Korean Circulation Journal

The Korean Society of Cardiology (대한심장학회)
권호 표지
DOI QR코드

DOI QR Code

Simvastatin, Sildenafil and Their Combination in Monocrotaline Induced Pulmonary Arterial Hypertension

  • Lee, Dong-Seok (Department of Pediatrics, Dongguk University School of Medicine) ;
  • Kim, Yung-Kyu (Department of Physiology, Dongguk University School of Medicine) ;
  • Jung, Yong-Wook (Department of Anatomy, Dongguk University School of Medicine)
  • Received : 2010.06.04
  • Accepted : 2010.07.30
  • Published : 2010.12.30
⟨ Previous Next ⟩

Abstract

Background and Objectives: Pulmonary arterial hypertension (PAH) is a life threatening disease characterized by progressive pulmonary arterial occlusion which may ultimately result in death. Currently, the available treatments are diverse, but no therapy alone can reverse the disease process although they may have some clinical benefits. This study was designed to investigate single and combination therapy of simvastatin and sildenafil, which have different mechanisms of action, in monocrotaline (MCT)-induced PAH. Meterials and Methods: Rats were randomized to receive saline (control, n=8) or MCT treatment (n=32). MCT treated rats were randomized to vehicle, simvastatin (2 mg/kg/day), sildenafil (25 mg/kg/day) and a combination simvastatin and sildenafil (n=8, respectively). Three weeks later, hemodynamic study and histologic changes of pulmonary arterioles were measured. Proliferating cell nuclear antigen (PCNA) as well as Western blot for endothelial nitric oxide synthase (eNOS) were performed. Results: Systolic right ventricular pressure was significantly decreased in monotherapy groups (simvastatin and sildenafil) and the combination group compared to MCT group (p<0.05). Right ventricular hypertrophy and medial wall thickness of pulmonary arterioles were significantly attenuated with sole and combination therapy (p< 0.05). However, combination therapy did not confer additive benefits over monotherapy. Altered PCNA or eNOS in lung tissue was normalized by either monotherapy or combination therapy. Conclusion: The results suggest that either simvastatin or sildenafil has the therapeutic potential in MCT-induced PAH, although combination therapy of these two drugs has failed to show greater benefits in the study.

Keywords

References

  1. Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular pa-thobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43(12 Suppl S):13S-24S. https://doi.org/10.1016/j.jacc.2004.02.029
  2. Martin KB, Klinger JR, Rounds SI. Pulmonary arterial hypertension: new insights and new hope. Respirology 2006;11:6-17. https://doi.org/10.1111/j.1440-1843.2006.00778.x
  3. Lee WS, Kim KH, Jeong DH, et al. Clinical characteristics and prognostic factors of patients with severe pulmonary hypertension. Korean Circ J 2007;37:265-70. https://doi.org/10.4070/kcj.2007.37.6.265
  4. Lee SH, Rubin LJ. Current treatment strategies for pulmonary arterial hypertension. J Intern Med 2005;258:199-215. https://doi.org/10.1111/j.1365-2796.2005.01542.x
  5. Humbert M, Sitbon O, Simmoneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1425-36. https://doi.org/10.1056/NEJMra040291
  6. Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther 1999;84:413-28. https://doi.org/10.1016/S0163-7258(99)00045-5
  7. Hu H, Sung A, Zhao G, et al. Simvastatin enhances bone morphogenetic protein receptor type II expression. Biochem Biophys Res Commun 2006;339:59-64. https://doi.org/10.1016/j.bbrc.2005.10.187
  8. Girgis RE, Li D, Zhan X, et al. Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Heart Circ Physiol 2003;285:H938-45. https://doi.org/10.1152/ajpheart.01097.2002
  9. Nishimura T, Vaszar LT, Faul JL, et al. Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation 2003;108:1640-5. https://doi.org/10.1161/01.CIR.0000087592.47401.37
  10. Taraseviciene-Stewart L, Scerbavicius R, Choe KH, et al. Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2006;291:L668-76. https://doi.org/10.1152/ajplung.00491.2005
  11. Sebkhi A, Strange JW, Phillips SC, Wharton J, Wilkins MR. Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension. Circulation 2003;107:3230-5. https://doi.org/10.1161/01.CIR.0000074226.20466.B1
  12. Schermuly RT, Kreisselmeier KP, Ghofrani HA, et al. Chronic sildena-fil treatment inhibits monocrotaline-induced pulmonary hypertension in rats. Am J Respir Crit Care Med 2004;169:39-45. https://doi.org/10.1164/rccm.200302-282OC
  13. Kothari SS, Duggal B. Chronic oral sildenafil therapy in severe pulmonary artery hypertension. Indian Heart J 2002;54:404-9.
  14. Sastry BK, Narasimhan C, Reddy NK, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 2004;43: 1149-53. https://doi.org/10.1016/j.jacc.2003.10.056
  15. Wilkins MR, Paul GA, Strange JW, et al. Sildenafil versus endothelin receptor antagonist for pulmonary hypertension (SERAPH) study. Am J Respir Crit Care Med 2005;171:1292-7. https://doi.org/10.1164/rccm.200410-1411OC
  16. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148-57. https://doi.org/10.1056/NEJMoa050010
  17. Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 2001;21:1712-9. https://doi.org/10.1161/hq1101.098486
  18. Laufs U, Fata VL, Liao JK. Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase. J Biol Chem 1997;272:31725-9. https://doi.org/10.1074/jbc.272.50.31725
  19. Son JW, Koh KK, You SM, et al. Effects of simvastatin alone or combined with ramipril on nitric oxide bioactivity and inflammation markers in hypercholesterolemic patients. Korean Circ J 2003;33:1053-9. https://doi.org/10.4070/kcj.2003.33.11.1053
  20. Girgis RE, Mozammel S, Champion HC, et al. Regression of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Lung Cell Mol Physiol 2007;292:L1105-10. https://doi.org/10.1152/ajplung.00411.2006
  21. Kim MY, Kim YK, Jung YW, Kim WT, Kwon TH, Lee DS. The protective effect of simvastatin on monocrotaline-induced pulmonary hypertension in rats. Korean Circ J 2008;38:313-9. https://doi.org/10.4070/kcj.2008.38.6.313
  22. Kao PN. Simvastatin treatment of pulmonary hypertension: an observational case series. Chest 2005;127:1446-52. https://doi.org/10.1378/chest.127.4.1446
  23. Hoeper MM, Markevych I, Spiekerkoetter E, Welte T, Niedermeyer J. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. J Eur Respir J 2005;26:858-63. https://doi.org/10.1183/09031936.05.00075305
  24. Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest 2007;131:1917-28. https://doi.org/10.1378/chest.06-2674
  25. Satoh M, Satoh A. 3-Hydroxy-3-methylglutaryl (HMG)-COA reductase inhibitors and phosphodiesterase type V inhibitors attenuate right ventricular pressure and remodeling in a rat model of pulmonary hypertension. J Pharm Pharm Sci 2009;11:118s-30s. https://doi.org/10.18433/J34K5Z
  26. Liu H, Liu ZY, Guan Q. Oral sildenafil prevents and reverses the development of pulmonary hypertension in monocrotaline-treated rats. Interact Cardiovasc Thorac Surg 2007;6:608-13. https://doi.org/10.1510/icvts.2006.147033
  27. Zhao L, Sebkhi A, Ali O, et al. Simvastatin and sildenafil combine to attenuate pulmonary hypertension. Eur Respir J 2009;34:948-57. https://doi.org/10.1183/09031936.00143508
  28. Kuang T, Wang J, Pang B, et al. Combination of sildenafil and simvastatin ameliorates monocrotaline-induced pulmonary hypertension in rats. Pulm Pharmacol Ther 2010;23:456-64. https://doi.org/10.1016/j.pupt.2010.02.003
  29. McMurtry MS, Bonnet S, Michelakis ED, Bonnet S, Haromy A, Archer SL. Statin therapy, alone or with rapamycin, does not reverse mo-nocrotaline pulmonary arterial hypertension: the rapamcyin-atorvastatin-simvastatin study. Am J Physiol Lung Cell Mol Physiol 2007;293: L933-40. https://doi.org/10.1152/ajplung.00310.2006

Cited by

  1. Randomized Clinical Trial of Aspirin and Simvastatin for Pulmonary Arterial Hypertension : ASA-STAT vol.123, pp.25, 2010, https://doi.org/10.1161/circulationaha.110.015693
  2. Transgenic expression of human matrix metalloproteinase-1 attenuates pulmonary arterial hypertension in mice vol.122, pp.2, 2012, https://doi.org/10.1042/cs20110295
  3. Therapeutic effects of the selective farnesoid X receptor agonist obeticholic acid in a monocrotaline-induced pulmonary hypertension rat model vol.42, pp.8, 2010, https://doi.org/10.1007/s40618-019-1009-2
  4. Advanced therapeutic inhalation aerosols of a Nrf2 activator and RhoA/Rho kinase (ROCK) inhibitor for targeted pulmonary drug delivery in pulmonary hypertension: design, characterization, aerosolizati vol.15, pp.None, 2010, https://doi.org/10.1177/1753466621998245