Skip to main content
SpringerLink
Log in

Regression of Chronic Hypoxia-Induced Pulmonary Hypertension, Right Ventricular Hypertrophy, and Fibrosis: Effect of Enalapril

  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Chronic hypoxia induces pulmonary hypertension and right ventricular hypertrophy. These changes are completely reversible, except for persistent myocardial fibrosis. The aim of the present study was to determine whether treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril can reduce the ventricular collagen content in animals recovering from chronic hypoxia. Adult male Wistar rats were exposed to intermittent high-altitude hypoxia simulated in a barochamber (7000 m, 8 hr/day, 5 days a week, 24 exposures), then transferred to normoxia and divided into two groups: (a) treated with enalapril (0.1 g/kg/day for 60 days) and (b) without treatment. The corresponding control groups were kept under normoxic conditions. Enalapril significantly decreased the heart rate, systemic arterial pressure, and absolute left and right ventricular weights in both hypoxic and control rats; on the other hand, the pulmonary blood pressure was unchanged. The content and concentration of collagen was reduced in both ventricles of enalapril-treated hypoxic and control animals by 10–26% compared with the corresponding untreated groups. These data suggest that the partial regression of cardiac fibrosis due to enalapril may be independent of the pressure load.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Durand J. Physiologic adaptation to altitude and hyperexis. In: Brendel W, Zink RA, eds. High Altitude Physiology and Medicine. New York: Springer-Verlag, 1982:209–211.

    Google Scholar 

  2. Widimský J, Urbanová D, Ressl J, Ošt'ádal B, Pelouch V, Procházka J. Effect of intermittent altitude hypoxia on the myocardium and lesser circulation in the rat. Cardiovasc Res 1973;7:798–808.

    Google Scholar 

  3. Herget J, Paleček F. Experimental chronic pulmonary hypertension. Int Rev Pathol 1978;18:347–406.

    Google Scholar 

  4. Ošt'ádal B, Kolář F, Pelouch V, Procházka J, Widimský J. Intermittent high altitude and the cardiopulmonary system. In: Nagano M, Takeda N, Dhalla NS, eds. Adapted Heart. New York: Raven Press, 1994;173–182.

    Google Scholar 

  5. Reid LM. Structure and function in pulmonary hypertension. New perceptions. Chest 1986;89:279–288.

    Google Scholar 

  6. Pelouch V, Ošt'ádal B, Procházka J, Urbanová D, Widimský J. Effect of high altitude hypoxia on the protein composition on the right ventricular myocardium. Progr Resp Res 1985;20:41–48.

    Google Scholar 

  7. Pelouch V, Dixon IMC, Golfman L, Beamish RE, Dhalla NS. Role of extracellular matrix proteins in heart function. Mol Cell Biochem 1994;129:101–120.

    Google Scholar 

  8. Ressl J, Urbanová D, Widimský J, Ošt'ádal B, Pelouch V, Procházka J. Reversibility of pulmonary hypertension and right ventricular hypertrophy induced by intermittent high altitude hypoxia in rats. Respiration 1974;31:38–46.

    Google Scholar 

  9. Ošt'ádal B, Procházka J, Pelouch V, Urbanová D, Widimský J, Staněk V. Pharmacological treatment and spontaneous reversibility of cardiopulmonary changes induced by intermittent high altitude hypoxia. Prog Respir Res 1985;29:17–25.

    Google Scholar 

  10. Weber KT, Brilla CG, Janicki JS. Signals for the remodeling of the cardiac interstitium in systemic hypertension. J Cardiovasc Pharmacol 1991;17:514–519.

    Google Scholar 

  11. Weber KT, Janicki JS. Angiotensin and the remodeling of the myocardium. Br J Clin Pharmacol 1989;28:141S–150S.

    Google Scholar 

  12. Brilla CG, Pick R, Tan LB, Janicki JS, Weber KT. Remodeling of the rat right and left ventricle in experimental hypertension. Circ Res 1990;67:1355–1364.

    Google Scholar 

  13. Brilla CG, Janicki JS, Weber KT. Cardioreparative effects of lisinopril in rats with genetic hypertension and left ventricular hypertrophy. Circulation 1991;83:1771–1779.

    Google Scholar 

  14. Baker KM, Boos GW, Dostal DE. Cardiac actions of angiotensin II: Role of an intracardiac renin-angiotensin system. Annu Rev Physiol 1992;54:227–241.

    Google Scholar 

  15. Linz W, Schaper J, Wiemer G, Albus U, Schölkens BA. Ramipril prevents left ventricular hypertrophy with myocardial fibrosis without blood pressure reduction: A one year study in rats. Br J Pharmacol 1992;107:970–975.

    Google Scholar 

  16. Linz W, Gohlke P, Unger T, Schölkens BA. Experimental evidence for effects of ramipril on cardiac and vascular hypertrophy beyond blood pressure reduction. Arch Mal Coeur Vaiss 1995;88:31–34.

    Google Scholar 

  17. Zakheim RM, Mattioli L, Molteni A, Mullis KB, Bartley KH. Prevention of pulmonary vascular changes of chronic alveolar hypoxia by inhibition of angiotensin I-converting enzyme in the rat. Lab Invest 1975;33:57–61.

    Google Scholar 

  18. Suggett AJ, Mohammed FH, Barer GR. Anginotensin, hypoxia, verapamil and pulmonary vessels. Clin Exp Pharmacol Physiol 1980;7:263–274.

    Google Scholar 

  19. Kentera D, Susic D, Cvetkovic D, Djorjevic G. Effect of SQ 14 225, an orally active inhibitor of angiotensin converting enzyme, on hypoxic pulmonary hypertension in rats. Basic Res Cardiol 1981;76:344–351.

    Google Scholar 

  20. Clozel JP, Saunier C, Harteman D, Fischli W. Effects of cilazapril, a novel angiotensin converting enzyme inhibitor, on the structure of pulmonary arteries of rats exposed to chronic hypoxia. J Cardiovasc Pharmacol 1991;17:36–40.

    Google Scholar 

  21. Kay JM, Keane PM, Suyama KL, Gauthier D. Angiotensin converting enzyme activity and evolution of pulmonary vascular disease in rats with monocrotaline pulmonary hypertension. Thorax 1982;37:88–96.

    Google Scholar 

  22. Molteni A, Ward WF, Tsao CH, Solliday NH. Monocrotaline-induced cardiopulmonary damage in rats: Amelioration by the angiotensin-converting enzyme inhibitor C 1242817 (24370). Proc Soc Exp Biol Med 1986;182:483–493.

    Google Scholar 

  23. Cassis LA, Rippetoe PE, Soltis EE, Painter DJ, Fitz R, Gillespie MN. Angiotensin II and monocrotaline-induced pulmonary hypertension: Effect of Losartan (DuP 753) a nonpeptide angiotensin type 1 receptor antagonist. J Pharmacol Exp Ther 1992;262:1168–1172.

    Google Scholar 

  24. Tanaka K., Honda M, Kuramochi T, et al. Different effects of an angiotensin converting enzyme inhibitor and a calcium antagonist on protein metabolism in rats with right ventricular hypertrophy. J Hypertens 1994;12:1147–1154.

    Google Scholar 

  25. Ishikawa K, Hashimoto H, Mitani S, Toki Y, Okumura K, Ito T. Enalapril improves heart failure induced by monocrotaline without reducing pulmonary hypertension in rats: Roles of preserved myocardial creatine kinase and lactate dehydrogenase isoenzymes. Int J Cardiol 1995;47:225–233.

    Google Scholar 

  26. Abraham WT, Raynolds MV, Gottschall B, et al. Importance of angiotensin-converting enzyme in pulmonary hypertension. Cardiology 1995;86:9–15.

    Google Scholar 

  27. Zierhut W, Zimmer HG, Gerdes AM. Influence of ramipril on ventricular hypertrophy induced by pulmonary artery stenosis in rats. J Cardiovasc Pharmacol 1990;16:480–486.

    Google Scholar 

  28. Zimmer HG. Development and modulation of experimental right ventricular hypertrophy in rats. J Cardiovasc Pharmacol 1992;20:S1–S6.

    Google Scholar 

  29. Pelouch V, Milerová M, Ošt'ádal B, Hučin B, Šamánek M. Differences between atrial and ventricular protein profiling in children with congenital heart disease. Mol Cell Biochem 1995;147:43–49.

    Google Scholar 

  30. Pelouch V, Dixon IMC, Sethi R, Dhalla NS. Alteration of collagenous profile in congestive heart failure secondary to myocardial infarction. Mol Cell Biochem 1994b-9:121–131.

    Google Scholar 

  31. Brilla CG, Maisch B, Rupp H, Funck R, Zhou B, Weber KT. Pharmacological modulation of cardiac fibroblast function. Herz 1995;20:127–134.

    Google Scholar 

  32. Zimmer HG, Gerdes AM, Lortet S, Mall G. Changes in heart function and cardiac cell size in rats with chronic myocardial infarction. J Mol Cell Cardiol 1990;22:1231–1243.

    Google Scholar 

  33. Weber KT, Brilla CG, Janicki JS. Myocardial fibrosis: Functional significance and regulatory factors. Cardiovasc Res 1994;27:341–348.

    Google Scholar 

  34. Parratt JR. Cardioprotection by angiotensin converting enzyme inhibitors: The experimental evidence. Cardiovasc Res 1994;28:183–189.

    Google Scholar 

  35. Nishimiki T, Yamagishi H, Takeuchi T, Takeda T. An angiotensin II receptor antagonist attenuated left ventricular dilatation after myocardial infarction in the hypertensive rat. Cardiovasc Res 1995;29:856–861.

    Google Scholar 

  36. Unger T, Gohlke P. Converting enzyme inhibitors in cardiovascular therapy: Current status and future potential. Cardiovasc Res 1994;28:146–158.

    Google Scholar 

  37. Sladek T, Sladkova J, Kolar F, Papousek F, Cicutti N, Korecky B, Rakusan K. The effect of AT1 receptor antagonist on chronic cardiac response to coronary artery ligation in rats Cardiovasc Res 1994;31:568–576.

    Google Scholar 

  38. Studer R, Reinecke H, Müller B, Holtz J, Drexler H. Increased angiotensin-I converting enzyme gene expression in the failing human heart: Quantification by competitive RNA polymerase chain reaction. J Clin Invest 1994;94:301–310.

    Google Scholar 

  39. Rodman DM, Voelkel NF. Regulation of vascular tone. In: Crystal RG, ed. The Lung. New York: Raven Press, 1991;1105–1119.

    Google Scholar 

  40. Weber KT, Sun Y, Guarda E. Structural remodeling in hypertensive heart disease and the role of hormones. Hypertension 1994;23:869–877.

    Google Scholar 

  41. Herget J, Pelouch V, Kolář F, Ošt'ádal B. The inhibition of angiotensin converting enzyme attenuates the effects of chronic hypoxia on pulmonary blood vessels in the rat. Physiol Res 1996;45:221–226.

    Google Scholar 

  42. Rabinovitch M, Gamble WJ, Williams G, Reid L. SQ 14,225 converting enzyme inhibitor diminishes pulmonary artery hypertension secondary to chronic hypoxia in the rat. Fed Proc 1980;39:765.

    Google Scholar 

  43. Iimoto DS, Covel JW, Harper E. Increase in cross-linking of type I and type III collagens associated with volume-overload hypertrophy. Circ Res 1988;63:399–408.

    Google Scholar 

  44. Eghbali M, Weber KT. Collagen and the myocardium: Fibrillar structure, biosynthesis, and degradation in relation to hypertrophy and its regression. Mol Cell Biochem 1990;96:1–14.

    Google Scholar 

  45. Mukherjee D, Sen S. Alteration of cardiac collagen phenotypes in hypertensive hypertrophy: Role of blood pressure. J Mol Cell Cardiol 1993;5:185–196.

    Google Scholar 

  46. Pelouch V, Jirmář R. Biochemical characteristics of cardiac collagen and its role in ventricular remodelling following infarction. Physiol Res 1993;42:283–292.

    Google Scholar 

  47. Tyagi SC, Kumar SG, Haas SJ, et al. Posttranscriptional regulation of extracellular matrix metalloproteinase in human end-stage failure secondary to ischemic cardiomyopathy. J Mol Cell Cardiol 1996;28:1415–1428.

    Google Scholar 

  48. Weber KT, Anversa P, Armstrong PW, et al. Remodeling and reparation of the cardiovascular system. J Am Coll Cardiol 1992;20:3–16.

    Google Scholar 

  49. Bruckschlegel G, Holmer SR, Jandeleit K, et al. Blockade of the renin-angiotensin system in cardiac pressure-overload hypertrophy in rats. Hypertension 1995;25:250–259.

    Google Scholar 

  50. Jouquey S, Stepniewski JP, Hamon G. Trandolapril dose-response in spontaneously hypertensive rats: Effects on ACE activity, blood pressure, and cardiac hypertrophy. J Cardiovasc Pharmacol 1994;23:S16–S18.

    Google Scholar 

  51. Keeley FW, Elmoselhi A, Leenen FHH. Enalapril suppresses normal accumulation of elastin and collagen in cardiovascular tissues of growing rats. Am J Physiol 1992;262:H1013–H1021.

    Google Scholar 

  52. ACC/AHA Task Force Heart Failure Guidelines. Guidelines for the evaluation and management of heart failure. J Am Coll Cardiol 1995;26:1376–1398.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Physiology, Academy of Sciences of the Czech Republic, Czech Republic

    V. Pelouch, F. Kolář, B. Ošt'ádal, M. Milerová & R. Čihák

  2. Institute of Postgraduate Medical Education, Prague, Czech Republic

    J. Widimský

Authors
  1. V. Pelouch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Kolář
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. Ošt'ádal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Milerová
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. Čihák
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. Widimský
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pelouch, V., Kolář, F., Ošt'ádal, B. et al. Regression of Chronic Hypoxia-Induced Pulmonary Hypertension, Right Ventricular Hypertrophy, and Fibrosis: Effect of Enalapril. Cardiovasc Drugs Ther 11, 177–185 (1997). https://doi.org/10.1023/A:1007788915732

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1007788915732

Search

Navigation