Digoxin Combined with Aerobic Interval Training Improved Cardiomyocyte Contractility

Gabriel Vasconcelos Abreu; Erick Roberto Gonçalves Claudio; Andreo Fernando Aguiar; Morenna Alana Giordani; Eveline Aparecida Isquierdo Fonseca de Queiroz; Ana Paula Lima-Leopoldo; André Soares Leopoldo; Mário Mateus Sugizaki

doi:10.1055/a-1300-2583

International Journal of Sports Medicine, Table of Contents

Int J Sports Med 2021; 42(08): 694-702
DOI: 10.1055/a-1300-2583

Physiology & Biochemistry

Digoxin Combined with Aerobic Interval Training Improved Cardiomyocyte Contractility

Gabriel Vasconcelos Abreu

¹Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Science, Federal University of Mato Grosso, Sinop, Brazil

,

Erick Roberto Gonçalves Claudio

²Center of Physical Education and Sports, Department of Sports, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil

,

Andreo Fernando Aguiar

³North University of Paraná (UNOPAR), Centre of Research in Biological and Healthy Sciences, Londrina, Paraná, Brazil

,

Morenna Alana Giordani

¹Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Science, Federal University of Mato Grosso, Sinop, Brazil

,

Eveline Aparecida Isquierdo Fonseca de Queiroz

¹Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Science, Federal University of Mato Grosso, Sinop, Brazil

,

Ana Paula Lima-Leopoldo

²Center of Physical Education and Sports, Department of Sports, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil

,

André Soares Leopoldo

²Center of Physical Education and Sports, Department of Sports, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil

,

Mário Mateus Sugizaki

¹Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Science, Federal University of Mato Grosso, Sinop, Brazil

› Author Affiliations

Abstract

Digoxin is a cardiotonic that increases the cardiac output without causing deleterious effects on heart, as well as improves the left ventricular performance during physical exercise. We tested whether the association between chronic digoxin administration and aerobic interval training (AIT) promotes beneficial cardiovascular adaptations by improving the myocardial contractility and calcium (Ca²⁺⁾ handling. Male Wistar rats were randomly assigned to sedentary control (C), interval training (T), sedentary digoxin (DIGO) and T associated to digoxin (TDIGO). AIT was performed on a treadmill (1h/day, 5 days/week) for 60 days, consisting of successive 8-min periods at 80% and 20% of VO₂máx for 2 min. Digoxin was administered by orogastric gavage for 60 days. Left ventricle samples were collected to analysis of Ca²⁺ handling proteins; contractility and Ca²⁺ handling were performed on isolated cardiomyocytes. TDIGO group had a greater elevation in fractional shortening (44%) than DIGO, suggesting a cardiomyocyte contractile improvement. In addition, T or TDIGO groups showed no change in cardiomyocytes properties after Fura2-acetoxymethyl ester, as well as in sarcoplasmic reticulum Ca^2+-ATPase (SERCA2a), phospholamban and calcineurin expressions. The main findings indicate that association of digoxin and aerobic interval training improved the cardiomyocyte contractile function, but these effects seem to be unrelated to Ca²⁺ handling.

Key words

digoxin - calcium - contractility - aerobic interval training

Full Text

References

References
1 Namara KM, Alzubaidi H, Jackson JK. Cardiovascular disease as a leading cause of death: How are pharmacists getting involved?. Integr Pharm Res Pract 2019; 8: 1-11
2 Lacombe J, Armstrong MEG, Wright FL. et al. The impact of physical activity and an additional behavioural risk factor on cardiovascular disease, cancer and all-cause mortality: A systematic review. BMC Public Health 2019; 19: 900
3 Wisløff U, Loennechen JP, Falck G. et al. Increased contractility and calcium sensitivity in cardiac myocytes isolated from endurance trained rats. Cardiovasc Res 2001; 50: 495-508
4 Locatelli J, de Assis LV, Isoldi MC. Calcium handling proteins: Structure, function, and modulation by exercise. Heart Fail Rev 2014; 19: 207-225
5 Sugizaki MM, Leopoldo AP, Conde SJ. et al. Upregulation of mRNA myocardium calcium handling in rats submitted to exercise and food restriction. Arq Bras Cardiol 2011; 97: 46-52
6 Paulino EC, Ferreira JC, Bechara LR. et al. Exercise training and caloric restriction prevent reduction in cardiac Ca²⁺-handling protein profile in obese rats. Hypertension 2010; 56: 629-635
7 Prímola-Gomes TN, Campos LA, Lauton-Santos S. et al. Exercise capacity is related to calcium transients in ventricular cardiomyocytes. J Appl Physiol (1985) 2009; 107: 593-598
8 Bauman JL, Didomenico RJ, Galanter WL. Mechanisms, manifestations, and management of digoxin toxicity in the modern era.. Am J Cardiovasc Drugs 2006; 6: 77-86
9 Meral I, Hsu W, Hembrough FB. Digoxin- and monensin-induced changes of intracellular ca2+ concentration in isolated guinea-pig ventricular myocyte. J Vet Med A Physiol Pathol Clin Med 2002; 49: 329-333
10 Neves CH, Tibana RA, Prestes J. et al. Digoxin induces cardiac hypertrophy without negative effects on cardiac function and physical performance in trained normotensive rats. Int J Sports Med 2017; 38: 263-269
11 Harriss DJ, Macsween A, Atkinson G. Ethical standards in sport and exercise science research: 2020 update. Int J Sports Med 2019; 40: 813-817
12 Manunta P, Hamilton J, Rogowski AC. et al. Chronic hypertension induced by oubain but not digoxin in the heart: Antihypertensive effect of digoxin and digitoxin. Hypertens Res 2000; 23: S77-S85
13 Ribner HS, Plucinski DA, Hsieh AM. et al. Acute effects of digoxin on total systemic vascular resistance in congestive heart failure due to dilated cardiomyopathy: A hemodynamic hormonal study. Am J Cardiol 1985; 56: 896-904
14 Manchado FB, Mota CSA, Ribeiro C. et al. Running training effects in different intensities on the aerobic capacity and lactate production by the muscle of Wistar rats. Motriz 2007; 13: 96-97
15 Neves CH, Aguiar AF, Aguiar DH. et al. Digoxin and verapamil promote cardiomyocyte hypertrophy in sedentary and/or trained rats. Rev Bras Med Esporte 2016; 22: 398-402
16 Yin FC, Spurgeon HA, Rakusan K. et al. Use of tibial length to quantify cardiac hypertrophy: application in the aging rat. Am J Physiol 1982; 24: H941-H947
17 Louch WE, Sheehan KA, Wolska BM. Methods in cardiomyocyte isolation, culture, and gene transfer. J Mol Cell Cardiol 2011; 51: 288-298
18 Wang Y, Wisloff U, Kemi OJ. Animal models in the study of exercise-induced cardiac hypertrophy. Physiol Res 2010; 59: 633-644
19 Rocha GLD, Crisp AH, Oliveira MRM. et al. Effect of high intensity interval and continuous swimming training on body mass adiposity level and serum parameters in high-fat diet fed rats. ScientificWorldJournal 2016; 2016: 2194120
20 Shen Y, Xu X, Yue K. et al. Effect of different exercise protocols on metabolic profiles and fatty acid metabolism in skeletal muscle in high-fat diet-fed rats. Obesity 2015; 23: 1000-1006
21 Mourier A, Gautier JF, De Kerviler E. et al. Mobilization of visceral adipose tissue related to the improvement in insulin sensitivity in response to physical training in NIDDM: Effects of branched-chain amino acid supplements. Diabetes Care 1997; 20: 385-391
22 Hauser C, Benetti M, Rebelo FPV. Weigth loss strategies. Rev Bras Cineantropom Desempenho Hum 2006; 6: 72-81
23 Rankin AJ, Rankin AC, MacIntyre P. et al. Walk or run? Is high-intensity exercise more effective than moderate intensity exercise at reducing cardiovascular risk?. Scott Med J 2012; 57: 99-102
24 Roxburgh BH, Nolan PB, Weatherwax RM. et al. Is moderate intensity exercise training combined with high intensity interval training more effective at improving cardio respiratory fitness than moderate intensity exercise training alone?. J Sports Sci Med 2014; 13: 702-707
25 Baar K. Training for endurance and strength: Lessons from cell signaling. Med Sci Sports Exerc 2006; 38: 1939-1944
26 Perry CGR, Heigenhauser GJF, Bonen A. et al. High-intensity aerobic interval training increases fat and carbohydrate metabolic capacities in human skeletal muscle. Appl Physiol Nutr Metab 2008; 33: 1112-1123
27 MacInnis MJ, Gibala MJ. Physiological adaptations to interval training and the role of exercise intensity. J Physiol 2017; 595: 2915-2930
28 Chrøis KM, Dohlmann TL, Søgaard D. et al. Mitochondrial adaptations to high intensity interval training in older females and males. Eur J Sport Sci 2020; 20: 135-145
29 Coates AL, Desmond K, Asher MI. et al. The effect of digoxin on exercise capacity and exercising cardiac function in cystic fibrosis. Chest 1982; 82: 543-547
30 Friesen WJ, Cumming GR. Effects of digoxin on the oxygen debt and the exercise electrocardiogram in normal subjects. Can Med Assoc J 1967; 97: 960-964
31 Campbell TJ, MacDonald PS. Digoxin in heart failure and cardiac arrhythmias. Med J Aust 2003; 179: 98-102
32 Sullivan M, Atwood E, Myers J. et al. Increased exercise capacity after digoxin administration in patients with heart failure. J Am Coll Cardiol 1989; 13: 1138-1143
33 Di Bianco R, Shabetai R, Kostuk W. et al. A comparison of oral milrinone, digoxin and their combination in the treatment of patients with chronic heart failure. N Engl J Med 1989; 320: 677-683
34 Fleg JL, Rothfeld B, Gottlieb SH. Effect of maintenance digoxin therapy on aerobic performance and exercise left ventricular function in mild to moderate heart failure due to coronary artery disease: a randomized, placebo-controlled, crossover trial. J Am Coll Cardiol 1991; 17: 743-751
35 Morisco C, Cuocolo A, Romano M. et al. Influence of digitalis on left ventricular functional response to exercise in congestive heart failure. Am J Cardiol 1996; 77: 480-485
36 Brooks GA. Intra-and extra-cellular lactate shuttles. Med Sci Sports Exerc 2000; 32: 790-799
37 Fernandes T, Baraúna VG, Negrão CE. et al. Aerobic exercise training promotes physiological cardiac remodeling involving a set of microRNAs. Am J Physiol Heart Circ Physiol 2015; 309: H543-H552
38 Ellison GM, Waring CD, Vicinanza C. et al. Physiological cardiac remodelling in response to endurance exercise training: Cellular and molecular mechanisms. Heart 2012; 98: 5-10
39 Azevedo PS, Polegato BF, Minicucci MF. et al. Cardiac remodeling: Concepts, clinical impact, pathophysiological mechanisms and pharmacologic treatment. Arq Bras Cardiol 2016; 106: 62-69.
40 Gharaat MA, Kashef M, Jameie B. et al. Regulation of PI3K and Hand2 gene on physiological hypertrophy of heart following high-intensity interval, and endurance training. J Res Med Sci 2019; 24: 32
41 Verboven M, Cuypers A, Deluyker D. et al. High intensity training improves cardiac function in healthy rats. Sci Rep 2019; 9: 5612
42 Riggs CE, Michaelides MA, Parpa KM. et al. The effects of aerobic interval training on the left ventricular morphology and function of VLCAD-deficient mice. Eur J Appl Physiol 2010; 110: 915-923
43 Johnson EJ, Dieter BP, Marsh SA. Evidence for distinct effects of exercise in different cardiac hypertrophic disorders. Life Sci 2015; 123: 100-106
44 Bernardo BC, Weeks KL, Pretorius L. et al. Molecular distinction between physiological and pathological cardiac hypertrophy: Experimental findings and therapeutic strategies. Pharmacol Ther 2010; 128: 191-227
45 Zarain-Herzberg A, Fragoso-Medina J, Estrada-Avilés R. Calcium-regulated transcriptional pathways in the normal and pathologic heart. IUBMB Life 2011; 63: 847-855
46 Shimizu I, Minamino T. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol 2016; 97: 245-262
47 Oliveira RSF, Ferreira JCB, Gomes ERM. et al. Cardiac anti-remodelling effect of aerobic training is associated with a reduction in the calcineurin/NFAT signalling pathway in heart failure mice. J Physiol 2009; 587: 3899-3910
48 Johnsen AB, Høydal M, Røsbjørgen R. et al. Aerobic interval training partly reverse contractile dysfunction and impaired Ca2+ handling in atrial myocytes from rats with post infarction heart failure. PLoS One 2013; 8: e66288
49 Ambrosy AP, Bhatt AS, Stebbins AL. et al. Prevalent digoxin use and subsequent risk of death or hospitalization in ambulatory heart failure patients with a reduced ejection fraction-Findings from the heart failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) randomized controlled trial. Am Heart J 2018; 199: 97-104
50 Ziff OJ, Kotecha D. Digoxin: The good and the bad. Trends Cardiovasc Med 2016; 26: 585-595
51 Hoffman BF, Bigger JT. Digitalis and allied cardiac glycosides. In: Gilman AG, Goodman LS, Gilman S. The Pharmacologic Basis of Therapeutics. New York: MacMillan; 1980: 729-760
52 Wisloff U, Ellingsen O, Kemi OJ. High-intensity interval training to maximize cardiac benefits of exercise training?. Exerc Sport Sci Rev 2009; 37: 139-146
53 Huang YC, Tsai HH, Fu TC. et al. High intensity interval training improves left ventricular contractile function. Med Sci Sports Exerc 2019; 51: 1420-1428
54 Kemi OJ, Wisloff U. Mechanisms of exercise induced improvements in the contractile apparatus of the mammalian myocardium. Acta Physiol (Oxf) 2010; 199: 425-439
55 Moore RL, Palmer BM. Exercise training and cellular adaptations of normal and diseased hearts. Exerc Sport Sci Rev 1999; 27: 285-315
56 Sordahl LA, Asimakis GK, Dowell RT. et al. Functions of selected biochemical systems from the exercised-trained dog heart. J Appl Physiol Respir Environ Exerc Physiol 1977; 42: 426-431
57 Rodrigues JA, Prímola-Gomes TN, Soares LL. et al. Physical exercise and regulation of intracellular calcium in cardiomyocytes of hypertensive rats. Arq Bras Cardiol 2018; 111: 172-179.