Abstract
Background and Objective: Levosimendan is a positive inotropic and a vasodilator agent with pleotropic characteristics that include antioxidation, anti-inflammation and smooth muscle vasodilation.
Methods: In this study, the effects of levosimendan (0, 0.1, 1, 10, and 20 µg/ml) on oxidative DNA damage and sister-chromatid exchanges (SCEs) were evaluated in human cultured lymphocytes.
Results: The results showed that levosimendan increased the frequency of SCEs in all examined concentrations (P<0.01) except for 0.1 µg/ml. On the other hand, levosimendan did not induce oxidative DNA damage as measured by the 8-OHdG biomarker (P > 0.05). In addition, neither mitotic arrest nor proliferation index was affected by levosimendan at all examined doses (P > 0.05).
Conclusion: In conclusion, levosimendan might be associated with increases in sister-chromatid exchanges in cultured human lymphocytes. In vivo studies are required to confirm the present findings.
Keywords: Levosimendan, mitotic index, 8-hydroxy-2-deoxy guanosine (8-OHdG), sister chromatid exchanges.
Graphical Abstract
[1]
Janssen, P.M.; Datz, N.; Zeitz, O.; Hasenfuss, G. Levosimendan improves diastolic and systolic function in failing human myocardium. Eur. J. Pharmacol., 2000, 404, 191-199.
[2]
Toller, W.G.; Stranz, C. Levosimendan, a new inotropic and vasodilator agent. Anesthesiology, 2006, 104, 556-569.
[3]
Pathak, A.; Lebrin, M.; Vaccaro, A.; Senard, J.M.; Despas, F. Pharmacology of levosimendan: inotropic, vasodilatory and cardioprotective effects. J. Clin. Pharm. Ther., 2013, 38, 341-349.
[4]
Ajiro, Y.; Hagiwara, N.; Katsube, Y.; Sperelakis, N.; Kasanuki, H. Levosimendan increases L-type Ca(2+) current via phosphodiesterase-3 inhibition in human cardiac myocytes. Eur. J. Pharmacol., 2002, 435, 27-33.
[5]
Kaheinen, P.; Pollesello, P.; Levijoki, J.; Haikala, H. Levosimendan increases diastolic coronary flow in isolated guinea-pig heart by opening ATP-sensitive potassium channels. J. Cardiovasc. Pharmacol., 2001, 37, 367-374.
[6]
Markou, T.; Makridou, Z.; Galatou, E.; Lazou, A. Multiple signalling pathways underlie the protective effect of levosimendan in cardiac myocytes. Eur. J. Pharmacol., 2011, 667, 298-305.
[7]
Gong, B.; Li, Z.; Yat Wong, P.C. Levosimendan Treatment for Heart Failure: A Systematic Review and Meta-Analysis. J. Cardiothorac. Vasc. Anesth., 2015, 29, 1415-1425.
[8]
Kasikcioglu, H.A.; Cam, N. A review of levosimendan in the treatment of heart failure. Vasc. Health Risk Manag., 2006, 2, 389-400.
[9]
Ambrosio, G.; Di Lenarda, A.; Fedele, F.; Gabrielli, D.; Metra, M.; Oliva, F.; Perna, G.; Senni, M.; De Maria, R. Inotrope therapy in acute heart failure: A critical review of clinical and scientific evidence for levosimendan in the context of traditional treatment. G. Ital. Cardiol. (Rome), 2009, 10, 422-433.
[10]
Plaschke, K.; Bent, F.; Wagner, S.; Zorn, M.; Kopitz, J. In contrast to its anti-inflammatory and anti-apoptotic peripheral effect, levosimendan failed to induce a long-term neuroprotective effect in a rat model of mild septic encephalopathy: A pilot study. Neurosci. Lett., 2014, 560, 117-121.
[11]
Karakus, E.; Halici, Z.; Albayrak, A.; Bayir, Y.; Aydin, A.; Unal, D.; Cadirci, E.; Ferah, I.; Odaci, E. Beneficial pharmacological effects of levosimendan on antioxidant status of acute inflammation induced in paw of rat: involvement in inflammatory mediators. Basic Clin. Pharmacol. Toxicol., 2013, 112, 156-163.
[12]
Babik, B.; Balogh, A.L.; Sudy, R.; Ivankovitsne-Kiss, O.; Fodor, G.H.; Petak, F. Levosimendan prevents bronchoconstriction and adverse respiratory tissue mechanical changes in rabbits. Am. J. Physiol. Lung Cell. Mol. Physiol., 2017, 313, L950-L956.
[13]
Sikora, J.; Pstragowski, K.; Skibinska, N.; Sobczak, P.; Sikora, A.; Marszall, M.P.; Fabiszak, T.; Grzesk, G.; Kubica, J. Impact of levosimendan on platelet function. Thromb. Res., 2017, 159, 76-81.
[14]
van Hees, H.W.; Dekhuijzen, P.N.; Heunks, L.M. Levosimendan enhances force generation of diaphragm muscle from patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med., 2009, 179, 41-47.
[15]
Ochala, J. Ca2+ sensitizers: An emerging class of agents for counterbalancing weakness in skeletal muscle diseases? Neuromuscul. Disord., 2010, 20, 98-101.
[16]
Rababa,h, A.; Singh, S.; Suryavanshi, S.V.; Altarabsheh, S.E.; Deo, S.V.; McConnell, B.K. Compartmentalization role of A-kinase anchoring proteins (AKAPs) in mediating protein kinase A (PKA) signaling and cardiomyocyte hypertrophy. Int. J. Mol. Sci., 2014, 16, 218-229.
[18]
Keely, S.L. Activation of cAMP-dependent protein kinase without a corresponding increase in phosphorylase activity. Res. Commun. Chem. Pathol. Pharmacol., 1977, 18, 283-290.
[19]
Packer, M.; Leier, C.V. Survival in congestive heart failure during treatment with drugs with positive inotropic actions. Circulation, 1987, 75, IV55-IV63.
[20]
Brixius, K.; Reicke, S.; Schwinger, R.H. Beneficial effects of the Ca(2+) sensitizer levosimendan in human myocardium. Am. J. Physiol. Heart Circ. Physiol., 2002, 282, H131-H137.
[21]
Wilson, D.M., III; Thompson, L.H. Molecular mechanisms of sister-chromatid exchange. Mutat. Res., 2007, 616, 11-23.
[22]
Khabour, O.F.; Enaya, F.M.; Alzoubi, K.; Al-Azzam, S.I. Evaluation of DNA damage induced by norcantharidin in human cultured lymphocytes. Drug Chem. Toxicol., 2016, 39, 303-306.
[23]
Mhaidat, N.M.; Alzoubi, K.H.; Khabour, O.F.; Alawneh, K.Z.; Raffee, L.A.; Alsatari, E.S.; Hussein, E.I.; Bani-Hani, K.E. Assessment of genotoxicity of vincristine, vinblastine and vinorelbine in human cultured lymphocytes: A comparative study. Balkan J. Med. Genet., 2016, 19, 13-20.
[24]
Al-Sweedan, S.A.; Khabour, O.; Isam, R. Genotoxicity assessment in patients with thalassemia minor. Mutat. Res., 2012, 744, 167-171.
[25]
Alsatari, E.S.; Azab, M.; Khabour, O.F.; Alzoubi, K.H.; Sadiq, M.F. Assessment of DNA damage using chromosomal aberrations assay in lymphocytes of waterpipe smokers. Int. J. Occup. Med. Environ. Health, 2012, 25, 218-224.
[26]
Slawsky, M.T.; Colucci, W.S.; Gottlieb, S.S.; Greenberg, B.H.; Haeusslein, E.; Hare, J.; Hutchins, S.; Leier, C.V.; LeJemtel, T.H.; Loh, E.; Nicklas, J.; Ogilby, D.; Singh, B.N.; Smith, W. Acute Hemodynamic and Clinical Effects of Levosimendan in Patients With Severe Heart Failure. Circulation, 2000, 102, 2222-2227.
[27]
Nieminen, M.S.; Fruhwald, S.; Heunks, L.M.; Suominen, P.K.; Gordon, A.C.; Kivikko, M.; Pollesello, P. Levosimendan: current data, clinical use and future development. Heart Lung Vessel., 2013, 5, 227-245.
[28]
Azab, M.; Khabour, O.F.; Alzoubi, K.H.; Hawamdeh, H.; Quttina, M.; Nassar, L. Assessment of genotoxicity of pyrethrin in cultured human lymphocytes. Drug Chem. Toxicol., 2017, 40, 251-255.
[29]
Alzoubi, K.; Khabour, O.; Khader, M.; Mhaidat, N.; Al-Azzam, S. Evaluation of vitamin B12 effects on DNA damage induced by paclitaxel. Drug Chem. Toxicol., 2014, 37, 276-280.
[30]
Khabour, O.F.; Alawneh, K.; Al-Kofahi, E.; Mesmar, F. Assessment of genotoxicity associated with Behcet,s disease using sister-chromatid exchange assay: Vitamin E versus mitomycin C. Cytotechnology, 2015, 67, 1051-1057.
[31]
Khabour, O.F.; Saleh, N.; Alzoubi, K.H.; Hisaindee, S.; Al-Fyad, D.; Al-Kaabi, L.; Dodeen, A.; Esmadi, F.T. Genotoxicity of structurally related copper and zinc containing Schiff base complexes. Drug Chem. Toxicol., 2013, 36, 435-442.
[32]
Alqudah, M.A.Y.; Al-Ashwal, F.Y.; Alzoubi, K.H.; Alkhatatbeh, M.; Khabour, O. Vitamin E protects human lymphocytes from genotoxicity induced by oxaliplatin. Drug Chem. Toxicol., 2018, 41, 281-286.
[33]
Alzoubi, K.H.; Bayraktar, E.; Khabour, O.; Al-Azzam, S.I. Vitamin B12 protects against DNA damage induced by hydrochlorothiazide. Saudi Pharm. J., 2018, 26, 786-789.
[34]
Daradka, H.M.; Khabour, O.F.; Alotaibi, M.K. Potent antioxidative DNA damage of selected Saudi medicinal plants in cultured human lymphocytes. Pak. J. Pharm. Sci., 2018, 31, 1511-1517.
[35]
Esmadi, F.T.; Khabour, O.F.; Abbas, K.; Mohammad, A.E.; Obeidat, R.T.; Mfady, D. Synthesis, characterization and biological activity of some unsymmetrical Schiff base transition metal complexes. Drug Chem. Toxicol., 2016, 39, 41-47.
[36]
Rognoni, A.; Lupi, A.; Lazzero, M.; Bongo, A.S.; Rognoni, G. Levosimendan: from basic science to clinical trials. Recent Pat. Cardiovasc. Drug Discov., 2011, 6, 9-15.
[37]
Graudins, A.; Lee, H.M.; Druda, D. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies. Br. J. Clin. Pharmacol., 2016, 81, 453-461.
[38]
Iijima, K.; Morimoto, K. Quantitative analyses of the induction of chromosome aberrations and sister-chromatid exchanges in human lymphocytes exposed to gamma-rays and mitomycin-C in combination. Mutat. Res., 1991, 263, 263-268.
[39]
Chakrabarti, S.; Duhr, M.A.; Senecal-Quevillon, M.; Richer, C.L. Dose-dependent genotoxic effects of styrene on human blood lymphocytes and the relationship to its oxidative and metabolic effects. Environ. Mol. Mutagen., 1993, 22, 85-92.
[40]
Uringa, E.J.; Lisaingo, K.; Pickett, H.A. Brind Amour, J.; Rohde, J.H.; Zelensky, A.; Essers, J.; Lansdorp, P.M. RTEL1 contributes to DNA replication and repair and telomere maintenance. Mol. Biol. Cell, 2012, 23, 2782-2792.
[41]
Sundberg, S.; Antila, S.; Scheinin, H.; Hayha, M.; Virtanen, M.; Lehtonen, L. Integrated pharmacokinetics and pharmacodynamics of the novel calcium sensitizer levosimendan as assessed by systolic time intervals. Int. J. Clin. Pharmacol. Ther., 1998, 36, 629-635.
[42]
Valavanidis, A.; Vlachogianni, T.; Fiotakis, C. 8-hydroxy- -deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis. J. Environ. Sci. Health C. Environ. Carcinog. Ecotoxicol. Rev., 2009, 27, 120-139.
Related Journals
Related Books
New Findings from Natural Substances
Pharmaceutical Chemistry and Production: An Introductory Textbook
Evidence-Based Research in Ayurveda against COVID-19 in Compliance with Standardized Protocols and Practices
Pharmaceuticals for Targeting Coronaviruses
Medical Applications of Beta-Glucan
Nanotechnology Driven Herbal Medicine for Burns: From Concept to Application
Postbiotics: Science, Technology and Applications
Biologically Active Natural Products from Asia and Africa: A Selection of Topics
Article Metrics
58
2
1