Skip to main content
Log in

The protective effect of amiodarone in lung tissue of cecal ligation and puncture-induced septic rats: a perspective from inflammatory cytokine release and oxidative stress

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Sepsis is a serious medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. Amiodarone is a class III antiarrhythmic agent, a multichannel blocker (Ca++, Na+, and K+), and a noncompetitive α- and β-adrenergic blocker in cardiac cells. The present study aimed to determine whether amiodarone was protective against experimentally induced cecal ligation and puncture sepsis in rat lung tissue. The relationship between its probable protective effect and antioxidant/anticytokine action biochemically and histopathologically was also examined. Five groups of rats were used, each composed of 20 rats: (1) the sham-operated control group; (2) the CLP group; (3) the 25-mg/kg amiodarone-treated control healthy group; (4) the 50-mg/kg amiodarone-treated CLP group; and (5) the 50-mg/kg amiodarone-treated CLP group. A CLP polymicrobial sepsis model was applied to the rats. All groups were sacrificed 16 h later, and lung and blood samples were analyzed histopathologically and biochemically. Twenty-five and 50 mg/kg amiodarone decreased the level of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in serum and 8-iso-prostaglandin F2α level in lung tissue. They increased the activities of superoxide dismutase and levels of total glutathione in lung tissues of rats. Histopathological scores and examinations were in accordance with the biochemical results. Histopathological analysis revealed significant differences in inflammation scores between the sepsis group and the other groups. The CLP + amiodarone 50 mg/kg group had the lowest inflammation score among CLP groups. Our results indicate that administration of amiodarone prevented oxidative stress and cytokine action and protected lung tissue during sepsis cascade.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Ajaikumar KB, Asheef M, Babu BH, Padikkala J (2005) The inhibition of gastric mucosal injury by Punicagranatum L. (pomegranate) methanolic extract. J Ethnopharmacol 96:171–176

    Article  PubMed  CAS  Google Scholar 

  • Akkuş T (1995) Serbest radikaller ve fizyopatolojik etkileri. Mimoza yayınları, Konya

    Google Scholar 

  • Albayrak A, Uyanik MH, Odabasoglu F, Halici Z, Uyanik A, Bayir Y, Albayrak F, Albayrak Y, Polat B, Suleyman H (2011) The effects of diabetes and/or polymicrobial sepsis on the status of antioxidant enzymes and pro-inflammatory cytokines on heart, liver, and lung of ovariectomized rats. J Surg Res 169:67–75

    Article  PubMed  CAS  Google Scholar 

  • Antonini JM, McCloud CM, Reasor MJ (1994) Acute silica toxicity: attenuation by amiodarone-induced pulmonary phospholipidosis. Environ Heal Perspect 102:372–378

    Article  CAS  Google Scholar 

  • Babayigit H, Kucuk C, Sozuer E, Yazici C, Kose K, Akgun H (2005) Protective effect of beta-glucan on lung injury after cecal ligation and puncture in rats. Intensive Care Med 31:865–870

    Article  PubMed  Google Scholar 

  • Basu S, Hellberg A, Ulus AT, Westman J, Karacagil S (2001) Biomarkers of free radical injury during spinal cord ischemia. FEBS Lett 508:36–38

    Article  PubMed  CAS  Google Scholar 

  • Bhatia M, Moochhala S (2004) Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol 202:145–156

    Article  PubMed  CAS  Google Scholar 

  • Blackwell TS, Christman JW (1996) Sepsis and cytokines: current status. Br J Anaesth 77:110–117

    Article  PubMed  CAS  Google Scholar 

  • Blake TL, DiMatteo M, Antonini JM, McCloud CM, Reasor MJ (1996) Subchronic pulmonary inflammation and fibrosis induced by silica in rats are attenuated by amiodarone. Exp Lung Res 22:113–131

    Article  PubMed  CAS  Google Scholar 

  • Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101:1644–1655

    Article  PubMed  CAS  Google Scholar 

  • Buttke TM, Sandstrom PA (1994) Oxidative stress as a mediator of apoptosis. Immunol Today 15:7–10

    Article  PubMed  CAS  Google Scholar 

  • Cadirci E, Altunkaynak BZ, Halici Z, Odabasoglu F, Uyanik MH, Gundogdu C, Suleyman H, Halici M, Albayrak M, Unal B (2010) Alpha-lipoic acid as a potential target for the treatment of lung injury caused by cecal ligation and puncture-induced sepsis model in rats. Shock 33:479–484

    PubMed  CAS  Google Scholar 

  • Cadirci E, Halici Z, Odabasoglu F, Albayrak A, Karakus E, Unal D, Atalay F, Ferah I, Unal B (2011) Sildenafil treatment attenuates lung and kidney injury due to overproduction of oxidant activity in a rat model of sepsis: a biochemical and histopathological study. Clin Exp Immunol 166:374–384

    Article  PubMed  CAS  Google Scholar 

  • Chung HS, Lee YC, Kyung Rhee Y, Lee SY (2011) Consumer acceptance of ginseng food products. J Food Sci 76:S516–S522

    Article  PubMed  CAS  Google Scholar 

  • Compton CN, Franko AP, Murray MT, Diebel LN, Dulchavsky SA (1998) Signaling of apoptotic lung injury by lipid hydroperoxides. J Trauma 44:783–788

    Article  PubMed  CAS  Google Scholar 

  • Coskun AK, Yigiter M, Oral A, Odabasoglu F, Halici Z, Mentes O, Cadirci E, Atalay F, Suleyman H (2011) The effects of montelukast on antioxidant enzymes and proinflammatory cytokines on the heart, liver, lungs, and kidneys in a rat model of cecal ligation and puncture-induced sepsis. TheScientificWorldJOURNAL 11:1341–1356

    Article  PubMed  CAS  Google Scholar 

  • Damas P, Ledoux D, Nys M, Vrindts Y, De Groote D, Franchimont P, Lamy M (1992) Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg 215:356–362

    Article  PubMed  CAS  Google Scholar 

  • Dombrovskiy VY, Martin AA, Sunderram J, Paz HL (2007) Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med 35:1244–1250

    Article  PubMed  Google Scholar 

  • Eisenhut M, Wallace H (2011) Ion channels in inflammation. Pflugers Archiv-Eur J Physiol 461:401–421

    Article  CAS  Google Scholar 

  • El-Missiry MA, El-Sayed IH, Othman AI (2001) Protection by metal complexes with SOD-mimetic activity against oxidative gastric injury induced by indomethacin and ethanol in rats. Ann Clin Biochem 38:694–700

    Article  PubMed  CAS  Google Scholar 

  • Endo S, Inada K, Inoue Y, Kuwata Y, Suzuki M, Yamashita H, Hoshi S, Yoshida M (1992) Two types of septic shock classified by the plasma levels of cytokines and endotoxin. Circ Shock 38:264–274

    PubMed  CAS  Google Scholar 

  • Fink MP (2002) Reactive oxygen species as mediators of organ dysfunction caused by sepsis, acute respiratory distress syndrome, or hemorrhagic shock: potential benefits of resuscitation with Ringer’s ethyl pyruvate solution. Curr Opin Clin Nutr Metab Care 5:167–174

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez ER, Kannewurf BS, Ornato JP (1998) Intravenous amiodarone for ventricular arrhythmias: overview and clinical use. Resuscitation 39:33–42

    Article  PubMed  CAS  Google Scholar 

  • Halici Z, Dengiz GO, Odabasoglu F, Suleyman H, Cadirci E, Halici M (2007) Amiodarone has anti-inflammatory and anti-oxidative properties: an experimental study in rats with carrageenan-induced paw edema. Eur J Pharmacol 566:215–221

    Article  PubMed  CAS  Google Scholar 

  • Halliwell B (1994) Free radicals, antioxidants, and human disease: curiosity, cause, or consequence? Lancet 344:721–724

    Article  PubMed  CAS  Google Scholar 

  • Huang GJ, Huang SS, Lin SS, Shao YY, Chen CC, Hou WC, Kuo YH (2010) Analgesic effects and the mechanisms of anti-inflammation of ergostatrien-3beta-ol from Antrodia camphorata submerged whole broth in mice. J Agric Food Chem 58:7445–7452

    Article  PubMed  CAS  Google Scholar 

  • Ide T, Tsutsui H, Kinugawa S, Utsumi H, Takeshita A (1999) Amiodarone protects cardiac myocytes against oxidative injury by its free radical scavenging action. Circulation 100:690–692

    Article  PubMed  CAS  Google Scholar 

  • Johnson J, Meyrick B, Jesmok G, Brigham KL (1989) Human recombinant tumor necrosis factor alpha infusion mimics endotoxemia in awake sheep. J Appl Physiol 66:1448–1454

    PubMed  CAS  Google Scholar 

  • Karpel JP, Mitsudo S, Norin AJ (1991) Natural killer cell activity in a rat model of amiodarone-induced interstitial lung disease. Chest 99:230–234

    Article  PubMed  CAS  Google Scholar 

  • Kim YH, Park SM, Kim M, Kim SH, Lim SY, Ahn JC, Song WH, Shim WJ (2012) Cardioprotective effects of rosuvastatin and carvedilol on delayed cardiotoxicity of doxorubicin in rats. Toxicol Mech Methods 22:488–498

    Google Scholar 

  • Kodama I, Kamiya K, Toyama J (1999) Amiodarone: ionic and cellular mechanisms of action of the most promising class III agent. Am J Cardiol 84:20R–28R

    Article  PubMed  CAS  Google Scholar 

  • Kruttgen A, Rose-John S (2012) Interleukin-6 in sepsis and capillary leakage syndrome. J Interf Cytokine Res: Off J Int Soc Interf Cytokine Res 32:60–65

    Article  Google Scholar 

  • Kuwano K, Hara N (2000) Signal transduction pathways of apoptosis and inflammation induced by the tumor necrosis factor receptor family. Am J Respir Cell Mol Biol 22:147–149

    Article  PubMed  CAS  Google Scholar 

  • Lawson JA, Rokach J, FitzGerald GA (1999) Isoprostanes: formation, analysis and use as indices of lipid peroxidation in vivo. J Biol Chem 274:24441–24444

    Article  PubMed  CAS  Google Scholar 

  • Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 31:1250–1256

    Article  PubMed  Google Scholar 

  • Li QF, Zhu YS, Jiang H, Xu H, Sun Y (2009) Heme oxygenase-1 mediates the anti-inflammatory effect of isoflurane preconditioning in LPS-stimulated macrophages. Acta Pharmacologica Sin 30:228–234

    Article  Google Scholar 

  • Martin GS, Mannino DM, Eaton S, Moss M (2003) The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348:1546–1554

    Article  PubMed  Google Scholar 

  • Momin FN, Kalai BR, Shikalgar TS, Naikwade NS (2012) Cardioprotective effect of methanolic extract of Ixora coccinea Linn. leaves on doxorubicin-induced cardiac toxicity in rats. Indian J Pharmacol 44:178–183

    Article  PubMed  Google Scholar 

  • Naito Y, Yoshikawa T, Yoshida N, Kondo M (1998) Role of oxygen radical and lipid peroxidation in indomethacin-induced gastric mucosal injury. Dig Dis Sci 43:30S–34S

    PubMed  CAS  Google Scholar 

  • Ozbakis-Dengiz G, Halici Z, Akpinar E, Cadirci E, Bilici D, Gursan N (2007) Role of polymorphonuclear leukocyte infiltration in the mechanism of anti-inflammatory effect of amiodarone. Pharmacol Rep: PR 59:538–544

    PubMed  CAS  Google Scholar 

  • Ozdulger A, Cinel I, Koksel O, Cinel L, Avlan D, Unlu A, Okcu H, Dikmengil M, Oral U (2003) The protective effect of N-acetylcysteine on apoptotic lung injury in cecal ligation and puncture-induced sepsis model. Shock 19:366–372

    Article  PubMed  CAS  Google Scholar 

  • Padmavathy B, Niranjali S, Devaraj H (1992) Lung injury by amiodarone, an antiarrhythmic drug, in male rats. Indian J Exp Biol 30:653–654

    PubMed  CAS  Google Scholar 

  • Sakamoto M, Takaki E, Yamashita K, Watanabe K, Tabuchi S, Watanabe T, Satoh K (2002) Nonenzymatic derived lipid peroxide, 8-iso-PGF2 alpha, participates in the pathogenesis of delayed cerebral vasospasm in a canine SAH model. Neurol Res 24:301–306

    Article  PubMed  CAS  Google Scholar 

  • Sands KE, Bates DW, Lanken PN, Graman PS, Hibberd PL, Kahn KL, Parsonnet J, Panzer R, Orav EJ, Snydman DR, Black E, Schwartz JS, Moore R, Johnson BL Jr, Platt R (1997) Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA: J Am Med 278:234–240

    Article  CAS  Google Scholar 

  • Santangeli P, Di Biase L, Burkhardt JD, Bai R, Mohanty P, Pump A, Natale A (2012) Examining the safety of amiodarone. Expert Opin Drug Saf 11:191–214

    Article  PubMed  CAS  Google Scholar 

  • Shayeganpour A, Hamdy DA, Brocks DR (2008) Pharmacokinetics of desethylamiodarone in the rat after its administration as the preformed metabolite, and after administration of amiodarone. Biopharm & Drug Dispos 29:159–166

    Article  CAS  Google Scholar 

  • Tohda C, Nakayama N, Hatanaka F, Komatsu K (2006) Comparison of Anti-inflammatory activities of six curcuma rhizomes: a possible curcuminoid-independent pathway mediated by Curcuma phaeocaulis extract. Evid Based Complement Alternat Med: eCAM 3:255–260

    Article  PubMed  Google Scholar 

  • Uyanik A, Unal D, Uyanik MH, Halici Z, Odabasoglu F, Altunkaynak ZB, Cadirci E, Keles M, Gundogdu C, Suleyman H, Bayir Y, Albayrak M, Unal B (2010) The effects of polymicrobial sepsis with diabetes mellitus on kidney tissues in ovariectomized rats. Ren Fail 32:592–602

    Article  PubMed  CAS  Google Scholar 

  • Wheeler AP, Jesmok G, Brigham KL (1990) Tumor necrosis factor’s effects on lung mechanics, gas exchange, and airway reactivity in sheep. J Appl Physiol 68:2542–2549

    PubMed  CAS  Google Scholar 

  • Xing Z, Braciak T, Jordana M, Croitoru K, Graham FL, Gauldie J (1994) Adenovirus-mediated cytokine gene transfer at tissue sites. Overexpression of IL-6 induces lymphocytic hyperplasia in the lung. J Immunol 153:4059–4069

    PubMed  CAS  Google Scholar 

  • Young RA, Mehendale HM (1989) Effects of short-term and long-term administration of amiodarone on hepatobiliary function in male rats. J Appli Toxicol: JAT 9:407–412

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Ataturk University Medical Research Council (grant number 2011/291).

Conflict of interest

There is no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Zekai Halici.

Additional information

This research was conducted in the Research Laboratory of Pharmacology at the Department of Pharmacology, School of Medicine, Atatürk University, Erzurum, TR 25240, Turkey.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Polat, B., Cadirci, E., Halici, Z. et al. The protective effect of amiodarone in lung tissue of cecal ligation and puncture-induced septic rats: a perspective from inflammatory cytokine release and oxidative stress. Naunyn-Schmiedeberg's Arch Pharmacol 386, 635–643 (2013). https://doi.org/10.1007/s00210-013-0862-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-013-0862-3

Keywords

Navigation