Exercise Training Plus Sildenafil Treatment: Role on Autonomic and Inflammatory Markers

Abstract

The current study aimed to determine the effects of sildenafil-associated aerobic exercise training (ET) on the physical performance, hemodynamic, autonomic and inflammatory parameters of rats. Male Wistar rats were randomly assigned to: sedentary rats placebo-treated (SP); sedentary rats sildenafil-treated (SS); trained rats placebo-treated (TP); and trained rats sildenafil-treated (TS). Sildenafil treatment consisted of 8 weeks of daily oral gavage (1.5 mg/kg), one hour before the session of ET (60–75% of maximal running speed, 5 days/week, for 8 weeks). After ET period, physical capacity, hemodynamic, autonomic and skeletal muscle inflammatory profile were assessed. Chronic sildenafil treatment causes an additional increase of physical capacity in aerobically trained rats. However, these beneficial effects were accompanied by unwanted alterations, as increased of arterial pressure and peripheral sympathetic modulation, as well as exacerbated inflammatory status on skeletal muscle of rats. Taken together, these data suggest the positive and negative effects of sildenafil chronic administration, associated to aerobic ET, at doses used in clinical practice. This report stresses the importance of paying greater attention to the indiscriminate use of this substance in high-performance sports.

Key words

aerobic training - phosphodiesterase-5 inhibition - blood pressure - autonomic nervous system - inflammation

• References

• 1 Arora RR, Timoney M, Melilli L. Acute myocardial infarction after the use of sildenafil. N Engl J Med 1999; 341: 700
• 2 Barboza C, Souza G, Oliveira J, Silva L, Mostarda C, Dourado P, Oyama L, Lira F, Irigoyen M, Rodrigues B. Cardioprotective properties of aerobic and resistance training against myocardial infarction. Int J Sports Med 2016; 37: 421-430
• 3 Barboza CA, Rocha LY, Mostarda CT, Figueroa D, Caperuto EC, De Angelis K, Irigoyen MC, Rodrigues B. Ventricular and autonomic benefits of exercise training persist after detraining in infarcted rats. Eur J Appl Physiol 2013; 113: 1137-1146
• 4 Bassi GS, Brognara F, Castania JA, Talbot J, Cunha TM, Cunha FQ, Ulloa L, Kanashiro A, Dias DPM, Salgado HC. Baroreflex activation in conscious rats modulates the joint inflammatory response via sympathetic function. Brain Behav Immun 2015; 49: 140-147
• 5 Bassi GS, Dias DPM, Franchin M, Talbot J, Reis DG, Menezes GB, Castania JA, Garcia-Cairasco N, Resstel LBM, Salgado HC. Modulation of experimental arthritis by vagal sensory and central brain stimulation. Brain Behav Immun 2017; 64: 330-343
• 6 Borovikova LV, Ivanova S, Zhang M, Yang H. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000; 405: 458-462
• 7 Chapleau MW, Hajduczok G, Abboud FM. Peripheral central mechanisms of baroreflex resetting. Clin Exp Pharmacol Physiol Suppl 1989; 15: 31-43
• 8 Coelho Junior HJ, Gambassi BB, Diniz TA, Fernandes IMdC, Caperuto ÉC, Uchida MC, Lira FS, Rodrigues B. Inflammatory mechanisms associated with skeletal muscle sequelae after stroke: Role of physical exercise. Mediators Inflamm 2016; 2016: 3957958
• 9 Corrêa WG, Durand MT, Becari C, Tezini GC, do Carmo JM, de Oliveira M, Prado CM, Fazan R, Salgado HC. Pyridostigmine prevents haemodynamic alterations but does not affect their nycthemeral oscillations in infarcted mice. Auton Neurosci 2015; 187: 50-55
• 10 Dopp JM, Agapitov AV, Sinkey CA, Haynes WG, Phillips BG. Sildenafil increases sympathetically mediated vascular tone in humans. Am J Hypertens 2013; 26: 762-769
• 11 Fazan Jr R, Huber DA, Silva CAA, Dias da Silva VJ, Salgado MCO, Salgado HC. Sildenafil acts on the central nervous system increasing sympathetic activity. J Appl Physiol (1985) 2008; 104: 1683-1689
• 12 Feriani DJ, Souza GI, Carrozzi NM, Mostarda C, Dourado PM, Consolim-Colombo FM, De Angelis K, Moreno H, Irigoyen MC, Rodrigues B. Impact of exercise training associated to pyridostigmine treatment on autonomic function and inflammatory profile after myocardial infarction in rats. Int J Cardiol 2017; 227: 757-765
• 13 Ghofrani HA, Reichenberger F, Kohstall MG, Mrosek EH, Seeger T, Olschewski H, Seeger W, Grimminger F. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: A randomized, double-blind, placebo-controlled crossover trial. Ann Intern Med 2004; 141: 169-177
• 14 Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hypertension in heart failure with preserved ejection fraction: A target of phosphodiesterase-5 inhibition in a 1-year study. Circulation 2011; 124: 164-174
• 15 Harriss DJ, Macsween A, Atkinson G. Ethical standards in sport and exercise science research: 2018 update. Int J Sports Med 2017; 38: 1126-1131
• 16 Hsu AR, Barnholt KE, Grundmann NK, Lin JH, McCallum SW, Friedlander AL. Sildenafil improves cardiac output and exercise performance during acute hypoxia, but not normoxia. J Appl Physiol (1985) 2006; 100: 2031-2040
• 17 Huston JM, Tracey KJ. The pulse of inflammation: Heart rate variability, the cholinergic antiinflammatory pathway and implications for therapy. J Intern Med 2011; 269: 45-53
• 18 Jackson G, Montorsi P, Cheitlin MD. Cardiovascular safety of sildenafil citrate (Viagra®): An updated perspective. Urology 2006; 68 3 Suppl 47-60
• 19 Jacobs KA, Kressler J, Stoutenberg M, Roos BA, Friedlander AL. Sildenafil has little influence on cardiovascular hemodynamics or 6-km time trial performance in trained men and women at simulated high altitude. High Alt Med Biol 2011; 12: 215-222
• 20 Kressler J, Stoutenberg M, Roos BA, Friedlander AL, Perry AC, Signorile JF, Jacobs KA. Sildenafil does not improve steady state cardiovascular hemodynamics, peak power, or 15-km time trial cycling performance at simulated moderate or high altitudes in men and women. Eur J Appl Physiol 2011; 111: 3031-3040
• 21 Kukreja RC, Salloum F, Das A, Ockaili R, Yin C, Bremer YA, Fisher PW, Wittkamp M, Hawkins J, Chou E. Pharmacological preconditioning with sildenafil: Basic mechanisms and clinical implications. Vascul Pharmacol 2005; 42: 219-232
• 22 La Fuente RN, Rodrigues B, Moraes-Silva IC, Souza LE, Sirvente R, Mostarda C, De Angelis K, Soares PP, Lacchini S, Consolim-Colombo F. Cholinergic stimulation with pyridostigmine improves autonomic function in infarcted rats. Clin Exp Pharmacol Physiol 2013; 40: 610-616
• 23 Leoni LAB, Leite GS, Wichi RB, Rodrigues B. Sildenafil: Two decades of benefits or risks?. Aging Male 2013; 16: 85-91
• 24 Lewis GD, Shah R, Shahzad K, Camuso JM, Pappagianopoulos PP, Hung J, Tawakol A, Gerszten RE, Systrom DM, Bloch KD. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation 2007; 116: 1555-1562
• 25 Lin C-S, Lin G, Xin Z-C, Lue TF. Expression, distribution and regulation of phosphodiesterase 5. Curr Pharm Des 2006; 12: 3439-3457
• 26 Lira FS, Rosa JC, Zanchi NE, Yamashita AS, Lopes RD, Lopes AC, Batista ML, Seelaender M. Regulation of inflammation in the adipose tissue in cancer cachexia: Effect of exercise. Cell Biochem Funct 2009; 27: 71-75
• 27 Lira FS, Yamashita AS, Rosa JC, Tavares FL, Caperuto E, Carnevali LC, Pimentel GD, Santos RV, Batista ML, Laviano A. Hypothalamic inflammation is reversed by endurance training in anorectic-cachectic rats. Nutr Metab (Lond) 2011; 8: 60
• 28 Lopes WA, Leite N, da Silva LR, Brunelli DT, Gáspari AF, Radominski RB, Chacon-Mikahil MPT, Cavaglieri CR. Effects of 12 weeks of combined training without caloric restriction on inflammatory markers in overweight girls. J Sports Sci 2016; 34: 1902-1912
• 29 Malliani A, Pagani M. Spectral analysis of cardiovascular variabilities in the assessment of sympathetic cardiac regulation in heart failure. Pharmacol Res 1991; 24 (Suppl. 01) 43-53
• 30 Perandini LA, de Sá-Pinto AL, Roschel H, Benatti FB, Lima FR, Bonfá E, Gualano B. Exercise as a therapeutic tool to counteract inflammation and clinical symptoms in autoimmune rheumatic diseases. Autoimmun Rev 2012; 12: 218-224
• 31 Phillips BG, Kato M, Pesek CA, Winnicki M, Narkiewicz K, Davison D, Somers VK. Sympathetic activation by sildenafil. Circulation 2000; 102: 3068-3073
• 32 Rao RS, Singh S, Sharma BB, Agarwal V, Singh V. Sildenafil improves six-minute walk distance in chronic obstructive pulmonary disease: A randomised, double-blind, placebo-controlled trial. Indian J Chest Dis Allied Sci 2011; 53: 81-85
• 33 Ricart A, Maristany J, Fort N, Leal C, Pagés T, Viscor G. Effects of sildenafil on the human response to acute hypoxia and exercise. High Alt Med Biol 2005; 6: 43-49
• 34 Richalet J-P, Gratadour P, Robach P, Pham I, Déchaux M, Joncquiert-Latarjet A, Mollard P, Brugniaux J, Cornolo J. Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. Am J Respir Crit Care Med 2005; 171: 275-281
• 35 Rinaldi B, Donniacuo M, Sodano L, Gritti G, Signoriello S, Parretta E, Berrino L, Urbanek K, Capuano A, Rossi F. Effects of sildenafil on the gastrocnemius and cardiac muscles of rats in a model of prolonged moderate exercise training. PLoS One 2013; 8: e69954
• 36 Rodrigues B, Figueroa DM, Mostarda CT, Heeren MV, Irigoyen M-C, De Angelis K. Maximal exercise test is a useful method for physical capacity and oxygen consumption determination in streptozotocin-diabetic rats. Cardiovasc Diabetol 2007; 6: 38
• 37 Rodrigues B, Lira FS, Consolim-Colombo FM, Rocha JA, Caperuto EC, De Angelis K, Irigoyen M-C. Role of exercise training on autonomic changes and inflammatory profile induced by myocardial infarction. Mediators Inflamm 2014; 2014: 702473
• 38 Rodway GW, Lovelace AJ, Lanspa MJ, McIntosh SE, Bell J, Briggs B, Weaver LK, Yanowitz F, Grissom CK. Sildenafil and exercise capacity in the elderly at moderate altitude. Wilderness Environ Med 2016; 27: 307-315
• 39 Rosas-Ballina M, Tracey KJ. The neurology of the immune system: Neural reflexes regulate immunity. Neuron 2009; 64: 28-32
• 40 Roseguini BT, Hirai DM, Alencar MC, Ramos RP, Silva BM, Wolosker N, Neder JA, Nery LE. Sildenafil improves skeletal muscle oxygenation during exercise in men with intermittent claudication. Am J Physiol Regul Integr Comp Physiol 2014; 307: R396-R404
• 41 Stauffer J-C, Ruiz V, Morard J-D. Subaortic obstruction after sildenafil in a patient with hypertrophic cardiomyopathy. N Engl J Med 1999; 341: 700-701
• 42 Thomas GD. Neural control of the circulation. Adv Physiol Educ 2011; 35: 28-32
• 43 Toro-Salinas AH, Fort N, Torrella JR, Pagès T, Javierre C, Viscor G. Sildenafil does not improve exercise capacity under acute hypoxia exposure. Int J Sports Med 2016; 37: 785-791