussler A. K., Di Silvio M., Billiar T. R., Hoffman R. A., Geller D. A., Selby R., Madariaga J., Simmons R. L. Stimulation of the nitric oxide synthase pathway in human hepatocytes by cytokines and endotoxin. J Exp Med. 1992 Jul 1;176(1):261–264. doi: 10.1084/jem.176.1.261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Nüssler A., Drapier J. C., Rénia L., Pied S., Miltgen F., Gentilini M., Mazier D. L-arginine-dependent destruction of intrahepatic malaria parasites in response to tumor necrosis factor and/or interleukin 6 stimulation. Eur J Immunol. 1991 Jan;21(1):227–230. doi: 10.1002/eji.1830210134. [DOI] [PubMed] [Google Scholar]
  77. Palmer R. M., Ferrige A. G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11;327(6122):524–526. doi: 10.1038/327524a0. [DOI] [PubMed] [Google Scholar]
  78. Panza J. A., Quyyumi A. A., Brush J. E., Jr, Epstein S. E. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990 Jul 5;323(1):22–27. doi: 10.1056/NEJM199007053230105. [DOI] [PubMed] [Google Scholar]
  79. Publicover N. G., Hammond E. M., Sanders K. M. Amplification of nitric oxide signaling by interstitial cells isolated from canine colon. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):2087–2091. doi: 10.1073/pnas.90.5.2087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Radomski M. W., Palmer R. M., Moncada S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet. 1987 Nov 7;2(8567):1057–1058. doi: 10.1016/s0140-6736(87)91481-4. [DOI] [PubMed] [Google Scholar]
  81. Rajfer J., Aronson W. J., Bush P. A., Dorey F. J., Ignarro L. J. Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. N Engl J Med. 1992 Jan 9;326(2):90–94. doi: 10.1056/NEJM199201093260203. [DOI] [PubMed] [Google Scholar]
  82. Ramagopal M. V., Leighton H. J. Effects of NG-monomethyl-L-arginine on field stimulation-induced decreases in cytosolic Ca2+ levels and relaxation in the rat anococcygeus muscle. Eur J Pharmacol. 1989 Dec 19;174(2-3):297–299. doi: 10.1016/0014-2999(89)90325-7. [DOI] [PubMed] [Google Scholar]
  83. Robertson F. M., Offner P. J., Ciceri D. P., Becker W. K., Pruitt B. A., Jr Detrimental hemodynamic effects of nitric oxide synthase inhibition in septic shock. Arch Surg. 1994 Feb;129(2):149–156. doi: 10.1001/archsurg.1994.01420260045005. [DOI] [PubMed] [Google Scholar]
  84. Rossaint R., Falke K. J., López F., Slama K., Pison U., Zapol W. M. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med. 1993 Feb 11;328(6):399–405. doi: 10.1056/NEJM199302113280605. [DOI] [PubMed] [Google Scholar]
  85. Schuman E. M., Madison D. V. A requirement for the intercellular messenger nitric oxide in long-term potentiation. Science. 1991 Dec 6;254(5037):1503–1506. doi: 10.1126/science.1720572. [DOI] [PubMed] [Google Scholar]
  86. Shah N., Jacob T., Exler R., Morrow S., Ford H., Albanese C., Wiener E., Rowe M., Billiar T., Simmons R. Inhaled nitric oxide in congenital diaphragmatic hernia. J Pediatr Surg. 1994 Aug;29(8):1010–1015. doi: 10.1016/0022-3468(94)90269-0. [DOI] [PubMed] [Google Scholar]
  87. Sherman P. A., Laubach V. E., Reep B. R., Wood E. R. Purification and cDNA sequence of an inducible nitric oxide synthase from a human tumor cell line. Biochemistry. 1993 Nov 2;32(43):11600–11605. doi: 10.1021/bi00094a017. [DOI] [PubMed] [Google Scholar]
  88. Shultz P. J., Raij L. Endogenously synthesized nitric oxide prevents endotoxin-induced glomerular thrombosis. J Clin Invest. 1992 Nov;90(5):1718–1725. doi: 10.1172/JCI116045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Sladek S. M., Regenstein A. C., Lykins D., Roberts J. M. Nitric oxide synthase activity in pregnant rabbit uterus decreases on the last day of pregnancy. Am J Obstet Gynecol. 1993 Nov;169(5):1285–1291. doi: 10.1016/0002-9378(93)90295-t. [DOI] [PubMed] [Google Scholar]
  90. Stuehr D. J., Marletta M. A. Mammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide. Proc Natl Acad Sci U S A. 1985 Nov;82(22):7738–7742. doi: 10.1073/pnas.82.22.7738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Stuehr D. J., Nathan C. F. Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med. 1989 May 1;169(5):1543–1555. doi: 10.1084/jem.169.5.1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Thiemermann C., Szabó C., Mitchell J. A., Vane J. R. Vascular hyporeactivity to vasoconstrictor agents and hemodynamic decompensation in hemorrhagic shock is mediated by nitric oxide. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):267–271. doi: 10.1073/pnas.90.1.267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Vallance P., Collier J., Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet. 1989 Oct 28;2(8670):997–1000. doi: 10.1016/s0140-6736(89)91013-1. [DOI] [PubMed] [Google Scholar]
  94. Vanderwinden J. M., Mailleux P., Schiffmann S. N., Vanderhaeghen J. J., De Laet M. H. Nitric oxide synthase activity in infantile hypertrophic pyloric stenosis. N Engl J Med. 1992 Aug 20;327(8):511–515. doi: 10.1056/NEJM199208203270802. [DOI] [PubMed] [Google Scholar]
  95. Vodovotz Y., Bogdan C., Paik J., Xie Q. W., Nathan C. Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor beta. J Exp Med. 1993 Aug 1;178(2):605–613. doi: 10.1084/jem.178.2.605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Weinberg J. B., Granger D. L., Pisetsky D. S., Seldin M. F., Misukonis M. A., Mason S. N., Pippen A. M., Ruiz P., Wood E. R., Gilkeson G. S. The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-L-arginine. J Exp Med. 1994 Feb 1;179(2):651–660. doi: 10.1084/jem.179.2.651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Werner-Felmayer G., Werner E. R., Fuchs D., Hausen A., Reibnegger G., Schmidt K., Weiss G., Wachter H. Pteridine biosynthesis in human endothelial cells. Impact on nitric oxide-mediated formation of cyclic GMP. J Biol Chem. 1993 Jan 25;268(3):1842–1846. [PubMed] [Google Scholar]
  98. Wilcox C. S., Welch W. J., Murad F., Gross S. S., Taylor G., Levi R., Schmidt H. H. Nitric oxide synthase in macula densa regulates glomerular capillary pressure. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):11993–11997. doi: 10.1073/pnas.89.24.11993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Xie Q. W., Kashiwabara Y., Nathan C. Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J Biol Chem. 1994 Feb 18;269(7):4705–4708. [PubMed] [Google Scholar]
  100. Xie Q. W., Whisnant R., Nathan C. Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide. J Exp Med. 1993 Jun 1;177(6):1779–1784. doi: 10.1084/jem.177.6.1779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Yim C. Y., Bastian N. R., Smith J. C., Hibbs J. B., Jr, Samlowski W. E. Macrophage nitric oxide synthesis delays progression of ultraviolet light-induced murine skin cancers. Cancer Res. 1993 Nov 15;53(22):5507–5511. [PubMed] [Google Scholar]
  102. Zhang J., Dawson V. L., Dawson T. M., Snyder S. H. Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity. Science. 1994 Feb 4;263(5147):687–689. doi: 10.1126/science.8080500. [DOI] [PubMed] [Google Scholar]

Articles from Annals of Surgery are provided here courtesy of Lippincott, Williams, and Wilkins

RESOURCES