https://doi.org/10.4081/ejh.2022.3563
Combination of tolvaptan and valsartan improves cardiac and renal functions in doxorubicin-induced heart failure in mice
Submitted: 21 September 2022
Accepted: 2 November 2022
Published: 11 November 2022
Accepted: 2 November 2022
Abstract Views: 894
PDF: 597
Supplementary: 62
HTML: 22
Supplementary: 62
HTML: 22
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Heart failure (HF) is often complicated by renal dysfunction. Tolvaptan and valsartan are two well-known agents for the treatment of HF. However, the role of tolvaptan/valsartan combination on HF with renal dysfunction remains unclear. To establish a mice model with HF with renal dysfunction, mice were intraperitoneally injected with doxorubicin (Dox). Echocardiogram was applied to assess the left ventricular function. Additionally, serum aldosterone (ALD) and angiotensin II (Ang II) level in mice were determined by ELISA. Meanwhile, western blot assay was used to evaluate the expressions of B cell lymphoma-2 (Bcl-2), Bcl-2 associated X (Bax) and cleaved caspase 3 in the heart and kidney tissues of mice. In this study, we found that compared to tolvaptan or valsartan alone treatment group, tolvaptan/valsartan combination obviously improved the left ventricular ejection fraction (LVEF) and the left ventricular fractional shortening (LVFS), and reduced serum ALD and Ang II level in Dox-treated mice. Additionally, tolvaptan/valsartan combination significantly prevented the inflammation and fibrosis of heart and kidney tissues in Dox-treated mice. Meanwhile, tolvaptan/valsartan combination notably inhibited the myocardial and renal cell apoptosis in Dox-treated mice via upregulation of Bcl-2 and downregulation of Bax and cleaved caspase 3, compared to the single drug treatment. Collectively, tolvaptan/valsartan combination could improve cardiac and renal functions, as well as prevent the fibrosis, inflammation and apoptosis of heart and kidney tissues in Dox-treated mice. Taken together, combining tolvaptan with valsartan might be a promising approach to achieve enhanced therapeutic effect for treatment of HF with renal dysfunction.
Snipelisky D, Chaudhry SP, Stewart GC. The many faces of heart failure. Card Electrophysiol Clin 2019;11:11-20.
DOI: https://doi.org/10.1016/j.ccep.2018.11.001
Smythe CM. Congestive heart failure. Tex Med 1993;89:52-7.
Wu T, Yao H, Zhang B, Zhou S, Hou P, Chen K. κ opioid receptor agonist inhibits myocardial injury in heart failure rats through activating Nrf2/HO-1 pathway and regulating Ca(2+)-SERCA2a. Oxid Med Cell Longev 2021;2021:7328437.
DOI: https://doi.org/10.1155/2021/7328437
Scally C, Abbas H, Ahearn T, Srinivasan J, Mezincescu A, Rudd A, et al. Myocardial and systemic inflammation in acute stress-induced (Takotsubo) cardiomyopathy. Circulation 2019;1391581-92.
DOI: https://doi.org/10.1161/CIRCULATIONAHA.119.041878
Yang W, Tu H, Tang K, Huang H, Ou S, Wu J. Reynoutrin Improves ischemic heart failure in rats via targeting S100A1. Front Pharmacol 2021;12:703962.
DOI: https://doi.org/10.3389/fphar.2021.703962
Post S, van den Broek AJ, Rensing BJ, Pasterkamp G, Goumans MJ, Doevendans PA. Reduced CD26 expression is associated with improved cardiac function after acute myocardial infarction: insights from the REPERATOR study. J Mol Cell Cardiol 2012;53:899-905.
DOI: https://doi.org/10.1016/j.yjmcc.2012.08.026
Weckbach LT, Grabmaier U, Uhl A, Gess S, Boehm F, Zehrer A, et al. Midkine drives cardiac inflammation by promoting neutrophil trafficking and NETosis in myocarditis. J Exp Med 2019;216:350-68.
DOI: https://doi.org/10.1084/jem.20181102
Farmakis D, Koeck T, Mullen W, Parissis J, Gogas BD, Nikolaou M, et al. Urine proteome analysis in heart failure with reduced ejection fraction complicated by chronic kidney disease: feasibility, and clinical and pathogenetic correlates. Eur J Heart Fail 2016;18:822-9.
DOI: https://doi.org/10.1002/ejhf.544
Ahmed A, Rich MW, Sanders PW, Perry GJ, Bakris GL, Zile MR, et al. Chronic kidney disease associated mortality in diastolic versus systolic heart failure: a propensity matched study. Am J Cardiol 2007;99:393-8.
DOI: https://doi.org/10.1016/j.amjcard.2006.08.042
Shiba N, Shimokawa H. Chronic kidney disease and heart failure - Bidirectional close link and common therapeutic goal. J Cardiol 2011;57:8-17.
DOI: https://doi.org/10.1016/j.jjcc.2010.09.004
Vinod P, Krishnappa V, Chauvin AM, Khare A, Raina R. Cardiorenal syndrome: Role of arginine vasopressin and vaptans in heart failure. Cardiol Res 2017;8:87-95.
DOI: https://doi.org/10.14740/cr553w
Giam B, Kaye DM, Rajapakse NW. Role of renal oxidative stress in the pathogenesis of the cardiorenal syndrome. Heart Lung Circ 2016;25:874-80.
DOI: https://doi.org/10.1016/j.hlc.2016.02.022
Gasparini S, Melo MR, Nascimento PA, Andrade-Franzé GMF, Antunes-Rodrigues J, Yosten GLC, et al. Interaction of central angiotensin II and aldosterone on sodium intake and blood pressure. Brain Res 2019;1720:146299.
DOI: https://doi.org/10.1016/j.brainres.2019.06.018
Itcho K, Oki K, Kobuke K, Ohno H, Yoneda M, Hattori N. Angiotensin 1-7 suppresses angiotensin II mediated aldosterone production via JAK/STAT signaling inhibition. J Steroid Biochem Mol Biol 2019;185:137-41.
DOI: https://doi.org/10.1016/j.jsbmb.2018.08.007
Goldsmith SR. Vasopressin receptor antagonists: mechanisms of action and potential effects in heart failure. Cleve Clin J Med 2006;73:S20-3; discussion S30-3.
DOI: https://doi.org/10.3949/ccjm.73.Suppl_2.S20
He FJ, Burnier M, Macgregor GA. Nutrition in cardiovascular disease: salt in hypertension and heart failure. Eur Heart J 2011;32:3073-80.
DOI: https://doi.org/10.1093/eurheartj/ehr194
Felker GM, Ellison DH, Mullens W, Cox ZL, Testani JM. Diuretic Therapy for patients with heart failure: JACC state-of-the-art review. J Am Coll Cardiol 2020;75:1178-95.
DOI: https://doi.org/10.1016/j.jacc.2019.12.059
Iida Y, Yoshitake A, Shimizu H. Safety and effectiveness of tolvaptan administration after total arch replacement. Ann Vasc Surg 2019;56:103-7.
DOI: https://doi.org/10.1016/j.avsg.2018.08.078
Shigefuku R, Iwasa M, Eguchi A, Tempaku M, Tamai Y, Suzuki T, et al. Serum copeptin and zinc-α2-glycoprotein levels are novel biomarkers of tolvaptan treatment in decompensated cirrhotic patients with ascites. Intern Med 2021;60:3359-68.
DOI: https://doi.org/10.2169/internalmedicine.7291-21
Rangarajan B, Binoy V, Hingmire SS, Noronha V. Tolvaptan. South Asian J Cancer 2014;3:182-4.
DOI: https://doi.org/10.4103/2278-330X.136811
Alskaf E, Tridente A, Al-Mohammad A. Tolvaptan for heart failure, systematic review and meta-analysis of trials. J Cardiovasc Pharmacol 2016;68:196-203.
DOI: https://doi.org/10.1097/FJC.0000000000000405
22 Futamura Y, Watanuki H, Okada M, Sugiyama K, Matsuyama K. The efficacy and renal protective effect of tolvaptan in chronic kidney disease patients after open-heart surgery. Ann Thorac Cardiovasc Surg 2021;27:317-21.
DOI: https://doi.org/10.5761/atcs.oa.20-00364
Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-75.
DOI: https://doi.org/10.1056/NEJMoa010713
Maslov MY, Foianini S, Mayer D, Orlov MV, Lovich MA. Interaction between sacubitril and valsartan in preventing heart failure induced by aortic valve insufficiency in rats. J Card Fail 2019;25:921-31.
DOI: https://doi.org/10.1016/j.cardfail.2019.09.008
Lesogor A, Cohn JN, Latini R, Tognoni G, Krum H, Massie B, et al. Interaction between baseline and early worsening of renal function and efficacy of renin-angiotensin-aldosterone system blockade in patients with heart failure: insights from the Val-HeFT study. Eur J Heart Fail 2013;15:1236-44.
DOI: https://doi.org/10.1093/eurjhf/hft089
Kang H, Zhang J, Zhang X, Qin G, Wang K, Deng Z, et al. Effects of sacubitril/valsartan in patients with heart failure and chronic kidney disease: A meta-analysis. Eur J Pharmacol 2020;884:173444.
DOI: https://doi.org/10.1016/j.ejphar.2020.173444
Chen L, Yan KP, Liu XC, Wang W, Li C, Li M, et al. Valsartan regulates TGF-β/Smads and TGF-β/p38 pathways through lncRNA CHRF to improve doxorubicin-induced heart failure. Arch Pharm Res 2018;41:101-9.
DOI: https://doi.org/10.1007/s12272-017-0980-4
Mann DL, Givertz MM, Vader JM, Starling RC, Shah P, McNulty SE, et al. Effect of treatment with sacubitril/valsartan in patients with advanced heart failure and reduced ejection fraction: A randomized clinical trial. JAMA Cardiol 2022;7:17-25.
DOI: https://doi.org/10.1001/jamacardio.2021.4567
Vaduganathan M, Claggett BL, Desai AS, Anker SD, Perrone SV, Janssens S, et al. Prior heart failure hospitalization, clinical outcomes, and response to sacubitril/valsartan compared with valsartan in HFpEF. J Am Coll Cardiol 2020;75:245-54.
DOI: https://doi.org/10.1016/j.jacc.2019.11.003
Cosentino ER, Degli Esposti D, Miceli R, Bentivenga C, Landolfo M, Fg Cicero A, et al. Sacubitril/valsartan improves both functional and echocardiographic parameters in patients with chronic heart failure with reduced ejection fraction. Curr Med Res Opin 2019;35:s9-12.
DOI: https://doi.org/10.1080/03007995.2019.1576481
Li WJ, Liao HH, Feng H, Zhou ZY, Mou SQ, Zhang N, et al. Combination treatment of perifosine and valsartan showed more efficiency in protecting against pressure overload induced mouse heart failure. J Pharmacol Sci 2020;143:199-208.
DOI: https://doi.org/10.1016/j.jphs.2020.04.001
Xu S, Wang Y, Yu M, Wang D, Liang Y, Chen Y, et al. LongShengZhi capsule inhibits doxorubicin-induced heart failure by anti-oxidative stress. Biomed Pharmacother 2020;123:109803.
DOI: https://doi.org/10.1016/j.biopha.2019.109803
Sugihara K, Fujimoto S, Motomiya Y, Hashimoto T, Nakamura S, Dohi K. Usefulness of long axis M-mode echocardiographic measurements for optimum dialysis in patients on maintenance hemodialysis: comparison with changes in plasma levels of atrial natriuretic peptide and brain natriuretic peptide. Clin Nephrol 2001;56:140-9.
Wang J, Fang F, Wai-Kwok Yip G, Sanderson JE, Feng W, Xie JM, et al. Left ventricular long-axis performance during exercise is an important prognosticator in patients with heart failure and preserved ejection fraction. Int J Cardiol 2015;178:131-5.
DOI: https://doi.org/10.1016/j.ijcard.2014.10.130
Struthers AD, MacDonald TM. Review of aldosterone- and angiotensin II-induced target organ damage and prevention. Cardiovasc Res 2004;61:663-70.
DOI: https://doi.org/10.1016/j.cardiores.2003.11.037
Frimodt-Møller M, Persson F, Rossing P. Mitigating risk of aldosterone in diabetic kidney disease. Curr Opin Nephrol Hypertens 2020;29:145-51.
DOI: https://doi.org/10.1097/MNH.0000000000000557
Oppedisano F, Mollace R, Tavernese A, Gliozzi M, Musolino V, Macrì R, et al. PUFA supplementation and heart failure: Effects on fibrosis and cardiac remodeling. Nutrients 2021;13:2965.
DOI: https://doi.org/10.3390/nu13092965
Bai M, Lei J, Wang S, Ding D, Yu X, Guo Y, et al. BMP1 inhibitor UK383,367 attenuates renal fibrosis and inflammation in CKD. Am J Physiol Renal Physiol 2019;317:F1430-f8.
DOI: https://doi.org/10.1152/ajprenal.00230.2019
Chen C, Chen H, Zhou HJ, Ji W, Min W. Mechanistic role of thioredoxin 2 in heart failure. Adv Exp Med Biol 2017;982:265-76.
DOI: https://doi.org/10.1007/978-3-319-55330-6_14
Ter Maaten JM, Damman K, Verhaar MC, Paulus WJ, Duncker DJ, Cheng C, et al. Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation. Eur J Heart Fail 2016;18:588-98.
DOI: https://doi.org/10.1002/ejhf.497
Tuegel C, Bansal N. Heart failure in patients with kidney disease. Heart 2017;103:1848-53.
DOI: https://doi.org/10.1136/heartjnl-2016-310794
Konstam MA, Gheorghiade M, Burnett JC, Jr., Grinfeld L, Maggioni AP, Swedberg K, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 2007;297:1319-31.
DOI: https://doi.org/10.1001/jama.297.12.1319
Jackson AM, Jhund PS, Anand IS, Düngen HD, Lam CSP, Lefkowitz MP, et al. Sacubitril-valsartan as a treatment for apparent resistant hypertension in patients with heart failure and preserved ejection fraction. Eur Heart J 2021;42:3741-52.
DOI: https://doi.org/10.1093/eurheartj/ehab499
de Ligt M, Hesselink MKC, Jorgensen J, Jocken JWE, Blaak EE, Goossens GH. The angiotensin II type 1 receptor blocker valsartan in the battle against COVID-19. Obesity (Silver Spring) 2021;29:1423-6.
DOI: https://doi.org/10.1002/oby.23221
Tamaki S, Sato Y, Yamada T, Morita T, Furukawa Y, Iwasaki Y, et al. Tolvaptan reduces the risk of worsening renal function in patients with acute decompensated heart failure and preserved left ventricular ejection fraction - Prospective randomized controlled study. Circ J 2017;81:740-7.
DOI: https://doi.org/10.1253/circj.CJ-16-1122
Kida K, Shibagaki Y, Tominaga N, Matsumoto N, Akashi YJ, Miyake F, et al. Efficacy of tolvaptan added to furosemide in heart failure patients with advanced kidney dysfunction: a pharmacokinetic and pharmacodynamic study. Clin Pharmacokinet 2015;54:273-84.
DOI: https://doi.org/10.1007/s40262-014-0194-6
McMurray JJV, Jackson AM, Lam CSP, Redfield MM, Anand IS, Ge J, et al. Effects of sacubitril-valsartan versus valsartan in women compared with men with heart failure and preserved ejection fraction: Insights from PARAGON-HF. Circulation 2020;141:338-51.
DOI: https://doi.org/10.1161/CIRCULATIONAHA.119.044491
Peikert A, Vaduganathan M, Mc Causland F, Claggett BL, Chatur S, Packer M, et al. Effects of sacubitril/valsartan versus valsartan on renal function in patients with and without diabetes and heart failure with preserved ejection fraction: insights from PARAGON-HF. Eur J Heart Fail 2022;24:794-803.
DOI: https://doi.org/10.1002/ejhf.2450
Martínez-Martínez E, Brugnolaro C, Ibarrola J, Ravassa S, Buonafine M, López B, et al. CT-1 (cardiotrophin-1)-Gal-3 (Galectin-3) axis in cardiac fibrosis and inflammation. Hypertension 2019;73:602-11.
DOI: https://doi.org/10.1161/HYPERTENSIONAHA.118.11874
Rao M, Wang X, Guo G, Wang L, Chen S, Yin P, et al. Resolving the intertwining of inflammation and fibrosis in human heart failure at single-cell level. Basic Res Cardiol 2021;116:55.
DOI: https://doi.org/10.1007/s00395-021-00897-1
Chang D, Xu TT, Zhang SJ, Cai Y, Min SD, Zhao Z, et al. Telmisartan ameliorates cardiac fibrosis and diastolic function in cardiorenal heart failure with preserved ejection fraction. Exp Biol Med (Maywood) 2021;246:2511-21.
DOI: https://doi.org/10.1177/15353702211035058
Ishikawa M, Kobayashi N, Sugiyama F, Onoda S, Ishimitsu T. Renoprotective effect of vasopressin v2 receptor antagonist tolvaptan in Dahl rats with end-stage heart failure. Int Heart J 2013;54:98-106.
DOI: https://doi.org/10.1536/ihj.54.98
Zhou G, Cheung AK, Liu X, Huang Y. Valsartan slows the progression of diabetic nephropathy in db/db mice via a reduction in podocyte injury, and renal oxidative stress and inflammation. Clin Sci (Lond) 2014;126707-20.
DOI: https://doi.org/10.1042/CS20130223
Wang J, Duan L, Gao Y, Zhou S, Liu Y, Wei S, et al. Angiotensin II receptor blocker valsartan ameliorates cardiac fibrosis partly by inhibiting miR-21 expression in diabetic nephropathy mice. Mol Cell Endocrinol 2018;472:149-58.
DOI: https://doi.org/10.1016/j.mce.2017.12.005
Chen QM, Tu VC. Apoptosis and heart failure: mechanisms and therapeutic implications. Am J Cardiovasc Drugs 2002;2:43-57.
DOI: https://doi.org/10.2165/00129784-200202010-00006
Wu T, Dong Z, Geng J, Sun Y, Liu G, Kang W, et al. Valsartan protects against ER stress-induced myocardial apoptosis via CHOP/Puma signaling pathway in streptozotocin-induced diabetic rats. Eur J Pharm Sci 2011;42:496-502.
DOI: https://doi.org/10.1016/j.ejps.2011.02.005
Ethics Approval
This study was approved by the Animal Experimental Committee of The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology.Rights
Scientific Research Project of Wuhan Health CommissionHow to Cite
Yan, F. ., Zhu, H., He, Y. ., Wu, Q. ., & Duan, X. . (2022). Combination of tolvaptan and valsartan improves cardiac and renal functions in doxorubicin-induced heart failure in mice. European Journal of Histochemistry, 66(4). https://doi.org/10.4081/ejh.2022.3563
Copyright (c) 2022 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
Similar Articles
- C. Cui, P. Lal, S. Master, Y. Ma, T. Baradet, Z. Bing, Expression of parafibromin in major renal cell tumors , European Journal of Histochemistry: Vol. 56 No. 4 (2012)
- A. Demirovic, S. Cesarec, Z. Marusic, D. Tomas, M. Milosevic, T. Hudolin, B. Kruslin, TGF-β1 expression in chromophobe renal cell carcinoma and renal oncocytoma , European Journal of Histochemistry: Vol. 58 No. 1 (2014)
- Jinshuang Li, Dawei Xu, Ce Shi, Chunqi Cheng, Ziheng Xu, Xingjuan Gao, Yong Cheng, Alarin regulates RyR2 and SERCA2 to improve cardiac function in heart failure with preserved ejection fraction , European Journal of Histochemistry: Vol. 68 No. 4 (2024)
- D. Fanni, N. Iacovidou, A. Locci, C. Gerosa, S. Nemolato, P. Van Eyken, G. Monga, S. Mellou, G. Faa, V. Fanos, MUC1 marks collecting tubules, renal vesicles, comma- and S-shaped bodies in human developing kidney , European Journal of Histochemistry: Vol. 56 No. 4 (2012)
- Michelle Steicke, Guang Yang, Tam Nguyen Dinh, Matthew Dunster-Jones, Owen Sargisson, Farah Ahmady, Jonathan Golledge, Yutang Wang, The penetration of methanol into bovine cardiac and hepatic tissues is faster than ethanol and formalin , European Journal of Histochemistry: Vol. 62 No. 1 (2018)
- Liuchang Feng, Zaoqiang Lin, Zeyong Tang, Lin Zhu, Shu Xu, Xi Tan, Xinyuan Wang, Jianling Mai, Qinxiang Tan, Emodin improves renal fibrosis in chronic kidney disease by regulating mitochondrial homeostasis through the mediation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) , European Journal of Histochemistry: Vol. 68 No. 2 (2024)
- Zhi Wang, Guihua Jian, Teng Chen, Yiping Chen, Junhui Li, Niansong Wang, The Qi-Bang-Yi-Shen formula ameliorates renal dysfunction and fibrosis in rats with diabetic kidney disease via regulating PI3K/AKT, ERK and PPARγ signaling pathways , European Journal of Histochemistry: Vol. 67 No. 1 (2023)
- S. Zara, V. Macchi, R. De Caro, M. Rapino, A. Cataldi, A. Porzionato, pPKCα mediated-HIF-1α activation related to the morphological modifications occurring in neonatal myocardial tissue in response to severe and mild hyperoxia , European Journal of Histochemistry: Vol. 56 No. 1 (2012)
- A. Rus, M.L. Del Moral, F. Molina, M.A. Peinado, Upregulation of cardiac NO/NOS system during short-term hypoxia and the subsequent reoxygenation period , European Journal of Histochemistry: Vol. 55 No. 2 (2011)
- E.V. Seliverstova, N.P. Prutskova, Receptor-mediated endocytosis of lysozyme in renal proximal tubules of the frog Rana temporaria , European Journal of Histochemistry: Vol. 59 No. 2 (2015)
You may also start an advanced similarity search for this article.
Publication Facts
Metric
This article
Other articles
Peer reviewers
4
2.4
Reviewer profiles N/A
Author statements
Author statements
This article
Other articles
Data availability
N/A
16%
External funding
N/A
32%
Competing interests
N/A
11%
Metric
This journal
Other journals
Articles accepted
57%
33%
Days to publication
50
145
- Editor & editorial board
- profiles
- Academic society
- N/A
- Publisher
- PAGEPress Publications, Pavia, Italy
To learn about these publication facts, click 
PF is maintained by the Public Knowledge Project
