Protective effects of gallic acid on cardiac electrophysiology and arrhythmias during reperfusion in diabetes

Document Type : Original Article


1 Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz Iran

2 Ahvaz Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz Iran

3 Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz Iran

4 Diabetes Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran


Objective(s): Gallic acid (GA), a potent anti-oxidant, plays an important role in reducing diabetic induced cardiac disorders. Therefore, the present investigation was purposed to determine the beneficial effect of GA in cardiac arrhythmias during reperfusion in diabetes induced by alloxan.
Materials and Methods: Male Sprague-Dawley rats (200–250 g) were randomly divided into three groups (eight in each group): control (C), diabetic (D), and diabetic treated with GA (D+G) groups. GA was administered by gavage (25 mg/kg, daily) for eight weeks. Diabetes was induced by a single intraperitoneal injection of alloxan (120 mg/kg). Ischemia-reperfusion (IR) injury was performed by ischemia and then reperfusion (30 and 120 min, respectively). The score and magnitude of arrhythmias, creatine kinase (CK-MB), and lactate dehydrogenase (LDH) of the heart, electrocardiographic, and hemodynamic parameters were measured. One-way ANOVA followed by LSD tests were used for the differences between groups. The percentage of incidence was also evaluated by Fisher’s exact test.
Results: The duration (P<0.05), onset (P<0.01), score and incidence of arrhythmia, QT interval (P<0.001), LDH, and CK-MB (P<0.05) were significantly elevated and the contractility of the heart (±dp/dt, P<0.01), LVSP, QRS complex voltage (P<0.05), and heart rate (P<0.01) were significantly reduced in the diabetic animals compared with the control rats. However, administration with GA significantly improved these alterations in the diabetic group compared with the diabetic animals.
Conclusion: This study indicated the beneficial effects of GA on cardiac electrophysiology and arrhythmias during reperfusion in diabetes.


Main Subjects

1. Haghighat Azari M, Najafi M. Role of Fructose as a Potent Antiarrhythmic and Anti-infarct agent in Isolated Rat Heart. Iran J Pharm Res 2014; 13:1303-1311.
2. Yang J, Yin HS, Cao YJ, Jiang ZA, Li YJ, Song MC, et al.  Arctigenin attenuates ischemia/reperfusion-induced ventricular arrhythmias by decreasing oxidative stress in rats. Cell Physiol Biochem 2018; 49:728-742.
3. Benhabbouche S, Crola da Silva C, Abrial M, Ferrera R. The basis of ischemia-reperfusion and myocardial protection. Ann Fr Anesth Reanim 2011; 30:1-16.
4. Ke Z, Gao A, Xu P, Wang J, Ji L, Yang J. Preconditioning with PEP-1-SOD1 fusion protein attenuates ischemia/reperfusion-induced ventricular arrhythmia in isolated rat hearts. Exp Ther Med 2015; 10:352-356.
5. Matejikova J, Kucharska J, Pancza D, Ravingerova T. The effect of antioxidant treatment and NOS inhibition on the incidence of ischemia-induced arrhythmias in the diabetic rat heart. Physiol Res 2008; 57:55-60.
6. Hackenhaar FS, Fumagalli F, Li Volti G, Sorrenti V, Russo I, Staszewsky L, et al. Relationship between post-cardiac arrest myocardial oxidative stress and myocardial dysfunction in the rat. J Biomed Sci 2014; 21:70-79.
7. Moens AL, Claeys MJ, Timmermans JP, Vrints CJ. Myocardial ischemia/reperfusion-injury, a clinical view on a complex pathophysiological process. Int J Cardiol 2005; 100:179-190.
8. Moukarbel GV, Ayoub CM, Abchee AB. Pharmacological therapy for myocardial reperfusion injury. Curr Opin Pharmacol 2004; 4:147-153.
9. Baharvand B, Esmailidehaj M, Alihosaini J, Bajoovand S, Esmailidehaj S, Hafizie Z. Prophylactic and therapeutic effects of oleuropein on reperfusion-induced arrhythmia in anesthetized rat. Iran Biomed J 2016; 20:41-48.
10. Vijayasarathy K, Shanthi Naidu K, Sastry BK. Melatonin metabolite 6-Sulfatoxymelatonin, Cu/Zn superoxide dismutase, oxidized LDL and malondialdehyde in unstable angina. Int J Cardiol 2010; 144:315-317.
11. Umadevi S, Gopi V, Simna SP, Parthasarathy A, Yousuf SM, Elangovan V. Studies on the cardioprotective role of gallic acid against AGE-induced cell proliferation and oxidative stress in H9C2 (2-1) cells. Cardiovasc Toxicol 2012; 12:304-311.
12. Mansouri MT, Soltani M, Naghizadeh B, Farbood Y, Mashak A, Sarkaki A. A possible mechanism for the anxiolytic-like effect of gallic acid in the rat elevated plus maze. Pharmacol Biochem Behav 2014; 117:40-46.
13. Stanely Mainzen Prince P, Priscilla H, Devika PT. Gallic acid prevents lysosomal damage in isoproterenol induced cardiotoxicity in Wistar rats. Eur J Pharmacol 2009; 615:139-143.
14. Patel SS, Goyal RK. Cardioprotective effects of gallic acid in diabetes-induced myocardial dysfunction in rats. Pharmacognosy Res 2011; 3:239-245.
15. Poornima IG, Parikh P, Shannon RP. Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res 2006; 98:596-605.
16. Howarth FC, Chandler NJ, Kharche S, Tellez JO, Greener ID, Yamanushi TT, et al. Effects of streptozotocin-induced diabetes on connexin43 mRNA and protein expression in ventricular muscle. Mol Cell Biochem 2008; 319:105-114.
17. Ceriello A, Quagliaro L, D’Amico M, Di Filippo C, Marfella R, Nappo F, et al. Acute hyperglycemia induces nitrotyrosine formation and apoptosis in perfused heart from rat. Diabetes 2002; 51:1076-1082.
18. Heidarian E, Keloushadi M, Ghatreh-Samani K, Valipour P. The reduction of IL-6 gene expression, pAKT, pERK1/2, pSTAT3 signaling pathways and invasion activity by gallic acid in prostate cancer PC3 cells. Biomed Pharmacother 2016; 84:264-269.
19. Miller LE, Hosick PA, Wrieden J, Hoyt E, Quindry JC. Evaluation of arrhythmia scoring systems and exercise-induced cardioprotection. Med Sci Sports Exerc 2012; 44:435-441.
20. Andreadou I, Iliodromitis EK, Mikros E, Constantinou M, Agalias A, Magiatis P, et al. The olive constituent oleuropein exhibits anti-ischemic, antioxidative, and hypolipidemic effects in anesthetized rabbits. J Nutr 2006; 136:2213-2219.
21. Wang L, Yu XF, Qu SC, Xu HL, Sui DY. Effects of CASI on myocardial ischemia-reperfusion arrhythmia in rats. Zhongguo Zhong Yao Za Zhi 2007; 32:2174-2177.
22. Sventzouri S, Nanas I, Vakrou S, Kapelios C, Sousonis V, Sfakianaki T, et al. Pharmacologic inhibition of the mitochondrial Na+/Ca2+ exchanger protects against ventricular arrhythmias in a porcine model of ischemia-reperfusion. Hellenic J Cardiol 2018; 59:217-222.
23. Singh VP, Rubinstein J, Arvanitis DA, Ren X, Gao X, Haghighi K, 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.
24. Liu T, O’Rourke B. Regulation of the Na+/Ca2+ exchanger by pyridine nucleotide redox potential in ventricular myocytes. J Biol Chem 2013; 288:31984-31992.
25. Pinet C, Le Grand B, John GW, Coulombe A. Thrombin facilitation of voltage-gated sodium channel activation in human cardiomyocytes: implications for ischemic sodium loading. Circulation 2002; 106:2098-2103.
26. Alvarez P, Tapia L, Mardones LA, Pedemonte JC, Farias JG, Castillo RL. Cellular mechanisms against ischemia reperfusion injury induced by the use of anesthetic pharmacological agents. Chem Biol Interact 2014; 218:89-98.
27. Gonca E, Bozdogan O. Both mitochondrial KATP channel opening and sarcolemmal KATP channel blockage confer protection against ischemia/reperfusion-induced arrhythmia in anesthetized male rats. J Cardiovasc Pharmacol Ther 2010; 15:403-411.
28. Yu W, Wang JJ, Gan WY, Lin GS, Huang CX. Effects of verapamil preconditioning on cardiac function in vitro and intracellular free Ca2+ and L-type calcium current in rat cardiomyocytes post ischemia-reperfusion injury. Zhonghua Xin Xue Guan Bing Za Zhi 2010; 38:225-229.
29. de Oliveira LM, de Oliveira TS, da Costa RM, de Souza Gil E, Costa EA, Passaglia Rde C, et al. The vasorelaxant effect of gallic acid involves endothelium-dependent and -independent mechanisms. Vascul Pharmacol 2016; 81:69-74.
30. Ogunsanwo OR, Oyagbemi AA, Omobowale TO, Asenuga ER, Saba AB. Biochemical and electrocardiographic studies on the beneficial effects of gallic acid in cyclophosphamide-induced cardiorenal dysfunction. J Complement Integr Med 2017; 14.
31. Xie Y, Liu S, Hu S, Wei Y. Cardiomyopathy-associated gene 1-sensitive PKC-dependent connexin 43 expression and phosphorylation in left ventricular noncompaction cardiomyopathy. Cell Physiol Biochem 2017; 44:828-842.
32. Chinda K, Sanit J, Chattipakorn S, Chattipakorn N. 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.
33. Palee S, Weerateerangkul P, Chinda K, Chattipakorn SC, Chattipakorn N. Mechanisms responsible for beneficial and adverse effects of rosiglitazone in a rat model of acute cardiac ischaemia-reperfusion. Exp Physiol 2013; 98:1028-1037.
34. Tamargo J, Caballero R, Gomez R, Delpon E. Cardiac electrophysiological effects of nitric oxide. Cardiovasc Res 2010; 87:593-600.
35. Ma L, Zhu XF, Wu YY, Chen KJ, Shi DZ, Yin HJ. Protective effect of propyl gallate against oxidized low-density lipoprotein-induced injury of endothelial cells. Chin J Integr Med 2015; 21:299-306.
36. Xi S, Zhou G, Zhang X, Zhang W, Cai L, Zhao C. Protective effect of total aralosides of Aralia elata (Miq) Seem (TASAES) against diabetic cardiomyopathy in rats during the early stage, and possible mechanisms. Exp Mol Med 2009; 41:538-547.
37. Yamaguchi O, Higuchi Y, Hirotani S, Kashiwase K, Nakayama H, Hikoso S, et al. Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling. Proc Natl Acad Sci U S A 2003; 100:15883-15888.
38. Sun D, Shen M, Li J, Li W, Zhang Y, Zhao L, et al. Cardioprotective effects of tanshinone IIA pretreatment via kinin B2 receptor-Akt-GSK-3beta dependent pathway in experimental diabetic cardiomyopathy. Cardiovasc Diabetol 2011; 10:1-8.
39. Sakabe K, Fukuda N, Fukuda Y, Wakayama K, Nada T, Morishita S, et al. QT-interval dispersion in type 2 diabetic and non-diabetic patients with post-myocardial infarction. Nutr Metab Cardiovasc Dis 2008; 18:121-126.
40. Di Filippo C, Ferraro B, Maisto R, Trotta MC, Di Carluccio N, Sartini S, et al. Effects of the new aldose reductase inhibitor benzofuroxane derivative BF-5m on high glucose induced prolongation of cardiac QT interval and increase of coronary perfusion pressure. J Diabetes Res 2016;1-8.
41. Mladenka P, Zatloukalova L, Filipsky T, Hrdina R. Cardiovascular effects of flavonoids are not caused only by direct antioxidant activity. Free Radic Biol Med 2010; 49:963-975.
42. Tadano N, Morimoto S, Takahashi-Yanaga F, Miwa Y, Ohtsuki I, Sasaguri T. Propyl gallate, a strong antioxidant, increases the Ca2+ sensitivity of cardiac myofilament. J Pharmacol Sci 2009; 109:456-458.