Published online before print May 5, 2003, doi: 10.1161/01.HYP.0000071180.12012.6E
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(Hypertension. 2003;41:1324.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na+/H+ Exchanger Inhibition
From Centro de Investigaciones Cardiovasculares (I.L.E., E.M.E., M.C.C.de H., H.E.C.), Cátedra de Histología B, Facultad de Ciencias Médicas, UNLP (G.M.C., G.C., C.G.D.); and Boehringer/Ingelheim Pharma KG (R.W.S), Biberach an der Riss, Germany. M.C.C.deH. and H.E.C. are established investigators of Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); G.M.C. is an established investigator of Comisión de Investigaciones Científicas Prov. Buenos Aires (CICBA).
Correspondence to Dr Irene L. Ennis, Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, UNLP 60 y 120 (1900), La Plata, Argentina. E-mail iennis{at}atlas.med.unlp.edu.ar
Cardiac hypertrophy is often associated with an increased sympathetic drive, and both in vitro and in vivo studies have demonstrated the development of cardiomyocyte hypertrophy in response to either 
- or ß-adrenergic stimulation. Because an association between the Na+/H+ exchanger and cellular growth has been proposed, this study aimed to analyze the possible role of the antiporter in isoproterenol-induced cardiac hypertrophy. Isoproterenol alone (5 mg/kg IP once daily) or combined with a selective inhibitor of the Na+/H+ exchanger activity (3 mg · kg-1 · d-1 BIIB723) was given to male Wistar rats for 30 days. Sex- and age-matched rats that received 0.9% saline IP daily served as controls. Echocardiographic follow-up showed a 33% increase in left ventricular mass in the isoproterenol-treated group, whereas it did not increase in the isoproterenol+BIIB723-treated group. Heart weight–to–body weight ratio at necropsy was 2.44±0.11 in controls and increased to 3.35±0.10 (P<0.05) with isoproterenol, an effect that was markedly attenuated by BIIB723 (2.82±0.07). Intense cardiomyocyte enlargement and severe subendocardial fibrosis were found in isoproterenol-treated rats, and both effects were attenuated by BIIB723. Myocardial Na+/H+ exchanger activity and protein expression significantly increased in isoproterenol-treated rats compared with the control group (1.45±0.11 vs 0.91±0.05 arbitrary units, P<0.05). This effect was significantly reduced by BIIB723 (1.17±0.02, P<0.05). In conclusion, our results show that Na+/H+ exchanger inhibition prevented the development of isoproterenol-induced hypertrophy and fibrosis, providing strong evidence in favor of a key role played by the antiporter in this model of cardiac hypertrophy.
Key Words: hypertrophy, cardiac • signal transduction • antiporters • fibrosis • adrenergic receptor agonists
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