Comparative Efficacy of Levosimendan, Ramipril, and Sacubitril/
Valsartan in Isoproterenol-induced Experimental Heart Failure: A
Hemodynamic and Molecular Approach

Md   Sayeed   Akhtar; Quamrul      Hassan; Obaid      Afzal; Abdulmalik      Altamimi; Mohd.   Zaheen   Hassan; Arun   Kumar   Sharma; Asif   Ansari Shaik   Mohammad; Fauzia      Tabassum

doi:10.2174/1874467215666220919104526

Abstract

Objective: Cardiac ischemia-related myocardial damage has been considered a major reason for heart failure. We aimed to investigate the role of levosimendan (LEVO) in comparison to ramipril and sacubitril/valsartan (Sac/Val) in preventing damage associated with isoproterenol (ISO) induced myocardial infarction.

Methods: Myocardial infarction was induced by injecting subcutaneous isoproterenol (5 mg/kg once for 7 consecutive days) to establish an experimental heart failure model. Simultaneously, LEVO (1 mg/kg/day), ramipril (3mg/kg/day) and Sac/Val (68 mg/kg/day) suspension were administered orally for four weeks.

Results: We observed a significant correlation between ISO-induced ischemia with cardiac remodeling and alterations in myocardial architecture. LEVO, ramipril, and Sac/Val significantly prevented lipid peroxidation and damaged antioxidant enzymes like superoxide dismutase, catalase, glutathione and thioredoxin reductase. We also observed their ameliorative effects in myocardium's cardiac hypertrophy, evidenced by reduced heart weight to body weight ratio and transforming growth factor β related collagen deposition. LEVO, ramipril, and Sac/Val also maintained cardiac biomarkers like lactate dehydrogenase, creatine kinase-MB, brain natriuretic peptide and cardiac Troponin-I, indicating reduced myocardial damage that was further demonstrated by histopathological examination. Decreased sarcoplasmic endoplasmic reticulum Ca2+ATPase2a and sodium-calcium exchanger-1 protein depletion after LEVO, ramipril, and Sac/Val administration indicated improved Ca2+ homeostasis during myocardial contractility.

Conclusion: Our findings suggest that LEVO has comparable effects to ramipril, and Sac/Val in preventing myocardial damage via balancing oxidant-antioxidant system, decreased collagen deposition, reduced myocardial stress as well as improved Ca2+ homeostasis during myocardial contractility.

Keywords: Levosimendan, Ramipril, Sacubitril/Valsartan, Myocardial infarction, Ca2+ modulation, myocardial contractility, balancing oxidant-antioxidant system

Graphical Abstract

[1]
World Health Organisation. Cardiovascular diseases (CVDs). 2022. Available from: https://www.who.int/en/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)

[2]
Virani, S.S.; Alonso, A.; Aparicio, H.J.; Benjamin, E.J.; Bittencourt, M.S.; Callaway, C.W.; Carson, A.P.; Chamberlain, A.M.; Cheng, S.; Delling, F.N.; Elkind, M.S.V.; Evenson, K.R.; Ferguson, J.F.; Gupta, D.K.; Khan, S.S.; Kissela, B.M.; Knutson, K.L.; Lee, C.D.; Lewis, T.T.; Liu, J.; Loop, M.S.; Lutsey, P.L.; Ma, J.; Mackey, J.; Martin, S.S.; Matchar, D.B.; Mussolino, M.E.; Navaneethan, S.D.; Perak, A.M.; Roth, G.A.; Samad, Z.; Satou, G.M.; Schroeder, E.B.; Shah, S.H.; Shay, C.M.; Stokes, A.; VanWagner, L.B.; Wang, N-Y.; Tsao, C.W. American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2021 Update: A report from the american heart association. Circulation,  2021, 143(8), e254-e743.
 [http://dx.doi.org/10.1161/CIR.0000000000000950] [PMID:  33501848]

[3]
Thygesen, K.; Jaffe, A.S. Adjusting the MI codes into the framework of the universal definition of myocardial infarction. J. Am. Coll. Cardiol.,  2021, 77(7), 858-860.
 [http://dx.doi.org/10.1016/j.jacc.2021.01.003] [PMID:  33602467]

[4]
Tibaut, M.; Mekis, D.; Petrovic, D. Pathophysiology of myocardial infarction and acute management strategies. Cardiovasc. Hematol. Agents Med. Chem.,  2017, 14(3), 150-159.
 [http://dx.doi.org/10.2174/1871525714666161216100553] [PMID:  27993119]

[5]
Periasamy, M.; Bhupathy, P.; Babu, G.J. Regulation of sarcoplasmic reticulum Ca2+ ATPase pump expression and its relevance to cardiac muscle physiology and pathology. Cardiovasc. Res.,  2008, 77(2), 265-273.
 [http://dx.doi.org/10.1093/cvr/cvm056] [PMID:  18006443]

[6]
Akin, B.L.; Hurley, T.D.; Chen, Z.; Jones, L.R. The structural basis for phospholamban inhibition of the calcium pump in sarcoplasmic reticulum. J. Biol. Chem.,  2013, 288(42), 30181-30191.
 [http://dx.doi.org/10.1074/jbc.M113.501585] [PMID:  23996003]

[7]
Gustafsson, F.; Guarracino, F.; Schwinger, R.H.G. The inodilator levosimendan as a treatment for acute heart failure in various settings. Eur. Heart J. Suppl.,  2017, 19(Suppl. C), C2-C7.
 [http://dx.doi.org/10.1093/eurheartj/sux001] [PMID:  29249904]

[8]
Pollesello, P.; Papp, Z.; Papp, J.G. Calcium sensitizers: What have we learned over the last 25 years? Int. J. Cardiol.,  2016, 203, 543-548.
 [http://dx.doi.org/10.1016/j.ijcard.2015.10.240] [PMID:  26580334]

[9]
Antoniades, C.; Tousoulis, D.; Koumallos, N.; Marinou, K.; Stefanadis, C. Levosimendan: Beyond its simple inotropic effect in heart failure. Pharmacol. Ther.,  2007, 114(2), 184-197.
 [http://dx.doi.org/10.1016/j.pharmthera.2007.01.008] [PMID:  17363065]

[10]
Erdei, N.; Papp, Z.; Pollesello, P.; Edes, I.; Bagi, Z. The levosimendan metabolite OR-1896 elicits vasodilation by activating the K(ATP) and BK(Ca) channels in rat isolated arterioles. Br. J. Pharmacol.,  2006, 148(5), 696-702.
 [http://dx.doi.org/10.1038/sj.bjp.0706781] [PMID:  16715115]

[11]
Yusuf, S.; Sleight, P.; Pogue, J.; Bosch, J.; Davies, R.; Dagenais, G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N. Engl. J. Med.,  2000, 342(3), 145-153.
 [http://dx.doi.org/10.1056/NEJM200001203420301] [PMID:  10639539]

[12]
Gu, J.; Noe, A.; Chandra, P.; Al-Fayoumi, S.; Ligueros-Saylan, M.; Sarangapani, R.; Maahs, S.; Ksander, G.; Rigel, D.F.; Jeng, A.Y.; Lin, T-H.; Zheng, W.; Dole, W.P. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J. Clin. Pharmacol.,  2010, 50(4), 401-414.
 [http://dx.doi.org/10.1177/0091270009343932] [PMID:  19934029]

[13]
Imran, M.; Hassan, M.Q.; Akhtar, M.S.; Rahman, O.; Akhtar, M.; Najmi, A.K. Sacubitril and valsartan protect from experimental myocardial infarction by ameliorating oxidative damage in wistar rats. Clin. Exp. Hypertens.,  2019, 41(1), 62-69.
 [http://dx.doi.org/10.1080/10641963.2018.1441862] [PMID:  29595329]

[14]
Solomon, S.D.; Zile, M.; Pieske, B.; Voors, A.; Shah, A.; Kraigher-Krainer, E.; Shi, V.; Bransford, T.; Takeuchi, M.; Gong, J.; Lefkowitz, M.; Packer, M.; McMurray, J.J.V. Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) Investigators. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: A phase 2 double-blind randomised controlled trial. Lancet,  2012, 380(9851), 1387-1395.
 [http://dx.doi.org/10.1016/S0140-6736(12)61227-6] [PMID:  22932717]

[15]
Braunwald, E. The path to an angiotensin receptor antagonist-neprilysin inhibitor in the treatment of heart failure. J. Am. Coll. Cardiol.,  2015, 65(10), 1029-1041.
 [http://dx.doi.org/10.1016/j.jacc.2015.01.033] [PMID:  25766951]

[16]
Volpe, M.; Bauersachs, J.; Bayés-Genís, A.; Butler, J.; Cohen-Solal, A.; Gallo, G.; Deichl, A.S.; Khan, M.S.; Battistoni, A.; Pieske, B.; Saito, Y.; Zieroth, S. Sacubitril/valsartan for the management of heart failure: A perspective viewpoint on current evidence. Int. J. Cardiol.,  2021, 327, 138-145.
 [http://dx.doi.org/10.1016/j.ijcard.2020.11.071] [PMID:  33301829]

[17]
Najafi, A. Sequeira, V.; Kuster, D.W.D.; van der Velden, J. β-adrenergic receptor signalling and its functional consequences in the diseased heart. Eur. J. Clin. Invest.,  2016, 46(4), 362-374.
 [http://dx.doi.org/10.1111/eci.12598] [PMID:  26842371]

[18]
Panda, S.; Kar, A.; Biswas, S. Preventive effect of agnucastoside C against isoproterenol-induced myocardial injury. Sci. Rep.,  2017, 7(1), 16146.
 [http://dx.doi.org/10.1038/s41598-017-16075-0] [PMID:  29170391]

[19]
Lowry, O.H.; Rosebrough, N.J.; Farr, A.L.; Randall, R.J. Protein measurement with the folin phenol reagent. J. Biol. Chem.,  1951, 193(1), 265-275.
 [http://dx.doi.org/10.1016/S0021-9258(19)52451-6] [PMID:  14907713]

[20]
Ohkawa, H.; Ohishi, N.; Yagi, K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem.,  1979, 95(2), 351-358.
 [http://dx.doi.org/10.1016/0003-2697(79)90738-3] [PMID:  36810]

[21]
Sedlak, J.; Lindsay, R.H. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with ellman’s reagent. Anal. Biochem.,  1968, 25(1), 192-205.
 [http://dx.doi.org/10.1016/0003-2697(68)90092-4] [PMID:  4973948]

[22]
Marklund, S.; Marklund, G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur. J. Biochem.,  1974, 47(3), 469-474.
 [http://dx.doi.org/10.1111/j.1432-1033.1974.tb03714.x] [PMID:  4215654]

[23]
Claiborne, A. Catalase activity. Handbook of methods for oxygen free radical research; Greenwald, R.A., Ed.; CRC Press: Boca Raton, FL, 1985, pp. 283-284.

[24]
Lum, G.; Gambino, S.R. A comparison of serum versus heparinized plasma for routine chemistry tests. Am. J. Clin. Pathol.,  1974, 61(1), 108-113.
 [http://dx.doi.org/10.1093/ajcp/61.1.108] [PMID:  4809144]

[25]
Young, D.S. Effects of drugs on clinical laboratory tests. Ann. Clin. Biochem.,  1997, 34(Pt 6), 579-581.
 [http://dx.doi.org/10.1177/000456329703400601] [PMID:  9366995]

[26]
Bhatia, J.; Tabassum, F.; Sharma, A.K.; Bharti, S.; Golechha, M.; Joshi, S.; Sayeed Akhatar, M.; Srivastava, A.K.; Arya, D.S. Emblica officinalis exerts antihypertensive effect in a rat model of DOCA-salt-induced hypertension: Role of (p) eNOS, NO and oxidative stress. Cardiovasc. Toxicol.,  2011, 11(3), 272-279.
 [http://dx.doi.org/10.1007/s12012-011-9122-2] [PMID:  21748534]

[27]
Feldman, A.T.; Wolfe, D. Tissue processing and hematoxylin and eosin staining.Histopathology.Methods in Molecular Biology (Methods and Protocols); Day, C., Ed.; Humana Press: New York, NY, 2014, Vol. 1180, pp. 31-43.
 [http://dx.doi.org/10.1007/978-1-4939-1050-2_3]

[28]
Vogel, B.; Siebert, H.; Hofmann, U.; Frantz, S. Determination of collagen content within picrosirius red stained paraffin-embedded tissue sections using fluorescence microscopy. MethodsX,  2015, 2, 124-134.
 [http://dx.doi.org/10.1016/j.mex.2015.02.007] [PMID:  26150980]

[29]
Cuello, A.C. Immunohistochemistry II; Wiley Press: New York, 1993. 

[30]
Thygesen, K.; Alpert, J.S.; Jaffe, A.S.; Chaitman, B.R.; Bax, J.J.; Morrow, D.A.; White, H.D. Executive group on behalf of the joint european society of cardiology (ESC)/American college of cardiology (ACC)/American heart association (AHA)/World Heart Federation (WHF) task force for the universal definition of myocardial infarction. Fourth universal definition of myocardial infarction. Glob. Heart,  2018, 13(4), 305-338.
 [http://dx.doi.org/10.1016/j.gheart.2018.08.004] [PMID:  30154043]

[31]
Dorn, G.W., II; Molkentin, J.D. Manipulating cardiac contractility in heart failure: Data from mice and men. Circulation,  2004, 109(2), 150-158.
 [http://dx.doi.org/10.1161/01.CIR.0000111581.15521.F5] [PMID:  14734503]

[32]
Suchal, K.; Malik, S.; Gamad, N.; Malhotra, R.K.; Goyal, S.N.; Bhatia, J.; Arya, D.S. Kampeferol protects against oxidative stress and apoptotic damage in experimental model of isoproterenol-induced cardiac toxicity in rats. Phytomedicine,  2016, 23(12), 1401-1408.
 [http://dx.doi.org/10.1016/j.phymed.2016.07.015] [PMID:  27765360]

[33]
Gyongyosi, A.; Zilinyi, R.; Czegledi, A.; Tosaki, A.; Tosaki, A.; Lekli, I. The role of autophagy and death pathways in dose-dependent isoproterenolinduced cardiotoxicity. Curr. Pharm. Des.,  2019, 25(19), 2192-2198.
 [http://dx.doi.org/10.2174/1381612825666190619145025] [PMID:  31258063]

[34]
Imlay, J.A.; Linn, S. DNA damage and oxygen radical toxicity. Science,  1988, 240(4857), 1302-1309.
 [http://dx.doi.org/10.1126/science.3287616] [PMID:  3287616]

[35]
Boarescu, P-M.; Boarescu, I. Bocșan, I.C.; Pop, R.M.; Gheban, D.; Bulboacă, A.E.; Nicula, C.; Râjnoveanu, R-M.; Bulboacă, S.D. Curcumin nanoparticles protect against isoproterenol induced myocardial infarction by alleviating myocardial tissue oxidative stress, electrocardiogram, and biological changes. Molecules,  2019, 24(15), 2802.
 [http://dx.doi.org/10.3390/molecules24152802] [PMID:  31374848]

[36]
Hassan, M.Q.; Akhtar, M.S.; Akhtar, M.; Ansari, S.H.; Ali, J.; Haque, S.E.; Najmi, A.K. Benidipine prevents oxidative stress, inflammatory changes and apoptosis related myofibril damage in isoproterenol-induced myocardial infarction in rats. Toxicol. Mech. Methods,  2015, 25(1), 26-33.
 [http://dx.doi.org/10.3109/15376516.2014.972531] [PMID:  25269373]

[37]
Penna, C.; Alloatti, G.; Gallo, M.P.; Cerra, M.C.; Levi, R.; Tullio, F.; Bassino, E.; Dolgetta, S.; Mahata, S.K.; Tota, B.; Pagliaro, P. Catestatin improves post-ischemic left ventricular function and decreases ischemia/reperfusion injury in heart. Cell. Mol. Neurobiol.,  2010, 30(8), 1171-1179.
 [http://dx.doi.org/10.1007/s10571-010-9598-5] [PMID:  21104119]

[38]
Ibarrola, J.; Matilla, L.; Martínez-Martínez, E.; Gueret, A.; Fernández-Celis, A.; Henry, J-P.; Nicol, L.; Jaisser, F.; Mulder, P.; Ouvrard-Pascaud, A.; López-Andrés, N. Myocardial injury after ischemia/reperfusion is attenuated by pharmacological galectin-3 inhibition. Sci. Rep.,  2019, 9(1), 9607.
 [http://dx.doi.org/10.1038/s41598-019-46119-6] [PMID:  31270370]

[39]
Iqbal, R.; Akhtar, M.S.; Hassan, M.Q.; Jairajpuri, Z.; Akhtar, M.; Najmi, A.K. Pitavastatin ameliorates myocardial damage by preventing inflammation and collagen deposition via reduced free radical generation in isoproterenol-induced cardiomyopathy. Clin. Exp. Hypertens.,  2019, 41(5), 434-443.
 [http://dx.doi.org/10.1080/10641963.2018.1501059] [PMID:  30192645]

[40]
Abdelzaher, W.Y.; Ahmed, S.M.; Welson, N.N.; Alsharif, K.F.; Batiha, G.E-S.; Labib, D.A.A. Dapsone ameliorates isoproterenol-induced myocardial infarction via Nrf2/HO-1; TLR4/TNF-α signaling pathways and the suppression of oxidative stress, inflammation, and apoptosis in rats. Front. Pharmacol.,  2021, 12669679
 [http://dx.doi.org/10.3389/fphar.2021.669679] [PMID:  34093197]

[41]
Wong, Z.W.; Thanikachalam, P.V.; Ramamurthy, S. Molecular understanding of the protective role of natural products on isoproterenol-induced myocardial infarction: A review. Biomed. Pharmacother.,  2017, 94, 1145-1166.
 [http://dx.doi.org/10.1016/j.biopha.2017.08.009] [PMID:  28826162]

[42]
Scalise, R.F.M.; De Sarro, R.; Caracciolo, A.; Lauro, R.; Squadrito, F.; Carerj, S.; Bitto, A.; Micari, A.; Bella, G.D.; Costa, F.; Irrera, N. Fibrosis after myocardial infarction: An overview on cellular processes, molecular pathways, clinical evaluation and prognostic value. Med. Sci. (Basel),  2021, 9(1), 16.
 [http://dx.doi.org/10.3390/medsci9010016] [PMID:  33804308]

[43]
Grobbel, M.R.; Shavik, S.M.; Darios, E.; Watts, S.W.; Lee, L.C.; Roccabianca, S. Contribution of left ventricular residual stress by myocytes and collagen: Existence of inter-constituent mechanical interaction. Biomech. Model. Mechanobiol.,  2018, 17(4), 985-999.
 [http://dx.doi.org/10.1007/s10237-018-1007-x] [PMID:  29478195]

[44]
Katus, H.A.; Remppis, A.; Looser, S.; Hallermeier, K.; Scheffold, T.; Kübler, W. Enzyme linked immuno assay of cardiac troponin T for the detection of acute myocardial infarction in patients. J. Mol. Cell. Cardiol.,  1989, 21(12), 1349-1353.
 [http://dx.doi.org/10.1016/0022-2828(89)90680-9] [PMID:  2632816]

[45]
Nohria, A.; Givertz, M.M. B-type natriuretic peptide and the stressed heart. J. Am. Coll. Cardiol.,  2006, 47(4), 749-751.
 [http://dx.doi.org/10.1016/j.jacc.2005.11.031] [PMID:  16487839]

[46]
Wolsk, E.; Claggett, B.; Pfeffer, M.A.; Diaz, R.; Dickstein, K.; Gerstein, H.C.; Lawson, F.C.; Lewis, E.F.; Maggioni, A.P.; McMurray, J.J.V.; Probstfield, J.L.; Riddle, M.C.; Solomon, S.D.; Tardif, J-C.; Køber, L. Role of B-Type natriuretic peptide and N-terminal prohormone BNP as predictors of cardiovascular morbidity and mortality in patients with a recent coronary event and Type 2 diabetes mellitus. J. Am. Heart Assoc.,  2017, 6(6)e004743
 [http://dx.doi.org/10.1161/JAHA.116.004743] [PMID:  28554908]

[47]
Wang, R.; Wang, M.; He, S.; Sun, G.; Sun, X. Targeting calcium homeostasis in myocardial ischemia/reperfusion injury: An overview of regulatory mechanisms and therapeutic reagents. Front. Pharmacol.,  2020, 11, 872.
 [http://dx.doi.org/10.3389/fphar.2020.00872] [PMID:  32581817]

[48]
Tsang, S.; Wong, S.S.C.; Wu, S.; Kravtsov, G.M.; Wong, T-M. Testosterone-augmented contractile responses to alpha1- and beta1-adrenoceptor stimulation are associated with increased activities of RyR, SERCA, and NCX in the heart. Am. J. Physiol. Cell Physiol.,  2009, 296(4), C766-C782.
 [http://dx.doi.org/10.1152/ajpcell.00193.2008] [PMID:  19336623]

[49]
Yu, L.; Yuan, K.; Park, B.M.; Kim, S.H. Modification of levosimendan-induced suppression of atrial natriuretic peptide secretion in hypertrophied rat atria. Eur. J. Pharmacol.,  2018, 829, 54-62.
 [http://dx.doi.org/10.1016/j.ejphar.2018.04.006] [PMID:  29653089]

Rights & Permissions Print Cite

Article Metrics

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

For Visitors

DOI https://dx.doi.org/10.2174/1874467215666220919104526	Print ISSN 1874-4672
Publisher Name Bentham Science Publisher	Online ISSN 1874-4702

Current Molecular Pharmacology

Comparative Efficacy of Levosimendan, Ramipril, and Sacubitril/ Valsartan in Isoproterenol-induced Experimental Heart Failure: A Hemodynamic and Molecular Approach

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract