Effects of Cilostazol and Diltiazem Hydrochloride on Ischemia-Reperfusion Injury in a Rat Hindlimb Model

Authors

  • Bekir Ä°NAN Department of Cardiothoracic Surgery, Bezmialem Medical School, Bezmialem Vakif University, Istanbul
  • Selma SÖNMEZ ERGÜN Department of Plastic, Reconstructive and Aesthetic Surgery, Bezmialem Medical School, Bezmialem Vakif University, Istanbul,
  • Asiye NURTEN Department of Physiology, Faculty of Medicine, Yeni Yuzyil University, Istanbul,
  • Canan KÜÇÜKGERGİN Department of Biochemistry, Istanbul Medical School, Istanbul University, Istanbul,
  • Aslı ZENGİN TÜRKMEN Department of Physiology, Faculty of Medicine, Yeni Yuzyil University, Istanbul,
  • Şule SEÇKİN Department of Biochemistry, Istanbul Medical School, Istanbul University, Istanbul,
  • Kerem ERKALP Department of Anesthesiology and Reanimation, Bağcılar Research and Educational Hospital, Istanbul,
  • Sedat ZÄ°YADE Department of Thoracic Surgery, Bezmialem Medical School, Bezmialem Vakif University, Istanbul,

DOI:

https://doi.org/10.1532/hsf.1663

Abstract

Objective: Free radicals and neutrophils are potent sources of ischemia-reperfusion injury (I/R) and they can be limited by the use of exogenous application of some therapeutic agents. The objective of this study was to compare the effects of cilostazol and diltiazem hydrochloride in a rat hind limb model of I/R injury. 

Methods: Skeletal muscles submitted to 2 hours of ischemia by placing an aneurysm clip to femoral artery and reperfused after 1, 2 and 4 hours. Seventy-two Wistar-Albino rats were randomly divided into mainly four groups according to treatment agents:  Group I (control group) was treated with saline; Group II was treated with diltiazem hydrochloride; Group III was treated with cilostazol in 30% dimethyl sulphoxide; and Group IV was treated with 30% dimethyl sulphoxide intraperitoneally. These four main groups also subdivided into three subgroups according to duration of the reperfusion times.  Blood samples were taken and all rats were sacrificed. 

Results: Cilostazol-treated groups demonstrated a significant decrease in tissue and serum malondialdehyde (MDA) levels, and tissue myeloperoxidase (MPO ) activity compared with other groups. Increase in serum nitric oxide (NOx) level was significantly higher in all subgroups of cilastazol, diltiazem hydrochloride, and dimethyl sulphoxide groups versus the control group.

Conclusion: Although these results suggest the beneficial effects of cilostazol and diltiazem hydrochloride on I/R injury, the effect of cilostazol on I/R injury seems to be more efficient than diltiazem hydrochloride.

Author Biographies

Bekir Ä°NAN, Department of Cardiothoracic Surgery, Bezmialem Medical School, Bezmialem Vakif University, Istanbul

Department of Cardiothoracic Surgery, Bezmialem Medical School,

Selma SÖNMEZ ERGÜN, Department of Plastic, Reconstructive and Aesthetic Surgery, Bezmialem Medical School, Bezmialem Vakif University, Istanbul,

Deparment of Plastic Reconstructive and Aesthetic Surgery, Bezmialem Medical School

Asiye NURTEN, Department of Physiology, Faculty of Medicine, Yeni Yuzyil University, Istanbul,

Department of Physiology, Faculty of Medicine,

Canan KÜÇÜKGERGİN, Department of Biochemistry, Istanbul Medical School, Istanbul University, Istanbul,

Department of Biochemistry, Istanbul Medical School,

Aslı ZENGİN TÜRKMEN, Department of Physiology, Faculty of Medicine, Yeni Yuzyil University, Istanbul,

Department of Physiology, Faculty of Medicine,

Şule SEÇKİN, Department of Biochemistry, Istanbul Medical School, Istanbul University, Istanbul,

Department of Biochemistry, Istanbul Medical School, 

Kerem ERKALP, Department of Anesthesiology and Reanimation, Bağcılar Research and Educational Hospital, Istanbul,

Department of Anesthesiology and Reanimation, 

Sedat ZÄ°YADE, Department of Thoracic Surgery, Bezmialem Medical School, Bezmialem Vakif University, Istanbul,

Department of Thoracic Surgery, Bezmialem Medical School,    

References

Blaisdell FW. 2002. The pathophysiology of skeletal muscle ischemia and reperfusion syndrome: a review. Cardiovasc Surg 10:620-30.

Buege JA, Aust SD. 1978. Microsomal lipid peroxidation. In: Methods in enzymology. P Fleischer, L Packer (eds). New York: Academic Press. vol. 52, pp. 302-10.

Chan RK, Austen WG Jr, Ibrahim S, et al. 2004. Reperfusion injury to skeletal muscle affects primarily type II muscle fibers. J Surg Research 122:54-60.

Ferrari RS, Andrade CF. 2015. Oxidative stress and lung ischemia-reperfusion injury.

Oxid Med Cell Longev 2015:590987.

Granger DN, Kvietys PR. 2015. Reperfusion injury and reactive oxygen species: The evolution of a concept. Redox Biol 6:524-51.

Hakaim AG, Cunningham L, White JL, Hoover K. 1999. Selective type III phosphodiesterase inhibition prevents elevated compartment pressure after ischemia/reperfusion injury. J Trauma 46:869-72.

Hori A, Shibata R, Morisaki K, Murohara T, Komori K. 2012. Cilostazol stimulates revascularisation in response to ischemia via an eNOS-dependent mechanism. Eur J Vasc Endovasc Surg 43:62-5.

Iba T, Kidokoro A, Fukunaga M, Takuhiro K, Ouchi M, Ito Y. 2006. Comparison of the protective effects of type III phosphodiesterase (PDE3) inhibitor (cilostazol) and acetylsalicylic acid on intestinal microcirculation after ischemia reperfusion injury in mice. Shock 26:522-6.

Kadambi A, Skalak TC. 2000. Role of leukocytes and tissue-derived oxidants in short-term skeletal muscle ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 278:H435-43.

Kalogeris T, Baines CP, Krenz M, Korthuis RJ. 2012. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol 298:229-317.

Krawisz JE, Sharon P, Stenson WF. 1984. Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Assessment of inflammation in rat and hamster models. Gastroenterology 87:1344-50.

Lindsay TF, Liauw S, Romaschin AD, Walker PM. 1990. The effect of ischemia/reperfusion on adenine nucleotide metabolism and xanthine oxidase production in skeletal muscle. J Vasc Surg 12:8-15.

Miyashita Y, Saito S, Miyamoto A, Iida O, Nanto S. 2011. Cilostazol increases skin perfusion pressure in severely ischemic limbs. Angiology 62:15-7.

Östman B, Michaelsson K, Rahme H, Hillered L. 2004. Tourniquet-induced ischemia and reperfusion in human skeletal muscle. Clin Orthop 418:260-5.

Parvuvums DV. 1999. The pathology of ischemia–reperfusion. In: Ischemia–reperfusion injury. PA Grace, RT Mathie (eds). London: Blackwell Science. pp. 3-19.

Rácz IB, Sarkadi L, Hamar J. 1996. The functional damages of ischemia/reperfused skeletal muscle. Acta Physiol Hung 84:205-16.

Rousseau G, St-Jean G, Latour JG, Merhi Y, Nattel S, Waters D. 1991. Diltiazem at reperfusion reduces neutrophil accumulation and infarct size in dogs with ischaemic myocardium. Cardiovasc Res 25:319-29.

Santos MR, Celotto AC, Capellini VK, Evora PR, Piccinato CE, Joviliano EE. 2012. The protective effect of cilostazol on isolated rabbit femoral arteries under conditions of ischemia and reperfusion: the role of the nitric oxide pathway. Clinics (Sao Paulo) 67:171-8.

Schlag MG, Harris KA, Potter RF. 2001. Role of leukocyte accumulation and oxygen radicals in ischemia-reperfusion-induced injury in skeletal muscle. Am J Physiol Heart Circ Physiol 280:H1716-21.

Smith PK, Krohn RI, Hermanson GT, et al. 1985. Measurement of protein using bicinchoninic acid. Anal Biochem 150:76-85.

Takeo S, Tanonaka K, Iwai T, Motegi K, Hirota Y. 2004. Preservation of mitochondrial function during ischemia as a possible mechanism for cardioprotection of diltiazem against ischemia/reperfusion injury. Biochem Pharmacol 67:565-74.

Tran TP, Tu H, Pipinos II, Muelleman RL, Albadawi H, Li YL. 2011. Tourniquet-induced acute ischemia-reperfusion injury in mouse skeletal muscles: involvement of superoxide. Eur J Pharmacol 650:328-34.

Turchányi B, Tóth B, Rácz I, Vendégh Z, Furész J, Hamar J. 2005. Ischemia reperfusion injury of the skeletal muscle after selective deafferentation. Physiol Res 54:25-31.

Published

2017-04-29

How to Cite

Ä°NAN, B., SÖNMEZ ERGÜN, S., NURTEN, A., KÜÇÜKGERGİN, C., ZENGİN TÜRKMEN, A., SEÇKİN, Şule, ERKALP, K., & ZÄ°YADE, S. (2017). Effects of Cilostazol and Diltiazem Hydrochloride on Ischemia-Reperfusion Injury in a Rat Hindlimb Model. The Heart Surgery Forum, 20(2), E058-E065. https://doi.org/10.1532/hsf.1663

Issue

Section

Articles

Most read articles by the same author(s)