Cardiovascular Drugs and Therapy

, Volume 28, Issue 6, pp 493–500 | Cite as

Tadalafil Prevents Acute Heart Failure with Reduced Ejection Fraction in Mice

  • Fadi N. Salloum
  • Vinh Q. Chau
  • Nicholas N. Hoke
  • Rakesh C. Kukreja



Phosphodiesterase-5 (PDE5) inhibitors were shown to exert powerful protection in various animal models of cardiomyopathy. Tadalafil is a long-acting and highly specific PDE5 inhibitor, which makes it the most attractive in its class for long-term management of patients with heart failure. We studied the effects of tadalafil in attenuating ischemic cardiomyopathy in mice.

Methods and Results

Adult male mice underwent myocardial infarction (MI) by permanent left coronary artery ligation and were treated daily with tadalafil (1 mg/kg; ip) or volume-matched 10 % DMSO for 4 weeks. Twenty four hours after coronary ligation, infarct size, measured by TTC staining, was reduced from 70.1 ± 3.1 % in DMSO-treated group to 49.3 ± 2.6 % with tadalafil (P < 0.05). Similarly, tadalafil treatment yielded a smaller fibrotic area (8.8 ± 2.8 % of LV), assessed by Masson’s trichrome staining, as compared to DMSO group (21.9 ± 3.9 %, P < 0.05). Apoptosis, measured by TUNEL assay, also declined with tadalafil (2.1 ± 0.2 %) as compared to DMSO (6.7 ± 0.4 %, P < 0.05) at 28 days post MI. Tadalafil also attenuated the increase in cardiac hypertrophy and pulmonary edema following infarction. These parameters reflect diminished left ventricular (LV) adverse remodeling and preserved fractional shortening with tadalafil at 7 and 28 days post infarction.


Tadalafil attenuates ischemic cardiomyopathy in mice and preserves LV function.


Infarct size Apoptosis LV function Cardiomyopathy Phosphodiesterase-5 inhibitors 



This work was supported by grants from the American Heart Association (10SDG3770011 and 14GRNT20010003) and the Virginia Commonwealth University Presidential Research Quest Fund to Fadi N. Salloum and grants from the National Institutes of Health (HL-51045, HL-79424, and HL-93685) to Rakesh C. Kukreja.

Tadalafil was kindly provided by Lily ICOS.

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling – concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol. 2000;35:569–82.PubMedCrossRefGoogle Scholar
  2. 2.
    Kukreja RC, Salloum FN, Das A. Cyclic guanosine monophosphate signaling and phosphodiesterase-5 inhibitors in cardioprotection. J Am Coll Cardiol. 2012;59:1921–7.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Ockaili R, Salloum F, Hawkins J, Kukreja RC. Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial KATP channels in rabbits. Am J Physiol Heart Circ Physiol. 2002;283:H1263–9.PubMedGoogle Scholar
  4. 4.
    Salloum FN, Takenoshita Y, Ockaili RA, Daoud VP, Chou E, Yoshida K, et al. Sildenafil and vardenafil but not nitroglycerin limit myocardial infarction through opening of mitochondrial K(ATP) channels when administered at reperfusion following ischemia in rabbits. J Mol Cell Cardiol. 2007;42:453–8.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Salloum FN, Abbate A, Das A, Houser JE, Mudrick CA, Qureshi IZ, et al. Sildenafil (Viagra) attenuates ischemic cardiomyopathy and improves left ventricular function in mice. Am J Physiol Heart Circ Physiol. 2008;294:H1398–406.PubMedCrossRefGoogle Scholar
  6. 6.
    Chau VQ, Salloum FN, Hoke NN, Abbate A, Kukreja RC. Mitigation of the progression of the progression of heart failure with sildenafil involves the inhibition of RhoA/Rho-Kinase pathway. Am J Physiol Heart Circ Physiol. 2011;300:H2272–9.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Das A, Smolenski A, Lohmann SM, Kukreja RC. Cyclic GMP-dependent protein kinase Ialpha attenuates necrosis and apoptosis following ischemia/reoxygenation in adult cardiomyocyte. J Biol Chem. 2006;281:38644–52.PubMedCrossRefGoogle Scholar
  8. 8.
    Bremer YA, Salloum F, Ockaili R, Chou E, Moskowitz WB, Kukreja RC. Sildenafil citrate (viagra) induces cardioprotective effects after ischemia/reperfusion injury in infant rabbits. Pediatr Res. 2005;57:22–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Salloum FN, Chau VQ, Hoke NN, Abbate A, Varma A, Ockaili RA, et al. Phosphodiesterase-5 Inhibitor, Tadalafil, Protects against Myocardial Ischemia/Reperfusion through Protein-Kinase G Dependent Generation of Hydrogen Sulfide. Circulation. 2009;120:S31–6.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Varma A, Das A, Hoke NN, Durrant DE, Salloum FN, Kukreja RC. Anti-Inflammatory and Cardioprotective Effects of Tadalafil in Diabetic Mice. PLoS ONE. 2012;7:e45243.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Koka S, Das A, Salloum FN, Kukreja RC. Phosphodiesterase-5 inhibitor tadalafil attenuates oxidative stress and protects against myocardial ischemia/reperfusion injury in type 2 diabetic mice. Free Radic Biol Med. 2013;60:80–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Daugan A, Grondin P, Ruault C, de AC LMG, Coste H, Kirilovsky J, et al. The discovery of tadalafil: a novel and highly selective PDE5 inhibitor: 1:5,6,11,11a-tetrahydro-1H-imidazo[1’,5’:1,6]pyrido[3,4-b]indole-1,3(2H)-dione analogues. J Med Chem. 2003;46:4525–32.PubMedCrossRefGoogle Scholar
  13. 13.
    Frey MK, Lang I. Tadalafil for the treatment of pulmonary hypertension. Expert Opin Pharmacother. 2012;13:747–55.PubMedCrossRefGoogle Scholar
  14. 14.
    Nagy O, Hajnal A, Parratt JR, Vegh A. Sildenafil (Viagra) reduces arrhythmia severity during ischaemia 24 h after oral administration in dogs. Br J Pharmacol. 2004;141:549–51.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Das A, Xi L, Kukreja RC. Phosphodiesterase-5 inhibitor, sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis: essential role of NO signaling. J Biol Chem. 2005;280:12944–55.PubMedCrossRefGoogle Scholar
  16. 16.
    Senzaki H, Smith CJ, Juang GJ, Isoda T, Mayer SP, Ohler A, et al. Cardiac phosphodiesterase 5 (cGMP-specific) modulates beta-adrenergic signaling in vivo and is down-regulated in heart failure. FASEB J. 2001;15:1718–26.PubMedCrossRefGoogle Scholar
  17. 17.
    Salloum F, Yin C, Xi L, Kukreja RC. Sildenafil induces delayed preconditioning through inducible nitric oxide synthase-dependent pathway in mouse heart. Circ Res. 2003;92:595–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Li Q, Guo Y, Xuan YT, Lowenstein CJ, Stevenson SC, Prabhu SD, et al. Gene therapy with inducible nitric oxide synthase protects against myocardial infarction via a cyclooxygenase-2-dependent mechanism. Circ Res. 2003;92:741–8.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Toldo S, Das A, Mezzaroma E, Chau VQ, Marchetti C, Durrant D, et al. Induction of microRNA-21 with exogenous hydrogen sulfide attenuates myocardial ischemic and inflammatory injury in mice. Circ Cardiovasc Genet. 2014;7:311–20.PubMedCrossRefGoogle Scholar
  20. 20.
    MacLellan WR, Schneider MD. Death by design. Programmed cell death in cardiovascular biology and disease. Circ Res. 1997;81:137–44.PubMedCrossRefGoogle Scholar
  21. 21.
    Westermann D, Becher PM, Lindner D, Savvatis K, Xia Y, Fröhlich M, et al. Selective PDE5A inhibition with sildenafil rescues left ventricular dysfunction, inflammatory immune response and cardiac remodeling in angiotensin II-induced heart failure in vivo. Basic Res Cardiol. 2012;107:308.PubMedCrossRefGoogle Scholar
  22. 22.
    Munjal C, Opoka AM, Osinska H, James JF, Bressan GM, Hinton RB. TGF-β mediates early angiogenesis and latent fibrosis in an Emilin1-deficient mouse model of aortic valve disease. Dis Model Mech. 2014;7:987–96.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Pokreisz P, Vandenwijngaert S, Bito V, Van den Bergh A, Lenaerts I, Busch C, et al. Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice. Circulation. 2009;119:408–16.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study. Circ Heart Fail. 2011;4:8–17.PubMedCrossRefGoogle Scholar
  25. 25.
    Guazzi M, Tumminello G, Di Marco F, Fiorentini C, Guazzi MD. The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J Am Coll Cardiol. 2004;44:2339–48.PubMedCrossRefGoogle Scholar
  26. 26.
    Lewis GD, Lachmann J, Camuso J, Lepore JJ, Shin J, Martinovic ME, et al. Sildenafil improves exercise hemodynamics and oxygen uptake in patients with systolic heart failure. Circulation. 2007;115:59–66.PubMedCrossRefGoogle Scholar
  27. 27.
    Giannetta E, Isidori AM, Galea N, Carbone I, Mandosi E, Vizza CD, et al. Chronic Inhibition of cGMP phosphodiesterase 5A improves diabetic cardiomyopathy: a randomized, controlled clinical trial using magnetic resonance imaging with myocardial tagging. Circulation. 2012;125:2323–33.PubMedCrossRefGoogle Scholar
  28. 28.
    Redfield MM, Borlaug BA, Lewis GD, Mohammed SF, Semigran MJ, Lewinter MM, et al. PhosphdiesteRasE-5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure (RELAX) trial: rationale and design. Circ. Heart Fail. 2012;5:653–9.CrossRefGoogle Scholar
  29. 29.
    Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, et al. RELAX Trial. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309:1268–77.PubMedCrossRefGoogle Scholar
  30. 30.
    Wirostko BM, Tressler C, Hwang LJ, Burgess G, Laties AM. Ocular safety of sildenafil citrate when administered chronically for pulmonary arterial hypertension: results from phase III, randomised, double masked, placebo controlled trial and open label extension. BMJ. 2012;344:e554.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Varma A, Shah KB, Hess ML. Phosphodiesterase inhibitors, congestive heart failure, and sudden death: time for Re-evaluation. Congest Heart Fail. 2012;18:229–33.PubMedCrossRefGoogle Scholar
  32. 32.
    Kanlop N, Shinlapawittayatorn K, Sungnoon R, Chattipakorn S, Lailerd N, Chattipakorn N. Sildenafil citrate on the inducibility of ventricular fibrillation and upper limit of vulnerability in swine. Med Sci Monit. 2008;14:BR205–9.PubMedGoogle Scholar
  33. 33.
    Amsallem E, Kasparian C, Haddour G, Boissel JP, Nony P. Phosphodiesterase III inhibitors for heart failure. Cochrane Database Syst Rev. 2005;1:CD002230.PubMedGoogle Scholar
  34. 34.
    Oudiz RJ, Brundage BH, Galiè N, Ghofrani HA, Simonneau G, Botros FT, et al. Tadalafil for the treatment of pulmonary arterial hypertension: a double-blind 52-week uncontrolled extension study. J Am Coll Cardiol. 2012;60:768–74.PubMedCrossRefGoogle Scholar
  35. 35.
    Santos RC, de Faria AP, Barbaro NR, Modolo R, Ferreira-Melo SE, Matos-Souza JR, et al. Eur J Clin Pharmacol. 2013;70:147–54.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Fadi N. Salloum
    • 1
  • Vinh Q. Chau
    • 1
  • Nicholas N. Hoke
    • 1
  • Rakesh C. Kukreja
    • 1
  1. 1.Pauley Heart Center, Division of Cardiology, Department of Internal MedicineVirginia Commonwealth UniversityRichmondUSA

Personalised recommendations