Skip to main content
SpringerLink
Log in

Roles of nitric oxide, superoxide, and peroxynitrite in myocardial ischemia-reperfusion injury and ischemic preconditioning

  • Chapter
Nitric Oxide and Inflammation

Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

Ischemic heart disease, a major cause of mortality in industrialized countries, is characterized by insufficient blood supply to certain regions of the myocardium which leads to tissue necrosis (infarction). It develops secondary to a variety of disorders such as hypertension, atherosclerosis, dyslipidemia, and diabetes. The treatment of this condition has entered a new era in which mortality can be approximately halved by procedures which allow for the rapid restoration of blood flow (reperfusion), to the ischemie zone of the myocardium. Reperfusion, however, may lead to further complications such as diminished cardiac contractile function (stunning) and arrhythmias. Therefore, development of cardioprotective agents to improve myocardial function, decrease the incidence of arrhythmias, lessen necrotic tissue mass, and delay the onset of necrosis as a result of ischemia-reperfusion is of great clinical importance. The heart was also found to have an inherent ability to adapt to ischemie stress called ischemie preconditioning (PC) [1]. It is a well described adaptive response in which brief exposure of the heart to brief episode(s) of ischemia (PC ischemia) markedly enhances its ability to withstand a subsequent ischemie injury (test ischemia) (see for review see [2]).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Murry C, Jennings R, Reimer K (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74: 1124–1136

    Article  PubMed  CAS  Google Scholar 

  2. Ferdinandy P, Szilvassy Z, Baxter GF (1998) Adaptation to myocardial stress in disease states: is preconditioning a healthy heart phenomenon? Trends Pharmacol Sci 19: 223–229

    Article  PubMed  CAS  Google Scholar 

  3. Beckman JS, Koppenol WH (1996) Nitric oxide, Superoxide, and peroxynitrite: the good, the bad and ugly. Am J Physiol 271: C1424–C1437

    PubMed  CAS  Google Scholar 

  4. Rubbo H, Darley-Usmar V, Freeman B (1996) Nitric oxide regulation of tissue free radical injury. Chem Res Toxicol 9: 809–820

    Article  PubMed  CAS  Google Scholar 

  5. Mohazzab-H. KM, Kaminski PM, Fayngersh RP, Wolin MS (1996) Oxygen-elicited responses in calf coronary arteries: role of H2O2 production via NADH-derived superoxide. Am J Physiol 270: H1044–H1053

    PubMed  CAS  Google Scholar 

  6. Dupont GP, Huecksteadt TP, Marshall BC, Ryan US, Michael JR, Hoidal JR (1992) Regulation of xanthine dehydrogenase and xanthine oxidase activity and gene expression in cultured rat pulmonary endothelial cells. J Clin Invest 89: 197–202

    Article  PubMed  CAS  Google Scholar 

  7. Hare JM, Colucci WS (1995) Role of nitric oxide in the regulation of myocardial function. Prog Cardiovasc Dis 38: 155–166

    Article  PubMed  CAS  Google Scholar 

  8. Xie YW, Wolin MS (1996) Role of nitric oxide and its interaction with Superoxide in the suppression of cardiac muscle mitochondrial respiration. Circulation 94: 2580–2586

    Article  PubMed  CAS  Google Scholar 

  9. Rubbo H, Radi R, Trujillo M, Telleri R, Kalyanaraman B, Barnes S, Kirk M, Freeman BA (1994) Nitric oxide regulation of Superoxide and peroxynitrite-dependent lipid peroxidation. J Biol Chem 269: 26066–26075

    PubMed  CAS  Google Scholar 

  10. Kubes P, Suzuki M, Granger DN (1991) Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 88: 4651–4655

    Article  PubMed  CAS  Google Scholar 

  11. Radomski MW, Palmer RMJ, Moncada S (1987) The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. Br J Pharmacol 92: 639–646

    Article  PubMed  CAS  Google Scholar 

  12. Villa LM, Salas E, Darley-Usmar VM, Radomski MW, Moncada S (1994) Peroxynitrite induces both vasodilatation and impaired vascular relaxation in the isolated perfused heart. Proc Natl Acad Sci USA 91: 12388–12387

    Article  Google Scholar 

  13. Moro MA, Darley-Usmar VM, Goodwin DA, Read NG, Zamora-Pino R, Feelisch M, Radomski MW, Moneada S (1994) Paradoxical fate and biological action of peroxynitrite in human platelets. Proc Natl Acad Sci USA 91: 6702–6706

    Article  PubMed  CAS  Google Scholar 

  14. Depré C, Hue L (1994) Cyclic GMP in the perfused rat heart. Effect of ischaemia, anoxia and nitric oxide synthase inhibitor. FEBS Lett 345: 241–245

    Article  PubMed  Google Scholar 

  15. Csonka C, Szilvassy Z, Pali T, Blasig IE, Tosaki A, Schulz R, Ferdinandy P (1999) Classic preconditioning decreases the harmful accumulation of nitric oxide during ischemia and reperfusion in rat hearts. Circulation 100: 2260–2266

    Article  PubMed  CAS  Google Scholar 

  16. Yasmin W, Schulz R (1995) Detection of peroxynitrite after ischemia-reperfusion in isolated hearts. Circulation 92: 1–563 (abstract)

    Article  Google Scholar 

  17. Yasmin W, Strynadka KD, Schulz R (1997) Generation of peroxynitrite contributes to ischemia-reperfusion injury in isolated rat hearts. Cardiovasc Res 33: 422–432

    Article  PubMed  CAS  Google Scholar 

  18. Wang P, Zweier JL (1996) Measurement of nitric oxide and peroxynitrite generation in the postischemic heart. J Biol Chem 271: 29223–29230

    Article  PubMed  CAS  Google Scholar 

  19. Siegfried MR, Erhardt J, Rider T, Ma X-L, Lefer AM (1992) Cardioprotection and attenuation of endothelial dysfunction by organic nitric oxide donors in myocardial ischemia-reperfusion. J Pharmacol Exp Ther 260: 508–512

    Google Scholar 

  20. Weyrich AS, Ma X-L, Lefer A (1992) The role of L-arginine in ameliorating reperfusion injury after myocardial ischemia in the cat. Circulation 86: 279–288

    Article  PubMed  CAS  Google Scholar 

  21. Richard V, Blanc T, Kaeffer N, Tron C, Thuillez C (1995) Myocardial and coronary endothelial protective effects of acetylcholine after myocardial ischemia and reperfusion in rats: role of nitric oxide. Br J Pharmacol 115: 1532–1538

    Article  PubMed  CAS  Google Scholar 

  22. Grisham MB, Granger DN, Lefer DJ (1998) Modulation of leukocyte-endothelial interactions by reactive metabolites of oxygen and nitrogen: relevance to ischemie heart disease. Free Rad Biol Med 25: 404–433

    Article  PubMed  CAS  Google Scholar 

  23. Liu P, Hock CE, Nagele R, Wong PY-K (1997) Formation of nitric oxide, Superoxide, and peroxynitrite in myocardial ischemia-reperfusion injury in rats. Am J Physiol 272: H2327–H2337

    PubMed  CAS  Google Scholar 

  24. Boveris A, Chance B (1973) The mitochondrial generation of hydrogen peroxide: general properties and effect of hyperbaric oxygen. Biochem J 134: 707–716

    PubMed  CAS  Google Scholar 

  25. Troy CM, Derossi D, Prochiantz A, Green LA, Shelanski ML (1996) Downregulation of Cu/Zn Superoxide dismutase leads to cell death via the nitric oxide-peroxynitrite pathway. J Neurosci 16: 253–261

    PubMed  CAS  Google Scholar 

  26. Janssen M, Koster JF, Bos E, de Jong JW (1993) Malondialdehyde and glutathione production in isolated perfused human and rat hearts. Circ Res 73: 681–68

    Article  PubMed  CAS  Google Scholar 

  27. Quijano C, Alvarez B, Gatti RM, Augusto O, Radi R (1997) Pathways of peroxynitrite oxidation of thiol groups. Biochem J 322: 167–173

    PubMed  CAS  Google Scholar 

  28. Cheung P-Y, Schulz, R (1997) Glutathione causes coronary vasodilation via a nitric oxide-and soluble guanylate cyclase-dependent mechanism. Am J Physiol 273: H1231–H1238

    PubMed  CAS  Google Scholar 

  29. Mayer BA, Schrammel A, Klatt P, Koesling D, Schmidt K (1995) Peroxynitrite-induced accumulation of cyclic GMP in endothelial cells and stimulation of purified soluble guanylate cyclase. J Biol Chem 270: 17355–17360

    Article  PubMed  CAS  Google Scholar 

  30. Wu M, Pritchard KA, Kaminski PM, Fayngersh RP, Hinze H, Wolin MS (1994) Involvement of nitric oxide and nitrosothiols in relaxation of pulmonary arteries to peroxynitrite. Am J Physiol 266: H2108–H2113

    PubMed  CAS  Google Scholar 

  31. Kirschenbaum LA, Singal P (1993) Increase in endogenous antioxidant enzymes protect hearts against reperfusion injury. Am J Physiol 265: H484–H493

    Google Scholar 

  32. Cheung P-Y, Wang W, Schulz R (2000) Glutathione protects against myocardial ischemia-reperfusion injury by detoxifying peroxynitrite. J Mol Cell Cardiol 32: 1669–1678

    Article  PubMed  CAS  Google Scholar 

  33. Lefer DJ, Scalia R, Campbell B, Nossuli T, Hayward R, Salamon M, Grayson J, Lefer AM (1997) Peroxynitrite inhibits leukocyte-endothelial cell interactions and protects against ischemia-reperfusion injury in rats. J Clin Invest 99: 684–691

    Article  PubMed  CAS  Google Scholar 

  34. Nossuli TO, Hayward R, Jensen D, Scalia R, Lefer AM (1998) Mechanisms of cardioprotection by peroxynitrite in myocardial ischemia and reperfusion injury. Am J Physiol 275: H509–H519

    PubMed  CAS  Google Scholar 

  35. Ma XL, Lopez BL, Liu G-L, Christopher TA, Ischiropoulos H (1997) Peroxynitrite aggravates myocardial reperfusion injury in the isolated perfused rat heart. Cardiovasc Res 36: 195–204

    Article  PubMed  CAS  Google Scholar 

  36. Masini E, Bianchi S, Mugnai L, Gambassi F, Lupini M, Pistelli A, Mannaioni PF (1991) The effect of nitric oxide generators on ischemia reperfusion injury and histamine release in isolated perfused guinea-pig heart. Agents & Actions 33: 53–56

    Article  CAS  Google Scholar 

  37. Schoelkens BA, Linz W (1992) Bradykinin-mediated metabolic effects in isolated perfused rat hearts. Agents & Actions 38 (Suppl Pt 2): 36–42

    CAS  Google Scholar 

  38. Massoudy P, Becker BF, Gerlach E (1995) Nitric oxide accounts for postischemic cardioprotection resulting from angiotensin-converting enzyme inhibition: indirect evidence for a radical scavenger effect in isolated guinea pig heart. J Cardiovasc Pharmacol 25: 440–447

    Article  PubMed  CAS  Google Scholar 

  39. Xi L, Jarrett NC, Hess ML, Kukreja RC (1999) Essential role of inducible nitric oxide synthase in monophosphoryl lipid A-induced late cardioprotection: evidence from pharmacological inhibition and gene knockout mice. Circulation 99: 2157–2163

    Article  PubMed  CAS  Google Scholar 

  40. Jones SP, Girod WG, Palazzo AJ, Granger DN, Grisham MB, Jourd’Heuil D, Huang PL, Lefer DJ (1999) Myocardial ischemia-reperfusion injury is exacerbated in absence of endothelial cell nitric oxide synthase. Am J Physiol 276: H1567–H1573

    PubMed  CAS  Google Scholar 

  41. Yang XP, Liu YH, Shesely EG, Bulagannawar M, Liu F, Carretero OA (1999) Endothelial nitric oxide gene knockout mice: cardiac phenotypes and the effect of angio-tensin-converting enzyme inhibitor on myocardial ischemia/reperfusion injury. Hypertension 34: 24–30

    Article  PubMed  CAS  Google Scholar 

  42. Flogel U, Decking UKM, Godecke A, Schrader J (1999) Contribution of NO to ischemia-reperfusion injury in the saline-perfused heart: a study in endothelial NO synthase knockout mice. J Mol Cell Cardiol 31: 827–836

    Article  PubMed  CAS  Google Scholar 

  43. Schulz R, Wambolt R (1995) Inhibition of nitric oxide synthesis protects the isolated working rabbit heart from ischemia-reperfusion injury. Cardiovasc Res 30: 432–439

    PubMed  CAS  Google Scholar 

  44. Depré C, Vanoverschelde J-L, Goudemant J-F, Mottet I, Hue L (1995) Protection against ischemic injury by nonvasoactive concentrations of nitric oxide synthase inhibitors in the perfused rabbit heart. Circulation 92: 1911–1918

    Article  PubMed  Google Scholar 

  45. Woolfson RG, Patel VC, Neild GH, Yellon DM (1995) Inhibition of nitric oxide synthesis reduces infarct size by an adenosine-dependent mechanism. Circulation 91: 1545–1551

    Article  PubMed  CAS  Google Scholar 

  46. Buxton ILO, Cheek DJ, Eckman D, Westfall DP, Sanders KM, Keef KD. (1993) NG-nitro L-arginine methyl ester and other alkyl esters of arginine are muscarinic receptor antagonists. Circ Res 72: 387–395.

    Article  PubMed  CAS  Google Scholar 

  47. Hoshida S, Yamashita N, Igarashi J, Nishida M, Hori M, Kamada T, Kuzuya T, Tada M (1995) Nitric oxide synthase protects the heart against ischemia-reperfusion injury in rabbits. J Pharmacol Exp Ther 274: 413–418

    PubMed  CAS  Google Scholar 

  48. Williams M, Taft C, Ramnauth S, Zhao Z-Q, Vinten-Johansen J (1995) Endogenous nitric oxide (NO) protects against ischemia-reperfusion injury in the rabbit. Cardiovasc Res 30: 79–86

    PubMed  CAS  Google Scholar 

  49. Ohoi I, Takeo S (1996) Involvement of Superoxide and nitric oxide in the genesis of reperfusion arrhythmias in rats. Eur J Pharmacol 306: 123–131

    Article  PubMed  CAS  Google Scholar 

  50. Vegh A, Szekeres L, Parratt J (1992) Preconditioning of the ischaemic myocardium; Involvement of the L-arginine nitric oxide pathway. Br J Pharmacol 107: 648–652

    Article  PubMed  CAS  Google Scholar 

  51. Bilinska M, Maczewski M, Beresewicz A (1996) Donors of nitric oxide mimic effects of ischaemic preconditioning on reperfusion induced arrhythmias in isolated rat heart. Mol Cell Biochem 160-161: 265–271

    Article  PubMed  CAS  Google Scholar 

  52. Ferdinandy P, Szilvassy Z, Horvath LI, Csont T, Csonka C, Nagy E, Szentgyörgyi R, Nagy I, Koltai M, Dux L (1997) Loss of pacing-induced preconditioning in rat hearts: role of nitric oxide and cholesterol-enriched diet. J Mol Cell Cardiol 29: 3321–3333

    Article  PubMed  CAS  Google Scholar 

  53. Ferdinandy P, Csont T, Csonka C, Torok M, Dux M, Nemeth J, Horvath LI, Dux L, Szilvassy Z, Jancso G (1997) Capsaicin-sensitive local sensory innervation is involved in pacing-induced preconditioning in rat hearts: role of nitric oxide and CGRP? Naunyn Schmiedebergs Arch Pharmacol 356: 356–363

    Article  PubMed  CAS  Google Scholar 

  54. Wang P, Zweier JL (1997) Ischemic preconditioning decreases nitric oxide (NO) formation and NO mediated injury in the postischemic heart. Circulation 96 (Suppl 1): 72 (Abstract)

    Google Scholar 

  55. Zweier JL, Wang P, Samuilov A, Kuppusamy P (1995) Enzyme-independent formation of nitric oxide in biological tissues. Nature Med 1: 804–809

    Article  PubMed  CAS  Google Scholar 

  56. Vallance P, Leone A, Calver A, Collier J, Moncada S (1992) Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339: 572–575

    Article  PubMed  CAS  Google Scholar 

  57. Lu HR, Remeysen P, De Clerck F (1995) Does the antiarrhythmic effect of ischemie preconditioning in rats involve the L-arginine nitric oxide pathway. J Cardiovasc Pharmacol 25: 524–530

    Article  PubMed  CAS  Google Scholar 

  58. Weselcouch EO, Baird AJ, Sleph P, Grover GJ (1995) Inhibition of nitric oxide synthesis does not affect ischemie preconditioning in isolated perfused rat hearts. Am J Physiol 268: H242–H249

    PubMed  CAS  Google Scholar 

  59. Tanaka M, Fujiwara H, Yamasaki K, Sasayama S (1994) Superoxide dismutase and N-2-mercaptopropionyl glycine attenuate infarct size limitation effect of ischaemic preconditioning in the rabbit. Cardiovasc Res 28: 980–986

    Article  PubMed  CAS  Google Scholar 

  60. Osada M, Sato T, Komori S, Tamura K (1991) Protective effect of preconditioning on reperfusion induced ventricular arrhythmias of isolated rat hearts. Cardiovasc Res 25: 441–444

    Article  PubMed  CAS  Google Scholar 

  61. Tritto I, D’Andrea D, Eramo N, Scognamiglio A, De Simone C, Violante A, Esposito A, Chiariello M, Ambrosio G (1997) Oxygen radicals can induce preconditioning in rabbit hearts. Circ Res 80: 743–748

    Article  PubMed  CAS  Google Scholar 

  62. Tosaki A, Cordis GA, Szerdahelyi P, Engelman RM, Das DK (1994) Effects of preconditioning on reperfusion arrhythmias, myocardial functions, formation of free radicals, and ion shifts in isolated ischemic/reperfused rat hearts. J Cardiovasc Pharmacol 23: 365–373

    PubMed  CAS  Google Scholar 

  63. Iwamoto T, Miura T, Adachi T, Noto T, Ogawa T, Tsuchida, Iimura O (1991) Myocardial infarct size-limiting effect of ischemie preconditioning was not attenuated by oxygen free-radical scavengers in the rabbit. Circulation 83: 1015–1022

    Article  PubMed  CAS  Google Scholar 

  64. Bolli R, Manchikalapudi S, Tang XL, Takano H, Qiu Y, Guo Y, Zhang Q, Jadoon AK (1997) The protective effect of late preconditioning against myocardial stunning in conscious rabbits is mediated by nitric oxide synthase. Evidence that nitric oxide acts both as a trigger and as a mediator of the late phase of ischemie preconditioning. Circ Res 81: 1094–1107

    Article  PubMed  CAS  Google Scholar 

  65. Jones WK, Flaherty MP, Tang XL, Takano H, Qiu Y, Banerjee S, Smith T, Bolli R (1999) Ischemie preconditioning increases iNOS transcript levels in conscious rabbits via a nitric oxide-dependent mechanism. J Mol Cell Cardiol 31: 1469–1481

    Article  PubMed  CAS  Google Scholar 

  66. Guo Y, Jones WK, Xuan YT, Tang XL, Bao W, Wu WJ, Han H, Laubach VE, Ping P, Yang Z et al (1999) The late phase of ischemie preconditioning is abrogated by targeted disruption of the inducible NO synthase gene. Proc Natl Acad Sci USA 96: 11507–11512

    Article  PubMed  CAS  Google Scholar 

  67. Imagawa J, Yellon DM, Baxter GF (1999.) Pharmacological evidence that inducible nitric oxide synthase is a mediator of delayed preconditioning. Br J Pharmacol 126: 701–708

    Article  PubMed  CAS  Google Scholar 

  68. Kis A, Vegh A, Papp JG, Parratt JR (1999) Repeated cardiac pacing extends the time during which canine hearts are protected against ischaemia-induced arrhythmias: role of nitric oxide. J Mol Cell Cardiol 31: 1229–1241

    Article  PubMed  CAS  Google Scholar 

  69. Bolli R, Dawn B, Tang XL, Qiu Y, Ping P, Xuan YT, Jones WK, Takano H, Guo Y, Zhang J (1998) The nitric oxide hypothesis of late preconditioning. Basic Res Cardiol 93: 325–338

    Article  PubMed  CAS  Google Scholar 

  70. Sun JZ, Tang XL, Park SW, Qiu YM, Turrens JF, Bolli R (1996) Evidence for an essential role of reactive oxygen species in the genesis of late preconditioning against myocardial stunning in conscious pigs. J Clin Invest 97: 562–576

    Article  PubMed  CAS  Google Scholar 

  71. Zhou X, Zhai X, Ashraf M (1996) Direct evidence that initial oxidative stress triggered by preconditioning contributes to second window of protection by endogenous antioxidant enzyme in myocytes. Circulation 93: 1177–1184

    Article  PubMed  CAS  Google Scholar 

  72. Takano H, Tang XL, Qiu Y, Guo Y, French BA, Bolli R (1998) Nitric oxide donors induce late preconditioning against myocardial stunning and infarction in conscious rabbits via an antioxidant-sensitive mechanism. Circ Res 83: 73–84

    Article  PubMed  CAS  Google Scholar 

  73. Szabó C (1996) The pathophysiological role of peroxynitrite in shock, inflammation, and ischemia-reperfusion injury. Shock 79-88

    Google Scholar 

  74. Cheung P-Y, Sawicki G, Wozniak M, Wang W, Radomski M, Schulz R (2000) Matrix metalloproteinase-2 contributes to ischemia-reperfusion injury in the heart. Circulation 101: 1833–1839

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, Faculty of Medicine, University of Szeged, Dóm tér 9, Szeged, 6720, Hungary

    Péter Ferdinandy

  2. Cardiovascular Research Group, Departments of Pediatrics and Pharmacology, 4–62 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada

    Richard Schulz

Authors
  1. Péter Ferdinandy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard Schulz
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. MetaPhore Pharmaceuticals, 3655 Vista Avenue, St. Louis, MO, 63110, USA

    Daniela Salvemini Ph.D.

  2. Department of Surgery, A1010 Presbyterian University Hospital, 200 Lothrop Street, Pittsburgh, PA, 15213, USA

    Timothy R. Billiar M.D.

  3. Department of Surgery, UPMC Montefiore, University of Pittsburgh, NW 653 3459 Fifth Avenue, Pittsburgh, PA, 15213, USA

    Yoram Vodovotz Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 2001 Springer Basel AG

About this chapter

Cite this chapter

Ferdinandy, P., Schulz, R. (2001). Roles of nitric oxide, superoxide, and peroxynitrite in myocardial ischemia-reperfusion injury and ischemic preconditioning. In: Salvemini, D., Billiar, T.R., Vodovotz, Y. (eds) Nitric Oxide and Inflammation. Progress in Inflammation Research. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8241-5_12

Download citation

  • DOI: https://doi.org/10.1007/978-3-0348-8241-5_12

  • Publisher Name: Birkhäuser, Basel

  • Print ISBN: 978-3-0348-9488-3

  • Online ISBN: 978-3-0348-8241-5

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation