Korean Circulation Journal

The Korean Society of Cardiology (대한심장학회)
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Gene Expression of Endothelin-1 and Endothelin Receptor A on Monocrotaline-Induced Pulmonary Hypertension in Rats After Bosentan Treatment

  • Lim, Kyoung-Ah (Department of Pediatrics, College of Medicine, CHA University) ;
  • Kim, Kwan-Chang (Department of Thoracic and Cardiovascular Surgery, School of Medicine, Ewha Womans University) ;
  • Cho, Min-Sun (Department of Pathology, School of Medicine, Ewha Womans University) ;
  • Lee, Bo-En (Department of Preventive Medicine, School of Medicine, Ewha Womans University) ;
  • Kim, Hae-Soon (Department of Pediatrics, School of Medicine, Ewha Womans University) ;
  • Hong, Young-Mi (Department of Pediatrics, School of Medicine, Ewha Womans University)
  • Received : 2009.12.20
  • Accepted : 2010.03.09
  • Published : 2010.09.30
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Abstract

Background and Objectives: Endothelin (ET)-1, a potent endothelium-derived vasoconstrictor peptide, has a potential pathophysiologic role in pulmonary hypertension. Bosentan, a dual ET receptor (ET$_A$/ET$_B$) antagonist, is efficacious in treatment of pulmonary hypertension. The objectives of this study were to investigate the expression of ET-1 and ET receptor A (ERA) genes and to evaluate the effect of bosentan in monocrotaline (MCT)-induced pulmonary hypertension. Materials and Methods: Four-week-old male Sprague-Dawley rats were treated as follows: control (n=36), subcutaneous (sc) injection of saline; MCT (n=36), sc injection of MCT (60 mg/kg); and bosentan (n=36), sc injection of MCT (60 mg/kg) plus 25 mg/kg/day bosentan orally. Results: Serum ET-1 concentrations in the MCT group were higher than the control group on day 28 and 42. Quantitative analysis of peripheral pulmonary arteries revealed that the increase in medial wall thickness after MCT injection was significantly attenuated in the bosentan group on day 28 and 42. In addition, the increase in the number of intra-acinar muscular arteries after MCT injection was reduced by bosentan on day 14, 28 and 42. The levels of ET-1 and ERA gene expression were significantly increased in the MCT group compared with control group on day 5, and bosentan decreased the expression of ET-1 on day 5. Conclusion: ET-1 contributes to the progression of cardiopulmonary pathology in rats with MCT-induced pulmonary hypertension. Administration of bosentan reduced ET-1 gene expression in MCT-induced pulmonary hypertension in rats.

Keywords

References

  1. Kim HW, Kim, Je HG, et al. Pulmonary arterial hypertension in children: a single center experience. Korean Circ J 2008;38:644-50. https://doi.org/10.4070/kcj.2008.38.12.644
  2. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411-5. https://doi.org/10.1038/332411a0
  3. Jung JW. Pulmonary arterial hypertension of congenital heart diseases: from reversible pulmonary hypertension to Eisenmenger syndrome. Korean Circ J 2007;37:287-97. https://doi.org/10.4070/kcj.2007.37.7.287
  4. Cody RJ, Haas GJ, Binkley PF, Capers Q, Kelley R. Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure. Circulation 1992;85:504-9. https://doi.org/10.1161/01.CIR.85.2.504
  5. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin- 1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732-9. https://doi.org/10.1056/NEJM199306173282402
  6. Teerlink JR, Loffler BM, Hess P, Maire JP, Clozel M, Clozel JP. Role of endothelin in the maintenance of blood pressure in conscious rats with chronic heart failure: acute effects of the endothelin receptor antagonist Ro 47-0203 (bosentan). Circulation 1994;90:2510-8. https://doi.org/10.1161/01.CIR.90.5.2510
  7. Tuder RM, Marecki JC, Richter A, Fijalkowska I, Flores S. Pathology of pulmonary hypertension. Clin Chest Med 2007;28:23-42, vii. https://doi.org/10.1016/j.ccm.2006.11.010
  8. Sakurai T, Yanagisawa M, Masaki T. Molecular characterization of endothelin receptors. Trends Pharmacol Sci 1992;13:103-8. https://doi.org/10.1016/0165-6147(92)90038-8
  9. Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 1990; 348:730-2. https://doi.org/10.1038/348730a0
  10. Zamora MA, Dempsey EC, Walchak SJ, Stelzner TJ. BQ123, an ETA receptor antagonist, inhibits endothelin-1-mediated proliferation of human pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol 1993;9:429-33. https://doi.org/10.1165/ajrcmb/9.4.429
  11. Vane J. Endothelins come home to roost. Nature 1990;348:673. https://doi.org/10.1038/348673a0
  12. de Nucci G, Thomas R, D'Orleans-Juste P, et al. Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci U S A 1988;85:9797-800. https://doi.org/10.1073/pnas.85.24.9797
  13. Dupuis J, Goresky CA, Stewart DJ. Pulmonary removal and production of endothelin in the anesthetized dog. J Appl Physiol 1994;76:694-700. https://doi.org/10.1152/jappl.1994.76.2.694
  14. Dupuis J, Goresky CA, Fournier A. Pulmonary clearance of circulating endothelin1 in dogs in vivo: exclusive role of ETB receptors. J Appl Physiol 1996;81:1510-5. https://doi.org/10.1152/jappl.1996.81.4.1510
  15. Sumner MJ, Cannon TR, Mundin JW, White DG, Watts IS. Endothelin ETA and ETB receptors mediate vascular smooth muscle contraction. Br J Pharmacol 1992;107:858-60. https://doi.org/10.1111/j.1476-5381.1992.tb14537.x
  16. Todd L, Mullen M, Olley PM, Rabinovitch M. Pulmonary toxicity of monocrotaline differs at critical periods of lung development. Pediatr Res 1985;19:731-7. https://doi.org/10.1203/00006450-198507000-00019
  17. Sohn DW, Kim HK, Kim MA, et al. Beneficial and adverse effects of bosentan treatment in Korean patients with pulmonary artery hypertension. Korean Circ J 2009;39:105-10. https://doi.org/10.4070/kcj.2009.39.3.105
  18. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin- receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358:1119-23. https://doi.org/10.1016/S0140-6736(01)06250-X
  19. Clozel M, Hess P, Rey M, Iglarz M, Binkert C, Qiu C. Bosentan, sildenafil, and their combination in the monocrotaline model of pulmonary hypertension in rats. Exp Biol Med 2006;231:967-73.
  20. Kim H, Yung GL, Marsh JJ, et al. Endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension. Eur Respir J 2000;15:640-8. https://doi.org/10.1034/j.1399-3003.2000.15d04.x
  21. Morice AH, Mulrennan S, Clark A. Combination therapy with bosentan and phosphodiesterase-5 inhibitor in pulmonary arterial hypertension. Eur Respir J 2005;26:180-1.
  22. Lim KA, Shin JY, Cho SH, Kim KW, Han JJ, Hong YM. Effect of endothelin receptor blokade on monocrotaline-induced pulmonary hypertension in rats. Korean J Pediatr 2009;52:689-95. https://doi.org/10.3345/kjp.2009.52.6.689
  23. Miyauchi T, Yorikane R, Sakai S, et al. Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotalin-induced pulmonary hypertension. Circ Res 1993;73:887-97. https://doi.org/10.1161/01.RES.73.5.887
  24. Itoh T, Nagaya N, Fujii T, et al. A combination of oral sildenafil and beraprost ameliorates pulmonary hypertension in rats. Am J Respir Crit Care Med 2004;169:34-8. https://doi.org/10.1164/rccm.200303-346OC
  25. Prie S, Leung TK, Cernacek P, Ryan JW, Dupuis J. The orally active ET(A) receptor antagonist (+)-(S)-2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl-propionic acid (LU 135252) prevents the development of pulmonary hypertension and endothelial metabolic dysfunction in monocrotaline-treated rats. J Pharmacol Exp Ther 1997;282:1312-8.
  26. Schermuly RT, Kreisselmeier KP, Ghofrani HA, et al. Chronic sildenafil 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
  27. Park HK, Park SJ, Kim CS, Paek YW, Lee JU, Lee WJ. Enhanced gene expression of renin-angiotensin system, TGF-beta1, endothelin-1 and nitric oxide synthase in right-ventricular hypertrophy. Pharmacol Res 2001;43:265-73. https://doi.org/10.1006/phrs.2000.0777
  28. Shiba R, Yanagisawa M, Miyauchi T, et al. Elimination of intravenously injected endothelin-1 from the circulation of the rat. J Cardiovasc Pharmacol 1989;13(Suppl 5):S98-101, discussion S102. https://doi.org/10.1097/00005344-198900135-00024
  29. Weber C, Schmitt R, Birnboeck H, et al. Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects. Clin Pharmacol Ther 1996;60:124-37. https://doi.org/10.1016/S0009-9236(96)90127-7
  30. Loffler BM, Breu V, Clozel M. Effect of different endothelin receptor antagonists and of the novel non-peptide antagonist Ro 46-2005 on endothelin levels in rat plasma. FEBS Lett 1993;333:108-10. https://doi.org/10.1016/0014-5793(93)80384-7
  31. Ichikawa KI, Hidai C, Okuda C, et al. Endogenous endothelin-1 medi-ates cardiac hypertrophy and switching of myosin heavy chain gene expression in rat ventricular myocardium. J Am Coll Cardiol 1996; 27:1286-91. https://doi.org/10.1016/0735-1097(95)00568-4
  32. Dai ZK, Tan MS, Chai CY, et al. Effects of sildenafil on pulmonary hypertension and levels of ET-1, eNOS, and cGMP in aorta-banded rats. Exp Biol Med 2006;231:942-7.

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