Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
5-Year IF – 2.0, IF – 1.9, JCI (2024) – 0.43
Scopus CiteScore – 4.3
Q1 in SJR 2024, SJR score – 0.598, H-index: 49 (SJR)
ICV – 161.00; MNiSW – 70 pts
Initial editorial assessment and first decision within 24 h

ISSN 1899–5276 (print), ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2014, vol. 23, nr 3, May-June, p. 343–351

Publication type: original article

Language: English

The Effects of Ketamine, Midazolam and Ketamine/Xylazine on Acute Lung Injury Induced by α-Naphthylthiourea in Rats

Mehmet Kivanc Erdem1,A,B, Gamze Yurdakan2,C, Emine Yilmaz-Sipahi3,A,B,C,D,E,F

1 Department of Medical Pharmacology, Health Science Institute, Bulent Ecevit University, Turkey

2 Department of Pathology, Faculty of Medicine, Bulent Ecevit University, Turkey

3 Department of Pharmacology, Faculty of Medicine, Bulent Ecevit University, Turkey

Abstract

Objectives. Ketamine is a drug used in human and veterinary medicine, primarily for the induction and maintenance of general anesthesia, analgesia (particularly in emergency medicine), and treatment of bronchospasm. Midazolam is the preferred drug in intensive care units for sedation and anesthesia. Ketamine/xylazine combination is used as an anesthetic agent in veterinary medicine and experimental animals. Aside from anaesthetic properties, these agents can cause physiologic and metabolic alterations and modulate and improve the inflammatory responses. The objective of the present study was to investigate the effects of ketamine, midazolam, and veterinary and experimentally used ketamine/xylazine combination in acute lung injury induced by α-naphthylthiourea (ANTU).
Material and Methods. ANTU was injected intraperitoneally (i.p.) in rats at the dose of 10 mg/kg. Ketamine (15, and 50 mg/kg, i.p.), midazolam (2 and 4 mg/kg, i.p.), and ketamine/xylazine (50/10 mg/kg, i.p.) administered to rats 30 min prior to ANTU. Four hours later, the lung weight/body weight (LW/BW) ratio and pleural effusion (PE) were measured. Histopathological changes were documented in each lung tissue, including intra-alveolar hemorrhage, alveolar edema and inflammation. The severity of the lung injury was scored (0–3).
Results. Ketamine, midazolam and ketamine/xylazine had a significant prophylactic effect on pleural effusion formation at all doses and significantly reduced pleural effusion. Ketamine caused a significant reduction of inflammation, hemorrhage and edema scoring and midazolam (2 mg/kg) and ketamine/xylazine caused a significant reduction of inflammation and edema scoring.
Conclusion. It can be concluded that ketamine and midazolam may attenuate lung injuries induced by ANTU. In addition to their anesthetic or sedative properties, the prophylactic effects of these agents on lung tissue damage will contribute to the treatment of intensive care unit diseases including acute lung injury. Similarly, the effects of these agents on lung pathophysiology should be considered in experimental applications.

Key words

acute lung injury, pulmonary edema, pleural effusion, anaesthetic agents, a-naphthylthiourea.

References (39)

  1. Jain R and DalNogare A: Pharmacological therapy for acute respiratory distress syndrome. Mayo Clin Proc 2006, 81, 205–212.
  2. Matthay MA, Zimmerman GA, Esmon C, Bhattacharya J, Coller B, Doerschuk CM: Future research directions in acute lung injury: summary of a National Heart, Lung, and Blood Institute Working Group. Am J Respir Crit Care Med 2003, 167, 1027–1035.
  3. Bellingan GJ: The pulmonary physician in critical care *6: The pathogenesis of ALI/ARDS. Thorax 2002, 57, 540–546.
  4. Monahan LJ: Acute respiratory distress syndrome. Curr Probl Pediatr Adolesc Health Care 2013, 43, 278–284.
  5. Hanci V, Yurdakan G, Yurtlu S, Turan IO, Sipahi EY: Protective effect of dexmedetomidine in a rat model of alpha-naphthylthiourea-induced acute lung injury. J Surg Res 2012, 1–7.
  6. Comert M, Sipahi EY, Ustun H, Isikdemir F, Numanoglu G, Barut F: Morphine modulates inducible nitric oxide synthase expression and reduces pulmonary oedema induced by alpha-naphthylthiourea. Eur J Pharmacol 2005, 511, 183–189.
  7. Sipahi E, Ustun H, Niyazi Ayoglu F: Acute effects of pentobarbital, thiopental and urethane on lung oedema induced by alpha-naphthythiourea (ANTU). Pharmacol Res 2002, 45, 235–239.
  8. Yu M, Shao D, Yang R, Feng X, Zhu S, Xu J: Effects of ketamine on pulmonary inflammatory responses and survival in rats exposed to polymicrobial sepsis. J Pharm Pharm Sci 2007, 10, 434–442.
  9. Yang J, Li W, Duan M, Zhou Z, Lin N, Wang Z: Large dose ketamine inhibits lipopolysaccharide-induced acute lung injury in rats. Inflamm Res 2005, 54, 133–137.
  10. Zhang X, Feng J, Zhu P, Zhao Z: Ketamine inhibits calcium elevation and hydroxyl radical and nitric oxide production in lipopolysaccharide-stimulated NR8383 alveolar macrophages. Inflammation 2013, 36, 1094–1100.
  11. Scott AM, Powell GM, Upshall DG, Curtis CG: Pulmonary toxicity of thioureas in the rat. Environ Health Perspect 1990, 85, 43–50.
  12. Richter CP: The physiology and cytology of pulmonary edema and pleural effusion produced in rats by alpha-naphthyl thiourea (ANTU). J Thorac Surg 1952, 23, 66–91.
  13. Cunningham AL, Hurley JV: Alpha-naphthyl-thiourea-induced pulmonary oedema in the rat: a topographical and electron-microscope study. J Pathol 1972, 106, 25–35.
  14. Torre D, Minoja G, Maraggia D, Chiaranda M, Tambini R, Speranza F: Effect of recombinant IL-1 beta and recombinant gamma interferon on septic acute lung injury in mice. Chest 1994, 105, 1241–1245.
  15. Calikoglu M, Tamer L, Sucu N, Coskun B, Ercan B, Gul A: The effects of caffeic acid phenetyl ester on tissue damage in lung after hindlimb ischemia-reperfusion. Pharmacol Res 2003, 48, 397–403.
  16. Sipahi EY, Ozel Tekin I, Comert M, Barut F, Ustun H, Sipahi TH: Oxidized low-density lipoproteins accumulate in rat lung after experimental lung edema induced by alpha-naphthylthiourea (ANTU). Pharmacol Res 2004, 50, 585–591.
  17. Sipahi E, Hodoglugil U, Ercan ZS, Türker RK: Acute effect of endothelin-1 on lung oedema induced by alphanaphthylthiourea (ANTU). Pharmacol Res 1996, 33, 375–378.
  18. Sipahi E, Hodoglugil U, Ustun H, Zengil H, Türker RK, Ercan ZS: An unexpected interaction between NG-nitro-L-arginine methyl ester and L-arginine in alpha-naphthylthiourea-induced pulmonary oedema in rats. Eur J Pharmacol 1997, 321, 45–51.
  19. Meyrick B, Miller J, Reid L: Pulmonary edema induced by ANTU or by high or low oxygen concentrations in rat—an electron microscopic study. Br J Exp Pathol 1972, 53, 347–358.
  20. Wiener-Kronish JP and Broaddus VC: Interrelationship of pleural and pulmonary interstitial liquid. Ann Rev Physiol 1993, 55, 209–226.
  21. Pankhania JJ, Bakhle YS: Effect of pulmonary oedema induced by alpha-naphthylthiourea on synthesis of cyclooxygenase products in rat isolated lungs. Prostaglandins 1985, 30, 37–49.
  22. Hardwick SJ, Skamarauskas JT, Smith LL, Upshall DG, Cohen GM: Protection of rats against the effects of alpha-naphthylthiuorea (ANTU) by elevation of non-protein sulphydryl levels. Biochem Pharmacol 1991, 42, 1203–1208.
  23. Rzeski W, Ikonomidou C, Turski L: Glutamate antagonists limit tumor growth. Biochem Pharmacol 2002, 64, 1195–1200.
  24. Said SI, Berisha HI, Pakbaz H: Excitotoxicity 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 1996, 93, 4688–4692.
  25. Zhu MM, Qian YN, Zhu W, Xu YM, Rong HB, Ding ZN: Protective effects of ketamine on allergen-induced airway inflammatory injure and high airway reactivity in asthma: Experiment with rats. Zhonghua Yi Xue Za Zhi 2007, 87, 1308–1313.
  26. Bowles ED and Gold ME: Rethinking the paradigm: evaluation of ketamine as a neurosurgical anesthetic. AANA J 2012, 80, 445–452.
  27. Allen JY, Macias CG: The efficacy of ketamine in pediatric emergency department patients who present with acute severe asthma. Ann Emerg Med 2005, 46, 43–50.
  28. Leal Filho MB, Morandin RC, de Almeida AR, Cambiucci EC, Borges G, Gontijo JA: Importance of anesthesia for the genesis of neurogenic pulmonary edema in spinal cord injury. Neurosci Lett 2005, 373, 165–170.
  29. Sun J, Li F, Chen J, Xu J: Effect of ketamine on NF-kappa B activity and TNF-alpha production in endotoxintreated rats. Ann Clin Lab Sci 2004, 34, 181–186.
  30. Helmer KS, Cui Y, Dewan A, Mercer DW: Ketamine/xylazine attenuates LPS-induced iNOS expression in various rat tissues. J Surg Res 2003, 112, 70–78.
  31. Weigand MA, Schmidt H, Zhao Q, Plaschke K, Martin E, Bardenheuer HJ: Ketamine modulates the stimulated adhesion molecule expression on human neutrophils in vitro. Anesth Analg 2000, 90, 206–212.
  32. Gokcinar D, Ergin V, Cumaoglu A, Menevse A, Aricioglu A: Effects of ketamine, propofol, and ketofol on proinflammatory cytokines and markers of oxidative stress in a rat model of endotoxemia-induced acute lung injury. Acta Biochim Pol 2013, 60, 451–456.
  33. Fessler HE, Otterbein L, Chung HS, Choi AM: Alpha-2 adrenoceptor blockade protects rats against lipopolysaccharide. Am J Respir Crit Care Med 1996, 154, 1689–1693.
  34. Szelenyi J, Kiss JP, Puskas E, Selmeczy Z, Szelényi M, Vizi ES: Opposite role of alpha2- and beta-adrenoceptors in the modulation of interleukin-10 production in endotoxaemic mice. Neuroreport 2000, 11, 3565–3568.
  35. Helmer KS, Cui Y, Chang L, Dewan A, Mercer DW: Effects of ketamine/xylazine on expression of tumor necrosis factor-alpha, inducible nitric oxide synthase, and cyclo-oxygenase-2 in rat gastric mucosa during endotoxemia. Shock 2003, 20, 63–69.
  36. Zavala F, Taupin V, Descamps-Latscha B: In vivo treatment with benzodiazepines inhibits murine phagocyte oxidative metabolism and production of interleukin 1, tumor necrosis factor and interleukin-6. J Pharmacol Exp Ther 1990, 255, 442–450.
  37. Joo HK, Oh SC, Cho EJ, Park KS, Lee JY, Lee EJ: Midazolam inhibits tumor necrosis factor-alpha-induced endothelial activation: involvement of the peripheral benzodiazepine receptor. Anesthesiology 2009, 110, 106–112.
  38. Kim SN, Son SC, Lee SM, Kim CS, Yoo DG, Lee SK: Midazolam inhibits proinflammatory mediators in the lipopolysaccharide-activated macrophage. Anesthesiology 2006, 105, 105–110.
  39. Tsao CM, Wu CC, Liaw WJ, Ho ST: Effects of midazolam on organ dysfunction in rats with endotoxemia induced by lipopolysaccharide. Acta Anaesthesiol Taiwan 2009, 47, 10–16.
© Wroclaw Medical University