Cardiovascular Drugs and Therapy

, Volume 28, Issue 2, pp 137–143 | Cite as

Protective Effects of Aliskiren on Atrial Ionic Remodeling in a Canine Model of Rapid Atrial Pacing

  • Zhiqiang Zhao
  • Xinghua Wang
  • Jian Li
  • Wansong Yang
  • Lijun Cheng
  • Yan Chen
  • Tong Liu
  • Enzhao Liu
  • Kangyin Chen
  • Guangping Li



Aliskiren inhibits the activation of the renin-angiotensin system. Here, we investigated the effects of aliskiren on chronic atrial iron remodeling in the experimental canine model of rapid atrial pacing.


Twenty-eight dogs were assigned to sham (S), control paced (C), paced + aliskiren (10 mg Kg−1 d−1, A1), and paced + aliskiren (20 mg Kg−1 d−1, A2) groups. Rapid atrial pacing at 500 bpm was maintained for 2 weeks, while group S was not paced. Levels of serum angiotensin-converting enzyme and angiotensin II after pacing were determined by ELISA. Whole-cell patch-clamp technique, western blot, and RT-PCR were applied to assess atrial ionic remodeling.


The density of I CaL and I Na currents (pA/pF) was significantly lower in group C compared with group S (I CaL: −4.09 ± 1.46 vs. −6.12 ± 0.58,P < 0.05; I Na: 30.48 ± 6.08 vs. 46.31 ± 4.73, P < 0.05). However, the high dose of aliskiren elevated the density of I CaL and I Na currents compared with group C (I CaL: −6.23 ± 1.35 vs. −4.09 ± 1.46, P < 0.05; I Na: 58.62 ± 16.17 vs. 30.48 ± 6.08, P < 0.01). The relative mRNA and protein expression levels of Cav1.2 and Nav1.5α were downregulated in group C respectively (Cav1.2: 0.46 ± 0.08; Nav1.5α: 0.52 ± 0.08, P < 0.01; Cav1.2: 0.31 ± 0.03; Nav1.5α: 0.41 ± 0.04, P < 0.01;), but were upregulated by aliskiren.


Aliskiren has protective effects on atrial tachycardia-induced atrial ionic remodeling.


Atrial fibrillation Atrial remodeling Aliskiren Ca2+ channel Na+ channel 



This work was supported by the Program of Natural Science Foundation of China (No. 81370300) and China Education Ministry Colleges and Universities Special Scientific Research Foundation for Doctoral Advisor Class (No. 20121202110004).


  1. 1.
    Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for management of atrial fibrillation: the task force for the management of atrial fibrillation of the european society of cardiology (ESC). Eur Heart J. 2010;31:2369–429.PubMedCrossRefGoogle Scholar
  2. 2.
    Nattel S. From guidelines to bench: implications of unresolved clinical issues for basic investigations of atrial fibrillation mechanisms. Can J Cardiol. 2011;27:19–26.PubMedCrossRefGoogle Scholar
  3. 3.
    Liu E, Yang S, Xu Z, Li J, Yang W, Li G. Angiotensin-(1–7) prevents atrial fibrosis and atrial fibrillation in long-term atrial tachycardia dogs. Regul Pept. 2010;162:73–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Liu E, Xu Z, Li J, Yang S, Yang W, Li G. Enalapril, irbesartan, and angiotensin-(1–7) prevent atrial tachycardia-induced ionic remodeling. Int J Cardiol. 2011;146:364–70.PubMedCrossRefGoogle Scholar
  5. 5.
    Rogart RB, Cribbs LL, Muglia LK, Kephart DD, Kaiser MW. Molecular cloning of a putative tetrodotoxin-resistant rat heart Na+ channel isoform. Proc Natl Acad Sci U S A. 1989;86:8170–4.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Villamil A, Chrysant SG, Calhoun D, et al. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J Hypertens. 2007;25:217–26.PubMedCrossRefGoogle Scholar
  7. 7.
    Cohen NC. Structure-based drug design and the discovery of aliskiren (Tekturna): perseverance and creativity to overcome a R&D pipeline challenge. Chem Biol Drug Des. 2007;70:557–65.PubMedCrossRefGoogle Scholar
  8. 8.
    Brown MJ. Aliskiren. Circulation. 2008;118:773–84.PubMedCrossRefGoogle Scholar
  9. 9.
    Fisher ND, Jan Danser AH, Nussberger J, Dole WP, Hollenberg NK. Renal and hormonal responses to direct renin inhibition with aliskiren in healthy humans. Circulation. 2008;117:3199–205.PubMedCrossRefGoogle Scholar
  10. 10.
    Stanton A. Now that we have a direct renin inhibitor, what should we do with it? Curr Hypertens Rep. 2008;10:194–200.PubMedCrossRefGoogle Scholar
  11. 11.
    Feldman DL. New insights into the renoprotective actions of the rennin inhibitor aliskiren in experimental renal disease. Hypertens Res. 2010;33:279–87.PubMedCrossRefGoogle Scholar
  12. 12.
    Nguyen G. The (pro)renin receptor: pathophysiological roles in cardiovascular and renal pathology. Curr Opin Nephrol Hypertens. 2007;16:129–33.PubMedCrossRefGoogle Scholar
  13. 13.
    Nattel S, Li D. Ionic remodeling in the heart: pathophysiological significance and new therapeutic opportunities for atrial fibrillation. Circ Res. 2000;87:440–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Yue L, Feng J, Li GR, Nattel S. Transient outward and delayed rectifier currents in canine atrium: properties and role of isolation methods. Am J Physiol. 1996;270:H2157–68.PubMedGoogle Scholar
  15. 15.
    Li D, Melnyk P, Feng J, et al. Effects of experimental heart failure on atrial cellular and ionic electrophysiology. Circulation. 2000;101:2631–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Gramley F, Himmrich E, Mollnau H, Theis C, Hammwohner M, Goette A. Recent advances in the pharmacological treatment of cardiac arrythmias. Drugs Today (Barc). 2009;45:807–24.PubMedGoogle Scholar
  17. 17.
    Goette A, Staack T, Röcken C, et al. Increased expression of extracellular signal-regulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation. J Am Coll Cardiol. 2000;35:1669–77.PubMedCrossRefGoogle Scholar
  18. 18.
    Goette A, Arndt M, Röcken C, et al. Regulation of Angiotensin II Receptor Subtypes During Atrial Fibrillation in Humans. Circulation. 2000;101:2678–81.PubMedCrossRefGoogle Scholar
  19. 19.
    Kumagai K, Nakashima H, Urata H, et al. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation. J Am Coll Cardiol. 2003;41:2198–203.Google Scholar
  20. 20.
    Zhang Y, Zhang P, Mu Y, et al. The role of renin-angiotensin system blockade therapy in the prevention of atrial Fibrillation: A meta-analysis of randomized controlled trials. Clin Pharmacol Ther. 2010;88:521–31.PubMedCrossRefGoogle Scholar
  21. 21.
    Müller DN, Luft FC. Direct renin inhibition with aliskiren in hypertension and target organ damage. Clin J Am Soc Nephrol. 2006;1:221–8.PubMedCrossRefGoogle Scholar
  22. 22.
    The GISSI-AF Investigators, Disertori M, Latini R, et al. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med. 2009;360:1606–17.PubMedCrossRefGoogle Scholar
  23. 23.
    Nakashima H, Kumagai K. Reverse-remodeling effects of angiotensin II type 1 receptor blocker in a canine atrial fibrillation model. Circ J. 2007;71:1977–82.PubMedCrossRefGoogle Scholar
  24. 24.
    Yue L, Feng J, Gaspo R, Li GR, Wang Z, Nattel S. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res. 1997;81:512–25.PubMedCrossRefGoogle Scholar
  25. 25.
    Brundel BJ, van Gelder IC, Henning RH, et al. Gene expression of proteins influencing the calcium homeostasis in patients with persistent and paroxysmal atrial fibrillation. Cardiovasc Res. 1999;42:443–54.PubMedCrossRefGoogle Scholar
  26. 26.
    Goette A, Honeycutt C, Langberg JJ. Electrical remodeling in atrial fibrillation. Time course and mechanisms. Circulation. 1996;94:2968–74.PubMedCrossRefGoogle Scholar
  27. 27.
    Ausma J, Dispersyn GD, Duimel H, Thone F, Ver Donck L, Allessie MA, et al. Changes in ultrastructural calcium distribution in goat atria during atrial fibrillation. J Mol Cell Cardiol. 2000;32:355–64.PubMedCrossRefGoogle Scholar
  28. 28.
    Sun H, Chartier D, Leblanc N, Nattel S. Intracellular calcium changes and tachycardia-induced contractile dysfunction in canine atrial myocytes. Cardiovasc Res. 2001;49:751–61.PubMedCrossRefGoogle Scholar
  29. 29.
    Wilde AA, Brugada R. Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac sodium channel. Circ Res. 2011;108:884–97.PubMedCrossRefGoogle Scholar
  30. 30.
    Darbar D, Kannankeril PJ, Donahue BS, et al. Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation. Circulation. 2008;117:1927–35.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Fischer R, Dechend R, Qadri F, et al. Dietary n-3 polyunsaturated fatty acids and direct renin inhibition improve electrical remodeling in a model of high human renin hypertension. Hypertension. 2008;51:540–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Solomon SD, Appelbaum E, Manning WJ, et al. Effect of the direct rennin inhibitor aliskiren, the angiotensin receptor blocker losartan, or both on left ventricular mass in patients with hypertension and left ventricular hypertrophy. Circulation. 2009;119:530–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Shang LL, Sanyal S, Pfahnl AE, et al. NF-kappaB-dependent transcriptional regulation of the cardiac scn5a sodium channel by angiotensin II. Am J Physiol Cell Physiol. 2008;294:C372–9.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Bkaily G, Sculptoreanu A, Wang S, et al. Angiotensin II-induced increase of T-type Ca2+ current and decrease of L-type Ca2+ current in heart cells. Peptides. 2005;26:1410–7.PubMedCrossRefGoogle Scholar
  35. 35.
    von Lewinski D, Kockskämper J, Rübertus SU, et al. Direct pro-arrhythmogenic effects of angiotensin II can be suppressed by AT1 receptor blockade in human atrial myocardium. Eur J Heart Fail. 2008;10:1172–6.CrossRefGoogle Scholar
  36. 36.
    Kumagai K, Nakashima H, Urata H, Gondo N, Arakawa K, Saku K. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation. J Am Coll Cardiol. 2003;41:2197–204.PubMedCrossRefGoogle Scholar
  37. 37.
    Ye Y, Qian J, Castillo AC, Perez-Polo JR, Birnbaum Y. Aliskiren and valsartan reduce myocardial AT1 receptor expression and limit myocardial infarct size in diabetic mice. Cardiovasc Drugs Ther. 2011;25:505–15.PubMedCrossRefGoogle Scholar
  38. 38.
    Fraune C, Lange S, Krebs C, et al. AT1 antagonism and renin inhibition in mice: pivotal role of targeting angiotensin II in chronic kidney disease. Am J Physiol Renal Physiol. 2012;303:F1037–48.PubMedCrossRefGoogle Scholar
  39. 39.
    Whaley-Connell A, Habibi J, Rehmer N, et al. Renin Inhibition and AT1R blockade improve metabolic signaling, oxidant stress and myocardial tissue remodeling. Metabolism. 2013;62:861–72.PubMedCrossRefGoogle Scholar
  40. 40.
    Choi DE, Jeong JY, Lim BJ, et al. Aliskiren ameliorates renal inflammation and fibrosis induced by unilateral ureteral obstruction in mice. J Urol. 2011;186:694–701.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Zhiqiang Zhao
    • 1
  • Xinghua Wang
    • 1
  • Jian Li
    • 1
  • Wansong Yang
    • 1
  • Lijun Cheng
    • 1
  • Yan Chen
    • 1
  • Tong Liu
    • 1
  • Enzhao Liu
    • 1
  • Kangyin Chen
    • 1
  • Guangping Li
    • 1
  1. 1.Department of Cardiology, Tianjin Institute of CardiologySecond Hospital of Tianjin Medical UniversityTianjinPeople’s Republic of China

Personalised recommendations