PDF herunterladen
Exp Clin Endocrinol Diabetes 2019; 127(05): 320-325
DOI: 10.1055/s-0043-122881
Article
© Georg Thieme Verlag KG Stuttgart · New York

The Beneficial Effects of Trimetazidine on Reperfusion–Induced Arrhythmia in Diabetic Rats

Fatemeh Ramezani-Aliakbari
1   Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahwaz Iran
,
Mohammad Badavi
1   Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahwaz Iran
2   Ahvaz Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahwaz Iran
3   Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahwaz Iran
,
Mahin Dianat
1   Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahwaz Iran
2   Ahvaz Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahwaz Iran
,
Seyed Ali Mard
1   Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahwaz Iran
2   Ahvaz Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahwaz Iran
,
Akram Ahangarpour
1   Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahwaz Iran
2   Ahvaz Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahwaz Iran
4   Diabetes Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahwaz, Iran
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 06. August 2017
revised 22. Oktober 2017

accepted 13. November 2017

Publikationsdatum:
05. März 2018 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Abstract

Trimetazidine (TMZ), as an anti-ischemic drug, plays a critical role in protecting against cardiovascular complications induced by diabetes. This study was therefore aimed to evaluate the protective effects of TMZ on reperfusion-induced arrhythmias in the diabetic rats. Male Sprague-Dawley rats (250±20 g) were randomly assigned to four (n=8): control rats (C), alloxan induced diabetic rats (D), diabetic rats treated with TMZ (10 mg/kg, D+T10), diabetic rats treated with TMZ (30 mg/kg, D+T30). TMZ was treated orally once daily for 8 weeks. Diabetes was induced by a single intraperitoneal injection of alloxan (120 mg/kg). Ischemia-reperfusion (I/R) was carried out via 30 min of ischemia and following120-min reperfusion. The magnitude and score of arrhythmia, the left ventricular function, infarct size, lactate dehydrogenase (LDH), myocardial creatine kinase (CK-MB) and troponin (cTnI) were measured. The findings were evaluated by two-way repeated measures and one-way ANOVA followed by LSD post hoc test and Fisher's exact test for incidence percentage. The duration, incidence and score of arrhythmia (p<0.001), infarct size (p<0.01) were significantly increased, the cardiac contractility (±dp/dt), LDH, CK-MB (p<0.001) and cTnI (p<0.05) were significantly decreased in the diabetic rats in comparison with the control group. However, treatment with TMZ in the diabetic rats was significantly improved the duration (p<0.001), incidence and score of arrhythmia,±dp/dt LDH, CK-MB, cTnI (p<0.05) and infarct size (p<0.01) in comparison with the untreated diabetic group. The present study indicates anti-arrhythmic effect of TMZ in reducing arrhythmias induced by reperfusion in the diabetic rats.

Key words

diabetes - trimetazidine - arrhythmia - reperfusion - rats
 

  • References

  • 1 Donahoe SM, Stewart GC, McCabe CH. et al. Diabetes and mortality following acute coronary syndromes. JAMA 2007; 298: 765-775
    CrossrefPubMedGoogle Scholar
  • 2 Ikizler M, Erkasap N, Dernek S. et al. Trimetazidine-induced enhancement of myocardial recovery during reperfusion: A comparative study in diabetic and non-diabetic rat hearts. Arch Med Res 2006; 37: 700-708
    CrossrefPubMedGoogle Scholar
  • 3 Norhammar A, Mellbin L, Cosentino F. Diabetes: Prevalence, prognosis and management of a potent cardiovascular risk factor. Eur J Prev Cardio 2017; 24: 52-60
    PubMedGoogle Scholar
  • 4 Malmberg K, Ryden L. Myocardial infarction in patients with diabetes mellitus. Eur Heart J 1988; 9: 259-264
    CrossrefPubMedGoogle Scholar
  • 5 Stettler C, Bearth A, Allemann S. et al. QTc interval and resting heart rate as long-term predictors of mortality in type 1 and type 2 diabetes mellitus: A 23-year follow-up. Diabetologia 2007; 50: 186-194
    PubMedGoogle Scholar
  • 6 Sakakibara M, Hirashiki A, Cheng XW. et al. Association of diabetes mellitus with myocardial collagen accumulation and relaxation impairment in patients with dilated cardiomyopathy. Diabetes Res Clin Pract 2011; 92: 348-355
    CrossrefPubMedGoogle Scholar
  • 7 Ghaly HA, Boyle PM, Vigmond EJ. et al. Simulations of reduced conduction reserve in the diabetic rat heart: Response to uncoupling and reduced excitability. Ann Biomed Eng 2010; 38: 1415-1425
    CrossrefPubMedGoogle Scholar
  • 8 Nygren A, Olson ML, Chen KY. et al. Propagation of the cardiac impulse in the diabetic rat heart: Reduced conduction reserve. J Physiol 2007; 580: 543-560
    CrossrefPubMedGoogle Scholar
  • 9 Lin H, Ogawa K, Imanaga I. et al. Remodeling of connexin 43 in the diabetic rat heart. Mol Cell Biochem 2006; 290: 69-78
    CrossrefPubMedGoogle Scholar
  • 10 Stilli D, Lagrasta C, Berni R. et al. Preservation of ventricular performance at early stages of diabetic cardiomyopathy involves changes in myocyte size, number and intercellular coupling. Basic Res Cardiol 2007; 102: 488-499
    CrossrefPubMedGoogle Scholar
  • 11 Penkoske PA, Sobel BE, Corr PB. Disparate electrophysiological alterations accompanying dysrhythmia due to coronary occlusion and reperfusion in the cat. Circulation 1978; 58: 1023-1035
    CrossrefPubMedGoogle Scholar
  • 12 Wu Y, Temple J, Zhang R. et al. Calmodulin kinase II and arrhythmias in a mouse model of cardiac hypertrophy. Circulation 2002; 106: 1288-1293
    CrossrefPubMedGoogle Scholar
  • 13 Oyamada M, Tsujii E, Tanaka H. et al. Abnormalities in gap junctions and Ca2+ dynamics in cardiomyocytes at the border zone of myocardial infarcts. Cell Commun Adhes 2001; 8: 335-338
    CrossrefPubMedGoogle Scholar
  • 14 Barsotti A, Di Napoli P. Trimetazidine and cardioprotection during ischemia-reperfusion. Ital Heart J 2004; 5: 29S-36S
    PubMedGoogle Scholar
  • 15 Liu YC, Li L, Su Q. et al. Trimetazidine pretreatment inhibits myocardial apoptosis and improves cardiac function in a Swine model of coronary microembolization. Cardiology 2015; 130: 130-136
    CrossrefPubMedGoogle Scholar
  • 16 Rosano GM, Vitale C, Sposato B. et al. Trimetazidine improves left ventricular function in diabetic patients with coronary artery disease: a double-blind placebo-controlled study. Cardiovasc Diabetol 2003; 2: 16
    CrossrefPubMedGoogle Scholar
  • 17 Belardinelli R, Solenghi M, Volpe L. et al. Trimetazidine improves endothelial dysfunction in chronic heart failure: An antioxidant effect. Eur Heart J 2007; 28: 1102-1108
    CrossrefPubMedGoogle Scholar
  • 18 Xiang YL, He L, Xiao J. et al. Effect of trimetazidine treatment on the transient outward potassium current of the left ventricular myocytes of rats with streptozotocin-induced type 1 diabetes mellitus. Braz J Med Biol Res 2012; 45: 205-211
    PubMedGoogle Scholar
  • 19 Weiss JN, Korge P, Honda HM. et al. Role of the mitochondrial permeability transition in myocardial disease. Circ Res 2003; 93: 292-301
    CrossrefPubMedGoogle Scholar
  • 20 Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion–a target for cardioprotection. Cardiovasc Res 2004; 61: 372-385
    CrossrefPubMedGoogle Scholar
  • 21 Baharvand B, Esmailidehaj M, Alihosaini J. et al. Prophylactic and therapeutic effects of oleuropein on reperfusion-induced arrhythmia in anesthetized rat. Iran Biomed J 2016; 20: 41-48
    PubMedGoogle Scholar
  • 22 Curtis MJ, Walker MJ. Quantification of arrhythmias using scoring systems: An examination of seven scores in an in vivo model of regional myocardial ischaemia. Cardiovasc Res 1988; 22: 656-665
    CrossrefPubMedGoogle Scholar
  • 23 Liu Z, Chen JM, Huang H. et al. The protective effect of trimetazidine on myocardial ischemia/reperfusion injury through activating AMPK and ERK signaling pathway. Metabolism 2016; 65: 122-130
    CrossrefPubMedGoogle Scholar
  • 24 Zhong Y, Zhong P, He S. et al. Trimetazidine protects cardiomyocytes against hypoxia/reoxygenation injury by promoting amp-activated protein kinase-dependent autophagic flux. J Cardiovasc Pharmacol 2017; 69: 389-397
    CrossrefPubMedGoogle Scholar
  • 25 Halestrap AP, Doran E, Gillespie JP. et al. Mitochondria and cell death. Biochem Soc Trans 2000; 28: 170-177
    CrossrefPubMedGoogle Scholar
  • 26 Niizuma K, Endo H, Chan PH. Oxidative stress and mitochondrial dysfunction as determinants of ischemic neuronal death and survival. J Neurochem 2009; 109: 133-138
    CrossrefPubMedGoogle Scholar
  • 27 Aon MA, Cortassa S, Marban E. et al. Synchronized whole cell oscillations in mitochondrial metabolism triggered by a local release of reactive oxygen species in cardiac myocytes. J Biol Chem 2003; 278: 44735-44744
    CrossrefPubMedGoogle Scholar
  • 28 Thummasorn S, Kumfu S, Chattipakorn S. et al. Granulocyte-colony stimulating factor attenuates mitochondrial dysfunction induced by oxidative stress in cardiac mitochondria. Mitochondrion 2011; 11: 457-466
    CrossrefPubMedGoogle Scholar
  • 29 Onay-Besikci A, Guner S, Arioglu E. et al. The effects of chronic trimetazidine treatment on mechanical function and fatty acid oxidation in diabetic rat hearts. Can J Physiol Pharmacol 2007; 85: 527-535
    CrossrefPubMedGoogle Scholar
  • 30 Kantor PF, Lucien A, Kozak R. et al. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 2000; 86: 580-588
    CrossrefPubMedGoogle Scholar
  • 31 Billman GE. Role of ATP sensitive potassium channel in extracellular potassium accumulation and cardiac arrhythmias during myocardial ischaemia. Cardiovasc Res 1994; 28: 762-769
    CrossrefPubMedGoogle Scholar
  • 32 Singh VP, Rubinstein J, Arvanitis DA. et al. Abnormal calcium cycling and cardiac arrhythmias associated with the human Ser96Ala genetic variant of histidine-rich calcium-binding protein. J Am Heart Assoc 2013; 2: e000460
    PubMedGoogle Scholar
  • 33 Dumas F, Manzo-Silberman S, Fichet J. et al. Can early cardiac troponin I measurement help to predict recent coronary occlusion in out-of-hospital cardiac arrest survivors?. Crit Care Med 2012; 40: 1777-1784
    CrossrefPubMedGoogle Scholar
  • 34 Metzler B, Hammerer-Lercher A, Jehle J. et al. Plasma cardiac troponin T closely correlates with infarct size in a mouse model of acute myocardial infarction. Clin Chim Acta 2002; 325: 87-90
    CrossrefPubMedGoogle Scholar
  • 35 Chinda K, Sanit J, Chattipakorn S. et al. Dipeptidyl peptidase-4 inhibitor reduces infarct size and preserves cardiac function via mitochondrial protection in ischaemia-reperfusion rat heart. Diab Vasc Dis Res 2014; 11: 75-83
    CrossrefPubMedGoogle Scholar