Vol 14, No 2 (2018): Incomplete Issue:46-52

The effect of different digoxin concentrations on heart tissue and antioxidant status in iron-overloaded rats

Beydolah Shahouzehi, Hamid Reza Nasri, Yaser Masoumi-Ardakani

DOI: http://dx.doi.org/10.22122/arya.v14i2.1642


BACKGROUND: Thalassaemia is a hereditary disorder and has an economic burden on patients and the government. The most prevalent complication in these patients is iron overload which is followed by cardiomyopathy. Digoxin is considered as a treatment against heart failure in thalassaemia. The present study evaluated the effect of two digoxin concentrations on iron content and antioxidative defense in cardiac tissue of iron-overloaded rats.

METHODS: The study was conducted on 48 rats which were divided into 6 groups. Group 1 was the control group and did not receive any treatment and group 2 was the iron overload group. In addition groups 3 and 4 were the digoxin control groups which received 1 and 5 mg/kg/day of digoxin, respectively. Groups 5 and 6 received 1 and 5 mg/kg/day of digoxin plus iron-dextran, respectively. After 1 month, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPX), and total antioxidant status (TAS) were assessed in cardiac tissues.

RESULTS: Co-administration of iron-dextran and digoxin (1 and 5 mg/kg/day) significantly increased SOD and TAS levels (P < 0.0010) and reduced MDA (P < 0.0010) in heart tissue compared to control and iron overload groups. GPX levels significantly reduced in groups 5 and 6 (iron + digoxin 1 (P < 0.0500) and iron + digoxin 5) (P < 0.0010) compared to the iron control group.

CONCLUSION: Digoxin remarkably facilitates iron uptake by cardiomyocytes by affecting other channels such as L-type and T-type Ca2+ channels (LTCC and TTCC). Digoxin administration in the iron-overloaded rat model deteriorated antioxidative parameters and increased iron entry into heart tissue at higher doses. Therefore, in patients with beta thalassaemia major, digoxin must be administered with great care and serum iron and ferritin must be regularly monitored.


Digoxin; Iron Overload; Superoxide Dismutase; Glutathione Peroxidase

Full Text:



Bhagat S, Sarkar PD, Suryakar AN, Hundekar PS. A study on the biomarkers of oxidative stress: The effects of oral therapeutic supplementation on the iron concentration and the product of lipid peroxidation in beta thalassemia major. J Clin Diagn Res 2012; 6(7): 1144-7.

Khodaei GH, Farbod N, Zarif B, Nateghi S, Saeidi M. Frequency of thalassemia in Iran and Khorasan Razavi. Int J Pediatr 2013; 1(1): 45-50.

Urbanski NK, Beresewicz A. Generation of *OH initiated by interaction of Fe2+ and Cu+ with dioxygen; Comparison with the Fenton chemistry. Acta Biochim Pol 2000; 47(4): 951-62.

Walter PB, Fung EB, Killilea DW, Jiang Q, Hudes M, Madden J, et al. Oxidative stress and inflammation in iron-overloaded patients with beta-thalassaemia or sickle cell disease. Br J Haematol 2006; 135(2): 254-63.

Gao X, Campian JL, Qian M, Sun XF, Eaton JW. Mitochondrial DNA damage in iron overload. J Biol Chem 2009; 284(8): 4767-75.

Handa P, Morgan-Stevenson V, Maliken BD, Nelson JE, Washington S, Westerman M, et al. Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice. Am J Physiol Gastrointest Liver Physiol 2016; 310(2): G117-G127.

Kuo KL, Hung SC, Lee TS, Tarng DC. Iron sucrose accelerates early atherogenesis by increasing superoxide production and upregulating adhesion molecules in CKD. J Am Soc Nephrol 2014; 25(11): 2596-606.

Gammella E, Recalcati S, Rybinska I, Buratti P, Cairo G. Iron-induced damage in cardiomyopathy: Oxidative-dependent and independent mechanisms. Oxid Med Cell Longev 2015; 2015: 230182.

Engle MA, Erlandson M, Smith CH. Late cardiac complications of chronic, severe, refractory anemia with hemochromatosis. Circulation 1964; 30:


Zurlo MG, De Stefano P, Borgna-Pignatti C, Di Palma A, Piga A, Melevendi C, et al. Survival and causes of death in thalassaemia major. Lancet 1989; 2(8653): 27-30.

Ladis V, Chouliaras G, Berdousi H, Kanavakis E, Kattamis C. Longitudinal study of survival and causes of death in patients with thalassemia major in Greece. Ann N Y Acad Sci 2005; 1054: 445-50.

Kremastinos DT, Farmakis D, Aessopos A, Hahalis G, Hamodraka E, Tsiapras D, et al. Beta-thalassemia cardiomyopathy: History, present considerations, and future perspectives. Circ Heart Fail 2010; 3(3): 451-8.

Lelie`vre LG, Lechat P. Mechanisms, manifestations, and management of digoxin toxicity. Heart Metab 2007; 35: 9-11.

Kurian M. The effect of digitalis on the heart-an update. J Pharm Sci Res 2015; 7(10): 861-3.

Tsushima RG, Wickenden AD, Bouchard RA, Oudit GY, Liu PP, Backx PH. Modulation of iron uptake in heart by L-type Ca2+ channel modifiers: Possible implications in iron overload. Circ Res 1999; 84(11): 1302-9.

Oudit GY, Sun H, Trivieri MG, Koch SE, Dawood F, Ackerley C, et al. L-type Ca2+ channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy. Nat Med 2003; 9(9): 1187-94.

Kumfu S, Chattipakorn S, Chinda K, Fucharoen S, Chattipakorn N. T-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice. Eur J Haematol 2012; 88(6): 535-48.

Chattipakorn N, Kumfu S, Fucharoen S, Chattipakorn S. Calcium channels and iron uptake into the heart. World J Cardiol 2011; 3(7): 215-8.

Chen MP, Cabantchik ZI, Chan S, Chan GC, Cheung YF. Iron overload and apoptosis of HL-1 cardiomyocytes: Effects of calcium channel blockade. PLoS One 2014; 9(11): e112915.

Kumfu S, Chattipakorn SC, Fucharoen S, Chattipakorn N. Dual T-type and L-type calcium channel blocker exerts beneficial effects in attenuating cardiovascular dysfunction in iron-overloaded thalassaemic mice. Exp Physiol 2016; 101(4): 521-39.

Nasri HR, Shahouzehi B, Masoumi-Ardakani Y, Iranpour M. Effects of digoxin on cardiac iron content in rat model of iron overload. ARYA Atheroscler 2016; 12(4): 180-4.

Lim CS, Vaziri ND. The effects of iron dextran on the oxidative stress in cardiovascular tissues of rats with chronic renal failure. Kidney Int 2004; 65(5): 1802-9.

Wood JC, Enriquez C, Ghugre N, Otto-Duessel M, Aguilar M, Nelson MD, et al. Physiology and pathophysiology of iron cardiomyopathy in thalassemia. Ann N Y Acad Sci 2005; 1054: 386-95.

Mishra AK, Tiwari A. Iron overload in Beta thalassaemia major and intermedia patients. Maedica (Buchar) 2013; 8(4): 328-32.

Sattari M, Sheykhi D, Nikanfar A, Pourfeizi AH, Nazari M, Dolatkhah R, et al. The financial and social impact of thalassemia and its treatment in Iran. Pharm Sci 2012; 18(3): 171-6.

Kumfu S, Chattipakorn S, Srichairatanakool S, Settakorn J, Fucharoen S, Chattipakorn N. T-type calcium channel as a portal of iron uptake into cardiomyocytes of beta-thalassemic mice. Eur J Haematol 2011; 86(2): 156-66.

Kumfu S, Chattipakorn S, Fucharoen S, Chattipakorn N. Ferric iron uptake into cardiomyocytes of b-thalassemic mice is not through calcium channels. Drug Chem Toxicol 2013; 36(3): 329-34.

Arispe N, Diaz JC, Simakova O, Pollard HB. Heart failure drug digitoxin induces calcium uptake into cells by forming transmembrane calcium channels. Proc Natl Acad Sci U S A 2008; 105(7): 2610-5.

de Valk B, Marx JJ. Iron, atherosclerosis, and ischemic heart disease. Arch Intern Med 1999; 159(14): 1542-8.

Lee TS, Shiao MS, Pan CC, Chau LY. Iron-deficient diet reduces atherosclerotic lesions in apoE-deficient mice. Circulation 1999; 99(9): 1222-9.


  • There are currently no refbacks.

Creative Commons Attribution-NonCommercial 4.0

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.