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Mesenteric Artery Clamping/Unclamping-Induced Acute Lung Injury Is Attenuated by N-Methyl-D-Aspartate Antagonist Dextromethorphan

Abstract

Lung N-methyl-D-aspartate receptors (NMDAR) may cause excitotoxic pulmonary edema if activated. Acute lung injury may be mediated by oxidative stress, frequently generated by local or remote ischemia and reperfusion (IR). This experimental study assessed the effects of intravenous dextromethorphan, an NMDAR antagonist, on reperfusion lung injury following superior mesenteric artery (SMA) clamping/unclamping. SMA of 48 (12 per group) anesthetized adult male Wistar rats was clamped for 90 min (IR); 48 additional rats underwent a sham laparotomy (control). The experimental timeframe was identical in all groups. Ten minutes before unclamping, three dextromethorphan doses were administered intravenously in three IR and three control groups, followed by 3 h of respiratory and hemodynamic assessment and postexperimental assessment of survival. Intravenous 10 and 20 mg/kg dextromethorphan attenuated an 85% increase in peak ventilatory pressure, a 45% reduction in PO2/FiO2, 4–12-fold increase in bronchoalveolar lavage-retrieved volume, and polymorphonuclear leukocytes/bronchoalveolar cells ratio, all associated with SMA unclamping in the IR-nontreated and the IR-40 mg/kg dextromethorphan-treated rats. Lung tissue polymorphonuclear leukocyte count, total xanthine oxidase activity, reduced glutathione, and wet-to-dry weight ratio were all within normal ranges in the two lower-dose-treated groups. These effective regimens were also associated with longer postexperimental animal survival. Dextromethorphan was not associated with changes in three control groups. Thus, Intravenous dextromethorphan mitigates lung reperfusion injury following SMA clamping/unclamping in a dose-dependent manner. This is a novel potential use of dextromethorphan in vivo.

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References

  1. Barnard ML, Baker RR, Matalon S (1993) Mitigation of oxidant injury to lung microvasculature by intratracheal instillation of antioxidant enzymes. Am J Physiol 265:L340–L345

    PubMed  CAS  Google Scholar 

  2. Ben-Abraham R, Matza M, Marmor S, et al. (2003) Electromechanical impairment of human auricle and rat myocardial strip subjected to exogenous oxidative stress. Eur J Cardiothorac Surg 23:66–73

    PubMed  Article  Google Scholar 

  3. Britton P, Lu XC, Laskosky MS, Tortella FC (1997) Dextromethorphan protects against cerebral injury following transient, but not permanent, focal ischemia in rats. Life Sci 60:1729–1740

    PubMed  CAS  Article  Google Scholar 

  4. Buchan AM, Silvka A, Xue D (1992) The effect of the NMDA receptor antagonist MK-801 on cerebral blood flow and infarct volume in experimental focal stroke. Brain Res 574:171–177

    PubMed  CAS  Article  Google Scholar 

  5. Church J, Shacklock JA, Baimbridge KG (1991) Dextromethorphan and phencyclidine receptor ligands: differential effects on K(+)- and NMDA-evoked increases in cytosolic free Ca2+ concentration. Neurosci Lett 124:232–234

    PubMed  CAS  Article  Google Scholar 

  6. Cotgreave IA, Grafström RC, Moldeus P (1986) Modulation of pneumotoxicity by cellular glutathione and precursors. Bull Eur Physiopathol Respir 22:263s–266

    PubMed  CAS  Google Scholar 

  7. Dickman KG, Youssef JG, Mathew SM, Said SI (2004) Ionotropic glutamate receptors in lungs and airways. Molecular basis for glutamate toxicity. Am J Respir Cell Mol Biol 30:139–144

    CAS  Article  Google Scholar 

  8. Emre S, Schwartz ME, Katz E, Miller CM (1993) Liver resection under total vascular isolation. Variations on a theme. Ann Surg 217:15–19

    PubMed  CAS  Article  Google Scholar 

  9. Friedl HP, Smith DJ, Till GO, et al. (1990) Ischemia-reperfusion in humans. Appearance of xanthine oxidase activity. Am J Pathol 136:491–495

    PubMed  CAS  Google Scholar 

  10. Galili Y, Ben-Abraham R, Weinbroum A, et al. (1998) Methylene blue prevents pulmonary injury following intestinal ischemia reperfusion. J Trauma 45:222–226

    PubMed  CAS  Google Scholar 

  11. Gelman S (1995) The pathophysiology of aortic cross-clamping and unclamping. Anesthesiology 82:1026–1060

    PubMed  CAS  Article  Google Scholar 

  12. Hansbrough JF, Wikstrom T, Braide M, et al. (1996) Neutrophil activation and tissue neutrophil sequestration in a rat model of thermal injury. J Surg Res 61:17–22

    PubMed  CAS  Article  Google Scholar 

  13. Hashimoto S (1974) A new spectrophotometric assay method of xanthine oxidase in crude tissue homogenate. Anal Biochem 62:426–435

    PubMed  CAS  Article  Google Scholar 

  14. Inagaki N, Kuromi H, Gonoi T, Okamoto Y, et al. (1995) Expression and role of ionotropic glutamate receptors in pancreatic islet cells. FASEB J 9:686–691

    PubMed  CAS  Google Scholar 

  15. Jain A, Mårtesson J, Stole E, Auld PAM, Meister A (1991) Glutathione deficiency leads to mitochondrial damage in brain. Proc Natl Acad Sci USA 88:1913–1917

    PubMed  CAS  Article  Google Scholar 

  16. Kim JJ, Moon DG, Koh SK (1998) The role of nitric oxide in vivo feline erection under hypoxia. Int J Impot Res 10:145–151

    PubMed  CAS  Article  Google Scholar 

  17. Koike K, Moore EE, Moore FA, et al. (1995) Gut phospholipase A2 mediates neutrophil priming and lung injury after mesenteric ischemia-reperfusion. Am J Physiol 268:G397–403

    PubMed  CAS  Google Scholar 

  18. Kretzschmar M, Klein U, Palutke M, Schirrmeister W (1996) Reduction of ischemia-reperfusion syndrome after abdominal aortic aneurysmectomy by N-acetylcysteine but not mannitol. Acta Anaesthesiol Scand 40: 657–664

    PubMed  CAS  Google Scholar 

  19. Larsen M, Webb G, Kennington S, et al. (2002) Mannitol in cardioplegia as an oxygen free radical scavenger measured by malondialdehyde. Perfusion 17:51–55

    PubMed  CAS  Article  Google Scholar 

  20. Lee F (1991) Oxidants injury to pulmonary endothelium. In: Said SI (ed) The Pulmonary Circulation and Acute Lung Injury, 2nd ed. Futura Publishing Co., Mount Kisco NY, pp 403–432

    Google Scholar 

  21. Leung JC, Travis BR, Verlander JW, et al. (2002) Expression and developmental regulation of the NMDA receptor subunits in the kidney and cardiovascular system. Am J Physiol Regul Integr Comp Physiol 283:R964–971

    PubMed  Google Scholar 

  22. Lu YT, Hellewell PG, Evans TW (1997) Ischemia-reperfusion lung injury: contribution of ischemia, neutrophils, and hydrostatic pressure. Am J Physiol 273:L46–54

    PubMed  CAS  Google Scholar 

  23. Nielsen VG, Weinbroum A, Tan S, et al. (1994) Xanthine oxidoreductase release after descending thoracic aorta occlusion and reperfusion in rabbits. J Thorac Cardiovasc Surg 107:1222–1227

    PubMed  CAS  Google Scholar 

  24. Polak MJ, Xiao S, Ashton CA, Baylis C (2002) NMDA alters the development of hypoxic pulmonary vasoconstriction and nitric oxide synthetase activity in the isolated perfused rat lung. Exp Lung Res 28:251–263

    PubMed  CAS  Article  Google Scholar 

  25. Price DD, Mao J, Frenk H, Mayer DJ (1994) The N-methyl-D-aspartate receptor antagonist dextromethorphan selectively reduces temporal summation of second pain in man. Pain 59:165–174

    PubMed  CAS  Article  Google Scholar 

  26. Reynolds IJ, Hastings TG (1995) Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. J Neurosci 15:3318–3327

    PubMed  CAS  Google Scholar 

  27. Said SI (1991) Glutamate receptors and asthmatic airway disease. Trends Pharmacol Sci 20:132–135

    Article  Google Scholar 

  28. Said SI, Berisha HI, Pakbaz H (1996) Excitoxicity in the lung: N-methyl-D-aspartate-induced, nitric oxide-dependent, pulmonary edema is attenuated by vasoactive intestinal peptide and by inhibitors of poly (ADP-ribose) polymerase. Proc Natl Acad Sci USA 93:4688–4692

    PubMed  CAS  Article  Google Scholar 

  29. Said SI, Pakbaz H, Berisha HI, Raza S, Foda HD (2000) NMDA receptor activation: critical role in oxidant tissue injury. Free Radic Biol Med 28:1300–1302

    PubMed  CAS  Article  Google Scholar 

  30. Schmid-Elsaesser R, Zausinger S, Hungerhuber E, Baethmann A, Reulen HJ (1998) Monotherapy with dextromethorphan or tirilazad—but not a combination of both—improves outcome after transient focal cerebral ischemia in rats. Exp Brain Res 122:121–127

    PubMed  CAS  Article  Google Scholar 

  31. Shen W, Zhang C, Zhang G (2002) Nuclear factor kappaB activation is mediated by NMDA and non-NMDA receptor and L-type voltage-gated Ca(2+) channel following severe global ischemia in rat hippocampus. Brain Res 933:23–30

    PubMed  CAS  Article  Google Scholar 

  32. Steinberg GK, Kunis D, DeLaPaz R, Poljak A (1993) Neuroprotection following focal cerebral ischaemia with the NMDA antagonist dextromethorphan, has a favourable dose response profile. Neurol Res 15:174–180

    PubMed  CAS  Google Scholar 

  33. Terada LS, Dormish JJ, Shanley PF, et al. (1992) Circulating xanthine oxidase mediates lung neutrophil sequestration after intestinal ischemia-reperfusion. Am J Physiol 263:L394–401

    PubMed  CAS  Google Scholar 

  34. Tortella FC, Britton P, Williams A, Lu XC, Newman AH (1999) Neuroprotection (focal ischemia) and neurotoxicity (electroencephalographic) studies in rats with AHN649, a 3-amino analog of dextromethorphan and low-affinity N-methyl-D-aspartate antagonist. J Pharmacol Exp Ther 291:399–408

    PubMed  CAS  Google Scholar 

  35. Weinbroum AA (2004) Methylene blue attenuates lung injury after mesenteric artery clamping/unclamping. Eur J Clin Invest 34:436–442

    PubMed  CAS  Article  Google Scholar 

  36. Weinbroum A, Nielsen VG, Tan S, et al. (1995) Liver ischemia-reperfusion increases pulmonary permeability in rat: role of circulating xanthine oxidase. Am J Physiol 268:G988–996

    PubMed  CAS  Google Scholar 

  37. Weinbroum AA, Goldman G, Kluger Y, et al. (1997) Bowel ischemia/reperfusion-induced liver and lung injury: elemental role of eicosanoids and oxygen free radicals. Med Sci Monit 3:624–630

    CAS  Google Scholar 

  38. Weinbroum AA, Hochhauser E, Rudick V, et al. (1999) Mediation of multiple organ dysfunction by radical oxygen species following remote circulatory arrest. Common mechanism of action? J Trauma 47:691–698

    PubMed  CAS  Google Scholar 

  39. Weinbroum AA, Kluger Y, Shapira I, Rudick V (2001) Methylene blue abolishes aortal tone impairment induced by liver ischemia-reperfusion in a dose response manner: an isolated-perfused double-organ rat model study. Shock 15:226–230

    PubMed  CAS  Article  Google Scholar 

  40. Weinbroum AA, Goldin I, Kluger Y, Szold A (2002) Methylene blue in preventing hemodynamic and metabolic derangement following superior mesenteric artery clamping/unclamping: an intratracheal vs. intraperitoneal dose-response study. Shock 17:372–376

    PubMed  Article  Google Scholar 

  41. Woolf CJ (1996) Windup and central sensitization are not equivalent. Pain 66:105–108

    PubMed  CAS  Article  Google Scholar 

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Correspondence to Avi A. Weinbroum.

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This study was supported in part by the Italian Anonymous Family Fund, Milan, Italy.

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Ben-Abraham, R., Guttman, M., Flaishon, R. et al. Mesenteric Artery Clamping/Unclamping-Induced Acute Lung Injury Is Attenuated by N-Methyl-D-Aspartate Antagonist Dextromethorphan. Lung 184, 309–317 (2006). https://doi.org/10.1007/s00408-006-0029-9

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Keywords

  • Ischemia-reperfusion
  • Intestine
  • Lung
  • Injury
  • N-methyl-D-aspartate receptor
  • Antagonist
  • Dextromethorphan