Copyright © 2004, European Society of Cardiology
Chronic inhibition of Na+/H+-exchanger attenuates cardiac hypertrophy and prevents cellular remodeling in heart failure
aExperimental Cardiology, Room M-0-052, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
bLaboratory of Physiology, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands
* Corresponding author. Tel.: +31 20 5663265; fax: +31 20 6975458. Email address: A.Baartscheer{at}AMC.UVA.NL
Objective: In patients with heart disease, the transition from compensatory hypertrophy to heart failure (HF) is associated with altered calcium handling. Up-regulated Na+/H+-exchanger (NHE-1) activity underlies increased [Na+]i and disturbance of cellular calcium handling in HF. We hypothesize that chronic inhibition of NHE-1 activity prevents the hypertrophic response, cellular remodeling, and development of HF.
Methods: Rabbits received a control or cariporide (inhibitor of NHE-1) diet for 3 months, starting after induction of combined volume and pressure overload. Age-matched animals served as control. Development of HF was examined echocardiographically and electrocardiographically after 3 months. [Na+]i, [Ca2+]i, pHi, and action potentials were measured in left ventricular midmural myocytes with SBFI, indo-1, SNARF, and di-4-anepps. Sarcoplasmic reticulum calcium content was calculated from the response of [Ca2+]i to rapid cooling. Calcium after-transients were elicited by cessation of rapid stimulation (3 Hz) in the presence of 100 nmol/l noradrenalin.
Results: Chronic treatment of rabbits with the specific Na+/H+-exchanger activity inhibitor cariporide greatly attenuated development of hypertrophy and entirely abolished development of HF; the heart/body weight ratio increased only little, no change in lung weight occurred, left ventricular dimensions and fractional shortening changed mildly, ascites was not present, QT duration did not increase, and sudden death did not occur. Chronic cariporide treatment also prevented cellular electrical and ionic remodeling. Myocyte dimensions were unaltered, action potentials were not prolonged, cytoplasmic sodium and NHE-1 activity did not increase, cytoplasmic and SR calcium handling remained undisturbed, and no increase of the incidence of calcium after-transient dependent delayed after depolarizations (DADs) occurred.
Conclusion: We conclude that enhanced activity of NHE-1 underlies cardiac cellular electrical and ionic remodeling in experimental heart failure, and that chronic dietary treatment with cariporide attenuates hypertrophy, development of HF, and cellular remodeling.
KEYWORDS Heart failure; Remodeling; Calcium (cellular); Na/H-exchanger; Na/Ca-exchanger; SR function; Myocytes
Time for primary review 28 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. D. Garciarena, C. I. Caldiz, E. L. Portiansky, G. E. Chiappe de Cingolani, and I. L. Ennis Chronic NHE-1 blockade induces an antiapoptotic effect in the hypertrophied heart J Appl Physiol, April 1, 2009; 106(4): 1325 - 1331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. D. Garciarena, C. I. Caldiz, M. V. Correa, G. R. Schinella, S. M. Mosca, G. E. Chiappe de Cingolani, H. E. Cingolani, and I. L. Ennis Na+/H+ exchanger-1 inhibitors decrease myocardial superoxide production via direct mitochondrial action J Appl Physiol, December 1, 2008; 105(6): 1706 - 1713. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. R. Bezzina and C. A. Remme Dilated Cardiomyopathy due to Sodium Channel Dysfunction: What Is the Connection? Circ Arrhythm Electrophysiol, June 1, 2008; 1(2): 80 - 82. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Yamamoto, T. Shirayama, T. Sakatani, T. Takahashi, H. Tanaka, T. Takamatsu, K. W. Spitzer, and H. Matsubara Enhanced activity of ventricular Na+-HCO3 cotransport in pressure overload hypertrophy Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1254 - H1264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. G. Perez, M. R. Piaggio, I. L. Ennis, C. D. Garciarena, C. Morales, E. M. Escudero, O. H. Cingolani, G. Chiappe de Cingolani, X.-P. Yang, and H. E. Cingolani Phosphodiesterase 5A Inhibition Induces Na+/H+ Exchanger Blockade and Protection Against Myocardial Infarction Hypertension, May 1, 2007; 49(5): 1095 - 1103. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. E. Cingolani and I. L. Ennis Sodium-Hydrogen Exchanger, Cardiac Overload, and Myocardial Hypertrophy Circulation, March 6, 2007; 115(9): 1090 - 1100. [Full Text] [PDF]
|
|
|
|
|
|
A. Kilic, A. Velic, L. J. De Windt, L. Fabritz, M. Voss, D. Mitko, M. Zwiener, H. A. Baba, M. van Eickels, E. Schlatter, et al. Enhanced Activity of the Myocardial Na+/H+ Exchanger NHE-1 Contributes to Cardiac Remodeling in Atrial Natriuretic Peptide Receptor-Deficient Mice Circulation, October 11, 2005; 112(15): 2307 - 2317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Stagg and C. M.N. Terracciano Less Na+/H+-exchanger to treat heart failure: a simple solution for a complex problem? Cardiovasc Res, January 1, 2005; 65(1): 10 - 12. [Full Text] [PDF]
|
|