Generic placeholder image

Cardiovascular & Hematological Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5257
ISSN (Online): 1875-6182

Research Article

Evaluation of the Effectiveness of Dantrolene Sodium against Digoxininduced Cardiotoxicity in Adult Rats

Author(s): Mahmoud Zardast, Kosar Behmanesh, Tahereh Farkhondeh*, Babak Roshanravan, Hamed Aramjoo, Michael Aschner, Saeed Samarghandian* and Zahra Kiani

Volume 22, Issue 1, 2024

Published on: 16 March, 2023

Page: [60 - 65] Pages: 6

DOI: 10.2174/1871525721666230125091826

Price: $65

Abstract

Background: Digoxin poisoning commonly occurs in people treated with digoxin. It has been suggested that treatment with dantrolene may be a suitable strategy for digoxin-induced cardiotoxicity.

Objective: The aim of this study was to evaluate the protective effect of dantrolene on digoxininduced cardiotoxicity in male rats.

Methods: This study was approved by the ethics committee of Birjand University of Medical Sciences (Ethical number: IR.BUMS.REC.1400.067). Forty-two Wistar rats weighing between 300- 350 gr were randomly allocated to 7 groups (n = 6) as follows: Normal Saline (NS) group, Normal Saline + Ethanol (NS + ETOH) group, Normal Saline + dantrolene 10 mg/kg (NS + Dan 10) group, Digoxin (Dig) group), Digoxin + dantrolene 5 mg/kg (Dig + Dan 5) group, Digoxin + dantrolene 10 mg/kg (Dig + Dan 10) group, Digoxin + dantrolene 20 mg/kg (Dig + Dan 20) group, Dig was injected intravenously at 12 mL / h (0.25 mg / mL). Dan (5, 10 and 20 mg/kg) was injected intravenously at 5-8 min/mL. After 1 hour, blood samples were obtained from the animals' cavernous sinus and each animal's heartremoved. The blood sample was rapidly centrifuged at 2,500 rpm for 10 minutes and the serum was separated for measurement of creatine phosphokinase (CPK), potassium (K), sodium (Na), calcium (Ca), and magnesium (Mg). The samples were stored at -20°C. The heart samples were fixed in formalin 10% for histopathological evaluation.

Results: K levels slightly increased in the dig group versus the NS group. A significant increase in the K levels was observed in the Dig + Dan 20 group versus the NS group (p < 0.001). Dig slightly decreased Ca levels in the treated group versus the NS group. The levels of Ca significantly increased in the Dig + Dan 10 group versus the Dig group (p < 0.05). Histological examination of the heart tissue in the dig group showed cardiomyocyte degeneration, increased edematous intramuscular space associated with hemorrhage, and congestion. Focal inflammatory cell accumulation in the heart tissue was also seen. Cardiomyocytes were clear and arranged in good order in the Dig + Dan 10 group.

Conclusion: dantrolene (10 mg/kg) was cardioprotective in a model of digoxin-induced cardiotoxicity, secondary to cardiac remodeling and hyperkalemia. However, further research is necessary to determine dantrolene's cardioprotective and cardiotoxic doses in animal models.

Keywords: Dantrolene sodium, digoxin, digitalis, dantrium, cardiotoxicity, rats.

Graphical Abstract
[1]
Khadhair, A.; Majeed, S.; Almoziel, M. Toxic effects of digoxin on heart and troponin level in laboratory rat. J. Kerbala Univ., 2017, 13(4), 42-47.
[2]
Yurtlu, B.S.; Özbilgin, Ş.; Yurtlu, D.A.; Boztaş, N.; Kamacı, G.; Akaltun, M.; Hancı, V.; Yılmaz, O. Intravenous lipid emulsion prolongs survival in rats intoxicated with digoxin. Am. J. Emerg. Med., 2016, 34(6), 1112-1116.
[http://dx.doi.org/10.1016/j.ajem.2016.03.038] [PMID: 27073138]
[3]
Nesher, M.; Shpolansky, U.; Rosen, H.; Lichtstein, D. The digitalis-like steroid hormones: New mechanisms of action and biological significance. Life Sci., 2007, 80(23), 2093-2107.
[http://dx.doi.org/10.1016/j.lfs.2007.03.013] [PMID: 17499813]
[4]
Farghaly, H.S.M.; Ashry, I.E.S.M.; Hareedy, M.S. High doses of digoxin increase the myocardial nuclear factor-kB and CaV1.2 channels in healthy mice. A possible mechanism of digitalis toxicity. Biomed. Pharmacother., 2018, 105, 533-539.
[http://dx.doi.org/10.1016/j.biopha.2018.05.137] [PMID: 29885637]
[5]
Eddleston, M.; Rajapakse, S. Rajakanthan; Jayalath, S.; Sjöström, L.; Santharaj, W.; Thenabadu, P.N.; Sheriff, M.H.R.; Warrell, D.A. Anti-digoxin Fab fragments in cardiotoxicity induced by ingestion of yellow oleander: a randomised controlled trial. Lancet, 2000, 355(9208), 967-972.
[http://dx.doi.org/10.1016/S0140-6736(00)90014-X] [PMID: 10768435]
[6]
Pincus, M. Management of digoxin toxicity. Aust. Prescr., 2016, 39(1), 18-20.
[http://dx.doi.org/10.18773/austprescr.2016.006] [PMID: 27041802]
[7]
Eyer, F.; Steimer, W.; Nitzsche, T.; Jung, N.; Neuberger, H.; Müller, C.; Schlapschy, M.; Zilker, T.; Skerra, A. Intravenous application of an anticalin dramatically lowers plasma digoxin levels and reduces its toxic effects in rats. Toxicol. Appl. Pharmacol., 2012, 263(3), 352-359.
[http://dx.doi.org/10.1016/j.taap.2012.07.009] [PMID: 22820422]
[8]
Emin, B.M.; Taysi, S.; Koç, M.; Bakan, N. Dantrolene protects erythrocytes against oxidative stress during whole‐body irradiation in rats. Cell Biochem. Funct., 2003, 21(2), 127-131.
[http://dx.doi.org/10.1002/cbf.1008]
[9]
Turan, C.A.; Ozturk, T.C.; Akoglu, E.U.; Ak, R.; Aygun, K.; Sahiner, A.; Sumer, E.; Somay, A.; Onur, O.E. The role of intralipid emulsion in the rat model of digoxin intoxication. Cardiovasc. Toxicol., 2018, 18(4), 329-336.
[http://dx.doi.org/10.1007/s12012-018-9444-4] [PMID: 29397554]
[10]
Brooks, R.R.; Carpenter, J.F.; Jones, S.M.; Gregory, C.M. Effects of dantrolene sodium in rodent models of cardiac arrhythmia. Eur. J. Pharmacol., 1989, 164(3), 521-530.
[http://dx.doi.org/10.1016/0014-2999(89)90260-4] [PMID: 2767123]
[11]
Acikel, M.; Buyukokuroglu, M.E.; Erdogan, F.; Aksoy, H.; Bozkurt, E.; Senocak, H. Protective effects of dantrolene against myocardial injury induced by isoproterenol in rats: biochemical and histological findings. Int. J. Cardiol., 2005, 98(3), 389-394.
[http://dx.doi.org/10.1016/j.ijcard.2003.10.054] [PMID: 15708169]
[12]
Farkhondeh, T.; Roshanravan, B.; Shirazi, F.M.; Mehrpour, O. Can dantrolene be used in the treatment of cardioglycosides poisonings?; Taylor & Francis, 2021, pp. 1-2.
[13]
Todorova, V.K.; Siegel, E.R.; Kaufmann, Y.; Kumarapeli, A.; Owen, A.; Wei, J.Y.; Makhoul, I.; Klimberg, V.S. Dantrolene attenuates cardiotoxicity of doxorubicin without reducing its antitumor efficacy in a breast cancer model. Transl. Oncol., 2020, 13(2), 471-480.
[http://dx.doi.org/10.1016/j.tranon.2019.12.006] [PMID: 31918212]
[14]
Hartmann, N.; Pabel, S.; Herting, J.; Schatter, F.; Renner, A.; Gummert, J.; Schotola, H.; Danner, B.C.; Maier, L.S.; Frey, N.; Hasenfuss, G.; Fischer, T.H.; Sossalla, S. Antiarrhythmic effects of dantrolene in human diseased cardiomyocytes. Heart Rhythm, 2017, 14(3), 412-419.
[http://dx.doi.org/10.1016/j.hrthm.2016.09.014] [PMID: 27650424]
[15]
Botelho, A.F.M.; Miranda, A.L.S.; Freitas, T.G.; Milani, P.F.; Barreto, T.; Cruz, J.S.; Melo, M.M. Comparative cardiotoxicity of low doses of digoxin, ouabain, and oleandrin. Cardiovasc. Toxicol., 2020, 20(6), 539-547.
[http://dx.doi.org/10.1007/s12012-020-09579-1] [PMID: 32488807]
[16]
Ruch, S.; Kennedy, R.H.; Seifen, E. Digoxin cardiotoxicity in aging anesthetized F344 rats. Mech. Ageing Dev., 1992, 65(2-3), 199-216.
[http://dx.doi.org/10.1016/0047-6374(92)90036-D] [PMID: 1434949]
[17]
Ku, D.; Akera, T.; Pew, C.L.; Brody, T.M. Cardiac glycosides: Correlations among Na+, K+-ATPase, sodium pump and contractility in the guinea pig heart. Naunyn Schmiedebergs Arch. Pharmacol., 1974, 285(2), 185-200.
[http://dx.doi.org/10.1007/BF00501153] [PMID: 4281068]
[18]
Deitmer, J.W.; Ellis, D. The intracellular sodium activity of cardiac Purkinje fibres during inhibition and re-activation of the Na-K pump. J. Physiol., 1978, 284(1), 241-259.
[http://dx.doi.org/10.1113/jphysiol.1978.sp012539] [PMID: 731536]
[19]
Lingrel, J.B. The physiological significance of the cardiotonic steroid/ouabain-binding site of the Na,K-ATPase. Annu. Rev. Physiol., 2010, 72(1), 395-412.
[http://dx.doi.org/10.1146/annurev-physiol-021909-135725] [PMID: 20148682]
[20]
Fabiato, A. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am. J. Physiol. Cell Physiol., 1983, 245(1), C1-C14.
[http://dx.doi.org/10.1152/ajpcell.1983.245.1.C1] [PMID: 6346892]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy