Spironolactone and eplerenone are cardioprotective during early phase of ischemia in rats submitted to acute coronary occlusion

Authors

DOI:

https://doi.org/10.33448/rsd-v11i3.26498

Keywords:

Acute myocardial infarction; ECG; Spironolactone; Eplerenone; Cardioprotective.

Abstract

Introduction: Mineralocorticoid receptor antagonists (MRAs) are effective in reducing left ventricle remodeling and sudden death after acute myocardial infarction (AMI). Objectives: MRAs in vitro display cardioprotective effects, independent of MR; however, it is unknown whether the rapid effects of MRAs are cardioprotective in vivo. This study evaluated the acute effects of spironolactone and eplerenone in the first minutes of AMI. Methods: Wistar Rats, submitted or not to bilateral adrenalectomy, were treated orally with spironolactone (20 mg/kg) or eplerenone (10 mg/kg), and submitted to the left coronary ligation, under anesthesia. Electrocardiogram (ECG) recordings were obtained to evaluate ST-T segment, QT, and QTc intervals. Arterial pressure was also measured before (baseline) and after coronary ligation. Results: Spironolactone or eplerenone given, one hour before coronary ligation, prevented ST-T segment elevation in adrenalectomized and non-adrenalectomized. QT interval analysis showed that MRAs prevented its prolongation after coronary ligation. QT and QTc intervals remained similar to baseline and were smaller than the values displayed by the non-treated group. Animals treated with spironolactone, regardless of adrenalectomy, showed a 3-fold reduced mortality rates compared to the control group. Conclusion: MRAs display acute cardioprotective effects in early phase of AMI, which are independent of aldosterone. 

Author Biographies

Gabriela de Cássia Sousa Amancio, Federal University of Ouro Preto

Cell Signaling Laboratory, Research Center in Biological Science (NUPEB), Institute of Exact and Biological Sciences (ICB), Federal University of Ouro Preto (UFOP), Ouro Preto, Brazil

Milla Marques Hermidorff, Federal University of Ouro Preto

Cell Signaling Laboratory, Research Center in Biological Science (NUPEB), Institute of Exact and Biological Sciences (ICB), Federal University of Ouro Preto (UFOP), Ouro Preto, Brazil

Ana Cláudia Alvarenga, Ouro Preto Federal University

Cell Signaling Laboratory, Research Center in Biological Science (NUPEB), Institute of Exact and Biological Sciences (ICB), Federal University of Ouro Preto (UFOP), Ouro Preto, Brazil

Wanderson Geraldo Lima, Federal University of Ouro Preto

Cell Signaling Laboratory, Research Center in Biological Science (NUPEB), Institute of Exact and Biological Sciences (ICB), Federal University of Ouro Preto (UFOP), Ouro Preto, Brazil

Homero Nogueira Guimarães, Federal University of Minas Gerais

Department of Electrical Engineering, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil.

Henrique Resende Rodrigues, Federal University of Ouro Preto

Cell Signaling Laboratory, Research Center in Biological Science (NUPEB), Institute of Exact and Biological Sciences (ICB), Federal University of Ouro Preto (UFOP), Ouro Preto, Brazil

Emília Calil Silva, Federal University of Ouro Preto

Cell Signaling Laboratory, Research Center in Biological Science (NUPEB), Institute of Exact and Biological Sciences (ICB), Federal University of Ouro Preto (UFOP), Ouro Preto, Brazil

Leonardo Vinícius Monteiro de Assis, University of São Paulo

Department of Physiology, Institute of Biosciences, University of São Paulo (USP), São Paulo, Brazil.

Andrea Grabe-Guimarães, Federal University of Ouro Preto

Cipharma, Pharmacy School, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil.

References

Acikel, M., Buyukokuroglu, M.E., Erdogan, F., Aksoy, H., Bozkurt, E. & Senocak, H. (2005). Protective effects of dantrolene against myocardial injury induced by isoproterenol in rats: biochemical and histological findings. Int J Cardiol 98, 389-394. https://doi:10.1016/j.ijcard.2003.10.054.

Ashton, A.W., Le, T.Y., Gomez-Sanchez, C.E., Morel-Kopp, M.C., McWhinney, B., Hudson, A. & Mihailidou, A.S. (2015). Role of Nongenomic Signaling Pathways Activated by Aldosterone During Cardiac Reperfusion Injury. Molecular endocrinology 29, 1144-1155. https://doi:10.1210/ME.2014-1410.

Baillard, C., Mansier, P., Ennezat, P.V., Mangin, L., Medigue, C., Swynghedauw, B. & Chevalier, B. (2000). Converting enzyme inhibition normalizes QT interval in spontaneously hypertensive rats. Hypertension 36, 350-354.

Beck, L., Blanc-Guillemaud, V., Cherif, O.K., Jover, B. & Davy, J.M. (2001). Effects of spironolactone and fosinopril on the spontaneous and chronic ventricular arrhythmias in a rat model of myocardial infarction. Cardiology 96, 85-93. https://doi:10.1159/000049089.

Beygui, F., Montalescot, G., Vicaut, E., Rouanet, S., Van Belle, E., Baulac, C., Degrandsart, A., Dallongeville, J. & Investigators, O. (2009). Aldosterone and long-term outcome after myocardial infarction: A substudy of the french nationwide Observatoire sur la Prise en charge hospitaliere, l'Evolution a un an et les caRacteristiques de patients presentant un infArctus du myocarde avec ou sans onde Q (OPERA) study. Am Heart J 157, 680-687. https://doi:10.1016/j.ahj.2008.12.013.

Beygui, F., Labbé, J.-P., Cayla, G., Ennezat, P.-V., Motreff, P., Roubille, F., Silvain, J., Barthélémy, O., Delarche, N., Van Belle, E., et al. (2013). Early mineralocorticoid receptor blockade in primary percutaneous coronary intervention for ST-elevation myocardial infarction is associated with a reduction of life-threatening ventricular arrhythmia. International Journal of Cardiology 167, 73-79. https://doi:http://dx.doi.org/10.1016/j.ijcard.2011.11.076.

Birnbaum, Y. & Drew, B.J. (2003). The electrocardiogram in ST elevation acute myocardial infarction: correlation with coronary anatomy and prognosis. Postgrad Med J 79, 490-504.

Bobryshev, P., Bagaeva, T. & Filaretova, L. (2009). Ischemic preconditioning attenuates gastric ischemia-reperfusion injury through involvement of glucocorticoids. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 60 Suppl 7, 155-160.

Chai, W., Garrelds, I.M., Arulmani, U., Schoemaker, R.G., Lamers, J.M. & Danser, A.H. (2005) Genomic and nongenomic effects of aldosterone in the rat heart: why is spironolactone cardioprotective? British journal of pharmacology 145, 664-671. https://doi:10.1038/sj.bjp.0706220.

Coppola, G., Carita, P., Corrado, E., Borrelli, A., Rotolo, A., Guglielmo, M., Nugara, C., Ajello, L., Santomauro, M. & Novo, S. (2013). ST segment elevations: always a marker of acute myocardial infarction? Indian heart journal 65, 412-423. https://doi:10.1016/j.ihj.2013.06.013.

Drazen, D.L., Coolen, L.M., Strader, A.D., Wortman, M.D., Woods, S.C. & Seeley, R.J. (2004). Differential effects of adrenalectomy on melanin-concentrating hormone and orexin A. Endocrinology 145, 3404-3412. https://doi:10.1210/en.2003-1760.

Fraccarollo, D., Galuppo, P., Schraut, S., Kneitz, S., van Rooijen, N., Ertl, G. & Bauersachs, J. (2008). Immediate mineralocorticoid receptor blockade improves myocardial infarct healing by modulation of the inflammatory response. Hypertension 51, 905-914. https://doi:10.1161/HYPERTENSIONAHA.107.100941.

Fraccarollo, D., Galuppo, P., Sieweke, J.-T., Napp, L.C., Grobbecker, P. & Bauersachs, J. (2015). Efficacy of mineralocorticoid receptor antagonism in the acute myocardial infarction phase: eplerenone versus spironolactone. ESC Heart Failure 2, 150-158. https://doi:10.1002/ehf2.12053.

Gravez, B., Tarjus, A. & Jaisser, F. (2013). Mineralocorticoid receptor and cardiac arrhythmia. Clinical and experimental pharmacology & physiology 40, 910-915. https://doi:10.1111/1440-1681.12156.

Gros, R., Ding, Q.M., Sklar, L.A., Prossnitz, E.E., Arterburn, J.B., Chorazyczewski, J. & Feldman, R.D. (2011). GPR30 Expression Is Required for the Mineralocorticoid Receptor-Independent Rapid Vascular Effects of Aldosterone. Hypertension 57, 442-U201. https://doi:10.1161/Hypertensionaha.110.161653.

Gros, R., Ding, Q.M., Liu, B.N., Chorazyczewski, J. & Feldman, R.D. (2013). Aldosterone mediates its rapid effects in vascular endothelial cells through GPER activation. Am J Physiol-Cell Ph 304, C532-C540. https://doi:10.1152/ajpcell.00203.2012.

Hermidorff, M.M., Faria, G.D., Amancio, G.D.S., de Assis, L.V.M. & Isoldi, M.C. (2015). Non-genomic effects of spironolactone and eplerenone in cardiomyocytes of neonatal Wistar rats: do they evoke cardioprotective pathways? Biochem Cell Biol 93, 83-93. https://doi:10.1139/bcb-2014-0110.

Hermidorff, M.M., de Assis, L.V.M. & Isoldi, M.C. (2017). Genomic and rapid effects of aldosterone: what we know and do not know thus far. Heart Failure Reviews 22, 65-89. https://doi:10.1007/s10741-016-9591-2.

Jugdutt, B.I. (1993). Prevention of Ventricular Remodeling Post Myocardial-Infarction - Timing and Duration of Therapy. Can J Cardiol 9, 103-114.

Kobayashi, N., Yoshida, K., Nakano, S., Ohno, T., Honda, T., Tsubokou, Y. & Matsuoka, H. (2006). Cardioprotective mechanisms of eplerenone on cardiac performance and remodeling in failing rat hearts. Hypertension 47, 671-679. https://doi:10.1161/01.HYP.0000203148.42892.7a.

Loan Le, T.Y., Mardini, M., Howell, V.M., Funder, J.W., Ashton, A.W. & Mihailidou, A.S. (2012). Low-dose spironolactone prevents apoptosis repressor with caspase recruitment domain degradation during myocardial infarction. Hypertension 59, 1164-1169. https://doi:10.1161/HYPERTENSIONAHA.111.190488.

Mihailidou, A.S., Loan Le, T.Y., Mardini, M. & Funder, J.W. (2009). Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction. Hypertension 54, 1306-1312. https://doi:10.1161/HYPERTENSIONAHA.109.136242.

Montalescot, G., Pitt, B., Lopez de Sa, E., Hamm, C.W., Flather, M., Verheugt, F., Shi, H., Turgonyi, E., Orri, M., Vincent, J., et al. (2014). Early eplerenone treatment in patients with acute ST-elevation myocardial infarction without heart failure: the Randomized Double-Blind Reminder Study. Eur Heart J 35, 2295-2302. https://doi:10.1093/eurheartj/ehu164.

Moran, A.E., Roth, G.A., Narula, J. & Mensah, G.A. (2014). 1990-2010 global cardiovascular disease atlas. Glob Heart 9, 3-16. https://doi:10.1016/j.gheart.2014.03.1220.

Paiva, M., Riksen, N.P., Davidson, S.M., Hausenloy, D.J., Monteiro, P., Goncalves, L., Providencia, L., Rongen, G.A., Smits, P., Mocanu, M.M., et al. (2009). Metformin prevents myocardial reperfusion injury by activating the adenosine receptor. J Cardiovasc Pharmacol 53, 373-378. https://doi:10.1097/FJC.0b013e31819fd4e7.

Passman, R. & Kadish, A. (2001) Polymorphic ventricular tachycardia, long Q-T syndrome, and torsades de pointes. The Medical clinics of North America 85, 321-341.

Pitt, B., Remme, W., Zannad, F., Neaton, J., Martinez, F., Roniker, B., Bittman, R., Hurley, S., Kleiman, J., Gatlin, M., et al. (2003). Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. The New England journal of medicine 348, 1309-1321. https://doi:10.1056/NEJMoa030207.

Pitt, B., White, H., Nicolau, J., Martinez, F., Gheorghiade, M., Aschermann, M., van Veldhuisen, D.J., Zannad, F., Krum, H., Mukherjee, R., et al. (2005) Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. Journal of the American College of Cardiology 46, 425-431. https://doi:10.1016/j.jacc.2005.04.038.

Resende, L.O., Resende, E.S. & Andrade, A.O. (2012) Assessment of the ST segment deviation area as a potential physiological marker of the acute myocardial infarction. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference 2012, 669-672. https://doi:10.1109/embc.2012.6346020.

Riksen, N.P. & Rongen, G.A. (2012). Targeting adenosine receptors in the development of cardiovascular therapeutics. Expert Rev Clin Pharmacol 5, 199-218. https://doi:10.1586/ecp.12.8.

Rogerson, F.M., Brennan, F.E. & Fuller, P.J. (2004). Mineralocorticoid receptor binding, structure and function. Molecular and cellular endocrinology 217, 203-212. https://doi:10.1016/j.mce.2003.10.021.

Schmidt, K., Tissier, R., Ghaleh, B., Drogies, T., Felix, S.B. & Krieg, T. (2010). Cardioprotective effects of mineralocorticoid receptor antagonists at reperfusion. Eur Heart J 31, 1655-1662. https://doi:10.1093/eurheartj/ehp555.

Schwartz, P.J. & Wolf, S. (1978) QT interval prolongation as predictor of sudden death in patients with myocardial infarction. Circulation 57, 1074-1077.

Selye, H., Bajusz, E., Grasso, S. & Mendell, P. (1960). Simple techniques for the surgical occlusion of coronary vessels in the rat. Angiology 11, 398-407. https://doi:10.1177/000331976001100505.

Silvestre, J.S., Heymes, C., Oubenaissa, A., Robert, V., Aupetit-Faisant, B., Carayon, A., Swynghedauw, B. & Delcayre, C. (1999). Activation of cardiac aldosterone production in rat myocardial infarction: effect of angiotensin II receptor blockade and role in cardiac fibrosis. Circulation 99, 2694-2701.

Song, T., Yang, J., Yao, Y., Li, H., Chen, Y., Zhang, J. & Huang, C. (2011). Spironolactone diminishes spontaneous ventricular premature beats by reducing HCN4 protein expression in rats with myocardial infarction. Mol Med Rep 4, 569-573. https://doi:10.3892/mmr.2011.455.

Struthers, A.D. (2004). The clinical implications of aldosterone escape in congestive heart failure. Eur J Heart Fail 6, 539-545. https://doi:10.1016/j.ejheart.2004.04.013.

van den Berg, T.N., Deinum, J., Bilos, A., Donders, A.R., Rongen, G.A. & Riksen, N.P. (2014). The effect of eplerenone on adenosine formation in humans in vivo: a double-blinded randomised controlled study. PLoS One 9, e111248. https://doi:10.1371/journal.pone.0111248.

Weber, K.T. (2001). Aldosterone in congestive heart failure. N Engl J Med 345, 1689-1697. https://doi:10.1056/NEJMra000050.

Yee, K.M., Pringle, S.D. & Struthers, A.D. (2001). Circadian variation in the effects of aldosterone blockade on heart rate variability and QT dispersion in congestive heart failure. J Am Coll Cardiol 37, 1800-1807.

Zannad, F., McMurray, J.J.V., Drexler, H., Krum, H., van Veldhuisen, D.J., Swedberg, K., Shi, H., Vincent, J. & Pitt, B. (2010). Rationale and design of the Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS-HF). European Journal of Heart Failure 12, 617-622. https://doi:10.1093/eurjhf/hfq049.

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Published

20/02/2022

How to Cite

AMANCIO, G. de C. S. .; HERMIDORFF, M. M.; ALVARENGA, A. C. .; LIMA, W. G.; GUIMARÃES, H. N. .; RODRIGUES, H. R.; SILVA, E. C. .; ASSIS, L. V. M. de; GRABE-GUIMARÃES, A. .; ISOLDI, M. C. Spironolactone and eplerenone are cardioprotective during early phase of ischemia in rats submitted to acute coronary occlusion. Research, Society and Development, [S. l.], v. 11, n. 3, p. e24011326498, 2022. DOI: 10.33448/rsd-v11i3.26498. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/26498. Acesso em: 27 jan. 2023.

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Health Sciences