Document Type : Original Article(s)
Authors
1 Associate Professor, Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
2 Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
3 Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
4 Associate Professor, Department of Pathology, Kerman University of Medical Sciences, Kerman, Iran
Abstract
BACKGROUND: Plasma iron excess can lead to iron accumulation in heart, kidney and liver. Heart failure is a clinical widespread syndrome. In thalassemia, iron overload cardiomyopathy is caused by iron accumulation in the heart that leads to cardiac damage and heart failure. Digoxin increases the intracellular sodium concentration by inhibition of Na+/K+-ATPase that affects Na+/Ca2+ exchanger (NCX), which raises intracellular calcium and thus attenuates heart failure. The mechanism of iron uptake into cardiomyocytes is not exactly understood. METHODS: We assessed the effect of different concentrations of digoxin on cardiac iron content in rat model of iron overload. Digoxin had been administrated intraperitoneally (IP) for one week before main study began to assure increased digoxin levels. Group 1 received four IP injections of iron-dextran (12.5mg/100g body weight) every 5 days evenly distributed over 20 days. Groups 2-4 received 0.5, 1 and 5 mg/kg/day IP digoxin, respectively. Last three groups 5-7 received iron-dextran as group 1 and digoxin concentrations 0.5, 1 and 5 mg/kg/day respectively. RESULTS: Cardiac iron contents were significantly higher in iron overload groups that received different concentrations (0.5, 1 and 5 mg/kg/day) of digoxin than their counterparts in control groups and this pattern was also observed in pathology assessment. CONCLUSION: It seems that digoxin plays an important role in iron transport into heart in iron overload state but exact mechanism of this phenomenon is not clear. L-type Ca2+ channels are good candidates that probably could be involved in iron accumulation in cardiomyocytes. Thus it would be better to reconsider digoxin administration in thalassemia and iron overload conditions
Keywords
- Andrews NC. Disorders of iron metabolism. N Engl J Med 1999; 341(26): 1986-95.
- Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell 2004; 117(3): 285-97.
- Templeton DM, Liu Y. Genetic regulation of cell function in response to iron overload or chelation. Biochim Biophys Acta 2003; 1619(2): 113-24.
- Oudit G, Moe G. Iron-overload Cardiomyopathy Associated with Iron-overload Conditions: Incidence, Pathophysiology, and Treatment [Online]. [cited 2007]; Available from: URL: http://www.cardiologyrounds.ca/crus/cardeng0407.pdf
- Kremastinos DT, Farmakis D, Aessopos A, Hahalis G, Hamodraka E, Tsiapras D, et al. Betathalassemia cardiomyopathy: history, present considerations, and future perspectives. Circ Heart Fail 2010; 3(3): 451-8.
- 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.
- Xu KY, Zhu W, Chen L, DeFilippi C, Zhang J, Xiao RP. Mechanistic distinction between activation and inhibition of (Na(+)+K(+))-ATPasemediated Ca2+ influx in cardiomyocytes. Biochem Biophys Res Commun 2011; 406(2): 200-3.
- Smith TW. Digitalis. Mechanisms of action and clinical use. N Engl J Med 1988; 318(6): 358-65.
- Oudit GY, Trivieri MG, Khaper N, Liu PP, Backx PH. Role of L-type Ca2+ channels in iron transport and iron-overload cardiomyopathy. J Mol Med (Berl) 2006; 84(5): 349-64.
- 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.
- Atar D, Backx PH, Appel MM, Gao WD, Marban E. Excitation-transcription coupling mediated by zinc influx through voltage-dependent calcium channels. J Biol Chem 1995; 270(6): 2473-7.
- Winegar BD, Kelly R, Lansman JB. Block of current through single calcium channels by Fe, Co, and Ni. Location of the transition metal binding site in the pore. J Gen Physiol 1991; 97(2): 351-67.
- Koren G, MacLeod SM. Postmortem redistribution of digoxin in rats. J Forensic Sci 1985; 30(1): 92-6.
- Ibrahim NG, Hoffstein ST, Freedman ML. Induction of liver cell haem oxygenase in ironoverloaded rats. Biochem J 1979; 180(2): 257-63.
- Whittaker P, Hines FA, Robl MG, Dunkel VC. Histopathological evaluation of liver, pancreas, spleen, and heart from iron-overloaded Sprague-Dawley rats. Toxicol Pathol 1996; 24(5): 558-63.
- Vassort G, Talavera K, Alvarez JL. Role of T-type Ca2+ channels in the heart. Cell Calcium 2006; 40(2): 205-20.
- 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.
- 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.