Sodium current inhibitor ranolazine amelioratesexperimentally induced diabetic cardiomyopathy

Sodium current inhibitor ranolazine amelioratesexperimentally induced diabetic cardiomyopathy

Ranolazine is an anti-ischemic drug with glucose lowering effect. Our study scrutinized the effect of ranolazine on Streptozotocin (STZ) induced diabetic cardiomyopathy, emphasizing role of Sarcoplasmic Endoplasmic Reticulum Calcium ATPase (SERCA) pump. STZ induced diabetic rats showed significant hyperglycaemia with weight loss, hyperlipidaemia, increased cardiovascular risk indices as well as atherogenic index of plasma, Left Ventricular (LV) dysfunction, abnormal electrocardiography (ECG) and elevated cardiac biomarkers (CK-MB, LDH and AST). Twelve weeks ranolazine treatment ameliorated diabetes associated biochemical alterations and LV function along with ECG. The diabetic heart showed increased lipid peroxidation and compromised antioxidant defence mechanism which was reversed by ranolazine treatment. Reduced SERCA expressions were recognised in STZ treated diabetic rats. Ranolazine amplified SERCA expressions thus by regulating intracellular calcium homeostasis and keeping diabetic cardiomyopathy at bay. Ranolazine also prevented histological alterations in the heart and pancreas. Our results may open novel avenues for designing treatment strategies using ranolazine against diabetic cardiomyopathy.

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  • [1] Wu B, Huang XY, Li L, Fan XH, Li PC, Huang CQ, et al. Attenuation of diabetic cardiomyopathy by relying on kirenol to suppress inflammation in a diabetic rat model. J Cell Mol Med. 2019; 23(11): 7651-63. [CrossRef]
  • [2] Jia G, Hill MA, Sowers JR. Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity. Circ Res. 2018; 122(4): 624-38. [CrossRef]
  • [3] Gulsin GS, Athithan L, McCann GP. Diabetic cardiomyopathy: prevalence, determinants and potential treatments. 2019; 10: 2042018819834869. [CrossRef]
  • [4] Liu Q, Wang S, Cai L. Diabetic cardiomyopathy and its mechanisms: Role of oxidative stress and damage. J Diabetes Investig. 2014; 5(6): 623-34. [CrossRef]
  • [5] Hu X, Bai T, Xu Z, Liu Q, Zheng Y, Cai L. Pathophysiological Fundamentals of Diabetic Cardiomyopathy. Compr Physiol. 2017; 7(2): 693-711. [CrossRef]
  • [6] Mourouzis I, Mantzouratou P, Galanopoulos G, Kostakou E, Dhalla AK, Belardinelli L, et al. The beneficial effects of ranolazine on cardiac function after myocardial infarction are greater in diabetic than in nondiabetic rats. J Cardiovasc Pharmacol Ther. 2014; 19(5): 457-69. [CrossRef]
  • [7] Bashir S, Kalabharathi HL. Ranolazine improves glucose and lipid homoestasis in streptozotocin induced diabetes mellitus in albino wistar rats. Int J Basic Clin Pharmacol. 2017; 5(4): 1477-80. [Crossref]
  • [8] Ning Y, Zhen W, Fu Z, Jiang J, Liu D, Belardinelli L, et al. Ranolazine increases beta-cell survival and improves glucose homeostasis in low-dose streptozotocin-induced diabetes in mice. J Pharmacol Exp Ther. 2011; 337(1): 50-58. [CrossRef]
  • [9] Timmis AD, Chaitman BR, Crager M. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J. 2006; 27(1): 42-8. [CrossRef]
  • [10] Chisholm JW, Goldfine AB, Dhalla AK, Braunwald E, Morrow DA, Karwatowska-Prokopczuk E, et al. Effect of ranolazine on A1C and glucose levels in hyperglycemic patients with non-ST elevation acute coronary syndrome. Diabetes Care. 2010; 33(6): 1163-1168. [CrossRef]
  • [11] Sossalla S, Maier LS. Role of ranolazine in angina, heart failure, arrhythmias, and diabetes. Pharmacol Ther. 2012; 133(3): 311-23. [CrossRef]
  • [12] Ghosh GC, Ghosh RK, Bandyopadhyay D, Chatterjee K, Aneja A. Ranolazine: Multifaceted Role beyond Coronary Artery Disease, a Recent Perspective. Heart Views. 2018; 19(3): 88-98. [CrossRef]
  • [13] Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart. 2006; 92 Suppl 4: iv6-iv14. [CrossRef]
  • [14] Fraser H, Belardinelli L, Wang L, Light PE, McVeigh JJ, Clanachan AS. Ranolazine decreases diastolic calcium accumulation caused by ATX-II or ischemia in rat hearts. J Mol Cell Cardiol. 2006; 41(6): 1031-8. [CrossRef]
  • [15] Rastogi S, Sharov VG, Mishra S, Gupta RC, Blackburn B, Belardinelli L, et al. Ranolazine combined with enalapril or metoprolol prevents progressive LV dysfunction and remodeling in dogs with moderate heart failure. Am J Physiol Heart Circ Physiol. 2008; 295(5): H2149-55. [CrossRef]
  • [16] Bhandari B, Subramanian L. Ranolazine, a partial fatty acid oxidation inhibitor, its potential benefit in angina and other cardiovascular disorders. Recent Pat Cardiovasc Drug Discov. 2007; 2(1): 35-9. [CrossRef]
  • [17] Aldasoro M, Guerra-Ojeda S, Aguirre-Rueda D, Mauricio MD, Vila JM, Marchio P, et al. Effects of ranolazine on astrocytes and neurons in primary culture. PLoS One. 2016; 11(3): e0150619. [CrossRef]
  • [18] Shimabukuro M, Higa S, Shinzato T, Nagamine F, Komiya I, Takasu N. Cardioprotective effects of troglitazone in streptozotocin-induced diabetic rats. Metabolism. 1996; 45(9): 1168-73. [CrossRef]
  • [19] Tang S-G, Liu X-Y, Wang S-P, Wang H-H, Jovanović A, Tan W. Trimetazidine prevents diabetic cardiomyopathy by inhibiting Nox2/TRPC3-induced oxidative stress. J Pharmacol Sci. 2019; 139(4): 311-8. [CrossRef]
  • [20] Li W, Yao M, Wang R, Shi Y, Hou L, Hou Z, et al. Profile of cardiac lipid metabolism in STZ-induced diabetic mice. Lipids Health Dis. 2018; 17(1): 231-43. [CrossRef]
  • [21] Stern S, Sclarowsky S. The ECG in Diabetes Mellitus. Circulation. 2009; 120(16): 1633-6. [CrossRef]
  • [22] Sheweita SA, Mashaly S, Newairy AA, Abdou HM, Eweda SM. Changes in Oxidative Stress and Antioxidant Enzyme Activities in Streptozotocin-Induced Diabetes Mellitus in Rats: Role of Alhagi maurorum Extracts. Oxid Med Cell Longev. 2016; 2016: 5264064. [CrossRef]
  • [23] Ligeti L, Szenczi O, Prestia CM, Szabo C, Horvath K, Marcsek ZL, et al. Altered calcium handling is an early sign of streptozotocin-induced diabetic cardiomyopathy. Int J Mol Med. 2006; 17(6): 1035-43.
  • [24] Horakova L, Strosova MK, Spickett CM, Blaskovic D. Impairment of calcium ATPases by high glucose and potential pharmacological protection. Free Radic Res. 2013; 47 Suppl 1: 81-92. [CrossRef]
  • [25] Zarain-Herzberg A, Garcia-Rivas G, Estrada-Aviles R. Regulation of SERCA pumps expression in diabetes. Cell Calcium. 2014; 56(5): 302-10. [CrossRef]
  • [26] Akula A, Kota MK, Gopisetty SG, Chitrapu RV, Kalagara M, Kalagara S, et al. Biochemical, histological and echocardiographic changes during experimental cardiomyopathy in STZ-induced diabetic rats. Pharmacol Res. 2003; 48(5): 429-35. [CrossRef]
  • [27] Badole SL, Chaudhari SM, Jangam GB, Kandhare AD, Bodhankar SL. Cardioprotective Activity of Pongamia pinnata in Streptozotocin-Nicotinamide Induced Diabetic Rats. Biomed Res Int. 2015; 2015: 403291. [CrossRef]
  • [28] Cai L, Kang YJ. Oxidative stress and diabetic cardiomyopathy. Cardiovasc Toxicol. 2001; 1(3): 181-93. [CrossRef]
  • [29] Fredersdorf S, Thumann C, Zimmermann WH, Vetter R, Graf T, Luchner A, et al. Increased myocardial SERCA expression in early type 2 diabetes mellitus is insulin dependent: In vivo and in vitro data. Cardiovasc Diabetol. 2012; 11: 57-68. [CrossRef]
  • [30] Soliman AM. Potential impact of Paracentrotus lividus extract on diabetic rat models induced by high fat diet/streptozotocin. JOBAZ. 2016; 77: 8-20. [CrossRef]
  • [31] Tawfik MK, Ameen AM. Cardioprotective effect of ranolazine in nondiabetic and diabetic male rats subjected to isoprenaline-induced acute myocardial infarction involves modulation of AMPK and inhibition of apoptosis. Can J Physiol Pharmacol. 2019; 97(7): 661-674. [CrossRef]
  • [32] Karia P, Patel KV, Rathod SSP. Breast cancer amelioration by Butea monosperma in-vitro and in-vivo. J Ethnopharmacol. 2018; 217: 54-62. [CrossRef]
  • [33] Boarescu P-M, Boarescu I, Bocșan IC, Pop RM, Gheban D, Bulboacă AE, et al. Curcumin Nanoparticles Protect against Isoproterenol Induced Myocardial Infarction by Alleviating Myocardial Tissue Oxidative Stress, Electrocardiogram, and Biological Changes. Molecules. 2019; 24(15): 2802-2821. [CrossRef]
  • [34] Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972; 18(6): 499-502.
  • [35] Al-Rasheed NM, Al-Rasheed NM, Hasan IH, Al-Amin MA, Al-Ajmi HN, Mohamad RA, et al. Simvastatin Ameliorates Diabetic Cardiomyopathy by Attenuating Oxidative Stress and Inflammation in Rats. Oxid Med Cell Longev. 2017; 2017: 1092015. [CrossRef]
  • [36] Chai W, Garrelds IM, Vries Rd, Danser AHJ. Cardioprotective Effects of Eplerenone in the Rat Heart. Hypertension. 2006; 47(4): 665-70. [CrossRef]
  • [37] Slater TF, Sawyer BC. The stimulatory effects of carbon tetrachloride and other halogenoalkanes on peroxidative reactions in rat liver fractions in vitro. General features of the systems used. Biochem J. 1971; 123(5): 805-14. [CrossRef]
  • [38] Moron MS, Depierre JW, Mannervik B. Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochim Biophys Acta. 1979; 582(1): 67-78. [CrossRef]
  • [39] Misra HP, Fridovich I. The oxidation of phenylhydrazine: superoxide and mechanism. Biochemistry. 1976; 15(3): 681- 7. [CrossRef]
  • [40] Hugo AEBI, Sonja R. WYSS, Bernhard SCHERZ, SKVARIL F. Heterogeneity of Erythrocyte Catalase I1 Isolation and Characterization of Normal and Variant Erythrocyte Catalase and Their Subunits. Eur J Biochem. 1974; 48: 137-45.
  • [41] Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951; 193(1): 265-75.
  • [42] Riccio G, Antonucci S, Coppola C, D'Avino C, Piscopo G, Fiore D, et al. Ranolazine Attenuates Trastuzumab-Induced Heart Dysfunction by Modulating ROS Production. Front Physiol. 2018; 9: 38-46. [CrossRef]
Journal of research in pharmacy (online)-Cover
  • Yayın Aralığı: Yılda 6 Sayı
  • Yayıncı: Marmara Üniversitesi
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