DOI QR코드

DOI QR Code

The effect of sildenafil on right ventricular remodeling in a rat model of monocrotaline-induced right ventricular failure

  • Bae, Hyun Kyung (Department of Pediatrics, Ewha Womans University School of Medicine) ;
  • Lee, Hyeryon (Department of Pediatrics, Ewha Womans University School of Medicine) ;
  • Kim, Kwan Chang (Department of Thoracic and Cardiovascular Surgery, Ewha Womans University School of Medicine) ;
  • Hong, Young Mi (Department of Pediatrics, Ewha Womans University School of Medicine)
  • 투고 : 2016.03.14
  • 심사 : 2016.05.10
  • 발행 : 2016.06.15

초록

Purpose: Pulmonary arterial hypertension (PAH) leads to right ventricular failure (RVF) as well as an increase in pulmonary vascular resistance. Our purpose was to study the effect of sildenafil on right ventricular remodeling in a rat model of monocrotaline (MCT)-induced RVF. Methods: The rats were distributed randomly into 3 groups. The control (C) group, the monocrotaline (M) group (MCT 60 mg/kg) and the sildenafil (S) group (MCT 60 mg/kg+ sildenafil 30 mg/kg/day for 28 days). Masson Trichrome staining was used for heart tissues. Western blot analysis and immunohistochemical staining were performed. Results: The mean right ventricular pressure (RVP) was significantly lower in the S group at weeks 1, 2, and 4. The number of intra-acinar arteries and the medial wall thickness of the pulmonary arterioles significantly lessened in the S group at week 4. The collagen content also decreased in heart tissues in the S group at week 4. Protein expression levels of B-cell lymphoma-2 (Bcl-2)-associated X, caspase-3, Bcl-2, interleukin (IL)-6, matrix metalloproteinase (MMP)-2, endothelial nitric oxide synthase (eNOS), endothelin (ET)-1 and ET receptor A (ERA) in lung tissues greatly decreased in the S group at week 4 according to immunohistochemical staining. According to Western blotting, protein expression levels of troponin I, brain natriuretic peptide, caspase-3, Bcl-2, tumor necrosis factor-${\alpha}$, IL-6, MMP-2, eNOS, ET-1, and ERA in heart tissues greatly diminished in the S group at week 4. Conclusion: Sildenafil alleviated right ventricular hypertrophy and mean RVP. These data suggest that sildenafil improves right ventricular function.

키워드

참고문헌

  1. Chesler NC, Roldan A, Vanderpool RR, Naeije R. How to measure pulmonary vascular and right ventricular function. Conf Proc IEEE Eng Med Biol Soc 2009;2009:177-80.
  2. Wilkins MR. Pulmonary hypertension: the science behind the disease spectrum. Eur Respir Rev 2012;21:19-26. https://doi.org/10.1183/09059180.00008411
  3. Vonk-Noordegraaf A, Haddad F, Chin KM, Forfia PR, Kawut SM, Lumens J, et al. Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol 2013;62(25 Suppl):D22-33. https://doi.org/10.1016/j.jacc.2013.10.027
  4. Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, et al. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation 2007;116:238-48. https://doi.org/10.1161/CIRCULATIONAHA.106.655266
  5. Kret M, Arora R. Pathophysiological basis of right ventricular remodeling. J Cardiovasc Pharmacol Ther 2007;12:5-14. https://doi.org/10.1177/1074248406298293
  6. Kucuker SA, Stetson SJ, Becker KA, Akgul A, Loebe M, Lafuente JA, et al. Evidence of improved right ventricular structure after LVAD support in patients with end-stage cardiomyopathy. J Heart Lung Transplant 2004;23:28-35. https://doi.org/10.1016/S1053-2498(03)00057-3
  7. Yoshiyama M, Takeuchi K, Hanatani A, Shimada T, Takemoto Y, Shimizu N, et al. Effect of cilazapril on ventricular remodeling assessed by Doppler-echocardiographic assessment and cardiac gene expression. Cardiovasc Drugs Ther 1998;12:57-70. https://doi.org/10.1023/A:1007789519005
  8. Bussani R, Abbate A, Biondi-Zoccai GG, Dobrina A, Leone AM, Camilot D, et al. Right ventricular dilatation after left ventricular acute myocardial infarction is predictive of extremely high periinfarctual apoptosis at postmortem examination in humans. J Clin Pathol 2003;56:672-6. https://doi.org/10.1136/jcp.56.9.672
  9. Lepore JJ, Maroo A, Bigatello LM, Dec GW, Zapol WM, Bloch KD, et al. Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: combined administration with inhaled nitric oxide. Chest 2005;127:1647-53. https://doi.org/10.1378/chest.127.5.1647
  10. Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148-57. https://doi.org/10.1056/NEJMoa050010
  11. Balarini CM, Leal MA, Gomes IB, Pereira TM, Gava AL, Meyrelles SS, et al. Sildenafil restores endothelial function in the apolipoprotein E knockout mouse. J Transl Med 2013;11:3. https://doi.org/10.1186/1479-5876-11-3
  12. Toward TJ, Smith N, Broadley KJ. Effect of phosphodiesterase-5 inhibitor, sildenafil (Viagra), in animal models of airways disease. Am J Respir Crit Care Med 2004;169:227-34. https://doi.org/10.1164/rccm.200211-1372OC
  13. Schwartz BG, Levine LA, Comstock G, Stecher VJ, Kloner RA. Cardiac uses of phosphodiesterase-5 inhibitors. J Am Coll Cardiol 2012;59:9-15. https://doi.org/10.1016/j.jacc.2011.07.051
  14. Urbanowicz T, Straburzyńska-Migaj E, Katyńska I, Araszkiewicz A, Oko-Sarnowska Z, Grajek S, et al. Sustained improvement of clinical status and pulmonary hypertension in patients with severe heart failure treated with sildenafil. Ann Transplant 2014;19:325-30. https://doi.org/10.12659/AOT.890657
  15. Guazzi M, Tumminello G, Di Marco F, Guazzi MD. Influences of sildenafil on lung function and hemodynamics in patients with chronic heart failure. Clin Pharmacol Ther 2004;76:371-8. https://doi.org/10.1016/j.clpt.2004.06.003
  16. Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hypertension in chronic heart failure: the role of the endothelium in pathophysiology and management. Circulation 2000;102:1718-23. https://doi.org/10.1161/01.CIR.102.14.1718
  17. Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF. The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest 2009;135:94-804. https://doi.org/10.1378/chest.07-3020
  18. McMurtry MS, Archer SL, Altieri DC, Bonnet S, Haromy A, Harry G, et al. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest 2005;115:1479-91. https://doi.org/10.1172/JCI23203
  19. Abraham D, Ponticos M, Nagase H. Connective tissue remodeling: cross-talk between endothelins and matrix metalloproteinases. Curr Vasc Pharmacol 2005;3:369-79. https://doi.org/10.2174/157016105774329480
  20. Ozaki M, Kawashima S, Yamashita T, Ohashi Y, Rikitake Y, Inoue N, et al. Reduced hypoxic pulmonary vascular remodeling by nitric oxide from the endothelium. Hypertension 2001;37:322-7. https://doi.org/10.1161/01.HYP.37.2.322
  21. Fagan KA, Fouty BW, Tyler RC, Morris KG Jr, Hepler LK, Sato K, et al. The pulmonary circulation of homozygous or heterozygous eNOS-null mice is hyperresponsive to mild hypoxia. J Clin Invest 1999;103:291-9. https://doi.org/10.1172/JCI3862
  22. Sirmagul B, Ilgin S, Atli O, Usanmaz SE, Demirel-Yilmaz E. Assessment of the endothelial functions in monocrotaline-induced pulmonary hypertension. Clin Exp Hypertens 2013;35:220-7. https://doi.org/10.3109/10641963.2012.721838
  23. Adamcova M, Sterba M, Simůnek T, Potacova A, Popelova O, Gersl V. Myocardial regulatory proteins and heart failure. Eur J Heart Fail 2006;8:333-42. https://doi.org/10.1016/j.ejheart.2005.09.007
  24. VanBuren P, Okada Y. Thin filament remodeling in failing myocardium. Heart Fail Rev 2005;10:199-209. https://doi.org/10.1007/s10741-005-5250-8
  25. Panagopoulou V, Deftereos S, Kossyvakis C, Raisakis K, Giannopoulos G, Bouras G, et al. NTproBNP: an important biomarker in cardiac diseases. Curr Top Med Chem 2013;13:82-94. https://doi.org/10.2174/1568026611313020002
  26. Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002;105:2398-403. https://doi.org/10.1161/01.CIR.0000016641.12984.DC
  27. Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 2005;11:214-22. https://doi.org/10.1038/nm1175
  28. Nagayama T, Hsu S, Zhang M, Koitabashi N, Bedja D, Gabrielson KL, et al. Sildenafil stops progressive chamber, cellular, and molecular remodeling and improves calcium handling and function in hearts with pre-existing advanced hypertrophy caused by pressure overload. J Am Coll Cardiol 2009;53:207-15. https://doi.org/10.1016/j.jacc.2008.08.069
  29. Lewis GD, Shah R, Shahzad K, Camuso JM, Pappagianopoulos PP, Hung J, et al. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation 2007;116:1555-62. https://doi.org/10.1161/CIRCULATIONAHA.107.716373
  30. Webster LJ, Michelakis ED, Davis T, Archer SL. Use of sildenafil for safe improvement of erectile function and quality of life in men with New York Heart Association classes II and III congestive heart failure: a prospective, placebo-controlled, double-blind crossover trial. Arch Intern Med 2004;164:514-20. https://doi.org/10.1001/archinte.164.5.514
  31. Shin HS, Bae SK, Lee MG. Pharmacokinetics of sildenafil after intravenous and oral administration in rats: hepatic and intestinal first-pass effects. Int J Pharm 2006;320:64-70. https://doi.org/10.1016/j.ijpharm.2006.04.005

피인용 문헌

  1. A Novel Therapeutic Approach in the Treatment of Pulmonary Arterial Hypertension: Allium ursinum Liophylisate Alleviates Symptoms Comparably to Sildenafil vol.18, pp.7, 2017, https://doi.org/10.3390/ijms18071436
  2. Effect of Riociguat and Sildenafil on Right Heart Remodeling and Function in Pressure Overload Induced Model of Pulmonary Arterial Banding vol.2018, pp.None, 2018, https://doi.org/10.1155/2018/3293584
  3. Effects of Simvastatin on Fetal Cardiac Impairment in the Diaphragmatic Experimental Hernia Model vol.46, pp.1, 2016, https://doi.org/10.1159/000490144
  4. Relationship between Invasive and Non-Invasive Hemodynamic Measures in Experimental Pulmonary Hypertension vol.16, pp.1, 2016, https://doi.org/10.2174/1573398x16666200516180118
  5. Metformin prevents the development of monocrotaline-induced pulmonary hypertension by decreasing serum levels of big endothelin-1 vol.20, pp.6, 2020, https://doi.org/10.3892/etm.2020.9278
  6. St. Thomas and del Nido cardioplegia are superior to Custodiol cardioplegia in a rat model of donor heart vol.55, pp.2, 2016, https://doi.org/10.1080/14017431.2020.1846772