Journal of Zhejiang University SCIENCE B

, Volume 7, Issue 3, pp 228–234 | Cite as

Effects of combination of irbesartan and perindopril on calcineurin expression and sarcoplasmic reticulum Ca2+-ATPase activity in rat cardiac pressure-overload hypertrophy

  • Jiang Qing-jun 
  • Xu Geng 
  • Mao Fei-fei 
  • Zhu You-fa 


Aim: To observe effects of angiotensin (Ang) II receptor antagonist (AT1) irbesartan and angiotensin-converting enzyme (ACE) inhibitor perindopril on rat myocardium calcineurin expression and sarcoplasmic reticulum Ca2+-ATPase activity in the model of pressure-overload cardiac hypertrophy. Methods: Forty male adult Sprague Dawley rats were divided into 5 groups. One group was treated by sham operation; four groups were myocardium hypertrophy cases caused by banding aortic above renal artery. Drugs were given one week after operation. Group 1: sham group, rats (n=8) were gavaged with normal saline 2 ml/(kg·d) (ig); Group 2: control group, rats (n=8) were treated with normal saline 2 ml/(kg·d) (ig); Group 3: rats (n=8) were given perindopril 2 mg/(kg·d) (ig); Group 4: rats (n=8) were treated with irbesartan 20 mg/(kg·d) (ig); Group 5: rats (n=8) were given irbesartan 20 mg/(kg·d) plus perindopril 2 mg/(kg·d) (ig). Morphometric determination, calcineurin expression and sarcoplasmic reticulum Ca2+-ATPase activity were done at the end of 6 week of drug intervention. Expression of calcineurin in myocardium was detected by immunohistochemistry. Results: Left ventricular mass index (LVMI), transverse diameter of myocardial cell (TDM), calcineurin activity were remarkably decreased after drug intervention and this decrease was most remarkable in the combination drug therapy group. Sarcoplasmic reticulum Ca2+-ATPase activity was increased after drug intervention, especially in the combined drug therapy group. Calcineurin expression in myocardium was remarkably decreased after drug intervention. LVMI was positively correlated with TDM and calcineurin, negatively correlated with sarcoplasmic reticulum Ca2+-ATPase. Conclusion: These data suggest that irbesartan and perindopril inhibit cardiac hypertrophy through the increased activity of sarcoplasmic reticulum Ca2+-ATPase and decreased expression of calcineurin. Their combination had better effects on regressing of ventricular hypertrophy.

Key words

Angiotensin (Ang) II receptor antagonist Angiotensin-converting enzyme inhibitor Calcineurin Sarcoplasmic reticulum Ca2+-ATPase Pressure overload Cardiac hypertrophy Rat 

CLC number



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  1. Barnes, D.M., Dublin, E.A., Fisher, C.J., Levison, D.A., Millis, R.R., 1993. Immunohistochemical detection of p53 protein in mammary carcinoma: an important new independent indicator of prognosis? Hum. Pathol., 24(5):469–476. [doi:10.1016/0046-8177(93)90158-D]CrossRefPubMedGoogle Scholar
  2. Bastie, D., Levitsky, D., Rappaport, L., 1990. Function of the sarcoplasmic reticulum and expression of its Ca2+-ATPase gene in pressure overload-induced cardiac hypertrophy in the rat. Circ. Res., 66(2):554–564.PubMedGoogle Scholar
  3. de Windt, L.J., Lim, H.W., Bueno, O.F., Liang, Q., Delling, U., Braz, J.C., Glascock, B.J., Kimball, T.F., Monte, F.D., Hajjar, R.J., Molkentin, J.D., 2001. Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo. Proc. Natl. Acad. Sci. USA, 98:3322–3327.PubMedGoogle Scholar
  4. Devereux, R.B., 1995. Left ventricular geometry, pathophysiology and prognosis. J. Am. Coll. Cardiol., 25(4):885–887. [doi:10.1016/0735-1097(94)00547-4]CrossRefPubMedGoogle Scholar
  5. Doering, C.W., Jalil, J.E., Janicki, J.S., 1988. Collagen network remodelling and diastolic stiffness of the rat left ventricle with pressure overload hypertrophy. Cardiovasc. Res., 22(10):686–695.PubMedGoogle Scholar
  6. Grossman, W., Jones, D., McLaurin, L.P., 1975. Wall stress and patterns of hypertrophy in the human left ventricle. J. Clin. Invest., 55:56–64.Google Scholar
  7. James, P., Inui, M., Tada, M., Chiesi, M., Carafoli, E., 1989. Nature and site of phospholamban regulation of the Ca2+ pump of sarcoplasmic reticulum. Nature, 342(6245):90–92. [doi:10.1038/342090a0]PubMedGoogle Scholar
  8. Jones, L.R., Besch, H.R., Fleming, J.W., McConnaughey, M.M., Watanabe, A.M., 1979. Separation of vesicles of cardiac sarcolemma from vesicles of cardiac sarcoplasmic reticulum. Comparative biochemical analysis of component activities. J. Biol. Chem., 254(2):530–539.PubMedGoogle Scholar
  9. Kawano, H., Do, Y.S., Kawano, Y., Stames, V., Barr, M., Law, R.E., Hsueh, W.A., 2000. Angiotensin II has multiple profibrotic effects in human cardiac fibroblasts. Circulation, 101(10):1130–1137.PubMedGoogle Scholar
  10. Kimura, Y., Kurzydlowski, K., Tada, M., MacLennan, D.H., 1996. Phospholamban regulates the Ca2+-ATPase through intramembrance interaction. J. Biol. Chem., 271(42):21726–21731. [doi:10.1074/jbc.271.42.25958]CrossRefPubMedGoogle Scholar
  11. Levy, D., Garrison, R.J., Savage, D.D., Kannel, W.B., Castelli, W.P., 1990. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham heart study. N. Engl. J. Med., 322:1561–1566.PubMedGoogle Scholar
  12. Lim, H.W., Molkentin, J.D., 1999. Calcineurin and human heart failure [letter] [see comments]. Nat. Med., 5(3):246–247. [doi:10.1038/6430]PubMedGoogle Scholar
  13. Lim, H.W., de Windt, L.J., Steinberg, L., Taigen, T., Witt, S.A., Kimball, T.R., Molkentin, J.D., 2000. Calcineurin expression, activation, and function in cardiac pressure-overload hypertrophy. Circulation, 101:2431–2437.PubMedGoogle Scholar
  14. Molkentin, J.D., Lu, J.R., Antos, C.L., Markham, B., Richardson, J., Robbins, J., Grant, S.R., Olson, E.N., 1998. A calcineurin dependent transcriptional pathway for cardiac hypertrophy. Cell, 93(2):215–228. [doi:10.1016/S0092-8674(00)81573-1]CrossRefPubMedGoogle Scholar
  15. Movsesian, M.A., Schwinger, R.H.G., 1998. Calcium sequestration by the sarcoplasmic reticulum in heart failure. Cardiovasc. Res., 37(2):352–359. [doi:10.1016/S0008-6363(97)00259-9]CrossRefPubMedGoogle Scholar
  16. Münch, G., Bölck, B., Karezewski, P., Schwinger, R.H.G., 2002. Evidence for calcineurin-mediated regulation of SERCA 2a activity in human myocardium. J. Mol. Cell. Cardiol., 34(3):321–334. [doi:10.1006/jmcc.2001.1515]CrossRefPubMedGoogle Scholar
  17. Sadoshima, J., Izumo, S., 1997. The cellular and molecular response of cardiac myocytes to mechanical stress. Ann. Rev. Physiol., 59(1):551–571. [doi:10.1146/annurev.physiol.59.1.551]Google Scholar
  18. Shen, H., Mirsalimi, S.M., Weiler, J.E., 1991. Effects of mild cardiac hypertrophy, induced by volume overload in turkeys, on myocardial sarcoplasmic reticulum calcium-pump and calcium-channel activities and on the creatine kinase system. Am. J. Vet. Res., 52(9):1527–1530.PubMedGoogle Scholar
  19. Shimoyama, M., Hayashi, D., Takimoto, E., Zou, Y., Oka, T., Uozumi, H., Kudoh, S., Shibasaki, F., Yazaki, Y., Nagai, R., Komuro, I., 1999. Calcineurin plays a critical role in pressure overload-induced cardiac hypertrophy. Circulation, 100(24):2449–2454.PubMedGoogle Scholar
  20. Sussman, M.A., Lim, H.W., Gude, N., Taigen, T., Olson, E.N., Robbins, J., Colbert, M.C., Gualberto, A., Wieczorek, D.F., Molkentin, J.D., 1998. Prevention of cardiac hypertrophy in mice by calcineurin inhibition. Science, 281(5383):1690–1693. [doi:10.1126/science.281.5383.1690]CrossRefPubMedGoogle Scholar
  21. Tada, M., Kirchberger, M.A., Katz, A.M., 1975. Phosphorylation of a 22000-dalton component of the cardiac sarcoplasmic reticulum by adenosine 3′-5′-monophosphate-dependent protein kinase. J. Biol. Chem., 250:2640–2647.PubMedGoogle Scholar
  22. Vikstrom, K.L., Leinwand, L.A., 1996. Contractile protein mutations and heart disease. Curr. Opin. Cell Biol., 8(1):97–105. [doi:10.1016/S0955-0674(96)80053-6]CrossRefPubMedGoogle Scholar
  23. Zhang, W., Kowal, R.C., Rusnak, F., 2000. Failure of calcineurin inhibitors to prevent pressure-overload left ventricular hypertrophy in rats. Circ. Res., 84(6):722–728.Google Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Jiang Qing-jun 
    • 1
    • 2
  • Xu Geng 
    • 1
  • Mao Fei-fei 
    • 3
  • Zhu You-fa 
    • 4
  1. 1.Department of Cardiology, the Second Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
  2. 2.Department of CardiologyNingbo Lihuili HospitalNingboChina
  3. 3.Department of Pharmacy, Children’s Hospital, School of MedicineZhejiang UniversityHangzhouChina
  4. 4.Department of Pathology, School of MedicineZhejiang UniversityHangzhouChina

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